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35–537 PDF 2007

S. HRG. 110–80

ALZHEIMER’S DISEASE: CURRENT AND FUTURE

BREAKTHROUGH RESEARCH

HEARING

BEFORE THE

SUBCOMMITTEE ON RETIREMENT AND AGING

OF THE

COMMITTEE ON HEALTH, EDUCATION, 

LABOR, AND PENSIONS

UNITED STATES SENATE

ONE HUNDRED TENTH CONGRESS

FIRST SESSION

ON

EXAMINING ALZHEIMER’S DISEASE, FOCUSING ON CURRENT AND 

FUTURE BREAKTHROUGH RESEARCH

MAY 15, 2007

Printed for the use of the Committee on Health, Education, Labor, and Pensions

(

Available via the World Wide Web: http://www.gpoaccess.gov/congress/senate 

COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS 

EDWARD M. KENNEDY, Massachusetts, Chairman 

CHRISTOPHER J. DODD, Connecticut 

TOM HARKIN, Iowa 

BARBARA A. MIKULSKI, Maryland 

JAMES M. JEFFORDS (I), Vermont 

JEFF BINGAMAN, New Mexico 

PATTY MURRAY, Washington 

JACK REED, Rhode Island 

HILLARY RODHAM CLINTON, New York 

BARACK OBAMA, Illinois 

BERNARD SANDERS (I), Vermont 

SHERROD BROWN, Ohio 

MICHAEL B. ENZI, Wyoming, 

JUDD GREGG, New Hampshire 

BILL FRIST, Tennessee 

LAMAR ALEXANDER, Tennessee 

RICHARD BURR, North Carolina 

JOHNNY ISAKSON, Georgia 

LISA MURKOWSKI, Alaska 

ORRIN G. HATCH, Utah 

PAT ROBERTS, Kansas 

WAYNE ALLARD, Colorado 

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 

JEFF BINGAMAN, New Mexico 

JACK REED, Rhode Island 

BERNARD SANDERS (I), Vermont 

SHERROD BROWN, Ohio 

EDWARD M. KENNEDY (ex officio), 

Massachusetts 

RICHARD BURR, North Carolina 

JUDD GREGG, New Hampshire 

LAMAR ALEXANDER, Tennessee 

JOHNNY ISAKSON, Georgia 

ORRIN HATCH, Utah 

MICHAEL ENZI (ex officio), Wyoming 

ELLEN-MARIE WHELAN, Staff Director 

(II) 

C O N T E N T S 

STATEMENTS

TUESDAY, MAY 15, 2007

Page 

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

(III) 

(1)

ALZHEIMER’S DISEASE: CURRENT AND 

FUTURE BREAKTHROUGH RESEARCH 

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. 

2

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 significant. 

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 money. 

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. 

3

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-Salembased company, working with AstraZeneca in the development of 

a pharmaceutical product for Alzheimer’s disease. 

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. 

[Laughter.] 

4

Senator MIKULSKI. Now, now. 

[Laughter.] 

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-andtake, 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 

5

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. 

STATEMENT OF PAUL AISEN, M.D., PROFESSOR OF NEUROLOGY AND MEDICINE, DIRECTOR OF THE GEORGETOWN 

MEMORY DISORDERS PROGRAM, GEORGETOWN UNIVERSITY, WASHINGTON, DC. 

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 midcentury, 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. 

6

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 essential. 

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 

7

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 process. 

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 testing. 

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 antiinflammatory 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 treatments.

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 

8

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 research.

Senator MIKULSKI. Thanks very much, Doctor. Actually, that’s a 

pretty stunning summary. 

Dr. Kramer. 

STATEMENT OF ARTHUR KRAMER, PH.D., PROFESSOR, UNIVERSITY OF ILLINOIS DEPARTMENTS OF PSYCHOLOGY AND 

NEUROSCIENCE, AND BECKMAN INSTITUTE, UNIVERSITY OF 

ILLINOIS, URBANA, ILLINOIS 

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 nonpharmacological, 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, fiVerDate 0ct 09 2002 13:06 Oct 25, 2007 Jkt 000000 PO 00000 Frm 00012 Fmt 6633 Sfmt 6601 S:\DOCS\35537.TXT SLABOR1 PsN: DENISE
9

nally, 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 

10

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

INTRODUCTION

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. 

11

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 selfreport 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 cognition. 

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). 

12

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. 

13

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 humans. 

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 extramaze 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 footshock 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 IGF1 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 upregulated 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. 

14

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., 2003) 

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 

15

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 assessment. 

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 studies. 

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 comVerDate 0ct 09 2002 13:06 Oct 25, 2007 Jkt 000000 PO 00000 Frm 00019 Fmt 6633 Sfmt 6621 S:\DOCS\35537.TXT SLABOR1 PsN: DENISE
16

pleting 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 

(FernandezBallesteros, 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 

17

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; RussoNeustadt 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 nonhuman 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 

18

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 activities. 

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Senator MIKULSKI. Well, that was very, very, very instructive, 

and we have tons of questions to ask. 

Mr. Essner. 

22

STATEMENT OF ROBERT ESSNER, CHAIRMAN AND CEO, 

WYETH, MADISON, 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 

23

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 answered. 

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 today. 

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 it. 

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. 

24

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 

25

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. 

26

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 betaamyloid, 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 imVerDate 0ct 09 2002 13:06 Oct 25, 2007 Jkt 000000 PO 00000 Frm 00030 Fmt 6633 Sfmt 6621 S:\DOCS\35537.TXT SLABOR1 PsN: DENISE
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prove 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 contributions. 

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:

28

• Challenges related to the design and implementation of clinical trial protocols; • The lack of urgency about the disease at a national level; and • The lack of scientific consensus about what it means to ‘‘modify’’ the course of 

the disease rather than merely treat its symptoms.

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 start. 

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 treatments. 

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 epidemic. 

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 

29

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. 

Doctor. 

STATEMENT OF J. DONALD deBETHIZY, PH.D., PRESIDENT AND 

CEO OF TARGACEPT, INC., WINSTON-SALEM, NORTH CAROLINA 

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 

30

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 area. 

31

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 disease. 

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 Executive

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 targets. 

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 disVerDate 0ct 09 2002 13:06 Oct 25, 2007 Jkt 000000 PO 00000 Frm 00035 Fmt 6633 Sfmt 6621 S:\DOCS\35537.TXT SLABOR1 PsN: DENISE
32

ease 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 clear. 

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 strengthened. 

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 schizophrenia. 

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. 

33

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 pharmaceuticals. 

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 

34

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. 

[Laughter.] 

Mr. ESSNER. I see. 

35

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——

[Laughter.] 

Senator MIKULSKI. I shouldn’t have used——

[Laughter.] 

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 

36

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 exercise——

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 

37

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 

everybody. 

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. 

38

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 not? 

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 point. 

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 

39

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 institutions? 

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. And——

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. 

40

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 

41

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 push? 

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, 

42

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 horseshoes. 

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 movement. 

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 

43

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 

44

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 this. 

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 modification. 

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? 

45

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 process. 

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 

46

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 disease. 

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 occur. 

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 

47

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 

CDC? 

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. 

48

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 future. 

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 difference. 

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 situation. 

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 

49

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 adjourned. 

[Whereupon, at 11:40 a.m., the hearing was adjourned.] 

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