[Senate Hearing 110-80]
[From the U.S. Government Printing Office]

                                                         S. Hrg. 110-80



                               BEFORE THE


                                 OF THE

                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                       ONE HUNDRED TENTH CONGRESS

                             FIRST SESSION


                         BREAKTHROUGH RESEARCH


                              MAY 15, 2007


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               EDWARD M. KENNEDY, Massachusetts, Chairman

CHRISTOPHER J. DODD, Connecticut     MICHAEL B. ENZI, Wyoming,
TOM HARKIN, Iowa                     JUDD GREGG, New Hampshire
BARBARA A. MIKULSKI, Maryland        BILL FRIST, Tennessee
JAMES M. JEFFORDS (I), Vermont       LAMAR ALEXANDER, Tennessee
JEFF BINGAMAN, New Mexico            RICHARD BURR, North Carolina
PATTY MURRAY, Washington             JOHNNY ISAKSON, Georgia
JACK REED, Rhode Island              LISA MURKOWSKI, Alaska
BARACK OBAMA, Illinois               PAT ROBERTS, Kansas
BERNARD SANDERS (I), Vermont         WAYNE ALLARD, Colorado
SHERROD BROWN, Ohio                  TOM COBURN, Oklahoma

           J. Michael Myers, Staff Director and Chief Counsel

           Katherine Brunett McGuire, Minority Staff Director


                  Subcommittee on Retirement and Aging

                BARBARA A. MIKULSKI, Maryland, Chairman

TOM HARKIN, Iowa                     RICHARD BURR, North Carolina
JEFF BINGAMAN, New Mexico            JUDD GREGG, New Hampshire
JACK REED, Rhode Island              LAMAR ALEXANDER, Tennessee
BERNARD SANDERS (I), Vermont         JOHNNY ISAKSON, Georgia
SHERROD BROWN, Ohio                  ORRIN HATCH, Utah
EDWARD M. KENNEDY (ex officio),      MICHAEL ENZI (ex officio), Wyoming

                   Ellen-Marie Whelan, Staff Director



                            C O N T E N T S



                         TUESDAY, MAY 15, 2007

Mikulski, Hon. Barbara A., Chairman, Subcommittee on Retirement 
  and Aging, opening statement...................................     1
Burr, Hon. Richard, a U.S. Senator from the State of North 
  Carolina, opening statement....................................     3
Aisen, Paul, M.D., Professor of Neurology and Medicine, Director 
  of the Georgetown Memory Disorders Program, Georgetown 
  University, Washington, DC.....................................     5
    Prepared statement...........................................     6
Kramer, Arthur, Ph.D., Professor, University of Illinois 
  Departments of Psychology and Neuroscience, and Beckman 
  Institute, University of Illinois, Urbana, Illinois............     8
    Prepared statement...........................................    10
Essner, Robert, Chairman and CEO, Wyeth, Madison, New Jersey.....    22
    Prepared statement...........................................    24
deBethizy, J. Donald, Ph.D., President and CEO of TARGACEPT, 
  Inc., Winston-Salem, North Carolina............................    29
    Prepared statement...........................................    31





                         TUESDAY, MAY 15, 2007

                                       U.S. Senate,
                     Subcommittee on Retirement and Aging, 
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.
    The subcommittee met, pursuant to notice, at 10:05 a.m. in 
Room SD-628, Dirksen Senate Office Building, Hon. Barbara 
Mikulski, chairman of the subcommittee, presiding.
    Present: Senators Mikulski and Burr.

                 Opening Statement of Senator Mikulski

    Senator Mikulski. Good morning, everybody. The subcommittee 
on Retirement and Aging will come to order to conduct a hearing 
on Alzheimer's disease, and specifically research that is going 
on that focuses on current and future breakthroughs.
    My very able and collegial colleague Senator Burr is on his 
way from Russell, but I'm going to open it with my remarks 
while we're waiting for him, because there is a vote at quarter 
of 12, and I think we want to leave time for both your 
testimony, and discussion on how we can accelerate the 
breakthrough process without jeopardizing safety.
    This morning we want to thank all of our witnesses for 
coming. We have two from the private sector and two from 
academic centers of excellence that are doing research. And 
I'll be introducing them shortly--these are researchers who are 
doing breakthrough Alzheimer's research--two supported by the 
NIH, and those that are also, as I said, from the private 
sector. We're going to be very excited to hear about the 
cutting-edge work that they are doing.
    The reason we, the committee, feel an urgency to do this is 
that we know that Alzheimer's is an epidemic. With the aging 
population living longer, with even new sophisticated tools of 
diagnosing Alzheimer's we're doing early detection at an even 
younger age than when people reach their 80s, which seems to be 
a catastrophic point.
    We know that both the direct and indirect cost of 
Alzheimer's and other forms of dementia amount to over $100 
billion annually, a tremendous cost to families, of high risk 
for long-term care insurance, and also, then, for the Federal 
Government, over $91 billion is spent on beneficiaries with 
Alzheimer's or other forms of dementia.
    They talk about Medicare, but I'm also deeply concerned 
about the cost of Medicaid. Medicaid--80 percent of the 
beneficiaries of Medicaid are children, but 80 percent of the 
Medicaid money goes to paying for long-term care and the 
catastrophic spend-down that, often, families face. If we could 
find even 2 or 3 years of cognitive stretch-out, the impact on 
the family budget and on the Medicaid budget, and on, really, 
private insurance willing to underwrite this, would really be 
    So, this is why we want to listen to you, to get your 
ideas. Millions of individuals have not yet been diagnosed, but 
there will be millions more to come.
    Like so many Americans, I'm familiar with this disease. My 
father was 1 of 5 million currently suffering. My father passed 
away more than a decade ago. My family and I know--even today, 
I get fairly emotional about it--the very long goodbye. My 
mother lived the 36-hour day, and it was our job, as a family, 
to try to help her. It was devastating to him, it was 
heartbreaking to my mother, and heart-wrenching for my sisters 
and I.
    What was so difficult about it is that we felt we were 
powerless, because there were no cures. Fortunately, we lived 
in Baltimore--we could get an appropriate geriatric evaluation, 
so we knew it wasn't just a vitamin B12 shot and sending mom 
and dad on a long-delayed cruise. We also had the benefit of, 
again, the work that was done under the pioneering thinker, Dr. 
Mason Lord. Dad could go to an adult daycare program that 
engaged in the new thinking on cognitive stretch-out. But, at 
the end, it was the end. And we all face this.
    So, our vow, as so many here in the Senate and in the 
Alzheimer's Association, is to try to find a breakthrough. 
Working on a bipartisan basis, we have legislation now that 
would double the funding for Alzheimer's research, that would 
bring us to a cure, possibly a vaccine, and certainly cognitive 
stretch-out. We want to create a summit on Alzheimer's to 
discuss the most promising breakthroughs and to chart a new 
course. We want to work on family support, which is also news 
that you could use, and working with our colleagues in the 
Finance Committee, a long-term-care tax deduction so people 
could give help to those practicing self-help, as well as a tax 
credit for helping with family caregiving.
    Today, what we want to hear about is the research. Ninety-
five percent of what we know about Alzheimer's disease, we've 
learned in the last 15 years. This is why, again, this 
acceleration of the breakthrough is so important. We also know 
that expanding the cognitive stretch-out for people, with 3 to 
5 years, could probably save $12 billion annually in public 
investments in Medicare and Medicaid alone. That's a lot of 
    So, what we want to do today is listen to you, so we can 
hear what you're doing, and how your Federal Government could 
be helpful. And I, too, will be interested in knowing what your 
thoughts would be as we look to NIH, FDA, and CDC on how we can 
move what we do know out to either patient information, news 
you can use, or to clinical practice. Many physicians, 
themselves, if they were--families will tell you, it's 
misdiagnosed--as well as what we can do to get FDA and CDC to 
realize this is really an epidemic that's facing America.
    I now want to turn to Senator Burr, who's a very able and 
most collegial colleague, for his thoughts, and then we want to 
hear from you.

                   Opening Statement of Senator Burr

    Senator Burr. Thank you, Madam Chairman, and my apologies 
for my tardiness, to you and to the witnesses.
    It is incredibly difficult when a disease affects us 
personally, or individuals that we know, and the reality is 
that it happens every day. But our firsthand experience, and 
our ability to share it, makes passion contagious. And, I 
think, in many cases, it's that contagious passion that we 
need, in order to solve some of the challenges that either get 
mired down in inevitable policy differences or the eventual 
effect of politics in this town, and in this institution. And I 
have deep respect for the chairman of this subcommittee, 
because she doesn't let politics trump policy. And it's 
refreshing, every time I come to a hearing, to know that we're 
focused on how to find policy solutions to real problems that 
affect real Americans.
    I join her in welcoming our guests, this morning, who are 
here to discuss the potential breakthroughs in Alzheimer's 
disease research. Thanks, to each one of you, for taking the 
time to be here, to share with us the promising research that 
you're doing to help develop new treatments for the 5 million 
people in the United States living with Alzheimer's disease, 
and many more who will get Alzheimer's as they age.
    Currently, it's very costly to treat Alzheimer's disease. 
According to the Alzheimer's Association, the direct and 
indirect cost of Alzheimer's and other dementias amount to $148 
billion annually. With the aging of our population, the total 
will continue to grow, at what I believe is an alarming rate.
    Academic, scientific, and biopharmaceutical institutions 
are trying to identify and to develop new treatments for 
Alzheimer's. I'm proud to have a North Carolina company here 
testifying today regarding their promising research. Targacept 
is a Winston-Salem-based company, working with AstraZeneca in 
the development of a pharmaceutical product for Alzheimer's 
    Targacept has an interesting history, Madam Chairman, as 
I'm sure Dr. deBethizy will describe. It started with research 
being done by R.J. Reynolds Tobacco Company on the therapeutic 
effects of nicotine, and now they're on the cusp of a 
breakthrough product for Alzheimer's and schizophrenia.
    Madam Chairman, one out of eight Americans over the age of 
65 is living with Alzheimer's. Your leadership, your passion 
for this issue could not have found a better time in history to 
be displayed. Thank you for shining a light on the need for a 
coordinated national strategy to accelerate the development of 
Alzheimer's treatments.
    I also welcome our friends from Wyeth, who have a presence 
in North Carolina, and to our friend from Georgetown and the 
University of Illinois, we've got some good academic 
institutions, but if you're ever looking at moving, we'd love 
to have you in North Carolina.
    Senator Mikulski. Now, now.
    Senator Mikulski. Now, now.
    Senator Burr. Madam Chairman, I----
    Senator Mikulski. Don't stretch it too--the bipartisanship.
    Senator Burr [continuing]. Never miss a recruitment 
opportunity for great minds, and it's these great minds across 
the country and around the world that I believe will help us to 
find a successful cure for this disease.
    I yield back. Thank you.
    Senator Mikulski. Well, thank you very much, Senator Burr. 
And, you know, it is true that in this country you would have 
both those engaged in publicly funded research, and privately 
funded research, at the same table.
    What I'm going to do is introduce Aisen, Kramer, and 
Essner. And I know you've already introduced your guest, unless 
you want to introduce him again--then I'll just ask you to go 
across the room giving your testimony, and then, because--it 
seems there are only two of us, because of what's going on, on 
the floor, we're going to then open it up almost like a 
roundtable. I'll kick it off, with some questions and Senator 
Burr, and I'd look for a freeflowing give-and-take, with so 
much talent, and also experience, both in doing--so much 
experience in both the field of Alzheimer's research, and in 
the field of dealing with the bureaucracies involved in 
Alzheimer's research.
    Let me just say that we welcome Dr. Aisen, who comes to us 
from Georgetown, a professor of neurobiology and medicine. He 
founded the Georgetown Memory Disorder Program in 1999, and is 
currently the acting director of the Alzheimer's Co-op Disease 
Study, which I know he'll tell us more about.
    Dr. Kramer is a professor at the University of Illinois, in 
the Department of Psychology in the Campus Neuroscience 
Program, a full-time faculty member at the famous Beckman 
Institute of Human Perception and Performance. And his field is 
cognitive neuroscience and aging attention and perception. 
Essentially, all these cognitive issues we're talking about. 
His research has been funded, interesting enough, from not only 
NIH, the National Science Foundation, but FAA, DARPA, and 
General Motors.
    And, of course, we welcome Mr. Robert Essner, the CEO and 
chairman of Wyeth, who has been with the company since 1989. 
Wyeth has, for the past 15 years, been focused on new and 
better treatment for Alzheimer's and investing, already, a half 
a billion dollars in this. And he's--we want to hear, really, 
where Wyeth--without going into propriety issues, of course, 
where you see it going. We also note that Mr. Essner is the 
chairman of the Children's Health Fund Corporate Council, and 
we salute you for that work.
    Senator Burr. Madam Chairman, in addition to what I said 
about Targacept and their great----
    Senator Mikulski. Is that how you say it, ``Targacept''?
    Senator Burr [continuing]. Targacept--and their great CEO--
Don was recognized by Ernst & Young as an Emerging Company 
Entrepreneur of the Year for his leadership in founding 
Targacept. He has served on the board of directors of the 
Winston-Salem Chamber of Commerce, Forsythe Technical Community 
College Foundation, a number of Winston-Salem-based 
organizations. I share that with you to tell you this is a 
person, and a company, that understands their role in the 
community that they're involved in, even though they're on the 
cutting edge, in the country, with some of the research they're 
doing. He was also recently elected to the emerging company's 
section governing board of the Biotechnology Industry 
Organization, BIO.
    So, Don, I welcome you here, as I do the other witnesses, 
and I, like the chairman, look forward to your testimony.
    Thank you.
    Senator Mikulski. Why don't we start there and just go 
right down the table.


    Dr. Aisen. Thank you.
    Madam Chairman, Senator Burr, thank you for the opportunity 
to address you this morning.
    Alzheimer's disease is among the world's most important 
healthcare problems. It's a disease of aging, and the 
population of this country is getting older. Senator Mikulski, 
as you said, we have about 5 million cases today, and, on the 
basis of the aging of the U.S. population, we may have 15 or 16 
million cases by mid-century, so effective treatment and 
prevention are essential.
    As you pointed out, most of the advances in AD research are 
recent. Our first treatment became available in 1993. Before 
that, there was a general assumption that this disease would 
never be treatable. A group of academic investigators 
demonstrated that we could improve memory in AD, and, through 
collaboration with the pharmaceutical industry, worked on the 
development of our current therapeutic options. They provide 
meaningful cognitive benefits, but, of course, we have a long 
way to go.
    Academic investigators with NIH funding continue to make 
major advances that will help us to the next step of 
breakthrough therapy for AD. What's the most important advance 
in the past decade in AD research? It's the discovery of the 
specific molecular cause of the disease, which is the amyloid 
peptide. It's a long story that I don't have a chance to go 
through, but I can tell you that, on the basis of the knowledge 
that every known genetic cause of this disease directly affects 
the generation of this peptide. The only conclusion is that 
this peptide is driving the disease process. What does that 
mean? It means that we have a specific target for therapeutic 
research. It means that it's appropriate for us to be 
optimistic that we will have breakthrough therapy soon. We have 
the target, we have the model systems in the laboratory that 
allow us to screen molecules and test them, and we're now 
bringing them to human trials.
    I believe that we can realistically expect to slow or halt 
the disease process in the relatively near future, and how long 
it will take us to get there depends upon the resources brought 
to bear.
    NIH funding has played an instrumental role in bringing us 
to where we are today and to where we will be in a few years. 
As you mentioned the Alzheimer's Disease Cooperative Study is a 
large consortium of academic centers in the United States 
funded by the National Institute on Aging to develop the tools 
and conduct trials to improve the treatment of Alzheimer's 
disease. ADCS investigators conducted the first major trial of 
Tacrine that led to the first treatment, in 1993. And this 
group is responsible for a number of milestones, including the 
establishment and refinement of the most widely used assessment 
tools in clinical trials today, establishment of the diagnostic 
criteria and study methodology for mild cognitive impairment, 
which is the prodromal stage of Alzheimer's, demonstration of 
the effectiveness of antioxidant therapy for AD, demonstration 
of the lack of efficacy of some widely used treatments, 
including anti-inflammatory drugs and estrogen, demonstration 
of the only known treatment effective at the stage of mild 
cognitive impairment. And the ADCS, with NIA funding, provides 
the infrastructure for the Alzheimer's Disease Neuroimaging 
Initiative, which is a landmark collaboration between NIH 
investigators and the pharmaceutical industry to establish the 
best biomarkers of this disease to better enable the 
development of disease-modifying therapies.
    The work of the ADCS has been pivotal in nearly every 
Alzheimer's disease trial conducted by the academic world and 
industry. We are currently investigating therapies used for 
other diseases for their potential in AD, including statin 
therapy. DHA, which is an Omega-3 fatty acid, turns out to be 
deficient in the brain. We've found that we can restore DHA 
levels with supplements, and are just now launching the first 
major trial of DHA supplementation for AD.
    The demonstration that pooled human immunoglobulin, that is 
used to treat inflammatory and immune diseases, contains 
naturally occurring antibodies targeting the molecular cause, 
the amyloid peptide, and we're about to launch a large 
multicenter trial of IVIg therapy to remove amyloid from the 
brain and slow the progression of Alzheimer's disease.
    There are many other examples, and I see that I'm just 
about out of time.
    I would just remind you that funding priority should be 
determined not only by the magnitude of the problem being 
addressed, but by the likelihood that investment will yield 
important results. And, at this point in time, there is no 
investment carrying more promise than funding for AD 
therapeutic research.
    Thank you.
    [The prepared statement of Dr. Aisen follows:]
               Prepared Statement of Paul S. Aisen, M.D.
    Alzheimer's disease is among the world's most important health care 
problem. It is a disease of aging, and as the U.S. population gets 
older, this problem grows: we have over 5 million cases today, and may 
reach 15 million by 2050. Effective prevention and treatment are 
    Useful treatments for the cognitive symptoms of AD have only been 
available since 1993. Today's treatments represent a significant 
advance, built on basic and clinical studies conducted by NIH-funded 
investigators, then followed through by the pharmaceutical industry. 
This pattern continues: academic investigators have made tremendous 
advances in recent years, and have worked with industry to move us 
closer to breakthrough disease-modifying treatment.
    Most important among these advances is identification of the 
specific molecular cause of AD: the amyloid peptide. This peptide is 
the principal component of the amyloid plaque, one of the hallmark 
lesions in the Alzheimer's disease brain. How do we know that this 
peptide is the pivotal molecule? Because every known genetic cause of 
the disease directly influences the generation of the amyloid peptide. 
The only reasonable conclusion is that this peptide drives the disease 
    Therapeutically, this means that we can now realistically expect to 
slow or halt the disease process. We have a specific, feasible target 
for therapeutic interventions. We have confidence that treatments that 
successfully reduce the accumulation of the amyloid peptide in human 
brain will slow or stop progression of this disease. And coupled with 
earlier identification of disease (even before the symptoms indicative 
of the diagnosis are present), we can hope to dramatically reduce the 
impact of Alzheimer's disease.
    We have the tools to develop effective anti-amyloid treatments. We 
have model systems in our laboratories that allow us to screen and test 
potential treatments for impact on amyloid accumulation. The result is 
that numerous promising therapies are reaching the stage of clinical 
    NIH funding has played an indispensable role in bringing us to this 
point, and will continue to be pivotal in the final clinical 
development programs.
    The Alzheimer's Disease Cooperative Study (ADCS) is a large 
research consortium funded by the National Institute on Aging to 
develop tools and conduct trials to improve the treatment of 
Alzheimer's disease. The ADCS has been continuously funded since 1991. 
Accomplishments of this program include:

     establishment and refinement of the most widely used 
assessment tools for clinical trials in AD;
     establishment of diagnostic criteria and study methodology 
for ``Mild Cognitive Impairment,'' the Alzheimer's prodromal syndrome;
     demonstration of the effectiveness of antioxidant therapy 
for AD treatment;
     demonstration of lack of effectiveness of widely used 
treatments including anti-inflammatory drugs and estrogen;
     demonstration of the only treatment effective in the 
management of Mild Cognitive Impairment; and
     the ADCS provides the infrastructure for the Alzheimer's 
Disease Neuroimaging Initiative, a landmark collaboration between the 
pharmaceutical industry and NIH to establish the best biomarkers of the 
disease, to better enable the development of disease-modifying 

    The work of the ADCS has been pivotal in nearly every major 
Alzheimer's trial conducted by the academic community and the 
pharmaceutical industry.
    The ADCS is currently conducting clinical studies of promising new 
treatments for Alzheimer's disease. The ADCS is particularly focused on 
the evaluation of treatments currently used for other indications, or 
not otherwise being pursued by the pharmaceutical industry as therapy 
for AD.
    For example:
    Statins are among the most widely prescribed drugs in the world. 
Laboratory studies have shown that cholesterol and statin drugs have an 
important influence on the accumulation of the amyloid peptide. The 
ADCS is now completing a definitive trial of a readily available statin 
(simvastatin) to determine whether it can slow the progression of AD.
    DHA (docosahexaenoic acid) is an omega-3 fatty acid present in 
algae and fish. DHA plays a critical role in the function of brain 
cells, and levels are depleted in the brains of individuals with 
Alzheimer's disease. Oral supplements with DHA are effective in 
restoring brain levels, and, for reasons incompletely understood, DHA 
markedly reduces amyloid accumulation in brain. The ADCS has just 
launched a large multicenter study to determine the impact of DHA 
supplementation on the rate of progression of AD.
    One very exciting approach to reducing amyloid accumulation 
involves the use of antibodies directed against the amyloid peptide. A 
number of pharmaceutical companies are conducting active and passive 
amyloid immunotherapy programs, using either vaccinations derived from 
amyloid or manufactured antibodies to reduce amyloid levels in brain. 
IVIg is pooled human immunoglobulin, essentially human antibodies 
derived from donated blood; it is a standard treatment for certain 
immune and inflammatory diseases. IVIg has been found to contain 
substantial amounts of naturally occurring anti-amyloid antibodies, and 
preliminary studies suggest that infusions of IVIg result in 
stabilization or improvement of AD. The ADCS is preparing to launch the 
first definitive study of the safety and effectiveness of IVIg 
infusions to treat AD.
    Huperzine A is a natural extract of a Chinese herb. The purified 
compound is a highly effective and well tolerated cognitive enhancer, 
and may be superior to currently available symptomatic treatments for 
AD. In addition, laboratory studies show that huperzine A protects 
brain cells against amyloid. The ADCS is currently completing the first 
controlled study of huperzine A conducted outside China.
    As we move closer to effective disease-modifying treatments for 
Alzheimer's, we are looking toward the testing of preventive measures. 
But to assess the impact of a preventive treatment, a large number of 
healthy older individuals must be studied for a number of years. We do 
not yet have workable tools to allow the efficient conduct of such 
studies. The ADCS is now conducting a study of Home-Based Assessments, 
cognitive assessment procedures utilizing computers, interactive phone 
systems and mail-in tools, to develop the most efficient methods for 
the conduct of prevention studies without requiring participants to 
leave their homes.
    This is an incredibly exciting time in the field of Alzheimer's 
disease therapeutic research. We are close enough to be confident of 
success in the development of breakthrough therapies. How fast we get 
there, whether it will take a few years or 15, depends on the resources 
brought to bear. With academic-industry cooperation, and adequate 
funding from both, progress will be rapid.
    There are potential breakthrough studies waiting for funding now. 
For example, a collaboration between NIH and Israeli scientists has led 
to the discovery of a compound called NAP. NAP is a fragment of a 
natural brain protein. In the lab, NAP is the most potent 
neuroprotective compound ever discovered; it can rescue brain cells 
from many toxins, including the amyloid peptide. Recently completed lab 
studies show a remarkable effect of NAP on the pathological cascade of 
Alzheimer's disease. Human studies of NAP have been initiated, but a 
definitive trial in AD requires NIH funding; an application is 
currently in review.
    Funding priorities should be determined not only by the magnitude 
of the problem being addressed, but by the likelihood that investment 
will yield important results. At this point in time, no investment 
carries more promise than funding for Alzheimer's disease therapeutic 

    Senator Mikulski. Thanks very much, Doctor. Actually, 
that's a pretty stunning summary.
    Dr. Kramer.


    Dr. Kramer. I'd like to thank Senators Mikulski and Burr 
for the invitation to speak with you today about our research, 
and that of other scientists, on maintaining healthy minds and 
brains throughout the adult life span.
    Over 200 years ago, John Adams, our second President, 
argued that, ``Old minds are like old horses, you must exercise 
them if you wish to keep them in working order.''
    My goal in the next 5 minutes or less is to tell you about 
the highlights and gaps in our scientific knowledge regarding 
non-pharmacological, or behavioral, approaches to maintaining, 
and even enhancing, our minds and brains as we age, and as 
we're older.
    The context of the research I'll tell you about is quite 
varied. It includes a number of different kinds of human 
studies, including prospective epidemiological studies in which 
some lifestyle factor is measured at one point in time, and 
then cognition, or diagnosis, of Alzheimer's or other forms of 
dementia are measured somewhat later, to look at the 
relationship between the choice of what we do and its 
implications. Human randomized clinical trials are the gold 
standard in medical research of various lifestyle factors. And, 
finally, invaluable research from our animal colleagues on 
molecular and cellular mechanisms of preventative effects of 
various lifestyle factors on Alzheimer's models, some gene-
knockout models and some others, of Alzheimer's, and--as well 
as cognitive decline.
    So, what do we know, with respect to the current state of 
scientific knowledge, about maintaining healthy brains and 
minds? And this will be oversimplified, but there's more 
information provided to the congressional record.
    Research has shown that exercise and physical activity is 
associated with better memory, attention, decisionmaking, 
executive control abilities, reduced risks--risk for 
Alzheimer's and other forms of dementia, and increased brain 
structure and function in clinical trials, that NIH has been so 
good to support, in older humans.
    How do all these effects happen? Well, we certainly don't 
know all of the mechanisms, but one set of mechanisms has to do 
with reduced risk for a variety of diseases that accompanies 
exercise, such as cardiovascular disease, type-2 diabetes, 
colon and breast cancer, and osteoporosis. But we also know a 
lot about molecular and cellular mechanisms--again, not enough, 
but quite a bit more than we did a decade ago. We know that 
exercise increases the expression of various neurotrophin 
factors, such as brain-derived neurotrophic factor and others; 
neurogenesis; or the creation of new neurons from adult stem 
cells, selectively in the brain; synaptogenesis, the creation 
of new neuronal connections; as well as angiogenesis, or the 
construction of new vascular structure, to support increased 
neuronal firing, and learning and memory.
    It's interesting that these exercise effects, the human 
effects--I've talked about the animal molecular and cellular 
mechanisms briefly--but the human effects are found with very 
moderate exercise. In our randomized clinical trials, we take 
older sedentary adults between the ages of 60 and 80, and put 
them on a walking protocol for 6 months, 3 days a week. By the 
end of the 6 months, everybody's walking further and a little 
bit faster, but nobody's winning any gold, silver, or bronze 
medals. So, these are very moderate effects that promote 
improvements in a variety of cognitive functions, as well as a 
healthier brain, which is quite interesting. And the really 
neat aspect of this, as my colleague Pat Heyn at the University 
of Colorado found, very similar effects in early AD patients. 
Exercise alone clearly isn't sufficient. There has been a good 
deal of research, and it continues, with support from NIH and 
other sources, on intellectual engagement, such as playing 
cards, chess, visiting museums, and so forth; social 
activities--participating in social, church, and volunteer 
activities; and diets--food that's high in antioxidants, Omega-
3 fatty acids, low in saturated and trans fats--have similar 
effects to exercise on cognition and reduction in risk of 
dementia. And this is mostly from observational prospective 
epidemiological studies.
    So, what don't we yet know? Well, we don't yet know quite a 
bit, and we need your help, Senators--and we need the help of 
NIH and other government science agencies--to help the 
scientific community to move along and develop more knowledge 
that'll be beneficial to our citizens.
    No. 1, we need to know much more about the mechanisms which 
underlie the beneficial effects of lifestyle factors, such as 
diet, social interaction, intellectual engagement, and 
exercise, on the maintenance of healthy minds and brains, so 
perhaps we don't get to the point of being diagnosed with mild 
cognitive impairment of Alzheimer's dementia for 2 or 3 years, 
or even longer, as Senator Mikulski has discussed earlier on.
    We need to know how and when, and how much, to best combine 
different behavioral and pharmacological treatments to maximize 
the payoffs, in terms of healthy minds and brains throughout 
the life span. I personally care little to live longer if I 
can't live well. And I think most of us feel the same way.
    We need to know more about how to capitalize on the rapidly 
expanding field of molecular genetics to customize individual 
treatments, both pharmacological and behavioral, to encourage 
healthy minds throughout the life span.
    And perhaps the hardest part is how best to encourage our 
citizens to continue what they start, in terms of exercise, 
intellectual engagement, social engagement, and eating right to 
ward off the effects of different forms of dementia, and 
maintain healthy brains and minds.
    Thank you.
    [The prepared statement of Dr. Kramer follows:]
                 Prepared Statement of Arthur F. Kramer
    The mantra of ``successful aging'' appears to be ever present in 
our fast paced high tech society. A visit to your local electronics 
store will quickly reveal an increasing number of computer games, such 
as Nintendo's Brain Age and Mattel's Brain Games, that are touted to 
train your brain and keep you mentally young. Of course, these 
products, and many others, are also easily downloadable, for a fee, 
from a multitude of Web sites. The number of books offering solutions 
to age-related declines in cognitive function, including many aspects 
of memory, are also proliferating at a rapid pace. Claims in the media, 
and on the shelf 's of health food stores, also abound with regard to 
the beneficial effects of nutraceuticals and supplements on health and 
functioning throughout the lifespan.
    The increasing interest in products and lifestyle factors that 
engender successful aging is driven, in large part, by the aging of 
populations in many industrialized nations as well as the change in our 
conception of aging. For example, as of 2004 there were 36.3 million 
Americans over the age of 65, 12.4 percent of the population. This 
number is projected to grow to 71.5 million individuals, approximately 
20 percent of the population, by 2030. Increasing numbers of 65+-year 
olds have been entering the workforce, both out of financial necessity 
and in search of continuing intellectual and social stimulation, and 
are expected to continue to do so in the future (Administration on 
Aging, 2005). Hence the desire to maintain cognitive as well as 
physical health.
    In the present document we primarily focus on one factor that has 
been suggested to have a positive influence on cognition and brain 
function, that is, physical activity and exercise. However, other 
factors such as intellectual engagement, social interactions, and 
nutrition are also discussed, albeit to a lesser extent, with regard to 
their potential beneficial effects on cognition and brain function. We 
evaluate the claim that staying physically active can maintain and even 
enhance cognition and brain function as well as reduce the risk of age-
associated neurological disorders such as Alzheimer's disease. We begin 
our review by examining the epidemiological or prospective 
observational literature which has explored this issue, often with 
middle age and older adults. Next, we examine randomized clinical 
trials which have examined the influence of fitness training programs 
on cognition and less frequently, measures of brain function and 
structure. We then provide a brief review of the ever expanding animal 
literature which has begun to elucidate the cellular and molecular 
mechanisms of physical activity effects on brain and cognition. Next, 
we briefly examine the role of other lifestyle factors such as the 
pursuit of intellectually engaging activities and social engagement in 
the maintenance of cognition and reduction in risk for age-related 
neurological disorders such as Alzheimer's disease. We then discuss a 
small but growing literature which examines the combination of 
different lifestyle factors, including intellectual engagement, social 
engagement, physical activity and nutrition as a means for enhancing 
cognitive and brain health of older adults. Finally, we conclude with a 
brief prescription of future directions for research on maintaining 
cognitive vitality across the adult lifespan.
      human observational studies of physical activity & exercise
    In recent years there has been an increasing interest in the 
relationship between physical activity and exercise at one point in the 
lifespan and cognition or the diagnosis of age-associated neurological 
diseases at a later point in time. Clearly, one reason for this 
interest is the burgeoning literature on the reduction in risk for a 
multitude of diseases, including cardiovascular disease, breast and 
colon cancer, obesity, and type II diabetes, associated with physical 
activity (Dishman et al., 2006). However, another important factor 
influencing the interest in physical activity and cognition is the 
animal research on the positive effects of enriched environments, which 
often include a physical activity component, on learning, memory and 
brain function (Rosenzweig & Bennett, 1996).
    Observational studies generally assess physical activity and 
exercise with self-
report questionnaires and then followup, often 2 to 9 years later, with 
an examination of cognitive function or diagnosis of Alzheimer's and 
other forms of dementia. Given that the decision to partake in physical 
activity is often related to other lifestyle choices and medical 
conditions these studies also assess such factors which are then used 
as covariates in the examination of physical activity effects on 
    A number of prospective observational studies have found a 
reduction of risk for Alzheimer's disease and other forms of dementia 
for more physically active individuals. For example Larson et al. 
(2006) assessed 1,740 adults over the age of 65 on the frequency of 
participation in a variety of physical activities (e.g. walking, 
hiking, bicycling, swimming). After a mean followup of 6.2 years 158 of 
the original participants had developed dementia. After adjusting for 
age, sex and medical conditions, individuals who exercised more than 3 
times per week during initial assessment were found to be 34 percent 
less likely to be diagnosed with dementia than those who exercised 
fewer than 3 times per week. Similar relationships between exercise and 
dementia have been reported in other studies (Laurin et al., 2001; 
Podewils et al., 2005; Scarmeas et al., 2001). Some studies have 
focused specifically on walking and its relationship to dementia. 
Abbott et al., (2004) examined the distance that 2257 physically 
capable men, aged 71 to 93, walked on a daily basis and then followed 
up an average of 4.7 years later with an assessment of dementia. After 
adjusting for cognitive ability, education and medical conditions at 
baseline, both walking speed and distance were associated with a 
reduced risk for dementia.
    A reduction of risk for cognitive decline, often measured with a 
general test of cognitive function such as the mini-mental State 
examination (MMSE), has also been found for physically active 
individuals who have not been diagnosed with dementia (Almeida et al., 
2006; Lytle et al., 2004; Weuve et al., 2004; Yaffe et al., 2001). A 
particularly noteworthy study was reported by Barnes et al. (2003) who 
obtained both subjective and objective measures of cardiorespiratory 
fitness in a sample of 349 individuals over 55. Six years later these 
individuals were tested on both the MMSE and more focused tests of 
executive control, attention, verbal memory and verbal fluency. Higher 
fit individuals at time 1 showed benefits on tests of all of these 
abilities at the final assessment and the relationship between fitness 
and cognition was stronger for the objective than for the subjective 
measure of fitness.
    Although in general the majority of the observational studies have 
found that physical activity has beneficial effects on cognition, it is 
important to note that some observational studies have failed to find a 
relationship between fitness and cognition or dementia (Sturman et al., 
2006; Verghese et al., 2003; Wilson et al., 2002; Yamada et al., 2003). 
It is difficult to know, given the current scientific literature, which 
factors are most important in moderating the influence of physical 
activity on later life cognition and dementia. However some 
possibilities that merit further research include: the distinction 
between aerobic and non-aerobic physical activities (Barnes et al., 
2003), the utility of self-report versus more objectively measured 
physical activities and fitness, the relative contribution of social, 
intellectual and physical factors to different everyday activities 
(Karp et al., 2006), the role of physical activity duration, intensity, 
and frequency (van Gelder et al., 2005), the nature of the components 
of cognition that serve as the criterion variables (Colcombe & Kramer, 
2003; Hall et al., 2001), the age of participants at initial and final 
assessment, and genetic factors (Etinier et al., 2007; Podewilis et 
al., 2005, Rovio et al., 2005; Schuit et al., 2001).
        beyond observation: randomized clinical trials in humans
    Observational studies have provided intriguing support for the 
relationship between physical activity and cognition. However, such 
studies cannot establish causal links between these constructs. Over 
the past several decades there have been a relatively small but 
increasing number of clinical trials in which relatively sedentary 
individuals, often over the age of 60, are randomized to an aerobic 
training group (i.e. walking, swimming, bicycling) and a control group 
that often entails non-aerobic activity such as toning and stretching. 
Training is usually conducted for an hour a day for several days a week 
and can last from several months to 2 years. Cognition, and less 
frequently brain function and structure, is examined prior to and 
subsequent to the interventions.
    Results of such studies have been mixed with some reporting that 
aerobic exercise differentially benefits aspects of cognition while 
other studies have failed to observe such a relationship. Several 
potential reasons for this mixed pattern of results include: (1) the 
manner in which cardiorespiratory fitness was characterized from 
resting heart rate to the gold standard, VO2 max, (2) the length, 
duration and intensity of exercise training, (3) the cognitive 
processes examined in the studies, and (4) the age, health, sex, and 
fitness levels of participants. Given the substantial variability in 
individual and experimental characteristics several meta-analyses have 
been conducted in recent years to determine, first, whether a robust 
relationship between exercise training and cognition can be discerned 
and second, which factors moderate such a relationship (Etnier et al., 
2006; Heyn et al., 2004; Kramer & Colcombe, 2003).
    The results are clear with respect to the first question, exercise 
training positively influences cognition. Several additional results 
are noteworthy. First, the effect size of exercise training, 
approximately .5 over analyses, is quite similar for both normal and 
cognitively impaired adults. Thus, older adults with early dementia 
appear able to benefit from exercise training, albeit from a different 
cognitive baseline. Second, studies with more women generally show a 
larger effect of exercise training on cognition than studies with fewer 
women. Third, while fitness training has relatively broad effects 
across a variety of perceptual and cognitive processes, the benefits of 
exercise training appear to be larger for executive control processes 
(e.g. planning, scheduling, working memory, dealing with distraction, 
multi-tasking). This observation is quite interesting given that 
executive control processes show substantial declines over the adult 
lifespan. Fourth, overall there was little evidence of a significant 
relationship between fitness change and cognitive change. At first 
glance this observation appears perplexing. However, upon further 
consideration this may not be surprising given that the measures of 
fitness obtained in these studies are global in nature (i.e. sensitive 
to both peripheral and central nervous system changes) and not specific 
to brain function.
    As compared to the study of the relationship between exercise 
training and cognition, relatively few studies have been conducted to 
examine exercise training influences on human brain structure and 
function. Colcombe et al. (2004) investigated changes in the neural 
network which supports attentional control, as indexed by fMRI 
activation obtained in a high field magnet, over the course of a 6 
month aerobic exercise program. Older adults performed the flanker 
task, which entails focusing on a subset of information presented on a 
visual display and ignoring task-irrelevant distractors, before and 
after the exercise training interventions. Individuals in the aerobic 
training group (i.e. walking) showed a reduced behavioral distraction 
effect and change in pattern of fMRI activation similar to that 
displayed by younger controls (i.e. increased right middle frontal 
gyrus and superior parietal activation). Participants in the toning and 
stretching control group did not show such behavioral and fMRI changes. 
More recently, Colcombe et al. (2006) reported increases in brain 
volume, as indexed by a semi-automated image segmentation technique 
applied to high resolution MRI data, for an aerobic but not for a non-
aerobic exercise training group. The individuals who walked 3 days a 
week for approximately 1 hour per day displayed increases in gray 
matter volume in the frontal and temporal cortex as well as increases 
in the volume of anterior white matter. Finally, Pereira et al. (2007) 
reported increases in MRI measures of cerebral blood volume (CBV) in 
the dentate gyrus of the hippocampus for a group of 11 middle aged 
individuals who participated in a 3-month aerobic exercise program. 
These CBV changes were related to both improvements in 
cardiorespiratory fitness and performance on a test of verbal learning 
and memory. Increases in CBV in a parallel study of exercising mice was 
found to be related to enhanced neurogenesis. Therefore, the results of 
this study are particularly exciting in suggesting that CBV may serve 
as a biomarker for neurogenesis in humans.
           animal research: cellular and molecular mechanisms
    Research using non-human animals complements human research in 
several ways. First, many of the uncontrolled variables in human 
research can be more easily controlled or systematically manipulated in 
non-human animal research, thereby allowing for a more precise 
examination of some of the factors influencing brain and cognition. 
Second, the capabilities to assess the molecular and cellular 
mechanisms of exercise are substantially greater in non-human animals 
than in humans. Therefore, animal research provides an important 
translational approach to understanding neurocognitive plasticity in 
    In rodents, voluntary exercise enhances the rate of learning on 
hippocampal dependent tasks such as the Morris Water maze, a task that 
requires the use of extra-maze cues to determine the location of a 
submerged platform (Adlard et al., 2004; Vaynman et al., 2004). For 
example, in older animals, van Praag et al. (2005) reported that 45 
days of access to a running wheel resulted in faster acquisition and 
greater retention on the water maze than age-matched sedentary 
controls. Other tasks, such as the passive avoidance task, in which 
animals are trained via foot-shock to refrain from entering into a dark 
chamber, also show performance improvements with exercise (Alaei et 
al., 2006). Similar behavioral benefits of exercise have been reported 
in rodent models of Alzheimer's disease (Adlard et al., 2005) and 
Huntington's disease (Pang et al., 2006). Therefore, there is ample 
evidence that exercise promotes faster rates of learning and improved 
retention on hippocampal-dependent tasks.
    Enhanced learning on water maze tasks has been associated with an 
increased production of neurotrophic molecules such as brain-derived 
neurotrophic factor (BDNF). BDNF is involved in neuroprotection and 
promotes cell survival, neurite outgrowth, and synaptic plasticity 
(Cotman & Berchtold, 2002). For example, direct administration of BDNF 
increases cell proliferation in the hippocampus, whereas blocking BDNF 
activity reduces cell proliferation. Voluntary exercise increases both 
mRNA and protein levels of BDNF in the hippocampus, cerebellum, and 
frontal cortex and blocking the binding of BDNF to its tyrosine kinase 
receptor abolishes the exercise-induced performance benefits on the 
Morris water maze (Vaynman et al., 2004). Therefore, exercise increases 
BDNF levels, which seem to be inextricably related to the behavioral 
improvements observed with an exercise treatment.
    BDNF is not the only molecule in the brain affected by exercise. 
For example, insulin-like growth factor-1 (IGF-1) is critical for both 
exercise-induced angiogenesis (Lopez-Lopez et al., 2004) and 
neurogenesis (Trejo et al., 2001). By blocking IGF-1 influx into the 
brain, exercise-induced cellular proliferation and BDNF production are 
effectively rescinded. In addition, IGF-1 also moderates the secretion 
of other molecules such as vascular endothelial growth factor (VEGF), a 
prominent growth factor involved in blood vessel growth. For example, 
Lopez-Lopez et al. (2004) reported that blocking IGF-1 blocked the 
secretion of VEGF, which resulted in a significant suppression of new 
capillaries. Furthermore, by blocking the influx of VEGF into the 
brain, exercise-induced neurogenesis is abolished, but baseline levels 
of neurogenesis are unaffected (Fabel et al., 2003). Therefore, a 
plethora of molecules and molecular cascades are up-regulated with 
exercise that influence learning and memory operations, cortical 
morphology, angiogenesis, and cell proliferation.
    Exercise induces the development of new capillaries in the 
hippocampus, cerebellum, and motor cortex of young rats (Black et al., 
1990; Kleim et al., 2002; Swain et al., 2003) and reduces the volume of 
cortical damage caused by the induction of stroke (Ding et al., 2004). 
One function of new capillaries is to deliver necessary nutrients to 
existing or newly dividing neurons. In relation to this, exercise 
increases both cell proliferation and cell survival, which has been 
related to enhanced learning rates on the Morris water maze (van Praag 
et al., 1999). Neurogenesis is diminished with age, but exercise 
reliably reverses the normal decline in neurogenesis accompanied by 
improved Morris water maze performance (van Praag et al., 2005; 
Kronenberg et al., 2006).
    It is clear from this review that rodent research provides strong 
support for the positive effects of exercise on the brain and 
cognition. Voluntary wheel running in rodents results in enhanced 
learning and retention on hippocampal-dependent tasks, the induction of 
a variety of molecular cascades including BDNF, IGF-1, VEGF, and an 
increase in neurotransmitter release in dopaminergic, cholinergic, and 
serotinergic systems. In addition, both angiogenesis and neurogenesis 
are up-regulated with exercise in young and old animals. This evidence 
provides an important mechanistic and molecular basis for understanding 
the effects of exercise on the human brain and cognition.
beyond physical activity & exercise: the influence of intellectual and 
   social engagement in promoting healthy minds throughout adulthood
    Similar to the studies of physical activity there have been an 
increasing number of longitudinal human studies to examine the 
influence of participation in intellectually stimulating activities 
such as reading, playing cards or chess, attending a play, doing 
crossword puzzles, taking classes, going to museums and other similar 
activities on the maintenance of cognitive health and reduction in risk 
for Alzheimer's disease in older adults. These studies generally assess 
number and frequency of participation in intellectually engaging 
activities at one point in time, in populations of adults between 60 
and 80 years of age, and then follow up six or more years later with an 
assessment of cognition and age-associated neurological disorders. The 
great majority of such studies conducted over the past decade have 
found that participation in a greater number (and with greater 
frequency) of intellectually engaging activities is associated with 
higher levels of cognitive function and reduced risk of dementia in 
older adults (Bosma et al., 2002; Verghese et al., 2003, 2006; Wang et 
al., 2006; Wilson et al., 2002, 2003).
    A similar approach has been taken to examine the influence of 
participation in social activities and maintaining social interactions 
on cognition and brain health of older adults. Studies that have 
examined social activities such as meeting friends, participating in 
cultural or social groups, engaging in family and charitable 
activities, and attending church activities have generally produced 
positive results both in terms of maintenance of cognition in normal 
elderly and in reducing the risk for Alzheimer's dementia (Barnes et 
al., 2004; Lovden et al., 2005; Wang et al., 2002). The size of social 
networks has produced a mixed pattern of results with some studies 
finding benefits for individuals with larger social networks and other 
studies failing to observe relationships between social network size 
and cognition or dementia risk (Fratiglioni et al., 2000; Helmer et 
al., 1999). Indeed, social relationship quality rather than social 
network size may be more important with regard to maintaining healthy 
minds and brains.
    One potential concern with these longitudinal studies, however, is 
whether reduced intellectual or social engagement at initial assessment 
may be an early sign of decline or dementia rather than a predictor of 
latter function. While reverse causation is always a concern in studies 
that do not involve randomized trials, the fact that some of the 
studies have found relationships between cognitive or social engagement 
over 15 or 20 years considerably reduces this concern (Crowe et al., 
 effects of multimodal lifestyle factors on cognition and brain health
    As described in the sections above, the great majority of 
laboratory studies of factors that influence the level and trajectories 
of cognitive function focus on single factors. This is a reasonable 
scientific approach given the potential complexity and cost of 
simultaneously studying multiple interacting factors. However, clearly 
a disadvantage of such an approach is that it may miss the potential 
power of interactions for maintaining and enhancing cognition.
    There are at least two different approaches that have been pursued 
in the literature to the study of multi-factor influences on cognition. 
One approach is represented by the early study of complex or enriched 
environments on brain function and performance of non-human animals 
(Black, Isaacs, Anderson, Alcantara & Greenough, 1990; Ehninger & 
Kempermann, 2003; Jones, Hawrylak, & Greenough, 1996; Kempermann, Kuhn 
& Gage, 1997; Rosenzweig & Bennett, 1996). Such an approach can 
establish the influence of some combination of either separately acting 
or interacting factors such as social interaction, cognitive challenge, 
physical activity and nutrition on performance and brain. However, this 
approach can not assess the relative contribution of individual factors 
(or their interaction). Nonetheless such an approach has been 
instrumental in establishing the importance of potential lifestyle 
factors in cognitive maintenance and enhancement. A second approach 
which has been represented in observational studies for some time and 
is beginning to evolve in human and non-human interventions is the 
orthogonal examination of multiple factors and their interactions in 
separate groups of subjects. Such an approach is costly in terms of 
time and the number of subjects required. However, this approach also 
has the potential to decompose the relative benefits of different 
factors and their potential mechanisms. Studies that have pursued each 
of these approaches will be discussed below.
    Prospective Observational Studies. A number of prospective 
observational studies, some of which have been reviewed above in the 
context of single lifestyle factors, have investigated the relative 
contribution of intellectual, physical and social engagement as 
predictors of cognitive change and transition to dementia. For example, 
Wilson et al (2002a&b) reported that while participation in cognitive 
activities (such as reading, listening to the radio, playing games) 
reduced the risk of succumbing to Alzheimer's Disease; participation in 
physical activities (such as jogging, gardening, bicycle riding, 
dancing) was unrelated to the development of AD 4 years in the future 
(see also Verghese et al., 2005; Wang et al., 2006). Both the cognitive 
and physical activities were assessed via self report and while the 
cognitive activities were assessed relative to a 1-year timeframe, 
physical activities were referenced to a 2-week period prior to the 
    A study by Sturman et al. (2006) is particularly interesting in 
that these investigators addressed the question of whether, over a 6.4 
year period, participation in physical activities by older adults 
reduces the rate of cognitive decline after accounting for 
participation in cognitively stimulating activities. Prior to 
adjustment for cognitive activities, each additional hour per week of 
physical activity was associated with a slower rate of cognitive 
decline. However, this relationship was no longer significant after 
adjusting for cognitive activities. On the other hand, Richards et al 
(2003) reported that physical activity at 36 years of age was 
associated with a slower rate of decline in memory from 43 to 53 years 
of age and this relationship was unchanged after adjusting for 
cognitive activities. Cognitive activities were not associated with 
change in memory over this interval.
    The studies described above generally employ different activities 
to represent cognitive or physical demands. However, a recent study by 
Karp and colleagues (2006) has taken a different approach to examining 
the relative contribution to cognitive, physical and social engagement 
to cognitive change and dementia. They argue that most leisure 
activities engage some combination of these three types of demands. On 
this basis, they had the researchers and a panel of older adults rate 
the relative intensity, on a scale of 0 to 3, of social, cognitive and 
physical demands of a set of 30 leisure activities. Agreement was quite 
high among raters. As an example of the ratings attending courses was 
rated 3,1 and 2 for mental, physical and social demands, respectively 
(with 3 being the most intense). These ratings were then applied to the 
activities pursued by 776 individuals over the age of 75 years of age 
to predict diagnosis of dementia 6 years in the future. After adjusting 
for a variety of covariates social, cognitive and physical activities 
were each found to be associated with a reduced risk for dementia. In 
any event, characterizing leisure activities in terms of their 
multidimensional nature is an interesting and potentially important 
alternative to the dichotomous approach adopted by other observational 
    In summary, in observational studies that examine more than one 
lifestyle factor, cognitive activities appear to be the strongest 
predictor of cognitive change. However, this could be the result of the 
several factors including: (1) rarely are physical activities 
characterized in terms of intensity, frequency and duration, (b) the 
period across which activities are assessed has been different for 
cognitive and physical activities, (c) with one exception, activities 
have been treated as unidimensional in nature. Clearly, these issues 
require additional consideration in future studies.
    Human Intervention Studies. To our knowledge there have been only 
two randomized trials that have examined the separate and combined 
influence of multiple lifestyle factors on the cognitive function of 
older adults. Both of these studies were conducted by the same research 
group and involved 2 months of training with eight 60- to 75-year-old 
participants in each of four experimental groups. In both studies 
subjects either participated in an aerobic training group (walking & 
jogging), a memory training group (including general encoding & 
retrieval instructions, association & attentional training), a combined 
group, and a control group. Fabre et al. (1999) found that all three 
training groups but not the control group showed improved performance 
on logical and paired associate memory tasks across the 2-month 
intervention. However, combined training did not show additional 
benefits as compared to the aerobic or memory training. Fabre et al. 
(2002) used an elaborated memory training protocol and a similar 
physical training protocol as compared to their previous study. A more 
thorough assessment of changes in memory was also used in this study. 
Results indicated improvements in a general memory metric in all three 
of the training groups. However, in this experiment, benefits were 
largest for the combined training group.
    The two studies described above attempted to decompose the relative 
contribution of cognitive and physical training to improvement in 
cognitive function. A number of other human intervention trials have 
taken a multimodal approach, much like enriched environment experiments 
with animals, in examining the influence of multiple lifestyle factors 
on cognition. The Experience Corps project, conducted at Johns Hopkins, 
is an example of one such project (Fried et al, 2004). This project 
places teams of older adults in inner city elementary schools to 
address unmet needs. The older adult participants are trained to 
provide literacy, numeracy, library and other support in kindergarten 
through 3rd grade. Once entering the program and completing training 
the older adults devote at least fifteen hours per week for an academic 
year to the schools. The Experience Corps program stresses a 
combination of social, cognitive and physical activity engagement in 
support activities in the schools. An intervention with 128 
participants who were randomized to the Experience Corps program and a 
wait list control group found that individuals with poor baseline 
executive function showed a 44 to 51 percent improvement in executive 
function and memory in the post intervention followup. These 
improvements were not observed for the control participants (Carlson et 
al., submitted). In another small randomized intervention (Carlson et 
al., 2006) Experience Corps subjects, but not control subjects, 
displayed improved efficiency in brain activation, as indexed by event-
related fMRI, and performance in an inhibitory control task.
    Another recently completed multimodal intervention was conducted by 
Small and colleagues (2006). In this study a small group of middle-aged 
participants were randomized either to a 2-week healthy lifestyle 
program or a wait-list control group. Subjects in the healthy lifestyle 
group, which included a healthy diet, physical exercise, relaxation 
training and memory training, showed improvements in verbal fluency and 
decreases in activation in left dorso-lateral prefrontal cortex as 
assessed via Positron Emission tomography. Other multimodal 
interventions that have combined social and cognitive components have 
also shown training specific benefits as compared to wait-list control 
groups in cognition and psychosocial function (Fernandez-
Ballesteros, 2005; Stine-Morrow et al., in press).
    In summary, thus far there are few studies that have systematically 
examined either the separate or combined contribution of multimodal 
interventions to enhanced cognitive and brain function in older adults. 
Clearly, the nature and mechanisms of multimodal intervention programs, 
particularly those that can be implemented in community setting such as 
the Experience Corps project, are important topics for future longer-
term studies.
    Multimodal Animal Research. As described above the great majority 
of animal studies that have examined the influence of multimodal 
interventions on brain function, learning and memory have done so in 
the context of enriched or complex environments in which animals are 
often housed together with the opportunity for physical activity and 
exploration of a multitude of novel objects (Black, Isaacs, Anderson, 
Alcantara & Greenough, 1990; Ehninger & Kempermann, 2003; Jones, 
Hawrylak, & Greenough, 1996; Kempermann, Kuhn & Gage, 1997; Rosenzweig 
& Bennett, 1996). These studies have generally found beneficial effects 
of this multimodal environment on brain structure, function and 
performance. However, a smaller set of studies have examined the 
separate and joint contributions of different interventions to brain 
health and cognition.
    Two studies have focused on the separate and combined effects of 
diet and cognitive training or exercise. Molteni et al. (2004) examined 
the effects of a high fat diet and voluntary exercise on learning and a 
variety of molecules which support neural function. Female rats were 
randomized into four different groups created by combining a regular or 
high fat diet with voluntary exercise or a sedentary environment. After 
2 months of the interventions the regular diet/exercise group was found 
to show the fastest spatial learning on the Morris Water maze task 
followed by the regular diet/sedentary and high fat/exercise groups, 
with the high fat/sedentary group showing the poorest learning. 
Additionally, a combination of a regular diet and exercise was observed 
to produce the largest increase in brain-derived neurotrophic factor 
(BDNF), a neuroprotective molecule that facilitates synaptic 
transmission, as compared to the regular diet/sedentary group. 
Furthermore, decreases in BDNF engendered by a high fat diet were 
abolished by exercise. Thus, these data suggest that the costs of a 
high fat diet can, under some conditions, be offset by regular 
exercise. Milgram et al. (2005) conducted a 2-year intervention with 
separate and combined diet (regular & enhanced anti-oxidant) and 
enriched (including discrimination training and exercise & non-enriched 
control) conditions with older beagles. Both the antioxidant diet and 
enriched environment groups displayed a number of benefits in learning 
in memory across a variety of discrimination tasks. Furthermore, the 
group that received both the antioxidant diet and enriched environment 
showed the most dramatic benefits in learning and memory. Indeed, these 
data suggest reduced cognitive decline, over the 2-year period of the 
study, for older dogs with behavioral enrichment and/or dietary 
fortification with antioxidants.
    In a recent study, Stranahan et al. (2006) examined the interaction 
between social isolation and exercise on neurogenesis in the 
hippocampus of adult male rats. Animals were either housed individually 
or in groups and either did or did not have access to a running wheel. 
Several interesting results were observed. First, individual housing 
precluded the positive effects of short term running on adult 
neurogenesis in hippocampus. Furthermore, in the presence of additional 
stressors the influence of short-term running was negative for the 
socially isolated animals, resulting in a net decrease in the number of 
neurons relative to sedentary animals. Second, group-housed runners 
produced the largest number of new neurons in the hippocampus. Finally, 
longer duration running was able to enhance cell proliferation of the 
socially isolated animals but not to the level of group-housed animals.
    In summary, the studies reviewed above and others (Berchtold et 
al., 2001; Russo-Neustadt et al., 1999) suggest potentially mutually 
interdependent relationships of a number of different lifestyle factors 
on brain and cognitive health of both young and older organisms. 
Clearly, however, although the extant literature provides some clues 
concerning the molecular and cellular pathways that support the 
interactive effects of different factors much remains to be discovered 
in additional research on multimodal interventions (Gobbo & O'Mara, 
2006; Wolf et al., 2006).
                           future directions
    Our brief review of the literature suggests that a number of 
lifestyle factors provide multiple routes to enhancing cognitive 
vitality across the lifespan--through the reduction of disease risk and 
in the improvement in the molecular and cellular structure and function 
of the brain. Thus, as has been suggested for other factors such as 
education (Elkins et al., 2006; Stern, 2006), physical activity, 
intellectual engagement, social interaction and nutrition appear to 
provide a cognitive reserve which buffers us against the many 
challenges experienced during the course of aging. However, despite all 
that we have learned about the benefits of exercise much remains to be 
discovered in future research.
    We present here several directions for future research to isolate 
and delineate the cognitive and neural effects of exercise. First, as 
reviewed in this manuscript, both animal and human research point to 
similar conclusions regarding the beneficial properties of exercise on 
the brain and cognition, but whether the underlying mechanisms are the 
same in both humans and rodents remains unresolved. An important avenue 
for future research will be to assess the concentration of molecular 
markers in human blood and brain tissue as a function of an aerobic 
exercise treatment (Pereira et al., 2007; Reuben et al., 2003). Such a 
link would provide compelling evidence that the same molecular 
mechanisms are functioning in both humans and rodents. Of course, the 
same issues are of interest for other lifestyle factors.
    A few studies have reported that the effects of aerobic exercise 
are not independent of factors such as estrogen, diet, and intellectual 
and social engagement (Vanyman & Gomez-Pinilla, 2006). However, the 
study of interactions among lifestyle factors is in its infancy and the 
degree and direction of these interactions needs to be more fully 
elucidated. An important future direction is to examine the effects of 
lifestyle factors within a multi-factorial framework which also 
incorporates pharmacological treatments for age-associated disorders 
and diseases.
    A third avenue involves determining the relationship between 
lifestyle factors and certain genetic profiles. For example, people 
with certain alleles have higher risks for dementia, disease, or 
cognitive dysfunction. Whether exercise, intellectual engagement, 
social engagement or good nutrition offsets or diminishes the risks 
associated with such genetic predispositions remains an understudied 
question. Characterizing the genetic profiles of those people who 
benefit the most and those that benefit the least from particular 
lifestyle regimens is clearly needed.
    In addition, the benefits and limitations of lifestyle factors in 
preventing or reversing the cognitive and neural deterioration 
associated with neurological diseases have not been fully investigated 
(Heyn et al., 2004). It will be important for future research to 
examine the efficacy of lifestyle factors such as exercise, 
intellectual, and social engagement in relation to symptom severity, 
duration of illness, comorbidity of diseases, the brain areas and 
molecular factors most affected in the disease, and possible 
interactions with pharmaceutical treatments. Given the medical and 
social significance of this research, these questions should be pursued 
with vigor.
    Another direction for future research is to specify which cognitive 
operations are most affected by different lifestyle factors. For 
example, it appears that in humans aerobic exercise affects executive 
functions more than other cognitive processes (Colcombe & Kramer, 
2003). However, what remains unaddressed is what aspect(s) of executive 
function is being most affected with exercise: response preparation, 
response selection, conflict detection, task-switching, task and goal 
maintenance in working memory, etc. The nature of exercise effects on 
tasks that rely on the temporal lobes, consistent with the 
demonstration of hippocampal neurogenesis in non-human animals (Pereira 
et al., 2007; Van Praag et al., 2005), is also an important research 
topic. Therefore, more refined task manipulations in the context of 
exercise and other interventions will allow for a detailed 
characterization of the relevant cognitive processes.
    Finally, very few experimental studies investigate whether the 
benefits of lifestyle factors extend outside the laboratory to everyday 
cognitive functioning. Although the effects are often assumed to 
transfer outside the laboratory, evidence to support such a claim does 
not currently exist. It will be important for any future research to 
also investigate the transfer of such cognitive and neural benefits to 
everyday activities involved in independent living and workplace 
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    Senator Mikulski. Well, that was very, very, very 
instructive, and we have tons of questions to ask.
    Mr. Essner.

                           NEW JERSEY

    Mr. Essner. Thank you. Thank you, Senator Mikulski and 
Senator Burr, for allowing me to testify on a subject that is 
very important to me, my company, Wyeth, and certainly 
Alzheimer's patients and their families.
    I'd like to share, very quickly, three key messages with 
you today. First, that, as you've all said, Alzheimer's disease 
is an epidemic that requires an epidemic-level response. 
Second, to tell you that Wyeth is very active in the war on 
Alzheimer's disease. And third, that our efforts would be aided 
by a focused national strategy targeting this disease. And let 
me give a little more detail on each of these.
    First, that Alzheimer's disease is an epidemic. That's what 
we're headed for as we go out into the future. I know many of 
you appreciate the scope of what we're facing, but, despite the 
wealth of data that's available, I'm concerned that, in 
general, the public does not see Alzheimer's disease as an 
epidemic, at least not yet. Avian flu and AIDS come to mind as 
epidemics. Alzheimer's just does not. And, frankly, I think we 
may have become almost desensitized to it. It was first 
identified over 100 years ago, and maybe, in some way, we've 
just gotten used to it.
    We're all familiar with the statistics on the economic and 
social burdens of this disease. I'm turning 60 this year, and 
I'm starting to take this personally, because today, as Senator 
Burr said, one out of eight Americans over 65 has Alzheimer's. 
I think even more startling is the statistic that says if you 
live to be 85--and I think many people in my generation have 
that expectation today--your chances of developing Alzheimer's 
disease are almost 50 percent.
    A second point is that Wyeth, the organization I lead, has 
committed itself to doing everything it can to control this 
epidemic. Wyeth, today, has the most extensive pipeline of 
Alzheimer's discovery and development programs in industry. 
We've been working on this disease, as was mentioned, for 15 
years, and are focused on identifying and developing novel 
approaches to it. We have spent, as you heard, almost half a 
billion dollars on Alzheimer's research in the past 5 years 
alone. Nearly 3,000 of our scientists participated in this 
work, and over 350 of them are dedicated exclusively to 
Alzheimer's disease.
    Currently, we have about 30 projects in various stages of 
development across each of our technology platforms. We work in 
pharmaceuticals, extensively in biotechnology, and also in 
vaccines. Of these projects, eight are currently being studied 
in Alzheimer's patients, and four more will move into clinical 
research in the near future, we hope.
    I think the most exciting part of the research is the work 
we're doing to delay, halt, or even reverse the progression of 
the disease, or maybe even to prevent it altogether with an 
Alzheimer's vaccine.
    Our two most advanced projects are work we do in 
partnership with Elan Corporation to develop 
immunotherapeutics. One approach uses an engineered monoclonal 
antibody to target the beta amyloid that Dr. Aisen mentioned, a 
substance that many, obviously, believe are a key cause of 
Alzheimer's disease. The other approach focuses on stimulating 
the body's own immune system to clear this amyloid. These 
approaches represent the two, we believe are the most promising 
and advanced programs in development today.
    We're working on a number of other approaches to ridding 
the brain of beta amyloid, including a gamma secretase 
inhibitor and a plasminogen activator inhibitor. And we're also 
working on treatments targeting the symptoms of Alzheimer's 
disease. Our symptomatic efforts include serotonin agonists and 
a novel oral medication that seeks to modulate neurotransmitter 
pathways to improve cognitive function. While we hope that each 
of these therapies will prove useful on its own, it may well be 
that it will take a combination of approach to manage this 
disease as well as possible.
    We intend to leave no stone unturned in this fight. We are 
targeting multiple approaches, because we believe that it is 
crucial that we explore all possible avenues. While we believe 
that beta amyloid is likely to be a key causative factor, we 
understand there well may be other factors that play a role in 
this disease. There are still many unanswered questions about 
the human brain and about Alzheimer's, and we hope to pursue as 
many valid targets as possible until these questions are 
    While Wyeth is proud of its position as a leader in 
Alzheimer's and of our pipeline, obviously we're not the only 
company engaged in the fight against this disease, and 
important work is occurring across the industry. And many large 
and small pharmaceutical companies are working on this disease 
    We hope that in the next few years regulatory filings for 
important new therapies will begin to reach FDA, giving 
patients and their families new reasons for hope.
    My third, final, message is that we could use your help in 
taking the fight against Alzheimer's to the next level by 
calling for a national strategy targeting the disease. While we 
are seeing a growing awareness of the problem of Alzheimer's, a 
real understanding of its epidemic proportions still has not 
penetrated the national consciousness. We need to increase the 
focus on this disease and accelerate our ability to respond to 
    As a nation, we have been successful in this type of effort 
before. The story of AIDS, I think, is both instructive and a 
little bit inspirational. In the war against AIDS, government 
regulatory agencies, other governmental groups, scientists in 
industry and academia, and patient groups worked hand-in-hand 
to develop new therapies and evaluate them as rapidly as 
possible. As a result of that focused effort, the first useful 
therapy for AIDS was available within 6 years of the time the 
phrase ``AIDS'' was actually coined, and the disease went from 
being a lethal diagnosis to a treatable chronic condition for 
many people.
    We approach Alzheimer's disease with the same urgency and 
coordination. We'll be able to accelerate scientific advances, 
and, we hope, alter the course of this epidemic.
    To that end, I would like to commend Senator Mikulski for 
her legislative efforts in this area. I'd like to particularly 
note the provision of S. 898, that calls for Secretary Leavitt 
to convene the Alzheimer's summit. Alzheimer's disease needs to 
move forward into the forefront of our national research 
agenda, and that proposal, I think, is an excellent start.
    Alzheimer's disease is an epidemic. We know it's coming. 
All the warning signs are in place. Unless we act now, the 
impact on our healthcare system, healthcare budgets, and, most 
importantly, our families, will be overwhelming. With active 
cooperation and commitment from all parties involved in this 
fight, we believe we can create tools that will be decisive in 
bringing this disease under control. We've done this before, 
with AIDS, and we can do it again, with Alzheimer's. With 
focused cooperation and support, we believe we can, and will, 
make a difference. As someone's who's turning 60 this year, the 
sooner the better.
    Thank you.
    [The prepared statement of Mr. Essner follows:]
                  Prepared Statement of Robert Essner
    Thank you to Senators Mikulski and Burr and the other members of 
the Subcommittee for holding this second hearing and allowing me to 
testify on a topic that is very important to me, my company Wyeth, and 
Alzheimer's patients and their families. It is my pleasure to share my 
thoughts on how the private sector is trying to harness science to 
overcome Alzheimer's disease.
    I'd like to address three key points with you today:

     Alzheimer's disease is a public health epidemic facing the 
Nation and as a result it requires an epidemic-level response.
     There is a tremendous amount of activity in the private 
sector aimed at identifying and developing therapeutic candidates to 
alter--or even prevent--the progression of this disease. My company 
Wyeth is a leader in these efforts.
     Our efforts would be greatly aided by a focused national 
strategy targeting Alzheimer's disease.
                alzheimer's as a public health epidemic
    This is an important time to be thinking about Alzheimer's and 
evaluating whether we are prepared for the coming epidemic. I say 
``epidemic'' because that's what we're headed for--an epidemic of 
enormous proportion. I know many of the members of this subcommittee 
understand the scale and scope of what we are facing. But despite the 
wealth of data documenting the threat of Alzheimer's disease, I am 
fairly certain that the population at large does not really see 
Alzheimer's disease as an epidemic--at least not yet.
    I have spoken about the pending threat of an Alzheimer's epidemic 
for several years now. During each of those opportunities--from the 
White House Conference on Aging to the Visions Roundtable Wyeth co-
hosted with Newt Gingrich and the Center for Health Transformation--I 
expressed my concern that the term ``epidemic'' does not raise the 
specter of Alzheimer's disease for most Americans. Instead, most people 
think of diseases like Avian flu or AIDS. There has been massive media 
attention on these two diseases. This attention served to focus 
people's fear about the unknown on these diseases and highlighted their 
potential for decimating the population.
    These fears are not entirely groundless. AIDS, particularly in the 
developing world, and Avian flu are serious concerns and should be 
matters of national interest. But it is important to remember that 
Avian flu--scary as it is--is only a potential threat that we may or 
may not actually have to deal with. And while AIDS does continue to 
ravage many developing countries, in many parts of the world a 
diagnosis is no longer an automatic death sentence.
    Unfortunately, the same cannot be said about Alzheimer's disease. 
This is a very real threat that we do have to deal with, and at this 
time a diagnosis is a death sentence.
    I have spent a great deal of time asking myself why avian flu and 
AIDS resonate as epidemics, but Alzheimer's does not. Is it their 
impact on the public health or the public's imagination? Is it the 
scientific etiology of the diseases or their widespread threat? Is it 
that AIDS and avian flu are ``new''--that they were identified and 
discovered within our lifetimes?
    Frankly, I think that the latter question is the pertinent one. 
Alzheimer's disease was first identified 100 years ago. It seems to 
have always been with us. We cannot remember a world without 
Alzheimer's. As a result, I think it's possible that we've simply 
gotten used to the presence of this disease. But that is a mistake. The 
disease is no less dangerous and carries no lesser burden simply 
because it predates all of us. If anything, the fact that the disease 
has continued virtually unabated for 100 years should draw our 
attention all the more.
    Alzheimer's disease dramatically affects the public health and 
stirs the public imagination, and we know what its impact will be--we 
can, in fact, predict with chilling accuracy its incidence and 
prevalence. A half-million new cases will be diagnosed in America every 
year, as 78 million baby boomers turn 65, the typical threshold age of 
the disease. That could mean 14 million people suffering and dying from 
Alzheimer's in our lifetime.
    The fact that startles me the most is that 1 out of every 100 60-
year-olds will develop the disease, because this year I turn 60. And if 
you are lucky enough to miss the disease at 60, there is the even more 
startling fact that one out of every two people over 85 will develop 
it. If my wife and I live to be 85, that means that one of us is likely 
to be stricken by Alzheimer's.
    We know the horrifying and ultimately fatal course of this illness. 
We know the collateral damage it does to the families of those who 
suffer from it--damage that often ironically carries a worse toll than 
the direct impact of the disease on its victims. And we can project 
with reasonable precision the enormous financial toll that caring for 
patients who suffer from it will take on our country's health care 
budget and our economy.
    Many people do not know that Alzheimer's disease is the third most 
costly disease to treat in the United States. And most do not know that 
annual Medicare costs for beneficiaries with Alzheimer's are expected 
to increase 75 percent over the next 5 years and that Federal and State 
Medicaid spending for nursing home care for Alzheimer's patients is 
expected to nearly double by 2025.
    And these estimates are limited to cost of care alone. Consider the 
staggering cost of Alzheimer's from a more holistic perspective: A new 
economics study announced yesterday by the ACT-AD Coalition calculated 
for the first time the combined monetary equivalent of supposedly 
subjective social issues like quality-of-patient life, productivity and 
longevity. If we could mobilize treatments to delay the onset of 
Alzheimer's by 1 to 3 years, this social value would reach $3.97 
trillion in the United States alone by the middle of this century.
    But the costs of Alzheimer's disease don't strike governments 
alone--they also strike individual families and our Nation's 
businesses. Over the course of the disease, Alzheimer's patients and 
their families spend more than $200,000 on health care per patient. And 
employers lose approximately $60 billion a year on lost productivity as 
adult caregivers are forced to leave their jobs--either permanently or 
on a temporary basis--to care for a family member with the disease.
    And while the economic picture is certainly grim, the social 
picture is even worse. What is so horrifying about Alzheimer's is not 
just that it kills but how it kills--it is the debilitating and 
dehumanizing nature of this disease that strikes me so forcefully. 
Alzheimer's essentially eats away at the very essence of its victims--
not just their physical and mental capabilities but also their 
personalities and the qualities that make us all human. As the disease 
progresses, everything falls away--connections, understanding, 
relationships, and even family. The threat of Alzheimer's is here, it 
is very real, and it needs to be stopped.
           the private sector is responding to this epidemic
    The general public still may not consider Alzheimer's disease to be 
an epidemic. But the world's scientists are starting to do so. They are 
not just sitting by and watching the devastation approach. Efforts to 
respond to the epidemic of Alzheimer's are under way across academia, 
industry and government.
    I would like to share the story of my company, Wyeth, and our 
journey into the field of Alzheimer's disease research. Wyeth is not 
the only company engaged in the fight against Alzheimer's. Important 
work is occurring everyday across the industry, with nearly all of the 
world's major pharmaceutical companies devoting time and resources to 
this disease. We are proud of our position as a leader in Alzheimer's 
research and of our pipeline--which is second-to-none in the industry.
The Genesis of Wyeth's Involvement in Alzheimer's Disease
    Wyeth has been involved in Alzheimer's disease research for 15 
years. Our research efforts were focused in the year 2000, when a group 
of our scientists came to me with a proposal. They wanted to enter into 
collaboration with another, much smaller company to advance a new 
technology against Alzheimer's. The team members told me that this was, 
in their opinion, the single best approach to creating a really 
effective treatment for this disease and that they thought it had the 
highest chance of success of anything in development. I, of course, had 
to ask a few questions.
    First, why were they so enthusiastic, and why did they think we had 
any chance of success in a disease that had proven so elusive? They 
explained that this technology was aimed at quickly ridding the brain 
of the beta-amyloid plaque that was--and still is--thought to be an 
important causal factor in Alzheimer's and that the work done so far on 
this principle in animal studies had produced the most dramatic results 
ever seen in these types of tests. So, second, I asked them how long it 
would take before we would have any real idea about whether or not this 
would be useful in people because we all know that animal work, 
particularly in diseases involving the brain, is not very predictive. 
They told me that they expected it would take about 3 or so years of 
research effort before they would know whether the project could move 
into full-scale development. Then I asked them a critical question: How 
much would we have to spend over those years to get even a preliminary 
appraisal of efficacy? After a little hemming and hawing, they told me 
they thought it could cost up to $100 million to do those studies.
    Then I asked the really hard question: If we invested that much 
money over the next 3 years, what was the probability that when we were 
done with that work the answer would be ``yes''--that we would have 
sufficient preliminary evidence about the drug's safety and efficacy to 
move into the larger-scale research studies necessary for approval. 
This brought a lot more hemming and hawing and a little shuffling about 
until someone said, ``There's maybe a 30 percent probability of 
success,''--to which I responded, ``Really!'' Then someone said, 
``Well, maybe it's more like 10 percent.'' When I challenged that, the 
real answer came out--which was that the odds of success were so low 
that no one could say what they were. In the end, we made the decision 
to go ahead--our scientists were so passionate that if I had turned 
them down, I would have had a mutiny.
    Wyeth created a partnership with the Irish company, Elan 
Corporation. It was an unprecedented effort in that, for the first 
time, we brought together scientists from Wyeth's three research 
divisions. We asked leaders from our central nervous system drug 
discovery and development units to work in day-to-day collaboration 
with some of our leading biotechnology specialists and experts from our 
vaccine research effort.
    The problem-solving abilities of these scientists, together with 
those of our partner, have brought to this project the unusually broad 
array of scientific tools and creativity that have kept us going. More 
than 5 years have gone by since we made our decision, and about all I 
can say after years of effort is that the program still has the 
tantalizing possibility of success. The development of our initial 
research program was stopped when we saw some early signs of a safety 
issue in a few patients. But we've come back with revised approaches, 
and our program is progressing very nicely.
Where We Are Today
    Wyeth has the most extensive pipeline of Alzheimer's discovery and 
development programs in the industry. We have been working on this 
disease for the past 15 years, and are focused on identifying and 
developing novel approaches to it. Wyeth has spent over $450 million on 
Alzheimer's research in the past 5 years--$125 million in 2006 alone. 
Nearly 3,000 of our scientists are or have been involved in this work, 
and over 350 are focused exclusively on it. Currently, we have 23 
projects in various stages of development, across each of our 
technology platforms--pharmaceuticals, biotechnology, and vaccines. Of 
these, 12 are drugs in clinical research.
    Wyeth is uniquely positioned to pursue novel approaches precisely 
because of our ability to work across these three platforms. As the 
only biopharma company with a presence in all three areas, we are able 
to draw on a wide pool of technological capabilities. Our Alzheimer's 
disease work is a great example of this.
    I think the most exciting part of this research is the work we are 
doing on compounds that show the potential to delay, halt or reverse 
the progression of the disease--or even to prevent it altogether. These 
projects bring together our biotech and small molecule neuroscience 
capabilities. Our most advanced projects are in passive and active 
immunotherapy, undertaken with our partner Elan Corporation. The 
passive approach uses an engineered monoclonal antibody to target toxic 
beta-amyloid, a substance many believe is a key cause of Alzheimer's. 
The active approach focuses on the use of the body's own immune system 
to clear the brain of the toxic amyloid plaques by stimulating an 
immune response so the body produces antibodies that attach to existing 
plaques and destroy them. These approaches represent some of the most 
promising efforts in Alzheimer's research today.
    We are also working on a number of alternative anti-amyloid 
approaches, including gamma secretase and plasminogen activator 
inhibitor small molecule pharmaceuticals. And we are also working on 
treatments targeting the symptoms of Alzheimer's disease. Our 
symptomatic therapy efforts include serotonin antagonists and a novel 
oral medication that seeks to modulate neurotransmitter pathways to 
improve cognitive dysfunction. Our scientists believe the key to 
Alzheimer's treatment likely lies in combination therapies, bringing 
together agents to affect the course of the disease and those to manage 
its symptoms.
    As you can tell, we intend to leave no stone unturned in this 
fight. We are targeting multiple approaches because we believe that it 
is crucial that we explore all possible avenues. While we believe the 
beta-amyloid theory is very likely to be a key causative factor, and 
therefore a promising target, we understand there may be other factors. 
There are still too many unanswered questions about the human brain and 
this disease, and we intend to pursue as many targets as possible until 
those questions are answered.
    And, by the way, that $100 million estimate has long ago been 
spent--in fact, our partnership has invested well over twice that. Our 
programs have the potential to be the kind of new tool we need to treat 
or even prevent Alzheimer's disease--if we get really lucky. But risks 
are high, and, in the current environment, even if things go 
perfectly--which they rarely do--we still are looking at potential 
approval toward the end of this decade. I can tell you with complete 
candor that if this were a program in virtually any other disease, it 
would have been terminated years ago.
    But the power of this disease and the challenge of conquering it 
drive us on. Wyeth is not alone on this path in trying to find a 
solution for Alzheimer's; there are other companies at work, as well as 
scientists in academia and research institutes who are making their own 
Industry-wide Efforts
    But Wyeth is not alone on this path. Important work is occurring 
everyday across the industry, with nearly all of the world's major 
pharmaceutical companies devoting time and resources to this disease. 
There are hundreds of therapies in development, and the first compounds 
with the potential to actually change the course of the disease are 
starting to reach FDA. The possibilities for improving the lives of 
patients and families are staggering.
    Among the leading drugs in development for disease modification, 
many of the most advanced agents are, like Wyeth's leading efforts, 
targeted at beta-amyloid. These compounds include immunotherapy as well 
as agents targeting amyloid aggregation and synthesis. In addition to 
these late-stage therapies, there are over 100 other potential disease-
modifying candidates in early-stage development with similar targets. 
Wyeth and other companies are targeting other mechanisms in the 
disease, including mechanisms that target tau, the protein that 
accumulates in neurofibrillary tangles, and neuroprotection.
    There are also over 80 symptomatic therapies in various development 
stages, many of which are believed to have the potential to 
significantly improve the quality of life of people with Alzheimer's, 
particularly when used in combination with the coming disease modifying 
agents. And generic versions of the leading symptomatic therapies are 
expected in the next several years, as the existing products reach 
patent expiry.
    In addition to the identification and development of promising drug 
candidates, there are significant research efforts into better 
diagnostic and screening tools. Currently, establishing a clear 
diagnosis of Alzheimer's disease is difficult, particularly in early 
stages. Nearly 50 percent of patients are only diagnosed after the 
disease has already progressed to its middle stage.
    One reason for this is a reluctance to assign a diagnosis of 
Alzheimer's disease, given the current state of treatment. But perhaps 
the most significant challenge is the difficulty in distinguishing 
signs of cognitive decline from normal aging, as we currently lack a 
sensitive and specific biomarker to aid diagnosis. Surrogate endpoints 
and biomarkers have the potential to dramatically alter how we identify 
patients--and potential patients--and measure their clinical outcomes 
over time, and their development is a major focus of the scientific 
efforts around Alzheimer's disease.
    An example of these efforts is the Alzheimer's Disease Neuroimaging 
Initiative, or ADNI, a 5-year public-private partnership. It brings 
together industry, academia and the National Institutes of Health to 
validate biomarkers and develop neuroimaging tools. This broad-based 
effort has the potential to dramatically alter how we predict the 
onset--and monitor the progression--of Alzheimer's. Diagnosis and 
monitoring are essential to any effort to study and eventually control 
this disease.
With Your Help, We Can Move Even Faster
    So why, given all the attention across various stakeholders, does 
the war against Alzheimer's disease continue to progress so slowly? 
There are a number of significant challenges facing Alzheimer's drug 
development. Among them:

     Challenges related to the design and implementation of 
clinical trial protocols;
     The lack of urgency about the disease at a national level; 
     The lack of scientific consensus about what it means to 
``modify'' the course of the disease rather than merely treat its 

    The problem is that while companies like Wyeth are moving forward 
as rapidly as possible, the war against Alzheimer's is multi-faceted, 
requiring advances on many fronts. Unlike my examples of AIDS and Avian 
flu, there is no national focus on Alzheimer's. Scientific work and 
drug development go on but at too slow a pace. Public health agencies 
are perhaps understandably engaged in dealing with the current 
devastation of the disease as much as working toward its cure. And 
regulatory agencies sometimes deal with Alzheimer's in the cautious way 
they do diseases where major therapeutic options already exist. On the 
regulatory front alone, worldwide cooperation between reviewers and 
researchers could significantly improve the probability that we will 
succeed and reduce development times by years.
    While we are seeing a growing awareness about the Alzheimer's 
epidemic, this growth is gradual and not keeping pace with the growth 
of the problem. It is critical that we increase the national focus on 
this disease and accelerate efforts to respond to it.
    What we need is a sense of commitment analogous to that which arose 
around AIDS or Avian flu. In the war against AIDS, government, 
regulatory agencies, scientists in industry and academia, and patient 
groups worked hand in hand to develop new therapies and to evaluate 
them as rapidly as possible. The results were remarkable. AIDS was 
first identified around 1980, and, just 6 years later, there was a 
breakthrough medication that helped people manage the symptoms. And, 
today, there are a number of therapies that, when used in combination, 
allow people with HIV/AIDS to live much longer than anyone would have 
dreamed possible in the early 1980s. The war has not been won, but we 
have made significant progress--progress that is lacking on the 
Alzheimer's front.
    To that end I would like to commend Senator Mikulski for her 
legislative efforts in this area. I would like to particularly note the 
provision in S. 898 that calls for Secretary Leavitt to convene an 
Alzheimer's summit. Alzheimer's disease needs to move to the forefront 
of our national research agenda, and this proposal is a very good 
    Knowing all of this, how do we convince the Nation that Alzheimer's 
is the next epidemic and truly drive a change in the way the disease is 
approached? Public awareness of the disease is high--so are 
assumptions, misconceptions and complacency. To many, the disease is 
still seen as a slow, progressive and inevitable step in the aging 
process; in fact, the disease can progress through its entire course in 
as few as 3 years. This misperception, compounded by the lack of 
treatments with long-term effectiveness and the social stigma attached 
to the disease, results in a health care system that often appears to 
be focused more on dealing with the seemingly inevitable devastation of 
the disease than in working toward its cure.
    Existing therapies for Alzheimer's disease address symptoms of the 
disease, but not its underlying causes. With the aging of the 
population, there is a critical need for therapies that will modify--or 
even halt--disease progression. We believe that this urgent need for 
innovative therapeutic agents warrants a formal governmental strategy 
to accelerate development of safe and efficacious disease modifying 
    The government has been successful in this area before. We need the 
kind of bold, innovative effort that has been generated in the past. 
The AIDS story is instructive and inspirational. The recognition of the 
urgent need for innovative therapies led to the development of new 
procedural strategies for drug review and approval and to the focusing 
of research efforts--and dollars. If we approach Alzheimer's with the 
same fervor and the same commitment, we will be able to harness the 
potential of scientific advances and truly alter the course of this 
    Within the pharmaceutical industry as a whole, there are dozens of 
Alzheimer's compounds in development. And, given the complexity of 
Alzheimer's, no single organization has the resources required to 
research all facets of this disease as quickly as we must. At Wyeth 
alone, we've committed hundreds of millions of dollars toward this 
research and we know our colleagues at other companies are doing the 
same. Right now, no one can say that any one approach will work. But, 
by taking multiple ``shots on goal'' in our research labs, we believe 
that a treatment can be found.
    But it is imperative for industry, scientists and government to 
work together to help us reach our goal even faster. It typically takes 
10 to 17 years to bring a new drug to market, but this is far too slow, 
given the imminent threat. We need a sense of urgency, a commitment to 
collaboration that will lead to a concerted, focused effort to prevent 
this impending epidemic. To eradicate Alzheimer's, we need to make it 
America's No. 1 research priority. We need the public and private 
sectors--the pharmaceutical industry, health care practitioners, the 
public, and legislators--to call for putting epidemic-strength 
resources toward eradicating Alzheimer's.
    For every month we hesitate, millions more Americans will tangle 
helplessly in the disease's lethal net and we will continue to find 
ourselves spending down the Nation's health care budget to care for the 
demise of millions of people. More wisely, we should be preparing now 
to cure them. We could make my generation the last to dread 
Alzheimer's. It is time to accelerate the pace of our efforts and take 
the battle to a level on a par with our hope.
    As I mentioned earlier, I turn 60 this year. I have been a witness 
to the impact of this disease and have watched family and friends fall 
prey to it. Without tools like those that Wyeth is currently 
developing, the impact on our budget--and our psyche--will devastate 
our Nation. The suffering that individuals and families endure must not 
be extended to our entire country. If we cannot develop therapies to 
halt this epidemic, we will either face untenable systemic costs that 
break our national bank or we will be put into the equally untenable 
position of having to deny treatment to those who need it.
    I commend you for your efforts and look forward to working with you 
in the war against Alzheimer's. If we can generate a passionate 
commitment analogous to that around AIDS or avian flu, I believe that 
within our lifetime we can turn this disease from a death sentence to a 
treatable chronic diagnosis. The sooner we begin, the better.
    Thank you.

    Senator Mikulski. Thank you.


    Dr. deBethizy. Good morning, Madam Chairman and Senator 
Burr and members of the subcommittee and their staff. Thank you 
for holding today's hearing and inviting me to provide 
testimony on this very important subject of breakthrough 
research on Alzheimer's disease.
    I'd like to speak, today, about the promising research our 
company is doing in the area of cognitive disorders, and 
specifically in Alzheimer's disease, a devastating disease that 
affects more than 37 million people worldwide.
    At Targacept, we're a small pharmaceutical company, but 
we're engaged in important innovation in the design, discovery, 
and development of a new class of drugs for the treatment of 
multiple diseases and disorders of the central nervous system.
    Alzheimer's disease is our primary focus, and we also have 
conducted clinical research in other conditions on the spectrum 
of cognitive decline that too often culminates in Alzheimer's. 
We call our pharmaceutical product candidates ``NNR 
therapeutics'' because they modulate the activity of a class of 
specialized proteins in the body known as neuronal nicotinic 
receptors, or NNRs.
    As you may recall from your basic biology class, nerve 
cells, or neurons, are the primary elements in conducting the 
activity in the nervous system. They almost act like electrical 
wires, sending signals from the brain--across the brain and 
through the body. However, unlike the kinds of electrical 
circuits we have in our homes, the communication between nerve 
circuits is not controlled mechanically, but actually 
chemically. In this process, the electrical impulses of a 
neuron are converted into essential chemicals, such as 
serotonin, dopamine, acetylcholine, and norepinephrine. It's 
these chemicals that are released by the neuron and then land--
essentially land on another neuron that sends the trigger to 
the next neuron, sends the impulse across the brain, and on and 
on and on, across many billions of neurons in the brain. This 
process repeats itself. And I'd like to use this metaphor, that 
NNRs are like the volume knob on the central nervous system. 
They boost the degree of neuron communication if the nervous 
system is understimulated, and they reduce the degree of neuron 
communication if the system is overstimulated, almost like a 
volume knob. If NNRs don't do their job correctly, it can lead 
to a chemical imbalance that is associated with a number of 
debilitating central nervous system diseases and disorders, 
such as Alzheimer's disease. That's why we have targeted NNRs 
as a very important therapeutic target.
    Now, Targacept is the leader in the development of NNR 
therapeutics. We have extensive experience in the biology and 
chemistry of the NNR receptor family, and hold the largest 
patent estate in the NNR space. Our history began with a 
program initiated at R.J. Reynolds Tobacco Company in 1982 to 
study the activity and therapeutic effects of nicotine, which 
is our prototypical NNR modulator. We don't work on nicotine, 
we don't work on tobacco, but we work on brand new small 
molecules that are discovered to enhance the ability that was 
discovered with nicotine on attention, learning, and memory, 
which are well documented. And there's also lower prevalence of 
Alzheimer's disease and Parkinson's disease in smokers compared 
to nonsmokers, which was really a clue that this was an 
important system.
    As another example, more than 70 percent of people 
suffering with schizophrenia smoke. It is believed that, in 
smoking, these people could be actually medicating themselves 
by providing nicotine that helps them focus and enhance their 
cognitive performance. So, nicotine, of course, is not viable 
as a drug, because it causes a number of deleterious side 
effects. The reason for this is that, in addition to NNRs in 
the brain, there are NNRs in the muscle and the ganglia that 
control heart rate and blood pressure, and you want to 
eliminate these side effects.
    So, the researchers at Reynolds recognize that drugs 
capable of modulating NNRs could remedy the chemical imbalance 
characteristic of these CNS diseases like Alzheimer's. However, 
to be useful, these drugs had to target specific NNRs while, at 
the same time, avoiding the interaction with these other 
receptors in the rest of the body. And really that's what led 
to the name of our company--``Targacept'' is for ``targeted 
receptors''--because over the last 20-plus years our scientists 
became very good at it, and it's led to these breakthrough 
technologies and therapeutics that are moving into the clinic 
and working so well.
    Now, we are conducting some of our most promising work in 
Alzheimer's, as well as other cognitive disorders. Our lead 
product candidate is a novel small molecule that we refer to as 
TC-1734. There'll be a test on that later. TC-1734 selectively 
modulates specific NNRs, which creates the potential for 
therapeutic benefit and reduces the risk of side effects. We've 
done 12 clinical trials in up to 540 subjects so far. Now, as a 
small company, this is a very large initial start with this 
drug, and, in fact, we licensed this drug to AstraZeneca, who 
has seen it to be very promising in the Alzheimer's-disease 
    As reported in a very recent issue of Nature Reviews, the 
economic burden of Alzheimer's is massive. We've already talked 
about it. It's $100 billion alone. We're also working in areas 
called age-associated memory impairment and mild cognitive 
impairment, which are earlier forms of cognitive impairment. 
Not all people with age-associated memory impairment go on to 
Alzheimer's, but 80 percent of people with mild cognitive 
impairment will go on to Alzheimer's disease within 6 years. 
So, the earlier we can get drugs in--and this is really a 
regulatory challenge, because, as you can imagine, as you move 
upstream to healthier people, drugs have to be safer. So, this 
is an area we can talk about later.
    So, in conclusion, we recognize that Alzheimer's disease 
has impacted the lives of millions of people and represents an 
area of enormous unmet medical need. It is extremely gratifying 
to us to contribute to the body of knowledge in this area and 
to help people understand the potential treatments for this 
    Thank you.
    [The prepared statement of Dr. deBethizy follows:]
            Prepared Statement of J. Donald deBethizy, Ph.D.
    Good morning, Madam Chairman, Senator Burr and members of the 
subcommittee. Thank you for holding today's hearing and for inviting me 
to provide testimony on the very important subject of breakthrough 
research on Alzheimer's disease.
    My name is Dr. J. Donald deBethizy, and I am President and Chief 
Officer of Targacept, Inc, a publicly traded biopharmaceutical company 
located in Winston-Salem, North Carolina. I would like to speak today 
about the promising research our company is doing in the area of 
cognitive disorders and specifically in Alzheimer's disease, a 
devastating disease that affects more than 37 million people worldwide.
    At Targacept, we are engaged in the design, discovery and 
development of a new class of drugs for the treatment of multiple 
diseases and disorders of the central nervous system. Alzheimer's 
disease is a primary area of focus for us, and we have also conducted 
clinical research in other conditions on the spectrum of cognitive 
decline that too often culminates in Alzheimer's.
    We call our pharmaceutical product candidates ``NNR Therapeutics'' 
because they modulate the activity of a class of specialized proteins 
in the body known as neuronal nicotinic receptors, or NNRs. As you may 
recall from your basic biology class, nerve cells, or neurons, are the 
primary element in the human nervous system and act like electrical 
wires to send various signals to the brain and throughout the body. 
However, unlike the kinds of electrical circuits we have in our homes, 
the communication between nerve circuits is not controlled 
mechanically, but chemically. In this process, the electrical impulses 
of a neuron are converted into essential chemicals such as serotonin, 
dopamine, acetylcholine and norepinephrine. These chemicals are 
released by the neuron and then land, so to speak, on another neuron--
where they trigger the release of essential chemicals by the second 
neuron. This process then repeats itself, usually resulting in the 
successful transmission of signals and the normal functioning of our 
nervous system. NNRs are the landing sites on the neurons and, as such, 
are responsible for modulating the transmission of these essential 
chemicals. I like to use the metaphor that NNRs are like the volume 
knobs of the central nervous system. They boost the degree of neuron 
communication if the nervous system is understimulated and reduce the 
degree of neuron communication if the system is overstimulated. If NNRs 
don't do their job correctly, it can lead to a chemical imbalance that 
is associated with a number of debilitating CNS diseases and disorders, 
such as Alzheimer's disease. This is why NNRs are important therapeutic 
    Targacept is the leader in the development of NNR Therapeutics. We 
have extensive experience in the biology and chemistry of the NNR 
receptor family and hold the largest patent estate in the NNR space. 
Our history began with a program initiated by R.J. Reynolds Tobacco 
Company in 1982 to study the activity and therapeutic effects of 
nicotine, which is the prototypical NNR modulator. Nicotine's ability 
to enhance attention, learning and memory is well documented, and there 
are a number of studies showing the lower prevalence of diseases such 
as Alzheimer's disease and Parkinson's disease in smokers as compared 
to non-smokers. As another example, more than 70 percent of people 
suffering with schizophrenia smoke. It is believed that in smoking, 
these people could be actually medicating themselves, by providing 
nicotine that helps them focus and enhances their cognitive 
performance. Nicotine, of course, is not viable as a drug because it 
causes a number of deleterious side effects. The reason for this is 
that, in addition to NNRs, nicotine affects other receptors in the 
body's muscles and ganglia that are associated with the side effects.
    The researchers at Reynolds recognized that drugs capable of 
modulating NNRs could remedy the chemical imbalance characteristic of 
nervous system diseases like Alzheimer's disease. However, to be 
useful, these drugs had to target specific NNRs while at the same time 
avoiding interaction with nicotinic receptors associated with harmful 
side effects. This recognition of the need to exploit only Targeted 
Receptors led to the creation of Targa Cept. Our scientists' 20-plus 
years of focused NNR research has led to a particular expertise in 
designing and developing pharmaceutical product candidates that have 
the required NNR selectivity.
    We are conducting some very promising work in the area of 
Alzheimer's disease as well as other cognitive disorders. Our lead 
product candidate is a novel small molecule that we refer to as TC-
1734. TC-1734 selectively modulates specific NNRs, which creates the 
potential for therapeutic benefit and reduces the risk of side effects. 
This product candidate has been evaluated in 12 clinical trials to 
date, involving a total of about 540 subjects.
    As reported in a very recent issue of Nature Reviews (Drug 
Discovery), the economic burden of Alzheimer's is massive, with an 
estimated direct and indirect annual cost of patient care estimated at 
$100 billion in the United States alone. The number of therapeutic 
options for Alzheimer's is severely limited and only a fraction of 
patients respond well to those that are on the market. Moreover, none 
of the approved treatments have demonstrated the ability to 
substantially delay the progressive deterioration and death of neurons 
in the brain that can lead to more severe stages of cognitive 
impairment and debilitation. The need for more effective drugs is 
    What we find very exciting about NNR-based therapeutics is their 
potential at every stage of cognitive dysfunction. As I mentioned 
earlier, Targacept has conducted clinical research in other conditions 
on the spectrum of cognitive decline. I'm speaking specifically of 
conditions known as age associated memory impairment, or AAMI, a 
condition associated with normal aging, and mild cognitive impairment, 
or MCI, which is a condition that is more severe than AAMI but less 
severe than Alzheimer's disease. In fact, we would argue that perhaps 
the most effective and efficient manner for addressing Alzheimer's 
disease would be to treat these earlier stages of cognitive decline, 
which could potentially mean that a patient may never suffer from 
Alzheimer's disease. TC-1734 has shown evidence of neuroprotective 
properties in our preclinical testing. This means that it had the 
effect of protecting neurons under conditions that would otherwise have 
caused them to deteriorate and die. If it has the same effect in 
humans, our position regarding prevention as the optimum way to address 
Alzheimer's disease and other neurodegenerative diseases would only be 
    In 2006, Targacept completed a Phase II clinical trial TC-1734 in 
age associated memory impairment (AAMI). In the trial, TC-1734 achieved 
statistically significant results on all three co-primary endpoints, 
demonstrating its cognitive-enhancing potential. The development of 
AAMI has been set aside in favor of Alzheimer's disease, for now, 
largely due to the difficult and uncertain path to regulatory approval 
for AAMI. However, if that path were clarified so as to support the 
substantial investment of large-scale Phase III clinical trials, we 
would be well on our way to developing a drug that could act in early 
intervention against cognitive dysfunction. Moreover, the data from 
these trials could be extremely useful as TC-1734 is developed to 
address Alzheimer's disease directly. A Phase II clinical trial of TC-
1734 in approximately 500 patients with mild to moderate Alzheimer's 
disease is scheduled to get underway in mid-2007, as is a similar size 
Phase II clinical trial in cognitively impaired patients with 
    We recognize that Alzheimer's disease has impacted the lives of 
millions of people and represents an area of enormous unmet medical 
needs. It is extremely gratifying to us to contribute to the body of 
knowledge in this area and to help people understand potential 
treatments for this disease.
    Thank you.

    Senator Mikulski. Let me just open with a question or two, 
turn to Senator Burr, and perhaps then a more freely give-and-
take with, really, a very able and engaging panel.
    Mr. Essner, I'm going to go to you first. First of all, 
one, I do agree that we're kind of numb to it. Alzheimer's, 100 
years ago, first diagnosed in Germany, then, for years, the 
kind of melancholy attitude--for example, with my own father, 
the diagnosis was in the mid-1980s, and all we could do was 
keep him comfortable and try some of those new things at the 
adult center at the Mason Lord Hopkins program.
    Tell me, from the private sector's viewpoint, what are the 
greatest impediments to you--meaning not only as a company, but 
the private sector--to moving forward in this? And, No. 2, what 
would you think would be the elements of a national strategy? 
In other words, there you are, you've put in a lot of money. 
Obviously, you've made a big bet of the company in this area. 
It is an epidemic----
    In other words, is it that we need to do more basic 
research? What is it that we need to work with the--because 
government is important, but government doesn't invent 
    Mr. Essner First, I think, the scientific challenges, you 
know, are great. I mean, our understanding of the brain is 
probably less than any other organ in the body. And certainly, 
Alzheimer's disease, although it's been known for a long time, 
is certainly not well understood, and more basic research would 
certainly be helpful. But, you know, as I said, we are now in 
clinical development, studying many of our drugs in Alzheimer's 
patients. And some of the obstacles there, I think, are maybe 
not that difficult to remedy. One issue today is, when you go 
to study a drug that you hope will have an impact on the 
progression of the disease, what, really, do you need to study? 
There are a multiplicity of different cognitive scales that can 
be used. There are various brain imaging techniques. What 
standards do you need to meet? And I think one of the most 
important things that could be done is to create a consensus 
between the scientific establishment, the regulatory agencies, 
and also industry, to say--if you're trying to develop a drug, 
to show a stabilization or a slowing down of the progression of 
the disease--what, in fact, do you need to study, for how long, 
and what do you need to demonstrate for those results to be 
acceptable? Right now, we're doing the work, but doing the work 
without a clear understanding of what standards those studies 
are going to have to meet to result in a drug that will 
actually be useful to people.
    Another smaller issue, but potentially a big stumbling 
block, is just the issue of informed consent. If you think 
about an Alzheimer's patient, getting their informed consent to 
participate in a trial is a genuine issue. And, although there 
are mechanisms to accomplish this through the family, those 
standards are different from place to place. So, if you're 
going to do a trial across the United States or a trial that 
involves patients in the United States and other countries, 
very frequently you can't do that, because the standards 
they're using are not acceptable in that particular location or 
in that particular country. So, it's a small obstacle, but a 
real one.
    And then, maybe, finally, trying to decide, in terms of the 
scientific evaluation and the regulatory process, what is the 
role of imaging techniques. Can they be primary endpoints in a 
clinical trial? In that, if you can show an improvement in 
brain size or brain functioning through imaging techniques, 
what role should that play in the ultimate decision of whether 
or not a drug is useful?
    So, creating a kind of consensus that would allow the Food 
and Drug Administration to say, ``Here are the standards that 
you should try to meet when you're developing a drug,'' I think 
would make it easier to evaluate drugs, have them move along 
more quickly and speed the development of this work.
    Senator Mikulski. Well, one of the things that my bill 
calls for is a summit, after the bill is passed, to identify 
what are the breakthrough areas and how they could be 
accelerated--again, always keeping safety in mind.
    Mr. Essner. Right.
    Senator Mikulski. What your recommendation is, you need a 
summit even before that to have a set of standards and 
measurements--or a set of standards that declare what is the 
measurements, in terms of the ability to evaluate, essentially, 
efficacy. Is that----
    Mr. Essner. I think that would----
    Senator Mikulski [continuing]. Correct?
    Dr. deBethizy [continuing]. That would be helpful. And that 
actually would encourage, I think, more development in this 
area, because once those standards are established, companies 
are able to more easily evaluate, Is it worth going ahead and 
trying to develop a specific compound?
    Senator Mikulski. Well, later on this summer we are going 
to get FDA, NIH, and CDC here, along with Dr. Hodis, who I 
think's been an outstanding leader. He couldn't be here today, 
because of a trip abroad. But we'll want to come back to that.
    Mr. Essner. Yeah, I----
    Senator Mikulski. My 5 minutes are up. Why don't--did you 
want to----
    Mr. Essner. No, I just said, if, at some point, industry 
could have a seat at that table, I think it turns into the most 
productive possible dialogue.
    Senator Mikulski. Well, essentially, this is why we're 
holding these hearings. And my colleague here is really, I 
think--he chaired a subcommittee of this committee, on public 
health. His big passion, as is mine, is public health, the 
prevention aspects of everything. And I know Dr. Coburn, who's 
on the floor now--when we were talking about drug safety, our 
big thing was also on what are those kind of tools that go into 
the preventive side----
    Mr. Essner. Right.
    Senator Mikulski [continuing]. For large populations, et 
cetera. But we believe that we need to begin to de-escalate the 
adversarial environment in our country. And so, we're so 
worried about antitrust, and, ``Can we be in the room?'' that 
we don't trust each other. And, I'll tell you, if we knew that 
5 million people were going to get avian flu 32 years from now, 
we sure in hell would all be in the same room doing shooters of 
Mylanta trying to figure this out.
    Mr. Essner. I see.
    Senator Mikulski. You see? So--and it was Senator Burr who 
actually got all of us in the room, in a war-game exercise on a 
breakout of a pandemic, that I think really led to very 
important legislation moving through. So, I think we 
understand--we, two, understand the elements of when we use the 
term ``epidemic,'' but, because Alzheimer's is not viewed as an 
infectious disease, and the history has been such a--this 
melancholy powerlessness that many of us felt. If we take our 
time, we'll get to it.'' But I don't believe that. And so----
    Senator Burr.
    Senator Burr. She has proven my passion for prevention. I'm 
trying to put Mylanta out of business. So----
    Senator Mikulski. I shouldn't have used----
    Senator Burr. Let me assure you, I've got questions for all 
of you, and I thank the Chairman for this format--using it for 
more of a roundtable.
    Let me ask, Bob, you expressed the lack of structure in, 
maybe, FDA's knowledge or direction on the clinical trial 
design. Do they have advisory panels that they can call upon 
regarding trial design?
    Mr. Essner. Yeah, absolutely, they do. And believe me, I'm 
not faulting FDA here, because this is an area where the 
knowledge is--really, has never been brought together in any 
kind of cohesive way to define----
    Senator Burr. Nor----
    Mr. Essner [continuing]. These trials. So----
    Senator Burr [continuing]. Nor is my question a shot at 
them, because I think this is one of the--from a layman's 
standpoint, looking at this, this is one of the most difficult 
things that I could imagine, How do you--what is it you choose 
to gauge?
    Mr. Essner. Right.
    Senator Burr. And what's the definition of a successful 
trial, given that you've got a disease which is a continued 
deterioration? When do you know it's stopped?
    Mr. Essner. Yeah. You know, I think the advisory committee 
system, which FDA has, and which, in general, works very well 
for them, may not be the best tool here, because I think this 
is going to be a complicated discussion that will require a lot 
of iterations. And I think the advisory committees tend to work 
best when there is a discrete question on which they can 
provide a discrete answer. So, my guess is something that was a 
longer-term organized collaboration between the various 
scientific organizations in the government, especially the NIH, 
and the regulator, would probably produce the best result.
    Senator Burr. Has there ever been an Alzheimer's 
application that was fast-tracked at the FDA?
    Mr. Essner. I don't know the answer to that. Bob, do you? 
Several have.
    Senator Burr. Okay.
    Dr. Kramer, you talked about exercise and diet. And I've 
got to admit, I know you're right, I know there's some piece 
there. But sitting here looking at the direction our country is 
going, and the generation that are the most obese we have ever 
raised, thinking of selling to my 86-year-old father the need 
for him to exercise, when the surroundings suggest, you know, 
diet and exercise are not that important, how do we change 
that? And can we have enough of an effect that it's worthwhile?
    Dr. Kramer. Yeah. I think, to start off with, we don't 
need--we don't know much about dose response effects, how much 
    Senator Mikulski. Dr. Kramer, pull your microphone closer.
    Dr. Kramer. Oh, sorry. We don't know much about dose 
response effects with respect to exercise and the brain, or 
cognition, but we do know, from a number of randomized clinical 
trials funded by the NIH and other government agencies all over 
the world, that fairly moderate exercise, even if you've been a 
couch potato for 60 years, can set back the clock 2 or 3 years 
with respect to cognitive decline in normal aging. So, we can 
think of this as a preventative measure.
    But I do agree with you, when we look at the United States, 
we look at how we advertise, what products we advertise, and 
the obesity rate, unless you're living in Boulder, Colorado, in 
which everybody looks good--kind of like Prairie Home 
Companion, I think--that, in the United States and in the 
Midwest, where I'm coming from, lack of exercise is a major 
problem. I think there are many ways to encourage exercise. 
Schools in my local town have taken the soda, or pop, machines 
out of the schools. The kids--my daughter is in the back here, 
and she'll testify to that, I think, if you'd like her to--hate 
it. But when you provide healthy snacks for young kids, you 
start to build a sense of what is important and the kinds of 
foods that they can enjoy in school. I think we could provide 
incentives with respect to insurance policies and healthcare 
policies, for exercise.
    And, again, I'm not talking about people getting out and 
running marathons or doing triathlons, I'm talking about 
walking 30 minutes to an hour a day.
    Senator Burr. Fine, I----
    Dr. Kramer. This is a tough nut to crack, I agree.
    Senator Burr [continuing]. I would agree with that last 
statement. And I know that Senator Mikulski and I will talk as 
the year goes on. It's impossible to believe that if 4,000 
employers in the United States negotiate all the healthcare for 
200 million people, that one's personal decisions which lead to 
healthier choices or the use of prevention are not going to be 
reflected in a reduction in their premiums; therefore, there is 
no financial incentive for them. It's only a marginalizational 
of the increase, and that's a model that we've got to change 
if, in fact, we want to have people make decisions based upon 
not only their longevity, but the cost for them to get there.
    Paul, let me turn to you just for a second, because you 
talked about the molecular causes and our ability to identify 
the molecular cause. Does that mean that we either have the 
ability to recognize a genetic marker or we are close to 
identifying a genetic marker that might give us an indication 
of a person's susceptibility to Alzheimer's, or is Alzheimer's 
and dementia something the entire population is susceptible to, 
and some preventative medication or exercise or diet will 
determine when we get it, or if we get it?
    Dr. Aisen. Alzheimer's comes in a number of types. Some are 
genetically determined, where a single gene mutation is driving 
the disease. These are rare, but there are families that carry 
this gene, and, in those families, everybody that inherits the 
gene, which means half of the children of an affected 
individual, will develop Alzheimer's disease at a young age. 
That subset of the disease is genetically determined. We refer 
to it as familial autosomal dominant AD. And it represents less 
than 1 percent of all cases, but is exceedingly important in 
understanding the disease, because the disease looks the same. 
It's the same as the sporadic disease that affects 5 million 
people, same plaques and tangles in the brain, and it was by 
determining what the genes do that cause the disease in those 
families that we understood that one molecule is pivotal in 
    Now, why do people who don't carry those genetic mutations 
that lead to excess amyloid peptide--why did they develop an 
amyloid peptide-mediated disease? Well, here it gets 
complicated. And there are many factors--apart from a single-
gene cause, many factors that influence the generation and 
trafficking of the amyloid peptide. Some of those factors are 
linked to aging; and, hence, this is an age-related disease. 
Some are linked to trauma, so head trauma up-regulates the 
precursor to this peptide. And lifestyle probably influences 
the accumulation of the amyloid peptide. So, we know, for 
example, that in animals that develop this peptide accumulates 
in the brain, if you exercise and stimulate those animals, you 
reduce the peptide.
    So, the peptide is the central player, it's the molecular 
cause. And many things can influence that peptide. And I 
believe that we are coming to an understanding of the 
mechanisms by which lifestyle changes, various types of 
medications, as well as specific treatments, can influence the 
accumulation of this peptide.
    The pivotal role of the peptide means that one thing we can 
do is develop a magic bullet for Alzheimer's. So, we can 
develop--we can educate the population as to the lifestyle 
changes that will tend to reduce this peptide. But we can also 
develop a specific antibody that will find the peptide and 
remove it from the brain. That's the idea behind the Wyeth/Elan 
collaboration on vaccines, passive and active vaccines. And I 
believe it is amazingly exciting that, in addition to learning 
how to influence the peptide with lifestyle changes, we can 
work, now, on a magic bullet to remove that peptide from brain.
    Senator Mikulski. Mr. Essner, did you want to elaborate on 
what he said, or did----
    Mr. Essner. No, I'd--I mean, he said it. You may notice I'm 
the only one without a ``Dr.'' before their name here, so I'm 
going to stay out of too much depth in the science. But I think 
that was a very good explanation of what we're trying to do.
    You know, people think of a--say, a flu vaccine--what a flu 
vaccine does is stimulate the body's immune system to basically 
rid the body of a virus. What we're trying to do is to create a 
vaccine that stimulates the body's immune system to rid the 
brain of this amyloid plaque.
    Senator Mikulski. Well, I've found many things compelling 
about your testimony, Dr. Aisen, but the fact that you said, 
``We now have confidence that treatments that successfully 
reduce the accumulation of amyloid peptides will slow or stop 
the disease,'' that's a blockbuster thing to declare. I mean, I 
think it ought to have us on the rooftops, that we've been able 
to, even since we last had our hearing, 2 years ago, to be that 
precise. And it might not be the only reason, but, for all 
indications, now, you would say it is the primary reason, which 
then can lead to the science.
    Let me kind of put this in layman and contemporary term. 
You talked about the genetics, lifestyle. Would you say that 
one day--or you would anticipate that we would look at 
Alzheimer's the way we now look at diabetes? No. 1, that it's a 
chronic condition, in some ways genetically driven, but also 
lifestyle--certainly lifestyle, either, driven or exacerbated. 
And, in my own family, this was a challenge that my mother 
faced. She was on oral insulin at 40. If she were alive today, 
there would be 300 different medications that her doctor could 
have, on back to identifying early insulin resistance, an A1C 
that could evaluate every 3 months, and a home detection tool 
with the fairly reasonable accuracy that looked like a 
stopwatch, for which she could monitor her food, her 
medications, and her exercise. Do you--is this, kind of, a 
framework where you think one day we would have? Because, for 
example, in some families, you might not be able to beat the 
genes, but you can delay the onset of the consequences of 
genes, dealing with insulin resistance, diet and exercise, 
aggressive monitoring, and the biofeedback that's associated 
with something like that.
    Dr. Aisen. Yes----
    Senator Mikulski. Is this a good way to think about it, or 
    Dr. Aisen. I think this may prove to be correct. So, we now 
have one molecule, this amyloid peptide, and it may be that we 
can treat that molecule the way we treat cholesterol in the 
prevention and management of arterial disease, and the way we 
treat blood sugar and hemoglobin A1c in the management of 
diabetes. It may be true, and we are moving in that direction. 
So, we now study the level of this peptide--the peptide does 
its damage in the brain--we now study the level of the peptide 
in blood, and we look for ways to reduce levels in blood. We 
study the peptide in the cerebral spinal fluid that we----
    Senator Mikulski. Excuse me, can you now do a blood test to 
see the peptide level?
    Dr. Aisen. Yes, you can, but it's not at the point where we 
know that reducing the level in blood will be helpful. This is 
still under investigation. It's the brain level of the peptide 
that's critical. There's a relationship between the blood level 
and the brain level, but it's complex, not predictable at this 
    One of the things that we're working on comes back to 
something else Mr. Essner said, which is ways of using 
neuroimaging. One of the very exciting neuroimaging modalities 
actually shows the accumulation of the peptide using a PET 
scanner. So, we have an amyloid PET-scanning method that we are 
currently testing, in collaboration with the pharmaceutical 
industry and with NIH, that will allow us to monitor the level 
of amyloid in the brain, and monitor the impact of medications 
or antibodies or vaccines or exercise on the level of amyloid 
in the brain. And we are thinking that, yes, down the road, 
this will be a controllable process that, by looking at the 
peptide in the periphery and in the brain, and intervening 
against that peptide before the symptoms start could be a way 
of preventing Alzheimer's disease.
    Senator Mikulski. Well, it's been the pattern of this 
committee to not treat legislation like prescriptions, so when 
we write our legislation, we want to create a framework that 
encourages breakthroughs, but not being so prescriptive as to 
micromanage our research field. So, let me come to this. Did a 
lot of what you're talking about come out of the Alzheimer's 
Disease Co-op Study? And would it be your recommendation as 
where we look for authorizing essentially a--we'll call it a 
breakthrough acceleration framework rather than new 
frameworks--that we stick to what's--that this is the place 
where a lot has been done, funded, and so on--could you----
    Dr. Aisen. Yeah----
    Senator Mikulski [continuing]. Along with the basic 
research. We're not talking about a zero-sum game here.
    Dr. Aisen. Right. So, I certainly think that the ADCS has 
played a critical role from the beginning in Alzheimer's 
therapeutics, and will continue to do so, and deserves a great 
deal of support----
    Senator Mikulski. But would you say that is ``the place'' 
that the breakthroughs are being stimulated?
    Dr. Aisen. I think that the breakthroughs come from a 
collaboration among industry, the FDA----
    Senator Mikulski. Which is what----
    Dr. Aisen [continuing]. Just as you're saying the----
    Senator Mikulski [continuing]. Essner was saying.
    Dr. Aisen [continuing]. The government agencies, industry, 
and academia. And we are moving very much in that direction, 
and I would continue to move in that direction. So, the 
Alzheimer's Disease Cooperative Study Group collaborates 
actively with industry. We share the methods that we develop. 
And with the----
    Senator Mikulski. But is it a consortium of academic 
    Dr. Aisen. It is. It is. Under NIH guidelines, we can work 
with industry. We can share all of what we learn, all of the 
tools, all that we learn about neuroimaging, about cognitive 
testing, about biomarkers in blood, in cerebral spinal fluid, 
with industry, and work with industry to develop the best 
clinical trials to test the best molecules. I have to emphasize 
again what you said, though, that the ADCS is a critical piece, 
but you have to keep working on the basic science, as well. 
    Senator Mikulski. It's ``yes/and,'' not ``either/or.''
    Dr. Aisen. Absolutely. And I would just point out that 
today, as I try to build my own department with young basic 
scientists, the funding rate for basic research now is about 10 
percent, meaning that about 10 percent of qualified 
applications to NIH are being funded, and it's very hard to get 
the best scientists to stay in the field when the likelihood of 
creating a career with NIH funding is such a longshot.
    Senator Mikulski. And it's been cut $310 million this year. 
That's one of the things the appropriators will be working on.
    Did you want to comment on this, Doctor?
    Dr. deBethizy. You know, there are three areas that are 
already in place, where just focused funding in the Alzheimer's 
disease would be important. Obviously, we had the Decade of the 
Brain in the '90s, which generated a tremendous amount of 
learning and really generated the therapies that exist today. 
So, basic NIH funding needs to be focused on Alzheimer's 
disease to fund these young scientists, because their ability 
to get grants has been reduced dramatically, and get through 
the peer-review process. The other part is by--Elias Zerhouni, 
the director of the NIH, has instituted this translational 
medicine initiative. This is exactly the kind of initiative 
that we were talking about, in terms of developing diagnostics 
and surrogate markers that you could use to get more rapidly to 
the answers that you want to address. Normally, this process 
takes forever, because you need a lot of validation, you need a 
lot of work, and it's really, essentially, the thing that holds 
up being able to get answers quickly.
    And then, the third component--and we haven't talked about 
this yet--is the interface with the regulatory body, the FDA. 
They have their critical path initiative, this path of getting 
things moving quickly. But it's very underfunded, and it's not 
focused on Alzheimer's disease at all. So, I think some focused 
effort in that area would be very helpful in terms of getting 
attention and really making it somewhat more receptive to us as 
we go in. Rather than going in and us having to make the 
arguments and persuade people, having people call us and say, 
``Look, can you come and help us do this?'' That would be a 
very--that would be a big change.
    Senator Mikulski. Well, that's why we want to get them in 
the same room later on--I think, within the next month. It's 
just really being able to get a Zerhouni, Gerberding, and 
Eschenbach in the same room, but we feel that's one of the ways 
to then think in terms of epidemic research, news you can use, 
CDC's role, as well as FDA. Well, thank you.
    Dr. Kramer, I'd like to come back to you and your research. 
And those of others that are in the--focusing on this 
prevention--and also, now, immediate intervention.
    Dr. Kramer. Right.
    Senator Mikulski. First of all, would you say that your 
work is now--kind of, that there is a consensus that diet, 
exercise, both physically and intellectually, now would be like 
a mainstream thought that we should be looking into doing?
    Dr. Kramer. Yeah, I----
    Senator Mikulski. Because I want to come back to the Office 
on Aging.
    Dr. Kramer. Sure. It goes beyond diet and exercise. It's 
also intellectual engagement. Many older folks--the old notion 
of retirement doesn't exist anymore, thank God, and shouldn't--
that older folks get involved in volunteer activities, in many 
kinds of activities, and we've found that continued 
intellectual engagement is also a way to slow down the 
transition to Alzheimer's, mild cognitive impairment; as is 
social interaction, being involved with others, which becomes a 
problem as we age, and we don't--we are some what socially 
isolated. But the CDC and the Alzheimer's Association has 
recently teamed up with NIH to work on getting out these public 
messages about lifestyle factors and how useful they can be, 
both to reduce a variety of different diseases, not just 
Alzheimer's, but type-2 diabetes and so forth.
    Senator Mikulski. Yes. This takes me to, then, my question.
    Dr. Kramer. Yes.
    Senator Mikulski. We're the subcommittee that has oversight 
over the Office of Aging. The Office of Aging runs the senior 
centers across the country.
    Dr. Kramer. Right.
    Senator Mikulski [continuing]. Throughout the United States 
of America. It also oversees the Meals on Wheels Program. It 
also oversees the so-called Eating Together programs, where 
seniors come for congregate meals. I'm not so sure--and I feel 
that right now, this would be the place to introduce this type 
of approach----
    Dr. Kramer. Right.
    Senator Mikulski. And, in many instances, I have a feeling 
that it's already being done. And then--but it also goes to the 
meals that we serve under government funding.
    Dr. Kramer. Exactly.
    Senator Mikulski. Would you share with us how you see this 
being implemented? Do you know if there's any interaction 
between the body of knowledge that you and your colleagues are 
developing that are going out to the Office on Aging? What is 
CDC doing? Is this what we should ask? Is this what we should 
    Dr. Kramer. I think we should always ask more. I think a 
lot of the approaches are relatively piecemeal. I went to a 
conference last year in Atlanta with CDC, the Alzheimer's 
Association, and NIH, and one of the things that they are 
considering is how to get out a public health message that 
these lifestyle factors are important, for a multitude of 
reasons, for a healthy brain and cognitive aging. But, I think, 
more of a concerted effort and focus through the Congress to 
make sure these things happen, and to make sure they happen in 
a coordinated way, would be very welcome.
    These are very tough issues, as Senator Burr referred to, 
to get people to exercise. We all know it's good for us. Why 
don't we do it? And the science is there. And more of the 
science is coming out every day; not just in our country, but 
throughout the world, you can see these studies. So, I think to 
have a focus through Congress, perhaps with some legislation or 
with some meetings, much in the same way that you're focusing 
on the development of new pharmaceuticals, taking the science 
on lifestyle factors, and getting it out to the public, making 
sure there are some incentives for maintaining a healthy 
lifestyle. And we are--you know, in terms of new research, we 
are pretty deficient in terms of looking at the interaction of 
lifestyle factors and pharmaceuticals. That's clearly an area 
for the future that gets very little treatment.
    Senator Mikulski. What do you mean?
    Dr. Kramer. Oh, the drug companies getting together, and 
the small and the large pharma, both getting together with 
academics and government agencies that work on lifestyle 
factors, and those who work on pharmaceuticals, and looking at 
the joint interaction of these multimodal interventions, which, 
in the end, have to be the way to go, to deal with Alzheimer's, 
to deal with prevention, and to deal with many other maladies 
that affect the mind and brain of our older citizens.
    Senator Mikulski. Senator Burr, you know, this Office on 
Aging--and when we listen to CDC, could be something to really 
encourage, when you think--I forget how many senior centers are 
available in the country. They exist in every State. Senator 
DeWine and I helped the reauthorization--where we could keep 
local flexibility, because rural America is different than 
urban America.
    Dr. Kramer. Sure.
    Senator Mikulski [continuing]. But I believe that this is 
the area where at least we know people come every day, or 
several times a week----
    Dr. Kramer. Right.
    Senator Mikulski [continuing]. To interact and to eat. And 
that's what you're saying is the key----
    Dr. Kramer. Yeah.
    Senator Mikulski [continuing]. One of the keys to 
prevention: interaction and the foods you consume. And I 
believe that one of the things we should ask is, Well, what is 
the food that goes out to most senior centers?
    Dr. Kramer. Yeah.
    Senator Mikulski. What is the food that goes out to most 
Meals on Wheels? That's one thing. So----
    Dr. Kramer. I think those are great questions.
    Senator Mikulski. So, do you all ask those?
    Dr. Kramer. We do assess diet. I do put people in MRI 
machines. I do a lot of----
    Senator Mikulski. No, no. No, you assess diet. But has 
anyone looked at what the government pays for, and----
    Dr. Kramer. I----
    Senator Mikulski [continuing]. Whether it's smart?
    Dr. Kramer. I don't, personally, know that. I'm sorry.
    Senator Mikulski. No, that's--no, we're not trying to--but, 
you see--that is a good question. And when we talk about 
exercise--I know Senator Burr was talking about his 85-year-old 
dad, but his father might like dancing, his father might like 
    Dr. Kramer. Exactly.
    Senator Mikulski. I think there is a variety of ways. 
Because when we hear ``exercise,'' we sometimes think of body-
beautifuls and spandex outfits and the latest cool clothes.
    Dr. Kramer. Right.
    Senator Mikulski. But what you're talking about is 
    Dr. Kramer. Exactly. And the----
    Senator Mikulski. Sustained----
    Dr. Kramer [continuing]. Intervention we use is walking.
    Senator Mikulski. Sustained, pleasurable movement.
    Dr. Kramer. Right.
    Senator Mikulski. Well, in some instances other people have 
problems with walking, so then what are other things that----
    Dr. Kramer. Aerobic----
    Senator Mikulski [continuing]. They can do?
    Dr. Kramer [continuing]. Exercise in the pool, riding a 
bicycle. There are many alternatives. Gardening, playing golf 
without the golf cart. Throwing horseshoes would be good. There 
are many ways to get physically active. And it doesn't have to 
be intense to reap some of the benefits that we've seen, and 
others have seen, in our research.
    Senator Mikulski. Senator Burr, did you want to pick up?
    Senator Burr. Yes, ma'am.
    Just for the record, my dad still works out at the ``Y'' at 
86 years old, 2 hours----
    Dr. Kramer. That's fantastic.
    Senator Burr [continuing]. A day. So----
    Dr. Kramer. That's fantastic.
    Senator Burr. I've tried to absorb everything that's been 
said while Senator Mikulski was asking questions. And I go back 
to--you started with an Adams quote. Let me, in my conclusion, 
end with a Jefferson quote,

          ``I'm not an advocate of frequent changes in laws and 
        constitutions, but laws and institutions must advance to keep 
        pace with the progress of the human mind.''

    I think that's what I've heard from all of you, is, you 
know, we're going down this pathway, and we're making 
tremendous progress toward learning, and the FDA has to change 
to reflect the framework of where we are as a field on this 
disease. NIH needs to change relative to where they're focused. 
And part of that, as you said, Don, Dr. Zerhouni has already 
done. And I'm not telling you anything new when I say that 
Washington fights change, in a huge way. It's not comfortable. 
I personally believe that 10 years from now the drug approval 
process in this country will look totally different than it 
does today. It will be every bit as safe, but there'll be no 
reason that we have to wait for the first clinical trial to be 
done to analyze the entire data from the trial before we design 
the second one, that we'll actually have reviewers that look at 
clinical data on a daily basis, that are assigned to an 
applicant, that are fairly certain, halfway through the first 
clinical trial, of what they want to look at for the second 
clinical trial, and that the results are that we're still able 
to meet that bar of safety and efficacy, but we're able to do 
it in a reduced amount of time, not just for Alzheimer's drugs, 
but for every drug.
    Don, you talked some in your testimony about prevention. I 
think you suggest the most effective, efficient way to address 
Alzheimer's disease would be to treat early stages of cognitive 
decline, which would mean a patient may never suffer 
Alzheimer's if, in fact, there was intervention--successful 
intervention at that time. But you've set aside research into 
the early stages, if I understand it right. Can you sort of 
expand on that?
    Dr. deBethizy. Sure. We originally started in age-
associated memory impairment, but recognized right away there's 
no approved therapies there. And just so I define that for you, 
these are people that are 50 to 80 years of age that have one 
standard deviation--statistical standard deviation unit below 
younger matched controls, so they don't have dementia, they 
don't have--only 3 percent of those people go on to Alzheimer's 
disease eventually. But these people are concerned. They think 
they have Alzheimer's. They're going into memory clinics. But 
there's no approved therapy, because these are normal, healthy 
people that have age-related cognitive decline. They would 
benefit from having a therapeutic, but that therapeutic would 
have to be safe. And that's the position the FDA has taken.
    But, since there's no clarity around that, and no agreement 
around that, and no agreement on the diagnosis, no agreement on 
the objective measures, no agreement on the subjective 
measures, we chose, with our partner, AstraZeneca, to go after 
Alzheimer's disease in a very clear path to approval, which is 
symptomatic improvement. So, right now all the drugs on the 
market have all been approved through a label around 
symptomatic improvement. We believe we have a superior drug, so 
we feel like we're--it's much better than the current 
therapies. But that's, sort of, the conservative approach to 
    I would recommend that there be some focus put on age-
associated memory impairment and mild cognitive impairment, 
because I fundamentally believe that a nicotinic drug, entering 
early in this progression, would be beneficial to delay disease 
    Senator Burr. Now, Bob, I think you alluded, in your 
testimony, as well, that we could save $4 billion in this 
country alone by delaying the onset of Alzheimer's by 1 to 3 
years, not dissimilar to delaying diabetes onset, I might say. 
But I think you referred to the fact that the regulatory 
agencies are cautious as it relates to Alzheimer's in a way 
similar to diseases where major therapeutic options already 
exist. Is that sort of in sync with what Don's saying?
    Mr. Essner. Well, I think, you know, in diseases like 
hypertension or cholesterol, where there are many good 
therapies today, certainly the regulatory agencies, I think 
appropriately, are very cautious with any new, less-well-
studied medication. But I think I was trying to draw a contrast 
to Alzheimer's disease, where today the therapies that are 
available are, you know, at best, marginally helpful for most 
patients, and where that kind of caution, may not be the right 
balance, given the fact that Alzheimer's patients have such a--
    Senator Burr. So----
    Dr. Kramer [continuing]. Sad future.
    Senator Burr [continuing]. The leak-over from the more 
prevalent model of caution leaks over even into some areas 
where we don't have that overlap of options.
    Dr. Kramer. Yeah. And, you know, if you put yourself in the 
chair of an FDA reviewer, and you look at the world in which 
they live, certainly--a certain amount of conservatism probably 
is appropriately built into their jobs. And what we're hoping 
is that a real spotlight--national spotlight shined on 
Alzheimer's disease will encourage FDA, as they have done in 
the past with some other diseases--AIDS, avian flu--to take a 
much more activist approach and do exactly what I think you 
described, work actively with companies to see that medicines 
are evaluated thoroughly, carefully for efficacy and safety, 
but do that in realtime rather than in the current very 
staccato way the drugs are developed and reviewed.
    Senator Burr. Don, there are a number of companies around 
the world that are investing a tremendous amount of money--
companies like yours. What do you see as the biggest hurdle 
before you that we need to overcome to achieve a success in 
Alzheimer's disease treatment?
    Dr. deBethizy. Well, you know--and this is appropriate. I 
agree that the FDA has to take a conservative approach and--
with focus on safety; because that's their job, to protect 
human health. But the time that it takes for us to get--so, we 
discovered 1734 in 1997, and so now it's 2007. That's 10 years 
later. Now, it hasn't been a straight path for us. You know, 
when you're a small company, you have to move with priorities. 
But I would say, you know, it's 12 to 15 years from discovery 
to the market for compounds. And your relative success rate is 
extremely low. It's about 10 percent for compounds that get out 
of the early discovery process.
    The challenge is the time. And part of that is the 
abundance of caution that we have built into the system. And 
I'm a toxicologist, originally, and I do know there's been 
tremendous efforts to try to streamline that process. We're 
starting to get there, but it's been very, very slow coming. 
These surrogate markers--everybody wants to go to the gold 
standard, and the gold standard is a whole animal study that's 
90 days or a year or 2 years, and then they want to do clinical 
trials, where there are thousands of patients, to make sure 
that it's safe, before you get into the market. There are some 
modifications of that you could do, where you could move 
quicker through the process, through the clinical trials, as 
you've said, by analyzing along the way, but it does bring some 
risk with it, and we're not very good at relative risk in this 
    Senator Burr. Last question, with the Chairman's 
indulgence. And it really goes to the heart of our ability to 
diagnose at an earlier point. And I'll open it to anybody that 
would like to comment. We've talked about MRIs, we've talked 
about PET. Clearly, imaging is a concern of mine, and that's 
one of the reasons we now have an institute at NIH, because 
imaging shouldn't just be the accumulation of imaging dollars 
that we used on cancer studies, it should be an effort to try 
to produce diagnostic tools that far exceed anything we've got 
today. And I think that effort is underway.
    We still annually fight--usually in Congress--an attempt to 
cut down on our ability to bring radioactive materials from 
outside the country, materials that are used, in many cases, in 
PET and other imaging tools. Can you share with Senator 
Mikulski and myself any advances in imaging that are happening 
that might give us better capabilities to diagnose, at an 
earlier period, a potential Alzheimer's patient?
    Dr. Aisen. Before I come to imaging, let me just broaden my 
answer and say that there's an effort to use many different 
tools to identify people at an early stage. There are genetic 
markers, so there are--even for sporadic AD, there are genetic 
markers that indicate something about risk. There are cognitive 
tests that actually work quite well, so I'm--cognitive tests 
that are sensitive to change years before a diagnosis of 
Alzheimer's disease. I think it's actually going to use 
information from multiple modalities that will allow us to 
identify people at the earliest stage. But, yes, imaging is 
definitely part of this.
    And we've learned a lot about this. We've known now, for 
example, that just using structural imaging, with MRI scans, 
and with our current magnet strength, we can see very, very 
small structures in the brain, and we know the structure where 
Alzheimer's disease starts; it's the hippocampus entorhinal 
cortex. And we can now see that clearly, and, using a couple of 
scans, 6 months or 12 months apart, we can determine the rate 
of shrinkage of that area of the brain where we know that 
Alzheimer's disease starts, many years before the symptoms 
appear. And that appears to be a very promising tool, using 
neuroimaging, for identifying people before there are any 
symptoms. That's structural imaging.
    We are also using functional imaging of a couple of types, 
using something called functional magnetic resonance imaging, 
as well as the standard PET scanning. So, I'm not talking now 
about amyloid PET scanning, but the standard metabolic PET 
scanning, which can show changes not of brain structure, but of 
brain function that occur prior to the symptoms of Alzheimer's 
    When we couple cognitive testing, genetic testing, 
biochemical marker measurement in blood--for example, the 
amyloid peptide--coupled with amyloid quantitation in brain, 
using PEP-PIB imaging and rate of structural atrophy in the 
brain, we're getting pretty accurate at identifying people 
before there are symptoms of disease. And since we're all, I 
think, optimistic that we're learning how to control the 
amyloid peptide. And that's key. I believe it's a reasonable 
possibility that before too many years arrive--too many years 
pass, we will be able to identify these people before symptoms, 
and treat the peptide, and stop the disease before the symptoms 
    Senator Burr. Anybody else?
    [No response.]
    Thank you, Madam Chairman.
    Senator Mikulski. Well, as part of my, kind of, concluding 
both comments and questions, we want to personally thank you 
for your participation, and I want to thank Senator Burr for 
such active engagement. I think we have heard a couple of 
things--one is that we need to lower the whole issue of 
adversarial conversation, both in the country and in the way we 
all work, so that there can be greater collaboration between 
academia, government, and the private sector. The other is, I 
would add, we've got to keep an open mind about what are the 
promises. Dr. deBethizy, as you spoke, I noted, in the 
audience, as soon as you were identified as being from R.J. 
Reynolds, or once were, and that you were looking at the 
nicotine, there were a lot of smiles and shrugs, and even 
smirks. But yet, I'm reminded of a time when we had thalidomide 
that caused terrible, terrible birth defects, but yet, I'm also 
now reminded that, for those who are facing certain forms of 
blood cancer, this is the first tool that we turn to. The very 
things that caused the birth defects are the very things that 
slow down this terrible blood cancer. So, I think we need to 
keep an open mind. I don't know if you're onto something. I 
don't know if you're not. But you very well might be. And you 
identified there were other very negative side effects to 
smoking, which we all now recognize, but, Who knows?
    So, I think, No. 1, let's keep an open mind. Research is 
about being smart. It's not always about being correct.
    The other is, this then goes to how the Federal agencies 
essentially help you do what you need to do, to do these 
breakthroughs. As I said, we hope to be bringing in NIH, FDA, 
and CDC. I also would like to have a meeting with the Office on 
Aging with Senator Burr to talk exactly about the type of work 
you, Dr. Kramer, and your other colleagues, are doing. So, if 
there's a consortium or something working on prevention, we'd 
like to be able to get that and ask the Office on Aging what 
they're doing. Who knows?
    But let's go to our future meeting, and then we'll go to a 
markup in the legislation later this summer.
    If you had those three gurus here, what would you 
recommend, questions that we would ask and/or ideas that we 
would encourage?
    Dr. Aisen? And we can just go right down the room.
    Dr. Aisen. Yeah, I think this is a great idea, and I think 
that, actually, I've seen a lot more cooperation in the last 
few years than in the past. So, already, I think, the idea that 
we need to have cooperation across industry and academia and 
the government has started to take hold, and absolutely needs 
to be encouraged so that there is open communication and 
sharing of methodology and industry pre-competitive 
collaboration, which is a very interesting notion that seems to 
be taking hold----
    Senator Mikulski. What would you ask either FDA, NIH, or 
    Dr. Aisen. The FDA needs to be involved at the earliest 
stages, including the development of the surrogate markers of 
disease. In other words, the FDA has to be talking to the 
companies and to the academic investigators about what they 
will need, and what they should need, to identify 
nontraditional populations for treatment, and how we will 
measure the effects of the treatment.
    Senator Mikulski. Which goes to what you were saying.
    Dr. Aisen. To NIH, you know, I think NIH needs a lot more 
money. I think they need a lot more money. I think there needs 
to be more money in clinical investigation of the sort that our 
group does, and more money in basic investigation, as well. I 
think we are so close that the amount of money we spend now 
will have a huge payoff.
    And finally, I think all these groups can work together to 
get the message out, which I think you started with, Senator 
Mikulski, that we need everyone to be aware of what's going on 
with this disease, not only in terms of what they can be doing 
now--preventive measures, diet, exercise--but also to support 
those of us who are trying to develop treatments. If we had a 
larger portion of the population at risk, and affected by this 
disease, volunteering to participate in clinical trials, then 
everything would move more quickly.
    Senator Mikulski. Very good.
    Dr. Kramer.
    Dr. Kramer. Yeah. I think I'd like to echo Dr. Aisen's 
suggestion that communication is critical here. And I think all 
too infrequently, the heads of CDC, FDA, and NIH communicate 
about these important issues.
    I also agree that funding for basic research, as well as 
applied research, has become problematic over the last several 
years at NIH. And I really do worry--and I'd like to echo 
that--that we're losing a generation of young scientists, who 
are getting extremely frustrated. I rotated off, about a year 
ago, an NIH study section, and, on the study section I was on, 
we were down to the 8th percentile of funding. This hasn't 
happened for a long time, and I hope funding comes back up 
again soon.
    I think there is the possibility of coordinated programs 
between NIH and the CDC. As I've mentioned before, I do go to a 
meeting with the NIH, CDC, and Alzheimer's Association. I think 
this is starting to happen. I think more cooperation on public 
health messages based on solid science makes a lot of sense and 
really needs to be incorporated to a much greater extent in the 
    Senator Mikulski. Thank you.
    Mr. Essner. Good. I agree with the comments the previous 
panelists have made, but I--maybe I'd add just two things. One 
is that the Food and Drug Administration also, in terms of the 
reviewing divisions, especially in this area, definitely needs 
more resources. And, without that, it would be very difficult 
for them to implement a number of the things that have been 
talked about.
    And, secondly, I would not underestimate the importance of 
just shining a massive spotlight on this disease, of having the 
heads of these two groups say, ``We want a war on Alzheimer's 
disease. We're setting goals here of, you know, creating really 
useful therapies to help control or reverse this disease, you 
know, in some period of time, and we're going to do everything 
in our power to make it happen.'' It has an impact on their 
staffs and on the public, that can, in itself, make a big 
    Senator Mikulski. Very good.
    Dr. deBethizy.
    Dr. deBethizy. I would agree with all that, and I would 
emphasize the role of leadership. I think just your leadership 
now, the focus that you're placing on it is incredibly 
important. And I think that will get people's attention. So, 
this pathway of the translational-medicine effort at NIH, you 
know, ask them specifically what are they doing for Alzheimer's 
disease in that process of bringing in these surrogate markers, 
because--then, going to the FDA with their critical-path 
initiative. They have very little funding for that critical-
path initiative. And I'm almost certain they have very little 
going on in the Alzheimer's disease area. But some of these 
imaging techniques would be outstanding for us to be able to 
use early in our clinical trials if we had agreement that they 
would be meaningful and acceptable to the agency as a surrogate 
marker for efficacy.
    Senator Mikulski. Well, first of all, I think those are 
excellent ideas. We're going to incorporate them, certainly, in 
our hearing. We would also add a sense of urgency, because I 
feel that time is not on our side, both in our own country and 
around the world. In our own country, the Boomers are aging. 
So, when we talk about how they're coming of age now, at 60-
ish, when you talk about these trials or things 10 years, 15 
years, they'll be 75 when--there are interventions we could be 
looking at now, preparing now, and viewing it, and essentially 
avoiding a catastrophic personal and governmentally fiscal 
    Second, our planet is aging. So, when you look at Europe, 
you look at industrialized countries, like Japan, there is an 
aging population. And they, too, will be looking at these 
issues. And what a great form of public diplomacy for us to be 
able to engage in how we can improve the lives of our citizens, 
how we can improve the lives of treasured allies. And maybe 
some people aren't so friendly with us now, but, nevertheless, 
we know--demography now could be destiny, and yet Alzheimer's 
doesn't have to be part of that destiny.
    So, we want to thank you, first of all--I believe each and 
every person at this table is making a difference, and we want 
to thank you for the difference you already are making. But, 
you know, when we work together, we can make change.
    So, thank you very much, and the committee stands 
    [Whereupon, at 11:40 a.m., the hearing was adjourned.]