Discovery andHope

2OO7 P R O G R E S S R E P O R T on

A L Z H E I M E R ’ S D I S E A S E

U.S. Department of 

Health and Human Services
National Institute on Aging

National Institutes of Health

U.S. Department of Health and Human Services

2OO7 P R O G R E S S R E P O R T on

A L Z H E I M E R ’ S D I S E A S E

Discovery andHope
7 Making the Most of 

Translational Research .........................30

8 Supporting the Gold Standard: 

AD Clinical Trials ..................................32

9 Helping Caregivers Cope .......................37

OUTLOOK FOR THE FUTURE ......... 40

 Improving Basic Understanding .................40

 Identifying Genetic Causes 

and Risk Factors ....................................40

 Understanding Disease Progression ..........41

 Making the Most of Translational 

Research and Clinical Trials ......................41

 Cultivating Research 

Infrastructure and Resources ...................41

CONCLUSION ................................... 42

REFERENCES ................................... 43

INTRODUCTION ..................................4

An Urgent National Health Priority ..............6

About This Report ....................................6

A Brief Primer on Alzheimer’s Disease .........8

PROGRESS IN AD 

RESEARCH CONTINUES ................. 10

1 Improving Our Basic 

Understanding of AD ............................10

2 Learning About Cognitive Aging ..............17

3 Normal Cognitive Aging, 

Cognitive Decline, and AD: 

What’s the Difference? .........................19

4 Accelerating the Search for 

Genetic Causes and Risk Factors ...........19

5 Attention to Nongenetic Risk and 

Protective Factors Pays Off ...................22

6 Exploring All Possibilities to 

Improve AD Diagnosis ..........................28

The National Institute on Aging (NIA), part of the Federal Government’s National Institutes of Health (NIH) at the U.S. Department of Health and 

Human Services, has primary responsibility for basic, clinical, behavioral, and 

social research in Alzheimer’s disease (AD) as well as research aimed at finding 

ways to prevent and treat AD. The Institute’s AD research program is integral to 

one of its main goals, which is to enhance the quality of life of older people by 

expanding knowledge about the aging brain and nervous system. This 2007 

Progress Report on Alzheimer’s Disease summarizes recent AD research conducted 

or supported by NIA and other components of NIH, including: 

 National Center for Research Resources (pages 16, 21)

 National Heart, Lung, and Blood Institute (pages 20, 21, 25, 26, 29, 36)

 National Human Genome Research Institute (page 21)

 National Institute of Biomedical Imaging and Bioengineering (page 13)

 National Institute of Diabetes and Digestive and Kidney Diseases (pages 16, 25)

 National Institute of Mental Health (pages 15, 20, 22, 25, 37, 38, 39)

 National Institute of Neurological Disorders and Stroke 

(pages 11, 12, 13, 14, 25, 27, 29)

 National Institute of Nursing Research (pages 18, 37, 38)

Modest AD research efforts also are supported by the National Cancer Institute, 

National Center for Complementary and Alternative Medicine, Eunice Kennedy Shriver 

National Institute of Child Health and Human Development, National Institute of 

Environmental Health Sciences, and John E. Fogarty International Center.

In Remembrance

The 2007 Progress Report on Alzheimer’s Disease is dedicated to Robert Katzman, M.D. 

(1925–2008), an internationally known AD research pioneer who fundamentally changed 

the way scientists and clinicians thought about the brain disorder we now know as Alzheimer’s 

disease, and the first to detail its prevalence and severity, in 1976. Dr. Katzman was 

founding director of the NIA-funded AD Research Center at the University of California 

San Diego, one of the original members of NIA’s National Advisory Council on Aging, 

and a founder of the Alzheimer’s Association. 

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Table of Contents

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Alzheimer’s disease is an age-related, irreversible 

 brain disorder that develops over many 

years. In the very early stage, people experience 

memory loss, which can be mistaken for memory 

changes that happen in normal aging. As the 

disease progresses, these symptoms gradually lead 

to dementia, a condition characterized by marked 

memory loss and behavior and personality changes. 

Eventually, the disease also leads to a decline in 

other cognitive abilities (such as decision making 

and language skills), an inability to recognize 

family and friends, and a severe loss of mental 

function. These losses are related to the breakdown 

of the connections between neurons (nerve cells) 

in the brain and the eventual death of many 

of these cells. 

The course of AD varies from person to person, 

as does the rate of decline. In most people, symptoms 

first appear after age 60. AD and other dementing 

disorders are caused by diseases that affect the 

brain, although age-related brain and body changes 

also can affect the development of dementia. 

Dr. Alois Alzheimer, a German psychiatrist 

and neuropathologist, first described what we 

now know as AD when he reported the case of 

51-year-old Auguste D. in 1906. He described 

the unusual features of her brain tissue—the 

numerous globs of sticky proteins in the spaces 

between neurons (what we now call beta-amyloid 

plaques) and tangled bundles of fibrils within 

neurons (what we now call neurofibrillary tangles). 

However, it was not until the 1960s and 1970s 

that scientists began to recognize AD as a pathology 

associated with aging (Katzman, 1976). 

The public AD research enterprise began in 

earnest in the 1970s. Initially, investigators focused 

on understanding the manifestations and natural 

progression of the disease. Findings from these 

studies, combined with advances in many 

scientific areas—diagnostic imaging, genetic 

analysis, molecular and cellular biology, and the 

Introduction

development of animal models, to name just a few—

have led to an explosion of knowledge about AD. 

Today, some 30 years later, the maturing field 

of AD research encourages the creativity and insights 

of individual investigators and targets special areas 

for emphasis. Enormous progress has been made, 

and many promising avenues lie ahead. However, 

if one theme predominates today, it is the growing 

appreciation of the pathological and clinical complexity of AD. It is clear that AD has no single 

cause but develops from multiple factors that 

interact over many years. A variety of scientific 

disciplines must collaborate if we are to understand 

the genetic and environmental influences, including 

lifestyle and health factors, that may increase or 

decrease an individual’s risk of developing cognitive 

decline, amnestic mild cognitive impairment, or AD. 

(Amnestic mild cognitive impairment, or aMCI, is a 

condition of greater-than-normal memory problems 

but no impairment in multiple cognitive domains.) 

The National Institutes of Health’s (NIH’s) 

broad program of AD research taps into those 

varied disciplines, with a growing emphasis on 

bringing what scientists learn in the laboratory 

to the clinical arena as rapidly as possible. 

It is clear that AD has 

no single cause but develops 

from multiple factors that 

interact over many years.

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Published estimates of the 

prevalence of AD vary. That’s 

because investigators use different 

methods for counting, and each 

method has its own strengths and 

weaknesses. 

NIA continues its research 

interest in studies to estimate AD 

prevalence because having an asaccurate-as-possible number indicates the scope of AD as a public 

health problem. This helps scientists, policy makers, health care 

providers, and health care insurers 

determine the costs of AD to the 

Nation and develop appropriate services and resources to address the 

problem. 

Equally important, the ability to 

reliably track trends in AD prevalence and incidence (the number 

of new cases in a specified time 

period) helps investigators correlate 

these trends with changes in environmental and biological factors. 

Results from these correlations 

may provide insights into potential 

risk and protective factors and help 

inform the design of prevention and 

treatment interventions.

Some scientists have obtained 

a prevalence count by using a 

they risk overlooking milder cases 

of AD or diagnosing AD in individuals who have another type 

of dementia. Further, prevalence 

studies generally test people at only 

one point in time, and the tests 

may not be able to pick up the 

disease in its early stages. Better 

diagnostic tools are needed to 

capture cognitive impairment and 

AD at their earliest stages, both in 

population studies and studies conducted in major AD clinical centers, 

so that we can get a better measure of the scope of the problem.

One of the toughest issues is 

who to include in the count, a decision that can be driven by budget 

and staff limitations as well as by 

study design considerations. For 

example, including only people older 

than 65 will miss younger people 

who may have the disease. If scientists exclude people in nursing 

homes and assisted living facilities, 

then they also are likely to end up 

with an underestimate. Also, many 

people choose not to participate 

in these kinds of studies because 

they don’t want to find out if they 

have AD or because participation is 

inconvenient. 

random sample of older adults 

that reflects characteristics of the 

overall U.S. population. Sample 

findings are then extrapolated to 

the entire population. Other scientists calculate a national estimate 

by projecting results from one or 

more studies of particular communities within the United States. 

No matter which method scientists 

use, getting a complete and accurate count of people with AD is a 

daunting challenge. 

Measuring AD in a population 

requires a different approach than 

diagnosing the disease in an individual at, for example, a major 

AD clinical center. In populations, 

researchers try to identify all the 

people in a selected group with AD, 

ruling out those who do not have 

the condition. There is no simple 

test to do this, and the count can 

be further compromised if individuals or their caregivers decline to 

participate in a study. 

To make population assessments 

easier and more cost-efficient to 

conduct, investigators often use 

screening tests and abbreviated 

cognitive test batteries. These 

study instruments may help, but 

How Many People Have AD? 

Our aging society makes AD an especially critical issue because the number of people with the 

disease doubles for every 5-year age interval beyond 

age 65. The U.S. Census Bureau estimates that the 

population age 65 and older is expected to double 

to about 72 million people in the next 25 years. 

Moreover, the 85-and-older age group is now the 

fastest growing segment of the U.S. population.

About This Report

The 2007 Progress Report on Alzheimer’s Disease 

describes NIH’s important AD research effort. It 

begins with a brief primer on AD that reviews the 

main features of the disease, discusses the causes, 

and describes how AD is diagnosed and treated. 

The next section, “Progress in AD Research 

Continues,” highlights recent advances in nine 

major areas. The Progress Report concludes with 

an outline of the diverse ways in which NIH is 

building on the momentum of 3 decades of 

groundbreaking AD research.

An Urgent National Health Priority

The urgency of the AD research task cannot 

be underestimated. AD is the most common 

form of dementia. Its impact on the Nation is 

illustrated by studies estimating its prevalence 

(the number of people with the disease at any 

one time). For example, recent estimates from 

a nationally representative sample in the Aging, 

Demographics, and Memory Study (part of the 

ongoing NIA-supported Health and Retirement 

Study), suggest that among Americans age 72 

and older, one in seven has dementia and about 

2.4 million have AD (Plassman et al., 2007). 

Other investigators, using projections from community-based studies, estimate that the number 

of Americans aged 65 or older with AD will be 

5.1 million in 2010 (Evans et al., 1990; Hebert 

et al., 2003). (See page 7 for more information 

about why prevalence estimates vary.)

Despite the differing methodologies and 

results of their studies, experts agree that 

the number of people with AD will increase 

significantly if current U.S. population 

trends continue and no prevention methods 

emerge (Hebert et al., 2003). 

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The healthy human brain is made 

up of billions of different kinds of 

neurons that are connected through 

chemical and electrical signals. A 

typical neuron has a nucleus in a cell 

body, an axon, and many dendrites. 

Neuronal function is supported by other 

kinds of cells called glial cells. 

As with all cells, the nucleus of 

a neuron contains the cell’s genetic 

blueprint and helps regulate the cell’s 

activities in response to signals from 

outside and inside the cell. The axon 

transmits messages to other neurons. 

Dendrites receive messages from axons 

of other nerve cells or from specialized 

sense organs. The survival of neurons 

depends on the healthy functioning of 

several interdependent processes:

Communication. When a neuron 

receives enough messages from surrounding cells, an electrical charge is 

generated that travels to the end of 

the axon. Here, it triggers the release 

of chemicals called neurotransmitters 

that move across a gap, or synapse, 

to the dendrites of neighboring 

neurons. Scientists estimate that 

the typical neuron has up to 15,000 

synapses. The neurotransmitters 

bind to specific receptor sites on the 

dendrites of neighboring neurons, triggering chemical changes and building 

up new electrical charges.

Metabolism. This process encompasses all the chemical reactions that 

take place in the cell. Efficient metabolism requires adequate blood circulation to supply the cells with oxygen 

and glucose, the brain’s major fuel.

Repair. Neurons are programmed to 

live a long time—even more than 100 

years—so they must constantly maintain, repair, and remodel themselves.

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How Does AD 

Affect the Brain?

In healthy aging, most types of brain 

neurons are not lost in large numbers. 

In AD, however, many neurons stop 

functioning, lose connections with 

other neurons, and die because communication, metabolism, and repair 

are disrupted.

At first, AD typically destroys 

neurons in parts of the brain that 

control memory, including the entorhinal cortex, the hippocampus, and 

related structures. AD later attacks 

areas responsible for language and 

reasoning. Eventually, many other 

areas of the brain are damaged, and 

the person becomes helpless and 

unresponsive to the outside world.

What Are the Main 

Characteristics of the 

Brain in AD?

Many changes take place in the 

brain of a person with AD. The three 

major characteristics that reflect the 

pathology, or damage, caused by the 

disease are:

Amyloid plaques. Found in the 

spaces between neurons, plaques 

consist of largely insoluble deposits of 

aggregated protein fragments called 

beta-amyloid peptides, other proteins, 

remnants of neurons, degenerating dendrites and axons, glia, and other cellular 

material. Scientists used to think that 

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and is caused by a mutation in one 

of three genes that a person has 

inherited from a parent. This form of 

the disease is called “early-onset” 

AD. Other early-onset cases are not 

caused by such mutations.

More than 90 percent of AD cases 

develop in people older than 60. The 

development and pathology of this form 

of AD, called “late-onset” AD, are very 

similar to those of early-onset AD. We 

don’t yet completely understand the 

causes of late-onset AD, but they probably include genetic, environmental, 

and lifestyle factors. The importance 

of these factors in increasing or 

decreasing the risk of developing AD 

differs from person to person. Scientists 

hope that what they learn about earlyonset AD also can be applied to the 

late-onset form of the disease.

Perhaps the greatest mystery is why 

AD largely strikes elderly people. Why 

does it take 30 to 50 years for people to 

develop signs of the disease? Research 

on how the brain changes normally as 

people age will help provide answers to 

this important question.

How Is AD Diagnosed?

Clinicians use a range of tools to 

diagnose “possible AD” (dementia that 

could be due to another condition) 

or “probable AD” (no other cause of 

dementia can be found). These tools 

include a medical history; physical 

exam; tests that measure memory, 

language skills, and other abilities 

related to brain functioning; and brain 

scans. Knowledge about the clinical 

and behavioral characteristics of the 

disease also helps in diagnosing AD. 

At this time, AD can be diagnosed 

conclusively only by an autopsy of the 

brain after death. However, in specialized research facilities, clinicians can 

diagnose AD in a living person with up 

to 90 percent accuracy.

Early, accurate diagnosis is 

crucial because it tells people whether 

they have AD or whether their symptoms are being caused by something 

else. Stroke, tumor, Parkinson’s 

disease, sleep disturbances, or side 

effects of medications are all known 

to affect cognitive function and 

memory. Early diagnosis also helps 

families plan for the future while the 

person with AD can still participate 

in making decisions. Researchers 

are making progress in developing 

accurate diagnostic tests and techniques that may one day be used in 

general medical practice to detect 

the disease early—ideally before 

symptoms emerge. 

plaques caused the damage to neurons 

seen in AD. Now, however, many think 

that earlier, more soluble forms of betaamyloid may be the major culprits.

Neurofibrillary tangles. Found 

inside neurons, neurofibrillary tangles 

are abnormal aggregates of a protein 

called tau. Healthy neurons are internally 

supported in part by structures called 

microtubules, which help guide nutrients 

and molecules from the cell body to the 

ends of the axon. Tau, which normally 

has a certain number of phosphate 

molecules attached to it, binds to microtubules and stabilizes them. In AD, an 

abnormally high number of additional 

phosphate molecules attach to the 

tau. As a result, tau disengages from 

the microtubules and begins to clump 

together with other threads of tau, eventually forming neurofibrillary tangles. 

When this happens, the microtubules 

disintegrate and the neuron’s transport 

system collapses. As with beta-amyloid, 

some scientists think that early soluble 

forms of abnormal tau may cause the 

damage to neurons. 

Loss of connections between 

cells and cell death. This feature of 

AD likely results from the accumulation of beta-amyloid and abnormal 

tau. When neurons lose their connections, they cannot function properly 

and eventually die. As neuronal death 

spreads through the brain, affected 

regions begin to shrink in a process 

called brain atrophy. By the final stage 

of AD, damage is widespread, and 

brain tissue has shrunk significantly.

What Causes AD?

Very rarely, people develop AD in their 

30s, 40s, and 50s. In many of these 

cases, the disease runs in families 

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How Is AD Treated?

A variety of treatments address behavioral and psychiatric problems that 

occur as AD progresses. Only a few 

medications have been approved by 

the U.S. Food and Drug Administration 

(FDA) to help control the cognitive 

loss that characterizes AD. Donepezil 

(Aricept®), rivastigmine (Exelon®), and 

galantamine (Razadyne®, formerly 

known as Reminyl®) are prescribed 

to treat mild to moderate AD symptoms. Donepezil also is approved 

to treat severe AD. These drugs act 

by stopping or slowing the action 

of acetylcholinesterase, an enzyme 

that breaks down acetylcholine (a 

neurotransmitter that helps in memory 

formation). The drugs maintain some 

patients’ abilities to carry out activities of daily living and may maintain 

some thinking, memory, or speaking 

skills. They also may help with certain 

behavioral symptoms. However, they 

do not stop or reverse AD and appear 

to help patients only for months to a 

few years. 

Another type of AD medication, 

memantine (Namenda®), is prescribed 

to treat moderate to severe AD symptoms. This drug appears to work by 

regulating levels of glutamate, another 

neurotransmitter involved in memory 

function. Like the cholinesterase 

inhibitors, memantine does not stop 

or reverse AD. 

In addition to these medications, 

physicians use other drugs and nondrug approaches to treat behavioral 

and psychiatric problems associated 

with AD. These problems include agitation, verbal and physical aggression, 

wandering, depression, sleep disturbances, and delusions. 

A Brief Primer on Alzheimer’s Disease

Visit the NIA Alzheimer’s 

Disease Education and Referral 

(ADEAR) Center website at 

www.nia.nih.gov/Alzheimers/

ADvideo to view a short video 

about AD and the brain. 

Healthy neuron Dying neuron

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I

n 2007, scientists supported by NIH 

made advances in a number of areas 

important to AD: 

Basic research on AD

Normal cognitive aging

 The interface between healthy cognitive 

aging and AD

Genetic causes and risk factors for AD

Nongenetic risk and protective factors for AD

Diagnosis

Translational research

AD clinical trials

Caregiver support

These areas of investigation focus on the 

central issues of AD—what occurs during the 

very first steps of the disease process, what we 

can do to promote healthy cognitive aging 

and prevent AD, and what we can do once 

the disease has taken hold. The following 

sections describe new knowledge in these 

areas that may hold the key to future prevention, treatment, and caregiving strategies.

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1Improving Our Basic Understanding of AD

From the beginning, studies at the cellular and 

molecular levels have focused on understanding 

the wide range of processes that interfere with, 

or enhance, the function and survival of neurons 

and their connections. The aim is to identify targets 

that can be translated and developed into AD 

therapies. Such therapies may avoid or reduce the 

cell dysfunction and cell death that occur as the 

disease progresses and also may keep memory intact. 

Interest in mechanisms at the basic level is 

ongoing, and the potential roles of different forms 

of beta-amyloid and abnormal tau in neuronal 

toxicity continue to be a source of intense investigation. 

Beta-amyloid

Scientists now know a fair amount about the 

metabolism of amyloid precursor protein (APP), 

a large protein associated with the cell membrane 

that is the starting point for the beta-amyloid that 

forms plaques. Scientists also know the basic steps 

of beta-amyloid and plaque formation. They know 

that three different enzymes—alpha-secretase, 

beta-secretase, and gamma-secretase—are involved 

in cleaving APP into discrete fragments, the functions of which are still not completely understood. 

Depending on which enzymes are involved and 

where the cleaving occurs, APP processing can 

follow one of two pathways—a pathway that is 

helpful to neurons or one that is harmful because 

it leads to the formation of beta-amyloid and plaques.

Studies in this area have evolved to the point 

that investigators have begun initial testing in 

humans of potential therapies aimed at halting 

the synthesis of beta-amyloid, reducing its levels, 

or degrading early aggregates before harmful 

complexes have formed. At the same time, basic 

science investigators are still probing the mysteries 

of plaque formation and seeking to understand 

the potentially toxic effects that beta-amyloid 

exerts on neurons. 

Because gamma-secretase is involved in the 

production of harmful beta-amyloid, scientists have 

hypothesized that it could be a useful therapeutic 

target. However, gamma-secretase also is involved 

in the helpful APP processing pathway and in the 

cleavage of other developmentally important proteins, 

so actions to strongly inhibit its activity could have 

negative side effects. Johns Hopkins University 

School of Medicine researchers supported by the 

National Institute of Neurological Disorders and 

Stroke (NINDS) and NIA demonstrated that 

genetically reducing gamma-secretase activity in 

mice by as little as about 30 percent is enough 

to reduce beta-amyloid formation but leave 

sufficiently high gamma-secretase levels for the 

enzyme’s other essential reactions (Li et al., 2007). 

These findings may have identified a possible 

anti-amyloid therapeutic strategy—gammasecretase inhibitors—as well as a way to preclude 

potentially harmful effects from the inhibitors. 

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ad

Contınues

Progress in

Research

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A key focus of beta-amyloid research has 

always been to understand how this protein 

peptide actually damages neurons. Recent research 

suggests that early, small, and soluble aggregates 

of amyloid, called beta-amyloid-derived diffusible 

ligands (ADDLs), or oligomers, may be the main 

culprits in harming neurons. Much evidence also 

suggests that synapses, the tiny gaps between 

neurons that are essential for neuronal communication, are oligomers’ prime targets. Several recent 

studies have examined the pathways that lead from 

beta-amyloid to eventual synaptic dysfunction 

or neuron death and studied how beta-amyloid 

oligomers target specific synaptic connections 

between neurons, causing them to deteriorate.

A research group at Northwestern University 

examined the ability of ADDLs to affect the 

composition, structure, and abundance of 

synapses (Lacor et al., 2007). In this test tube 

study of neurons situated in the hippocampus, 

the researchers found that ADDLs bound to 

synapses of a specific subset of hippocampal 

neurons, promoting a detrimental change in 

the composition, structure, and abundance of 

those synapses. Continued exposure to ADDLs 

also damaged the neurons’ dendritic spines (the 

structures that receive messages from other neurons), affecting their ability to function properly.

A study in mice by scientists at the Salk 

Institute for Biological Studies in La Jolla, 

California, provides evidence that the APP 

cleavage at a site known as D664 may be necessary for the synaptic dysfunction characteristic 

of AD to occur (Saganich et al., 2006). The 

research team, supported by NINDS and 

NIA, found that synaptic loss and behavioral 

abnormalities were completely prevented by 

a mutation at D664, even in mice that had 

high levels of beta-amyloid and many plaques. 

Uncovering the mechanism by which the 

D664 cleavage contributes to dysfunction may 

ultimately help researchers understand synaptic 

loss in AD and develop treatment strategies. 

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Another continuing line of research focuses 

on the possibility of harnessing an immunization response in people with AD that involves 

antibodies to beta-amyloid. Immunizing people 

against disease has been a cornerstone of medical 

practice for decades, and investigators have 

pursued the idea that it might be possible to 

immunize people against AD by injecting them 

with a beta-amyloid-related immunogen (a 

substance designed to elicit an immune response). 

This kind of injection would cause a person’s 

immune system to make antibodies that, in 

turn, would lower the levels of brain amyloid. 

This technique, called active immunization, 

has been tested in AD transgenic mice that 

were actively immunized with a beta-amyloid 

immunogen. (Transgenic animals are those that 

have been specially bred to develop AD-like 

features, such as beta-amyloid plaques.) The mice 

had fewer plaques and improved performance on 

memory tests. This finding led to a clinical trial 

in humans to test the safety and effectiveness 

of active immunization with the beta-amyloid 

immunogen. However, about 6 percent of participants in the trial developed brain inflammation in 

response to the treatment, so the trial was stopped. 

Despite this setback, interest in developing an 

AD vaccine remains high. 

Research into new ways of shaping the antibody 

response continues in the laboratory, and more 

refined antibody approaches are being tested in 

clinical trials. 

Using several strains of mice, including 

transgenic and normal mice, Harvard Medical 

School investigators tested four different partial 

fragments of beta-amyloid as potential immunogens (Maier et al., 2006). The researchers found 

that the immunogens evoked the desired immune 

response in both sets of mice, reducing plaque 

levels in their brains without an accompanying 

inflammatory reaction. The transgenic mice also 

showed slight improvements in memory tests. 

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In a second approach to protecting against 

AD, called passive immunization, antibodies are 

produced or manufactured outside the body. 

For example, humanized antibodies to betaamyloid have been made in cell cultures using 

recombinant DNA techniques. The antibodies 

can then be isolated and administered to subjects. 

Scientists presume that passive immunotherapy 

produces less of an inflammatory response 

than active immunotherapy, and a number 

of investigators are pursuing this approach.

Cerebral amyloid angiopathy (CAA) is the 

accumulation of beta-amyloid in the walls of 

arteries in the brain. Because CAA is commonly 

found in AD, many scientists are interested 

in how beta-amyloid deposits in blood vessels 

and neurons may generate human disease and 

whether they can be treated by immunotherapy. 

Researchers at Massachusetts General Hospital, 

supported by NIA and the National Institute of 

Biomedical Imaging and Bioengineering, used 

microscopy at different time intervals to monitor 

CAA in a mouse model of AD to evaluate the 

effects of anti-beta-amyloid passive immunotherapy (Prada et al., 2007). The investigators 

saw clearance of CAA deposits within 1 week after 

a single administration of antibody directly to 

the brain, but the effect was short-lived. Chronic 

administration of antibody over 2 weeks led to 

better clearance without evidence of hemorrhage 

or other destructive changes. This imaging study 

directly demonstrated that CAA in a transgenic 

mouse model can be cleared with an enhanced 

immunotherapy regimen. 

Additional insights about beta-amyloid have 

come from studies of neuronal networks. These 

studies show how beta-amyloid may damage 

normal electrical activity of hippocampal neurons, 

thereby diminishing the cells’ ability to communicate 

with each other. 

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A research group at the Gladstone Institute of 

Neurological Research in San Francisco discovered 

that, compared with normal mice, transgenic 

mice show anatomical and biochemical alterations 

in certain brain regions as well as abnormal 

excitatory electrical activity (Palop et al., 2007). 

The study focused on the hippocampus (a 

region of the brain that is key to learning and 

memory). These findings are important because 

they suggest another damaging effect of betaamyloid—namely, that beta-amyloid presumably 

triggers abnormal electrical activity throughout 

the brain. This abnormal activity in turn triggers compensatory inhibitory activity, perhaps 

contributing to AD-related network dysfunction. 

Other aspects of beta-amyloid also are 

yielding their secrets to AD researchers.

Scientists at the Buck Institute for Age 

Research in Novato, California, bred transgenic 

mice to develop features of AD and to overproduce neuroglobin, a protein expressed 

predominantly in neurons that is closely related 

to hemoglobin, the oxygen-carrying protein in 

the blood. Neuroglobin is abundant in the brains 

of vertebrates. The function of this globin family 

protein is largely unknown, but the expression 

of neuroglobin can be induced when oxygen 

levels in the brain are lowered, as in a stroke. The 

transgenic mice performed significantly better on 

memory tasks and had fewer beta-amyloid plaques 

than did transgenic mice that only developed 

AD features (Khan et al., 2007). The researchers, 

supported by NINDS, speculate that increasing 

neuroglobin levels may merit additional research 

as a therapeutic target, not only for cerebrovascular disease but also for beta-amyloid toxicity.

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12 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 13
Tau

Tau is a leading player in AD pathology and 

is generating new excitement as an area of 

study. The focus on tau was spurred by the 

finding that a mutant form of this protein is 

responsible for frontotemporal dementia and 

parkinsonism linked to chromosome 17, another 

neurodegenerative disorder that shares some 

features with AD. That finding indicated that 

abnormalities in tau can cause dementia. 

Recent research has provided other new 

insights. For example, some studies have suggested that tau’s influence on cell death may have 

more to do with its interference in the normal 

cell cycle process than with its involvement in the 

formation of neurofibrillary tangles. Other studies 

suggest that, like beta-amyloid, early soluble 

forms of abnormal tau (not the final neurofibrillary tangle) may be the trigger for cell death.

Transgenic mouse models have played a big 

role in pushing forward tau research because 

they can be studied methodically for clues 

to human diseases. For example, the “triple 

transgenic” mouse forms plaques and tangles 

similar to those in human AD over time in brain 

regions. Another new transgenic mouse model, 

which contains only human tau, forms clumps 

of damaging tau filaments in a region-specific 

fashion similar to that seen in humans with AD. 

A research group from the Gladstone Institute 

of Neurological Research supported by NIA 

and NINDS explored the possibility that a 

treatment aimed at tau could block the cognitive impairments that result from beta-amyloid 

accumulation (Roberson et al., 2007). In this 

study with AD transgenic mice that normally are 

cognitively impaired, the scientists eliminated the 

Ñ

animals’ tau gene. The resulting lower levels of 

tau produced by the mice prevented behavioral 

problems that usually occur when too much 

beta-amyloid is produced, even though betaamyloid levels remained high. This surprising 

result suggested that reducing tau levels may 

present another target for future AD treatments. 

AD and Other 

Neurodegenerative Diseases

Studies of brain abnormalities resulting from common 

mechanisms in a number of neurodegenerative 

diseases are providing important insights into AD. 

Diseases such as AD, Lewy body disease, Huntington’s 

disease, frontotemporal dementia, amyotrophic 

lateral sclerosis (ALS, also known as Lou Gehrig’s 

disease), Parkinson’s disease, and Creutzfeldt-Jacob 

disease have similar clinical symptoms, including 

memory loss, movement problems, and sleepwake disorders.

People with any of these disorders also exhibit 

the same pathological hallmark—misfolded and 

mutant proteins in the brain. Under normal 

conditions, most misfolded proteins are either 

repaired or degraded, but when too many of 

these proteins are produced over a long period 

of time, the body’s repair and clearance process 

may be overwhelmed. The toxic misfolded proteins 

accumulate and lead to the age-related neurodegenerative disorder. 

In 2007, several studies provided valuable 

insights into how this process may occur and 

why some neurodegenerative diseases have 

overlapping features.

Scientists at the University of Pennsylvania 

School of Medicine identified, for the first time, 

a protein called TDP-43 as a component of the 

protein aggregates that form in ALS and in some 

forms of frontotemporal dementia (Neumann et 

al., 2006). Finding the same molecular signature 

in the two diseases suggests that they may represent different facets of the same neurodegenerative 

disorder. It may be that a number of neurodegenerative diseases that affect different groups 

of neurons have similar disease processes. If that is 

true, then developing therapies for these disorders 

and other similar diseases may be simplified.

Another research team, working at 

Northwestern University, explored how the 

expression of a single protein that is prone to 

abnormal aggregation can lead to the disruption 

of many cellular pathways. These researchers 

also examined whether one general mechanism 

might explain the many common features of 

protein misfolding diseases (Gidalevitz et al., 

2006). The investigators used the worm C. 

elegans as a model to test whether expression of a 

pathogenic protein known as a “polyQ protein” 

(similar to the abnormal huntingtin protein 

that causes Huntington’s disease) could affect 

the folding or degradation of other proteins.

Worms with the polyQ protein were crossed 

with worms that expressed other mutant proteins 

in either muscle or brain cells. The researchers 

found that the offspring of those worms showed 

chronic expression of the aggregation-prone 

polyQ protein, which caused the other proteins to 

become toxic under conditions where they were 

normally innocuous. Moreover, the toxic action 

was reciprocal in that the other mutant proteins, 

Ñ

Ñ

which had no adverse effect under normal 

physiological conditions, could enhance the 

aggregation of polyQ proteins. These clues about 

the interactions between abnormal proteins and 

their effects on neurons may provide a valuable 

boost to efforts to target potential treatments for 

various age-related neurodegenerative diseases. 

Researchers at the University of Texas 

Southwestern Medical Center used transgenic 

mice to explore relationships between AD 

and Parkinson’s disease. This study, supported 

by the National Institute of Mental Health 

(NIMH), showed that in the spinal cords of 

mice made to overexpress human normal and 

mutant alpha-synuclein (a protein implicated 

in Parkinson’s disease) a change occurred in the 

ubiquitin/proteasome system. This is a cellular 

system that degrades misfolded proteins (Gallardo 

et al., 2008). Curiously, the mice also exhibited 

a fourfold increase in levels of the ApoE protein 

(ApoE is a genetic risk factor implicated in AD; 

see page 19 for more on ApoE). This overexpression produced marked increases in aggregates 

of alpha-synuclein and insoluble beta-amyloid. 

Deleting the APOE gene, which makes ApoE, 

had a number of positive effects in the transgenic 

mice—alpha-synuclein-induced neurodegeneration was delayed, survival increased, accumulation 

of alpha-synuclein aggregates decreased, and 

accumulation of beta-amyloid was suppressed. 

These findings suggest that ApoE is involved 

in the response to alpha-synuclein toxicity, and 

that AD and Parkinson’s disease may share a 

molecular link through the ubiquitin/proteasome system. This insight may have important 

implications for preventing and treating these 

devastating diseases. 

Ñ

Transgenic mouse models 

have played a big role in pushing 

forward tau research.

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AD and Aging

Another set of insights about AD derives from 

an apparent risk factor common to a number 

of neurodegenerative diseases: aging itself. 

Age-related changes, such as inflammation, 

changes in expression of certain proteins, and 

the generation of free radicals, may precede, 

follow, or exacerbate the neuronal damage that 

occurs in AD. In addition, age-related changes 

in one or more of the hundreds of varieties of 

proteins could result in inefficient functioning 

of certain synapses, predisposing neurons to 

failed communication and death. Scientists 

are investigating all of these possibilities.

In a study using the C. elegans worm, scientists 

at the Salk Institute for Biological Studies 

introduced a gene that increased the lifespan of 

the worms and a gene that made beta-amyloid 

(Cohen et al., 2006). The investigators found 

that the worms containing the increased-lifespan 

gene also suppressed the aggregation-related 

toxicity of beta-amyloid. These findings suggest 

that aging itself plays a role in the rate at which 

beta-amyloid aggregates, and investigators 

identified two genes essential for this process. 

An intramural research group at NIA identified disease-specific changes in gene expression 

in different regions of brain tissue from people 

with AD, people with other types of dementia, 

and cognitively healthy people (Weeraratna et 

al., 2007). The analysis revealed that genes that 

differed in expression the most between the 

groups were related to nervous system development and function and neurological disease, 

followed by genes involved in inflammation and 

immunological signaling. A specific group of 

genes associated with beta-amyloid accumulation 

and clearance was found to be significantly 

Ñ

Ñ

altered in the AD group. The most significantly 

down-regulated gene in this dataset was one 

containing the genetic information necessary 

to make an enzyme implicated in beta-amyloid 

clearance. Together, these findings open up new 

avenues of investigation and possible therapeutic 

strategies targeting inflammation and enzymes 

associated with amyloid clearance in AD patients. 

Scientists at the University of North Dakota 

School of Medicine and Health Sciences supported by the National Center for Research 

Resources (NCRR) have been investigating 

cytokines, substances produced by immune 

system cells. These substances are secreted by 

cells during the body’s response to inflammation. The investigators found that a cytokine 

called tumor necrosis factor alpha, which is 

present in the brain during an inflammatory 

response, can begin a process in nerve cells that 

ultimately leads to cell death (Jara et al., 2007). 

This finding may help explain one mechanism 

leading to cell death in AD and related diseases.

Free radicals—oxygen or nitrogen molecules 

that combine easily with other molecules—are 

important in the aging process and may be important in AD as well. Free radicals can help cells in 

some ways, but overproduction of these highly 

reactive molecules can damage neurons in a process called oxidative stress. A substance called 

4-hydroxy nonenal (4-HNE), formed as a result 

of oxidative stress, is increased in AD. 4-HNE 

also is found in AD plaques. Scripps Research 

Institute scientists, supported by the National 

Institute of Diabetes and Digestive and Kidney 

Diseases (NIDDK), found that 4-HNE modifies 

beta-amyloid fragments, triggering the formation 

of toxic beta-amyloid oligomers (Siegel et al., 2007). 

These findings provide impetus for additional 

research on whether, or to what extent, oxidative 

stress is a risk factor or a consequence of AD.

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2Learning About Cognitive Aging 

Improvements in public health, medical care, 

nutrition, and living standards mean that we are 

now living longer than ever. Many older adults 

enjoy active, productive lives, but they also face 

the risk of cognitive and memory problems. 

This challenge has provided a major impetus 

for research into healthy cognitive aging. Scientists 

want to know how and why some people remain 

cognitively healthy all their lives while others 

do not. Answers to these questions also can 

help researchers understand what goes wrong in 

AD and other neurodegenerative diseases and 

can point the way to interventions that might 

maintain successful brain and cognitive aging. 

Working memory is an important kind of 

short-term memory that maintains information 

in a temporary “buffer” that can be continually 

updated as needed. This type of memory is 

important for cognitive and emotional function, 

allowing us to inhibit inappropriate actions and 

plan future actions. Working memory appears 

to depend on recurring activity in networks 

Ñ

Until recently, scientists believed that neurons in 

mammals were formed only during 

the fetal period and for a short 

time after birth. The belief was 

that once a mammal had reached 

a certain level of maturity early 

in life, neurons could only be lost. 

The notion that new neurons could 

develop later in life was radical. 

Finding that this was, in fact, true 

was revolutionary.

This shift in thinking over the 

past few years was based on 

studies showing that neurogenesis 

(the formation of new neurons) 

takes place in the adult brain, at 

least in a limited number of brain 

regions, such as the hippocampus. 

Neurogenesis declines during aging 

but can be stimulated by environmental influences, including physical 

activity and learning tasks.

This evidence raises a big question: Do these new neurons actually 

help brain regions function or are 

they merely a reservoir to replace 

enhanced “excitability,” new neurons 

may help process information and 

form memories in the hippocampus 

(Ramirez-Amaya et al., 2006). The 

researchers also found that certain 

types of stress disrupted neurogenesis by decreasing the survival of the 

new neurons (Thomas et al., 2007). 

These and other similar findings may help researchers develop 

future interventions that maintain 

or enhance the formation of new 

neurons, thereby helping to slow 

age-related cognitive decline. 

dying neurons? Several recent 

studies, conducted by scientists 

from Johns Hopkins University, 

the Chicago Medical School of 

the Rosalind Franklin University 

of Medicine and Science, and the 

University of Arizona, have helped 

answer this question.

In studies with mice and rats, 

investigators showed that new 

neurons produced in the adult 

hippocampus are better able to adapt 

(an attribute called “plasticity”) and 

to mature (Ge et al., 2007). In fact, 

they found that because of their 

New Insights into New Neurons

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involving neurons in the front part of the brain 

(the prefrontal cortex). This activity allows 

neurons to continue firing during periods 

of delay when the stimulus or event to be 

remembered is not present in the environment, 

thus maintaining a representation of the information over time, even in the face of distracting 

stimuli or information. With increasing age, 

working-memory deficits become a consistent 

feature of declines in cognitive performance.

Investigators at the Yale University School 

of Medicine conducted an extensive series of 

experiments in rats and nonhuman primates 

and found that stimulating neuronal receptors 

in the prefrontal cortex improved working 

memory (Wang et al., 2007). They also found 

that weakened connections within neuronal 

networks in this brain region may underlie some 

of the cognitive deficits seen in older adults. 

A research team at the University of Kentucky 

and Memory Pharmaceuticals Corporation in 

Montvale, New Jersey, took another approach 

to studying cognitive aging (Rowe WB et al., 

2007). This study in rats combined analyses 

of changes in expression of many genes with 

behavioral testing to determine gene changes 

that are selectively associated with age-related 

cognitive dysfunction in the hippocampus. 

Results showed clear differences in expression 

of genes that occurred in the brain between the 

Ñ

cognitively impaired and cognitively healthy 

rats, suggesting a model for age-related cognitive 

impairment. In this model, if decreases in expression of genes important for the use of glucose 

and in energy production by cells that support 

neuronal function were coupled with deficiencies in neuronal energy production, neurons 

would be unable to trigger activity that enables 

plasticity and memory formation in response to 

learning tasks. In this model, these deficiencies 

also might generate signals that activate harmful 

pathways, further disrupting cognitive processes. 

The multi-site Advanced Cognitive Training 

for Independent and Vital Elderly (ACTIVE) 

clinical trial, funded by NIA and the National 

Institute of Nursing Research (NINR), is designed 

to test the effects of brief cognitive training in 

older adults. In one component, researchers at the 

Indiana University School of Medicine examined 

the effects of cognitive training on participants 

who exhibited declines in cognitive function 

(Unverzagt et al., 2007). Participants received 

training in memory, reasoning, or speed of 

processing of visual information. 

Compared with a control group that received 

no training, the participants who received the 

memory training and had normal memory at the 

start of the study showed significant improvement 

in memorization skills. Among participants with 

pre-existing declines in memory function, however, 

those in the memory training group showed no 

benefit. Those who received the reasoning or the 

speed-of-processing training showed improvement 

comparable to participants with normal memory. 

These findings suggest that older adults with 

pre-existing mild memory impairment may not 

benefit from memory training as much as those 

with normal memory function, but they benefit 

just as much from certain forms of cognitive 

training that do not rely on memorization. This 

training may be able to improve the ability of 

older adults to maintain skills that allow them 

to carry out daily tasks and lead a higher 

quality of life. 

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3 Normal Cognitive Aging, Cognitive Decline, and AD: 

What’s the Difference?

As knowledge grows about normal cognitive aging, 

AD, and the stages in between, it is increasingly 

evident that there is no clear line between a 

completely healthy brain and a diseased brain. 

Evidence shows that most people develop some 

plaques and tangles in their brains as they get 

older, but not everyone develops cognitive problems, amnestic MCI, or AD. At what point does 

an age-related process become a disease-causing 

process? Several recent studies have explored 

this question.

Evidence from the Religious Orders Study 

and the Memory and Aging Project—two community-based epidemiologic studies conducted 

by Rush University Medical Center scientists—

indicated that about one-third of individuals 

between the ages of 82 to 85 who did not have 

clinical dementia or aMCI when they died still 

met the neuropathologic criteria for intermediate 

or high likelihood of AD (Bennett et al., 2006a). 

In earlier tests of memory and other cognitive 

functions, those who met the AD neuropathologic criteria scored a little lower on tests of 

episodic memory (the ability to place information 

in long-term storage for later retrieval) than other 

study participants but showed no differences on 

other cognitive domains.

The development of Pittsburgh Compound-B 

(PiB) has allowed scientists to take huge steps 

forward in their understanding of normal and 

abnormal age-related changes in the brain (Klunk 

et al., 2004). PiB is a radiolabeled compound that 

binds to beta-amyloid plaques in the brain and 

can be imaged in living people using positron 

emission tomography (PET) scans. Two recent 

studies conducted by researchers at Washington 

University School of Medicine and the Centre 

for PET in Victoria, Australia, showed that 

approximately 20 percent of 66- to 86-year-olds 

with normal cognition showed positive PiB 

Ñ

Ñ

binding, indicating an abundance of beta-amyloid in 

the brain (Mintun et al., 2006; Rowe CC et al., 2007). 

These and other findings show that studies 

to explore further the interface between a 

pathological process (formation of beta-amyloid 

plaques) and the aging process are both feasible 

and necessary. Future studies will clarify the 

relationship between AD brain pathology and the 

eventual diagnosis of aMCI and AD, as well as 

when the diagnosis can be made with certainty. 

4 Accelerating the Search for Genetic Causes and 

Risk Factors

Until recently, only four of the approximately 

30,000 genes in the human genome were 

conclusively shown to affect the development 

of AD. Mutations in three genes—the APP 

gene found on chromosome 21, the presenilin 1 

gene on chromosome 14, and the presenilin 2 

gene on chromosome 1—are linked to the rare 

early-onset form of familial AD. The APP gene 

is responsible for making APP, the precursor to 

beta-amyloid. The presenilin genes contain the 

information necessary to make the proteins that 

are part of one of the enzymes that help to cleave 

APP to form beta-amyloid. Mutations in each of 

these genes promote the breakdown of APP in 

a way that leads to increased production of 

harmful beta-amyloid.

The fourth gene, APOE, found on chromosome 19, contains the information necessary to 

make a protein called apolipoprotein E (ApoE). 

ApoE carries lipids in the bloodstream and is 

important in clearing lipids from the blood. 

APOE has three common forms, or alleles—ε2, 

ε3, and ε4. The ε2 form may provide some 

protection against AD, and ε3 is thought to play 

a neutral role. The ε4 form is a known risk-factor 

gene for the common late-onset form of AD, and 

many studies are underway to clarify its impact. 

Scientists want to know 

how and why some people 

remain cognitively healthy all their 

lives while others do not.

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Boston University School of Medicine scientists 

supported by the National Heart, Lung, and 

Blood Institute (NHLBI) and NIA examined 

whether APOE ε4 affects the relationship between 

brain volume and cognitive performance in 

1,477 participants in the Framingham Study 

population (see page 25 for more information 

about the Framingham Study) (Palumbo et 

al., 2007). Those with an APOE ε4 allele and 

smaller brain volume did less well on tests of 

visual memory, new learning, and executive 

function than those without APOE ε4, who 

also had smaller brain volumes. It may be that 

having APOE ε4 not only increases the risk of 

AD, but also leads to poorer outcomes in those 

who do not yet have symptoms of the disease.

People who have two copies of the APOE ε4 

allele may be at high risk of developing AD at an 

earlier age of onset and for experiencing far more 

rapid declines in memory performance, compared 

with people without this allele and people with 

only one copy. Such memory declines, even 

within a normal range of performance, could be 

early markers of disease, detectable before the 

individual experiences clear symptoms of the 

disorder. Investigators supported by NIMH and 

NIA examined how performance on neuropsychological tests by a sample of healthy adults in 

their 50s and 60s related to their APOE ε4 status 

(Caselli et al., 2007). The investigators, with 

the Mayo Clinic in Scottsdale, Arizona, and the 

University of Arizona, found that even before a 

diagnosis of aMCI, individuals with two copies 

of APOE ε4 showed higher rates of cognitive 

decline than those at lower genetic risk for AD.

These findings support the notion of a presymptomatic state of disease, the identification of 

which might aid in early detection and diagnosis 

of AD among people at increased genetic risk. 

Further prospective studies are needed to examine 

how rates of cognitive decline relate to rates 

Ñ

Ñ

of AD disease progression and conversion to a 

final diagnosis of AD. Results from these studies 

may suggest new targets for possible interventions to delay onset or progression of AD.

Though scientists know that APOE ε4 is a 

risk factor for cognitive decline that eventually leads to AD, they have yet to understand 

the steps in that process. Many think that it 

involves an interaction between genetic and 

environmental factors. One study, supported 

by NIMH and conducted by a research team 

at the University of California San Diego, 

examined the role of one such environmental 

factor, prolonged psychological stress (Peavy et 

al., 2007). Stress generally involves elevations in 

the hormone cortisol, which have been linked 

to hippocampal atrophy and to memory and 

learning impairments. This study assessed APOE 

status, stress levels, salivary cortisol, and memory 

performance of 91 older adults without dementia.

The researchers found that having either 

one or two APOE ε4 alleles and high stress were 

associated with reduced memory performance. 

In addition, the investigators found significant 

interactions between stress and APOE ε4; 

participants with high levels of stress and the 

APOE ε4 allele consistently manifested worse 

memory and higher cortisol concentrations than 

other participants. These findings point the way 

to future studies that could follow individuals 

over time to determine whether stress levels and 

APOE status in combination could be used to 

predict future development of cognitive decline 

leading to clinically diagnosable dementia.

Most experts believe that in addition to 

APOE ε4, at least half a dozen more genes 

may influence the development of late-onset 

AD in some way. Geneticists around the 

world are searching for these genes. 

Ñ

In 2007, a worldwide collaboration of 

scientists supported by NIA, the National 

Human Genome Research Institute, NCRR, 

the Canadian Institutes of Health Research, 

and private foundations in the United States, 

Canada, and Japan unveiled their discovery of a 

new AD risk-factor gene called SORL1 (Rogaeva 

et al., 2007). This gene is involved in recycling 

APP from the surface of cells, and its association 

with AD was identified and confirmed in three 

separate studies (Lee JH et al., 2008; Lee JH et 

al., 2007; Meng et al., 2007). The researchers 

found that when SORL1 is expressed at low 

levels or in a variant form, harmful beta-amyloid 

levels increase, perhaps by moving APP away 

from its normal pathways and toward cellular 

compartments that generate beta-amyloid.

Studies are ongoing to clarify SORL1’s role in 

the AD process. For example, NHLBI-supported 

scientists at Boston University School of Medicine 

conducted a genome-wide association study on 

Framingham Study participants using cognitive 

data collected in an NIA-funded add-on study 

(Seshadri et al., 2007). A genome-wide association study tests for linkage between genes and a 

particular disease across all the genes in a specific 

population of individuals. The researchers found 

that the SORL1 gene was associated with measures 

of abstract reasoning and that another gene, 

CDH4, was related to total cerebral brain volume. 

This association of an AD risk-factor gene with 

cognitive function suggests there may be a common 

pathway in the brain aging process and in AD.

NIA’s Alzheimer’s Disease Genetics Initiative 

(ADGI) provides critical support to all of this 

work. Launched in 2003, this study aims to 

identify at least 1,000 families with members 

who have late-onset AD and members who 

do not have the disease. Investigators are collecting blood samples and other clinical data 

from participating volunteers. These biological 

specimens allow investigators to create and 

maintain “immortalized” cell lines—cells that 

are continuously regenerated in the laboratory. 

Ñ

The cell lines will be used in DNA analyses 

to further understand SORL1 and to identify 

additional AD risk-factor genes, a critical 

task even if individual risk-factor genes may 

have relatively small effects on AD development. More than 4,000 new cell lines 

are now available for researchers to study 

risk-factor genes for late-onset AD.

A second investigator-led initiative, the 

Alzheimer’s Disease Genetics Consortium, was 

launched in 2007 to accelerate the application of 

genetics technologies to late-onset AD through 

collaborations among leading researchers in 

AD genetics. The ultimate goal of this effort is 

to obtain genetic material from 10,000 people 

with AD and 10,000 cognitively healthy people 

and then to scan the entire genome for the 

remaining AD risk-factor genes, as well as genes 

for age-related cognitive decline. Some of the 

genetic material will be drawn from existing 

samples of blood and tissue that are mostly held 

at Alzheimer’s Disease Centers. Other genetic 

material will be collected from new participants.

With such efforts, the search for the genetic 

underpinnings of late-onset AD is intensifying, 

allowing investigators to identify who is at 

high risk of developing AD, understand the 

mechanisms at work, and focus on new pathways amenable to prevention or treatment.

Most experts believe 

that in addition to APOE ε4, at 

least a half a dozen more genes 

may influence the development of 

late-onset AD in some way. 

20 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 21
5 Attention to Nongenetic 

Risk and Protective 

Factors Pays Off

Epidemiologic studies, animal studies, and 

clinical trials are all important in identifying 

potential factors that may contribute to or protect 

people from AD risk—separately or interactively 

with genetics. In the past several years, two areas 

of focus have emerged: lifestyle factors and the 

management of health conditions. Scientists also 

have continued their research interest in looking 

at estrogen and AD.

Lifestyle Factors and AD 

Several elements of a healthy lifestyle, including 

a nutritious diet, regular physical activity, not 

smoking, and strong social networks, can help 

people stay healthy as they grow older. An 

important reason for this benefit is that lifestyle 

choices strongly affect the risk of several chronic 

diseases, including heart disease, diabetes, and 

stroke, that commonly affect people as they age. 

Evidence is emerging that AD may share some of 

these risk factors. Findings from epidemiologic 

research, basic studies in animals, and limited 

clinical trials suggest that an array of lifestyle 

factors may influence the risk of developing 

age-related cognitive decline, aMCI, or even AD. 

As part of a large longitudinal study of 

older women, researchers at the San Francisco 

Coordinating Center and California Pacific 

Medical Center Research Institute examined 

the relationship between quality of sleep and 

cognitive function (Blackwell et al., 2006). The 

investigators found that disruptions to sleep, 

rather than the total amount of sleep, were consistently related to reductions in cognitive function. 

Another study of cognitively healthy women 

living in the community found a similar association between cognitive decline and sleep quality 

but not total sleep time (Yaffe et al., 2007).

It is well recognized that the damage of AD 

often adds to and interacts with other changes 

in the brain to cause cognitive impairment. Two 

studies from the Memory and Aging Project 

provide supporting evidence for this observation. 

In one analysis of more than 600 cognitively 

healthy people, investigators found that chronic 

psychological distress was associated with a nearly 

threefold increased risk of AD; change in a global 

measure of cognition; and change in episodic 

memory, the clinical hallmark of AD (Wilson et 

al., 2006). In a separate study, researchers found 

that social engagement might also modify the 

severity of dementia (Bennett et al., 2006b). 

Although individuals with larger social networks 

did not have fewer plaques or tangles than more 

isolated individuals in the study, AD pathology 

had a smaller effect on the cognition of the more 

socially connected individuals. This correlation 

was similar to the protective effect provided by 

years of formal education. 

Investigators with the Group Health Cooperative 

in Seattle, Washington, have been following 1,740 

older adults in the Adult Changes in Thought 

Study (Larson et al., 2006). Every 2 years, participants undergo physical and cognitive tests, answer 

questions about their lifestyles, and are assessed 

for dementia. After 6 years, the investigators found 

that the risk of AD in people who exercised three or 

more times per week, at least 15 minutes per day, 

Ñ

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was 31 percent lower than in those who exercised 

fewer than three times per week. This result suggests 

that regular exercise is associated with a delay in 

the onset of AD. 

Epidemiologic studies correlate lifestyle factors 

with altered cognitive function. Epidemiology 

cannot, however, establish a cause-and-effect 

relationship. To directly examine cause and effect, 

NIA is sponsoring several clinical trials to test 

the questions raised by observational and animal 

studies and to specifically look at the effects 

of one lifestyle factor—physical activity and 

exercise—on cognitive function in older adults. 

Researchers from the University of Illinois 

at Urbana-Champaign conducted functional 

magnetic resonance imaging tests on older 

adults before and after a 6-month program of 

brisk walking (Erickson et al., 2007). Results 

showed that neuronal activity in the frontal 

cortex increased with increases in participants’ 

cardiovascular fitness. A similar trial conducted 

by University of Illinois investigators showed 

that brain volume increased as a result of a 

walking program (Colcombe et al., 2006). 

These findings suggest a strong biological basis 

for the role of aerobic fitness in helping to 

maintain the health and cognitive functioning 

of adults as they age, at least in the short term. 

A small-scale clinical trial is looking at the 

effects of 1 year of aerobic fitness training on 

cognition and brain activity and structure in older 

adults. Other small trials are examining the role of 

aerobic exercise on electrocortical and behavioral 

measures in older adults and assessing the effects 

of a short aerobic conditioning program on 

cognitive function in older adults with aMCI. 

Ñ

Ñ

Rapid advances in AD genetics  research are fostered though 

several other essential initiatives 

funded by NIA and NIH.

National Cell Repository 

for Alzheimer’s Disease 

(NCRAD) 

www.ncrad.org

This research resource, located 

at Indiana University, is the central 

repository for the AD Genetics 

Initiative and provides the cell lines 

and DNA needed for genetic 

analyses.

Genetics of Alzheimer’s 

Disease Data Storage Site

www.niageneticsdata.org

Scientists who use NCRAD 

samples and other NIA-funded 

from multiple studies done 

using different types of analysis 

can then be merged. This process 

allows data from thousands of 

study participants to be analyzed 

together, with increased probability 

of gene discovery. 

National Institute of 

Mental Health Genetics 

Dataset

www.nimh.nih.gov 

NIMH has established a national 

resource of demographic, clinical, 

and genetic data from 1,411 

individuals from families with AD. 

Housed at Washington University, 

the NIMH AD Genetics Dataset 

offers researchers clinical and 

genetics data from both NIMH 

and NIA. 

AD geneticists are required by 

NIA to submit their published 

data to this site, which was established in 2006 at Washington 

University in St. Louis. The data 

then undergo additional analysis 

by AD genetics experts. 

Database of Genotype and 

Phenotype (dbGaP)

www.ncbi.nlm.nih.gov/entrez/

query/Gap/gap_tmpl/about.

html 

This NIH collaboration was 

developed to archive and 

distribute the results of largescale genome-wide association 

studies, gene sequencing 

studies, and analyses of the 

association between genotype 

and genetic traits. Datasets 

Other Genetics Initiatives Are Key to Successful AD Research

22 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 23
A 3-year trial of a group exercise and 

health education intervention in people with 

aMCI is examining a variety of issues, such as 

whether the exercise intervention will slow the 

progression from aMCI to dementia. More 

recently, researchers at Wake Forest University 

started a pilot study to assess whether an 

intervention involving physical activity and 

cognitive training reduces significant cognitive 

decline in memory-impaired older individuals. 

The Seniors Health and Activity Research 

Program-Pilot (SHARP-P) will compare the 

outcomes of physical activity, cognitive training, 

and combined physical activity and cognitive 

training with those of health education. 

Ñ Additional clinical trials are critical to discern 

whether physical activity and exercise can, 

in fact, prevent or delay long-term cognitive 

decline or AD and, if so, to determine the type 

and amount of physical activity necessary. 

Health Conditions and AD 

A growing body of evidence suggests that the 

metabolic changes that occur in a variety of 

age-related chronic diseases, such as heart disease, 

stroke, high blood pressure, and type 2 diabetes, 

may contribute to the development of AD, affect 

the severity of AD, or cause vascular dementia 

(a loss of thinking and reasoning abilities caused 

by stroke or other forms of brain injury related 

to damage to the brain’s blood vessels). However, 

these relationships are complex. Several studies in 

the past year have attempted to untangle them. 

Investigators with the Memory and Aging Project 

examined the brain tissue of deceased participants 

who had donated their brains to the study (Schneider 

et al., 2007). Results showed that about one-third 

of the participants had evidence of strokes, which 

increased the odds of having AD-related reductions 

in memory function. 

At least four long-term studies have linked 

diabetes with a decline in cognitive function. 

In one of these studies, a Columbia University 

research team examined whether diabetes is 

related to an increased risk of aMCI (Luchsinger 

et al., 2007). Working with a large multiethnic 

population with a high prevalence of diabetes, 

the researchers found that diabetes was associated 

with a significantly increased risk of aMCI as 

well as other types of MCI. 

Evidence increasingly suggests that overweight 

and obesity may increase AD risk. Two studies 

explored this issue by examining the relationship 

of obesity or overweight at midlife and cognitive 

Ñ

Ñ

Ñ

performance or AD in later life. In the first 

study, conducted at the Kaiser Permanente 

Division of Research in Oakland, California, and 

supported by NIDDK, investigators found that 

participants who were obese (a body mass index 

of 30 or more) during midlife had a threefold 

increase in AD risk (Whitmer et al., 2007). 

Those who were overweight (a body mass index 

of 25 to 29) had a twofold increase in AD risk.

In the second study, Boston University 

School of Medicine researchers used data 

from 1,814 Framingham Study participants 

to examine whether obesity at midlife affected 

the impact of hypertension (a key risk factor 

for heart disease) on cognitive abilities (Wolf 

et al., 2007). The study, supported by NIA, 

NHLBI, and NINDS, found that participants 

with a high measure of abdominal obesity and 

hypertension did worse on tests of executive 

function and visuomotor skills than did those 

who weighed less and had normal blood pressure. Furthermore, hypertensive participants 

who were most obese did less well on the 

tests compared with those who were not as 

obese. This finding suggests that obesity may 

have exacerbated the impact of hypertension 

on the brain. The researchers concluded that 

controlling abdominal obesity and blood 

pressure in midlife may help reduce the risk of 

cognitive problems and dementia in later life.

The Framingham Heart Study, begun in 1948, is a long-term investigation of physical and environmental factors that influence the development of cardiovascular disease in healthy individuals. The study, funded 

by NHLBI, is still following the remaining members of the 

original study group, as well as the remaining members 

of a group of 5,000 people who were recruited in 1971 

into the Framingham Offspring Study. Investigators are 

now working with the third generation of volunteers in 

this landmark epidemiologic study. 

One of the distinguishing elements of the study 

has been “add-on” components funded by other NIH 

institutes, including NIA and NIMH. These add-on components have provided a cost-effective opportunity for 

scientists to examine additional issues using existing 

study populations. 

The Framingham Study’s rich harvest of data has 

allowed researchers to explore many dimensions 

of the relationship between cardiovascular risk factors, cognitive health, and AD. The fact that it has 

been going on for so many years also gives scientists 

a unique opportunity to study certain aspects of an 

issue. For example, in describing the burden of any 

disease, scientists often refer to incidence, or the 

number of people who may develop the disease in a 

given time period, usually a year. However, some investigators have argued that “lifetime risk,” or the risk of 

developing a disease across the remaining estimated 

lifespan, may provide a more accurate measure of the 

possible burden to a population than does incidence. 

They note that lifetime risk reflects risk across a longer 

period of time rather than risk over a single year. 

Framingham investigators at the Boston University 

School of Medicine conducted a lifetime risk analysis 

using many years of follow-up data from the original 

group of Framingham participants. This analysis, which 

was supported by NHLBI, NIA, and NINDS, focused on 

the lifetime risk of stroke and AD, two conditions of 

enormous public health concern. 

Using 51 years of follow-up data, the analysis 

showed that the lifetime risk of stroke was 1 in 5 for 

a middle-aged woman and 1 in 6 for a middle-aged 

man. For AD, using 29 years of follow-up data, lifetime 

risk was 1 in 5 for a middle-aged woman but only 1 

in 10 for a middle-aged man. The authors concluded 

that measures of age- and sex-specific lifetime risk 

indicate that a middle-aged person has a 1 in 3 chance 

of having a stroke or becoming demented. These rates 

have serious implications for the provision and cost of 

future health care services. 

Framingham Study Data Provide Insights into 

the Lifetime Risk of Stroke and Dementia

Advising the Public 

Before All the Scientific 

Results Come In

Although the evidence to date suggests that  physical activity and other lifestyle choices, 

such as mentally stimulating activity, a healthy 

diet, and social engagement, have positive effects 

on brain function and may reduce risks of cognitive 

decline and AD, results from definitive clinical trials 

will not be available for several years. 

Even so, experts can recommend that older 

adults (and other age groups) participate in these 

activities. These low-risk, low-cost interventions 

have many proven benefits for overall healthy aging. 

For example, regular physical activity and a healthy 

diet help reduce the risk of age-related diseases 

and conditions, such as heart disease and type 2 

diabetes. Social activities with friends and family 

and the pursuit of mentally stimulating activities 

help people feel engaged. 

24 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 25
As noted earlier, epidemiologic studies 

cannot determine cause-and-effect relationships 

even though they provide valuable information 

about associations between chronic diseases and 

aMCI or AD. As a result, NIA is supporting 

several clinical trials to see whether managing 

these conditions might reduce the risk of 

cognitive decline and dementia. 

Clinical trials have examined whether two 

treatments—simvastatin (a cholesterol-lowering 

drug) and vitamin supplements that reduce 

homocysteine (an amino acid linked to heart 

disease and AD)—could slow the rate of cognitive decline in older adults with AD. These 

trials were recently completed, and the data 

are being analyzed. 

Other clinical trials are underway to examine 

whether diabetes-related interventions can prevent 

or delay the progression of cognitive decline or AD: 

ACCORD-MIND (ACCORD-Memory in 

Diabetes). This NIA-funded trial is nested within 

NHLBI’s Action to Control Cardiovascular 

Risk in Diabetes (ACCORD) trial, which is 

evaluating whether intensive glucose, blood 

pressure, and lipid management can reduce 

cardiovascular disease in people with type 2 

diabetes. ACCORD-MIND will test whether 

these interventions also can reduce the rates of 

cognitive decline and structural brain change 

in 2,800 of the ACCORD study participants 

over a 4-year period. Participants will undergo 

periodic cognitive testing and MRI scans to assess 

change over time (Williamson et al., 2007).

●

RECALL. In this 18-month multi-center trial, 

researchers from the University of Washington 

will test the effects of the drug rosiglitazone on 

attention and memory skills in older adults with 

aMCI. Rosiglitazone has anti-inflammatory 

properties and improves the body’s ability to use 

insulin. This trial will examine the medication’s 

effects on brain structures that support memory 

and other cognitive abilities, as well as on 

biological markers associated with inflammation, 

insulin resistance, and cardiovascular disease. 

As with most clinical trials, participants will 

be divided into two groups—one will receive 

rosiglitazone, the other a placebo (an inactive substance). Participants also will have MRIs before 

and at the end of treatment to determine whether 

rosiglitazone slows the rate of atrophy in brain 

structures that support memory. The RECALL 

trial will provide valuable data about the effects of 

improved insulin sensitivity, reduced insulin levels 

in the body, and reduced inflammation on cognitive function and biological markers in aMCI.

SNIFF 120. This 4-month clinical trial will 

examine the effects of a nasal-spray form of 

insulin on cognitive function, ability to carry 

out daily activities, glucose metabolism in the 

brain, and levels of beta-amyloid in people 

with aMCI or AD. AD is associated with 

reduced levels of insulin in cerebrospinal fluid, 

and treatment with insulin has been shown to 

improve memory performance. Insulin injections 

can be problematic because they can result in 

hypoglycemia (low blood sugar). A nasal spray 

delivers insulin directly to the brain. Preliminary 

data on this way to administer insulin show that 

●

●

people with AD improved their verbal memory 

and did not develop hypoglycemia. This clinical 

trial will provide useful data on the safety, feasibility, 

and potential efficacy of this innovative treatment 

approach, which investigators may use to plan 

future large-scale clinical trials.

Metformin. This NIA-funded clinical trial’s 

primary aim is to determine whether metformin, 

a drug used safely and effectively to treat diabetes, 

reduces the risk of cognitive decline. Very high 

blood insulin levels have surfaced as a potential 

risk factor for AD. Half of the population 60 

years and older may have such high insulin 

levels, and the prevalence is increasing with the 

epidemic of overweight and obesity. The research 

team at Columbia University hypothesized that 

metformin could prevent cognitive decline by 

reducing insulin levels in overweight and obese 

people who do not have diabetes but who do 

have aMCI. In this new, 12-month pilot trial, 60 

people with aMCI will receive either metformin 

(1,000 mg twice a day) or a placebo. The investigators also want to determine whether metformin 

prevents the decrease in brain metabolism that is 

characteristic of the transition from aMCI to AD. 

POEM (Pioglitazone or Exercise). Metabolic 

syndrome is an increasingly prevalent medical 

condition that raises a person’s risk of developing 

diabetes and heart disease. Its cardinal features are 

insulin resistance (a condition in which muscle, 

fat, and liver cells are not able to use insulin 

properly), physical inactivity, and abdominal 

obesity. Recently, several large studies have 

linked metabolic syndrome to the development 

of cognitive impairment. In a new NIA-funded 

pilot trial, investigators at the University of 

Colorado, Denver, will examine whether treatments for metabolic syndrome in older people 

with aMCI can improve, stabilize, or lessen the 

decline in cognitive function compared with a 

no-treatment group. Investigators plan to test 

the diabetes drug pioglitazone and endurance 

exercise training, both of which have been shown 

●

●

to ameliorate many components of metabolic 

syndrome, including insulin resistance, and to 

have positive effects on cognition. This pilot 

trial also will evaluate how the interventions 

affect cognition and inflammatory biomarkers. 

Estrogen and AD

Production of estrogen, a hormone made by a 

woman’s ovaries, declines dramatically after 

the childbearing years. During the past 25 

years, laboratory and animal research and 

human observational studies have suggested 

that estrogen may protect the brain. Experts 

have wondered whether using estrogen could 

reduce the risk of AD or slow its progression. 

Clinical trials have shown that estrogen does 

not slow the progression of already-diagnosed 

AD and does not effectively treat or prevent the 

disease if treatment begins in later life. However, 

questions remain as to whether some forms 

of estrogen might help if started somewhat 

earlier than the older ages already tested. 

These questions are now being investigated. 

NINDS-supported investigators at the Mayo 

Clinic College of Medicine have found that 

women who had one or both ovaries removed 

before menopause had an increased risk of cognitive impairment or dementia compared with a 

control population (Rocca et al., 2007). They 

also found that ovary removal at a young age 

(younger than age 45) further increased the risk of 

dementia. This risk was significantly diminished 

when women were treated with estrogen until 

the age of natural menopause. These findings 

underscore the relationship between estrogen and 

cognition and open additional avenues of investigation into estrogen’s full therapeutic effects.

Ñ

26 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 27
6 Exploring All Possibilities 

to Improve AD Diagnosis

AD pathology begins to develop long before 

clinical symptoms are readily apparent. However, 

AD diagnosis currently depends on assessing 

a range of cognitive and behavioral changes 

over time. Finding a way to detect the disease 

at the earliest point possible will allow clinicians to treat it as early as possible. One active 

area of AD research focuses on the development of sensitive screening instruments and 

neuropsychological tests to diagnose cognitive 

decline, aMCI, and AD as early as possible. 

Ambitious efforts also are underway to find 

new ways to measure changes in the structure and 

function of the brain and in other biomarkers, 

such as substances in cerebrospinal fluid (CSF), 

and blood. These biomarkers may hint at 

pathological changes that occur before clinical 

signs of aMCI or AD are evident or when they 

emerge. Improvements in brain imaging and 

new findings about CSF biomarkers are already 

yielding results. For example, the development 

of PiB has enabled scientists to visualize betaamyloid plaques in the living brain (see page 

19 for more on PiB). Advances like this may 

lead to very early diagnosis of AD and will 

help researchers and clinicians develop new 

treatments and monitor their effectiveness. 

Clinicians need practical tools to help them 

differentiate memory and thinking changes 

that come with normal aging from those 

of very mild dementia. Existing cognitive 

tests may not be sensitive enough to detect 

problems in highly educated individuals or 

may falsely identify people with poor lifelong 

cognitive functioning as demented. Other tests 

are not practical for general clinical use. 

Ñ

Investigators at the Washington University 

School of Medicine developed a new tool, the 

AD8, which takes advantage of the knowledge 

that family and close friends have of a person 

with memory or cognitive problems. The 

AD8 asks about changes in the way a person 

remembers or acts in various circumstances, such 

as forgetting appointments or having difficulty 

handling financial affairs. Since the AD8 was 

published in 2005, two studies (Galvin et al., 

2006; Galvin et al., 2007) have demonstrated 

its reliability, validity, and flexibility. The tool 

can be used in face-to-face encounters or over 

the phone, and it can even be completed by a 

person with memory problems. These studies 

suggest that a tool like the AD8 could improve 

dementia diagnoses in primary care, where 

dementia often goes undetected. This tool also 

may be valuable in screening for clinical trials, 

community surveys, and epidemiologic studies.

Because AD is a progressive disease, investigators want to be able to predict the progression 

from normal cognition to aMCI to AD. Two 

studies used neuropsychological tests to explore 

this area. The first study, by scientists at Harvard 

Medical School, indicated that the risk of 

progressing from normal cognition to aMCI was 

greater in individuals with relatively low scores 

on tests of episodic memory, and that the risk of 

progressing from aMCI to AD was increased in 

people with relatively low scores on tests of both 

episodic memory and executive function (Blacker 

et al., 2007). In the second study, conducted 

within the Alzheimer’s Disease Cooperative Study 

(ADCS), investigators found that the best predictor of progression from aMCI to AD over the 

36-month trial period was a combination of four 

easily administered cognitive measures (Fleisher 

et al., 2007) (see page 32 for more about the 

ADCS). The results of these studies not only may 

help in diagnosing aMCI and AD, but also will 

be important in evaluating the efficacy of interventions to modify the progression of the disease. 

Ñ

Investigators at the Washington University 

School of Medicine assessed the ability of 

biomarkers found in CSF to identify people 

who were likely to get AD (as defined by 

clinical criteria or the presence of beta-amyloid 

as shown with PiB on PET scans) within a 

group of nondemented older people (Fagan et 

al., 2007). Previous work has shown that levels 

of beta-amyloid in CSF typically decrease in 

AD, but that levels of tau in CSF increase. This 

study had three main findings. First, people 

with very mild symptoms of AD showed the 

same CSF biomarker profile as those in more 

advanced stages of the disease, suggesting that 

it may be possible to diagnose AD accurately at 

an early stage. Second, combining CSF amyloid 

measures with amyloid imaging in the PET scans 

revealed that low CSF amyloid levels can predict 

whether individuals have amyloid deposits in 

the brain, regardless of the presence of dementia. 

Information about CSF amyloid levels may 

therefore be a useful preclinical biomarker of 

AD. Third, the investigators found the same 

relative ratio of beta-amyloid and tau as earlier 

studies have done, suggesting that this ratio may 

have promise as a biomarker to predict future 

dementia in cognitively normal older adults.

In recent years, scientists have become 

increasingly interested in the role of inflammation in AD. A research team at Beth Israel 

Deaconess Medical Center, Harvard Medical 

School, and Boston University conducted a 

study, supported by NIA, NHLBI, and NINDS, 

to assess whether the presence of markers of 

inflammation was linked to increased risk of 

AD (Tan et al., 2007). From 1990 to 1994, 

the researchers measured several inflammatory 

markers, including CRP, IL-6, IL-1, TNF-α, 

and IL-1-RA, in 691 original participants in the 

Framingham Study. The participants were then 

followed for 7 years to see whether they developed 

AD. Participants who produced the most of two 

markers, IL-1 or TNF-α, showed a greater risk 

Ñ

Ñ

of developing AD than those who produced 

the least. The researchers concluded that high 

levels of some inflammatory substances may be 

an early risk marker of AD, and that inflammation may play a role in AD development.

Although people with aMCI are at high risk 

of developing AD, not everyone with aMCI 

goes on to develop AD. Researchers want to 

develop diagnostic markers that can predict 

whether someone with aMCI will eventually 

progress to AD. Two studies, by researchers 

at the University of California Davis and at 

Columbia University, used MRIs to monitor the 

extent of atrophy (shrinkage) in critical brain 

regions (DeCarli et al., 2007; Devanand et al., 

2007). Both studies showed that atrophy of 

structures in the brain’s medial temporal lobe, 

including the hippocampus and entorhinal 

cortex (two structures heavily damaged by 

AD), could predict development of AD and the 

rate of progression from aMCI to AD. These 

results suggest that combining MRI tests with 

standard clinical tests during an evaluation of 

aMCI could help to identify which people with 

this condition are more likely to develop AD.

Ñ

28 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 29
To advance this area of diagnosis research, 

NIA and other Federal and private-sector 

organizations launched the AD Neuroimaging 

Initiative (ADNI) in 2004. ADNI is following 

about 200 cognitively healthy individuals and 

400 people with aMCI for 3 years, and 200 

people with early AD for 2 years. Early results 

from ADNI suggest that the data generated will 

help in evaluating disease progression and may 

reduce the time and expense of clinical trials by 

improving methods and developing uniform 

standards for imaging and biomarker analysis. 

ADNI also has created a publicly accessible 

database containing thousands of MRI and PET 

scan brain images as well as clinical data that 

is available to qualified researchers worldwide. 

More than 300 researchers already have accessed 

ADNI data and images, and ADNI has inspired 

similar efforts in Europe, Japan, and Australia. 

In another relatively new area of AD diagnosis 

research, investigators are examining other 

types of physical changes that may hint at AD, 

opening the door to other potential tools to help 

clinicians diagnose AD early and accurately.

Researchers have studied changes in visual 

abilities as a possible early indicator of aMCI or 

AD. Scientists at the Boston University School of 

Medicine found that, in some people with AD, 

tangles and plaques develop early in the disease 

process in the back of the cortex, a brain region 

deeply involved in visual processing (McKee et 

al., 2006). A second group of scientists, at the 

University of Rochester Medical Center, used 

several highly sensitive tests to examine how 

old age and AD affect various visual abilities, 

including “optic flow”—the way in which the 

surrounding environment appears to flow past 

Ñ

as a person moves through space (Mapstone et 

al., 2006). The investigators found that in visual 

ability tests, healthy older people did better 

with optic flow than with other abilities, while 

those with AD had trouble with optic flow as 

well as other visual abilities. These findings may 

help create objective diagnostic tests for AD. 

Investigators at the Rush Alzheimer’s Disease 

Center in Chicago assessed whether impaired 

odor identification is related to increased risk 

of aMCI (Wilson et al., 2007). Consistent with 

previous studies, they found that, compared with 

people whose ability to identify odors was intact, 

those with impaired odor identification had a 

lower cognitive level and more rapid decline in 

certain cognitive abilities. More importantly, the 

researchers found that a person’s score on the 

odor identification test was able to predict 

the development of aMCI. 

Another study, conducted at the Rush 

University Medical Center, found that a higher 

level of frailty at the beginning of the study and a 

more rapid increase in frailty were both associated 

with an increased risk of developing AD

(Buchman et al., 2007).

7 Making the Most of Translational Research 

Translational research is a multidisciplinary 

effort that creates a two-way bridge between 

basic science studies and clinical research. In 

essence, it allows valuable knowledge from the 

laboratory to be applied as quickly as possible 

to potential new tests or interventions in the 

clinical setting. Translational research also offers 

an important opportunity for collaboration 

between scientists concerned with the cellular, 

molecular, and pathologic dimensions of disease 

and clinicians who focus on treating people. 

NIA is engaged in a variety of translational 

initiatives to expand possible avenues for AD 

Ñ

Ñ

therapies and, eventually, the number of clinical 

trials to test them in humans. For example, NIA 

is working to stimulate the discovery, development, and preclinical testing of various novel 

compounds to prevent and treat the cognitive 

impairment and behavioral symptoms of aMCI, 

AD, and age-related cognitive impairment. 

The Institute’s Translational Research Initiative 

aims to increase the number of submissions of 

investigational new drug (IND) applications 

to the FDA, so that more clinical trials to test 

promising therapies can be started and can use 

a wider variety of intervention strategies.

In addition, NIA supports toxicology services 

for investigators and small companies that have a 

potentially viable drug for AD treatment but lack 

the resources to begin the formal drug toxicology 

testing process needed for an IND. Two program 

announcements have been issued for this initiative—

one for early-phase drug discovery grants and 

another for later-phase cooperative agreement drug 

development grants. The first cooperative agreement awards under the drug development initiative 

were made in 2006. The first annual Investigators 

Meeting for Translational Research was held in 

September 2007. 

 To date, NIA has funded more than 60 

translational research grants, using various 

funding mechanisms, directed at discovery or 

development of multiple therapeutic targets,

including: 

Anti-amyloid approaches. Researchers are 

conducting studies to identify compounds that 

can activate alpha-secretase (an enzyme that 

cleaves APP in such a way that harmful betaamyloid is not formed), liver X-receptor activators, 

and different metal-complexing strategies. 

Anti-tau approaches. Researchers are discovering 

and developing drugs that stabilize microtubules, 

the structures that guide nutrients and other molecules from the cell body to the end of the axon. 

Cognitive enhancer approaches. Researchers 

are working to discover novel nonsteroidal 

●

●

●

anti-inflammatory drugs (NSAIDs), nitric oxide/

cyclic guanosine monophosphate/CREB pathway 

enhancers, and dual gamma-aminobutyric acid 

and nicotinic receptor activators, all of which are 

designed to enhance cognitive processes. 

In other funded translational research projects, 

investigators are developing a range of novel compounds and drugs that may eventually be used 

to treat AD. 

Investigators at the Center for Drug Discovery 

and Chemical Biology at Northwestern University 

have developed an innovative, safe, and watersoluble small molecule that prevents increases in 

selected injury-induced inflammatory proteins 

in the brain (Hu et al., 2007). The development 

of this molecule presents scientists with an 

opportunity to explore new approaches for 

potentially useful AD therapies. 

Because of the associations between diabetes 

and AD, scientists are looking at whether a 

class of drugs that includes rosiglitazone, 

which increase a person’s sensitivity to insulin, 

may be useful in treating AD. However, the 

mechanisms underlying the potential beneficial 

effects of rosiglitazone in AD remain unclear. 

A study conducted by scientists at Creighton 

University Medical Center, in Omaha, Nebraska, 

demonstrates that rosiglitazone lessens learning 

and memory deficits in a transgenic mouse 

model of AD (Pederson et al., 2006). The drug’s 

beneficial effects on learning and memory were 

associated with reduced accumulation of 

beta-amyloid in the brain. The data also suggest that these effects may be mediated by the 

glucocorticoid-lowering actions of the drug. A 

clinical trial is underway to test rosiglitazone’s 

effects on attention and memory in adults with 

aMCI (see page 26 for a description of this trial).

Ñ

Ñ

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8 Supporting the Gold 

Standard: AD Clinical Trials

Clinical trials, which compare a potential new 

treatment with a standard treatment or a placebo, 

are the only way to prove whether a drug or other 

type of treatment is effective. These complex, 

expensive studies can involve hundreds or even 

thousands of people and often are conducted 

over a long period of time. Some clinical trials 

focus on prevention strategies to help people 

reduce the risk of developing AD in the future. 

Others focus on AD treatment strategies to 

preserve cognitive function for as long as 

possible, to alleviate behavioral or psychiatric 

problems, or to slow disease progression. 

For example, a recently funded clinical trial 

will use gene therapy to treat AD with nerve 

growth factor (NGF). NGF potently prevents the 

death and augments the function of cholinergic 

neurons (neurons that produce the neurotransmitter acetylcholine) in regions of the brain that 

are extensively damaged in AD. This trial builds 

on the results of an earlier clinical trial of NGF 

gene delivery in early-stage AD patients. That 

earlier trial demonstrated robust growth responses 

of cholinergic neurons to NGF in the AD brain, 

possible effects on cognition over 22 months, and 

a significant increase in cortical glucose uptake 

in participants who received the treatment.

The new 24-month, multi-center clinical trial 

of NGF gene delivery in AD will test whether this 

therapy slows the clinical progression of AD by 

preventing cell loss and augmenting neuronal 

function. Fifty people with mild to moderate AD 

will be randomly assigned to receive two injections 

of NGF in their brains or to have a control surgical

procedure with no injections of NGF. University 

of California San Diego investigators will conduct 

cognitive, clinical, and safety assessments as well

as PET scans. If the preliminary results are 

favorable, participants who received the control 

surgery will be offered active NGF treatment. 

Federal and non-Federal agencies and 

organizations are currently supporting more than 

50 AD-relevant clinical trials (see the table on 

pages 34 to 36 that lists trials funded by NIA). 

A cornerstone of NIA’s efforts in clinical-trials 

research is the Alzheimer’s Disease Cooperative 

Study (ADCS), launched in 1991. This 

consortium of about 70 sites focuses on trials of 

compounds developed by individual investigators or small companies with limited resources 

for clinical trials. A recent focus has been on 

partnering with larger companies. In addition to 

testing new compounds, the ADCS is developing 

new methods for conducting dementia trials.

The most recent round of ADCS trials, funded 

in October 2006, explore a variety of topics:

Docosahexaenoic acid (DHA). This ongoing 

trial is examining whether treatment with DHA, 

an omega-3 fatty acid found in fish, will slow 

cognitive decline in AD. Observational studies 

associate high fish consumption with reduced risk 

of AD in people, and studies in mouse models 

of AD show that dietary DHA reduces levels 

of beta-amyloid in the brain, oxidative damage 

associated with beta-amyloid, and neurotoxicity. 

Immune globulin intravenous (IGIV). 

Interest in passive AD immunization strategies is 

growing (see page 13 for more on this research). 

IGIV, a blood product that is administered intravenously, contains naturally occurring antibodies 

against beta-amyloid. Preliminary studies have 

shown that it may improve cognition. Other 

research has demonstrated that IGIV increased 

levels of anti-beta-amyloid antibodies in plasma 

and promoted clearance of beta-amyloid from 

CSF. The new ADCS trial will study whether 

IGIV is useful clinically for treating AD. 

Lithium. The biological activity of lithium, 

shown in animal studies to block abnormal changes 

in tau, has created interest in this drug as a novel 

treatment for AD. ADCS investigators plan to 

undertake a pilot biomarker trial to see whether 

●

●

●

lithium can lower tau and beta-amyloid levels in 

CSF and be safely tolerated in older AD patients. 

Home-based assessment. In this ADCS 

trial, conducted in people age 75 and older, 

researchers at 26 sites will test three home-based 

methods to assess cognition, daily functioning, 

mood, and other factors. The first involves 

the use of a computer “kiosk” that combines a 

touch-screen monitor with a telephone handset 

to answer a series of questions. The second is an 

interactive voice-response system that prompts 

a person to answer questions out loud. The 

third involves filling out and mailing in paper 

forms and completing a validated cognitive 

assessment by telephone. Each of these methods 

will be compared with traditional in-person 

methods. The findings will provide information about the use of home-based assessments 

to reduce the cost and increase the feasibility 

of participation in long-term clinical trials. 

Resveratrol. Investigators conducting this trial 

will evaluate the impact of resveratrol treatment 

on AD biomarkers and clinical outcomes in 

people with mild to moderate AD. Resveratrol, 

a molecule that promotes neuronal survival, has 

been shown to prevent learning impairments 

in mouse models of neurodegenerative diseases. 

Participants in this trial will receive either 

resveratrol or a placebo in addition to existing 

FDA-approved AD medical management. 

●

●

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Trial Name Principal Investigator Intervention Population

 Hormones

Alzheimer’s Disease: Potential 

Benefit of Isoflavones

Carey Gleason Novasoy (soy isoflavones–phytoestrogens) People with AD

ELITE (Early Versus Late 

Intervention with Estradiol)

Howard Hodis 17β-estradiol Healthy early (less than 

6 years) and late (10 

years+) menopausal 

women 

KEEPS-CA (Kronos Early 

Estrogen Prevention Study—

Cognitive and Affective Study)‡

Sanjay Asthana Oral conjugated equine 

estrogen (CEE, or 

Premarin®) and transdermal 17β-estradiol 

Healthy perimenopausal women, 

ages 42-58

Raloxifene for Women with 

Alzheimer’s Disease

Victor Henderson Raloxifene (selective 

estrogen receptor 

modulator, or SERM)

Older women with AD 

SMART (Somatotrophics, 

Memory, and Aging Research 

Trial)

Michael Vitiello Growth hormone 

releasing hormone 

(GHRH)

People with aMCI and 

healthy people, ages 

55-80

Testosterone Supplementation 

in Men with MCI

Monique Cherrier Testosterone Older men with aMCI 

and low testosterone 

Diabetes

Glucose Regulation and Memory 

in Alzheimer’s Disease

Suzanne Craft Diet, triglyceride emulsion, rosiglitazonePeople with AD (all 

studies), age-matched 

healthy older adults (diet) 

Metformin in Amnestic MCI Jose Luchsinger Metformin Overweight people 

with aMCI

RECALL (Rosiglitazone Effects on 

Cognition for Adults in Later Life)

Suzanne Craft Rosiglitazone People with aMCI

SNIFF 120 (Study of Insulin to 

Fight Forgetfulness, 120 Days)

Suzanne Craft Intranasal insulin People with aMCI 

and AD

Diabetes and Exercise

POEM (Pioglitazone or Exercise 

to Treat Mild Cognitive 

Impairment)

Robert Schwartz Pioglitazone, endurance 

exercise training

Older people with 

aMCI and metabolic syndrome 

Exercise

Exercise and Cognitive Aging Robert Krikorian Aerobic exercise People with aMCI 

Exercise and Health Promotion 

for MCI: A Controlled Trial

Linda Teri Two exercise programs People with aMCI and 

cognitively intact older 

people

NIA-Funded Clinical Trials for the Prevention and Treatment 

of AD, aMCI, and Cognitive Decline*

Trial Name Principal Investigator Intervention Population

 Antioxidants

Alzheimer’s Disease in Down 

Syndrome: Antioxidant Trial

Ira Lott Vitamins E and C, 

alpha-lipoic acid

People ages 40+ with 

Down syndrome and AD

Antioxidant Trial** Douglas Galasko Vitamins E and C, alpha 

lipoic acid, coenzyme Q

People with AD

GEM (Ginkgo Evaluation of 

Memory)†

Steven DeKosky Ginkgo biloba People ages 75+

PREADVISE (Prevention of 

Alzheimer’s Disease by Vitamin 

E and Selenium)‡

William Markesbery Vitamin E, selenium, 

Vitamin E + selenium

Men ages 60-90 

participating in 

SELECT

Vitamin E in Aging Persons with 

Down Syndrome

Arthur Dalton Vitamin E People ages 50+ with 

Down syndrome, at high 

risk of developing AD

 Cardiovascular

ACCORD-MIND (Action to 

Control Cardiovascular Risk 

in Diabetes—Memory in 

Diabetes)‡

Lenore Launer Intensive glucose, blood 

pressure, and lipid 

management

People ages 40-79 

with type 2 diabetes

CLASP (Cholesterol Lowering 

Agent to Slow Progression of 

Alzheimer’s Disease Study)**

Mary Sano Simvastatin People with AD

ESPRIT (Evaluating 

Simvastatin’s Potential Role in 

Therapy)

Cynthia Carlsson Simvastatin People ages 35-69 at 

high risk of AD (family 

history) 

 Omega-3 Fatty Acids

AREDS2 (Age-Related Eye 

Disease Study 2)†

Emily Chew and John 

Paul SanGiovanni

Macular xanthophylls 

(lutein and zeaxanthin) 

and/or omega-3 fatty 

acids (DHA and EPA)

People ages 50-85 with 

age-related macular 

degeneration (AMD)

DHA (Docosahexaenoic Acid), 

an Omega-3 Fatty Acid, in 

Slowing the Progression of 

Alzheimer’s Disease**

Joseph Quinn DHA People with AD

 Passive Immunization

Immune Globulin Intravenous 

(IGIV) for Treatment of 

Alzheimer’s Disease**

Norman Relkin IGIV People with AD

Continued on next page

34 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 35
9Helping Caregivers Cope

Caring for a person with AD presents unique 

challenges, and considerable research has explored 

the physical, emotional, and mental stresses on 

AD caregivers. This area of research is an important component of NIH’s overall AD research 

effort. Investigators supported by NIA, NIMH, 

and NINR continue to study ways to understand 

better the effects of caring for a loved one with 

AD and to find improved methods of caregiving.

An emerging body of findings suggests that 

chronic stress has a negative impact on the 

immune system. A study by NIA intramural 

investigators compared the immune cells of AD 

caregivers and a control group. They found strong 

evidence that the chronic stress of caregiving 

adversely affected the caregivers’ immune function 

(Damjanovic et al., 2007). In addition, the investigators found negative effects on the regulatory 

processes controlling cell replication and aging. 

An ultimate goal of AD research is to find ways 

to reduce stress and burden on caregivers. For example, 

agitation, psychosis, and disruptive behaviors can be 

difficult for caregivers to cope with. Investigators are 

exploring a diverse array of treatment approaches to 

help both the person with AD and the caregiver by 

reducing psychiatric and behavioral symptoms through 

drug therapies and other means.

A clinical trial is examining whether the 

drug valproate can delay or prevent agitation 

and psychosis in people with mild to moderate 

AD. Researchers also are interested in seeing 

whether valproate’s possible neuroprotective 

properties can slow the rate of cognitive decline. 

A clinical trial supported by NIMH has tested 

the safety and effectiveness of two medications to 

treat psychosis in people with dementia (Pollock 

et al., 2007). One group received the antidepressant citalopram and the other group received the 

second-generation, or “atypical,” antipsychotic 

Ñ

Ñ

Ñ

risperidone, which is commonly prescribed to treat 

agitation and psychosis in people with dementia. 

The trial, conducted by scientists at the Rotman 

Research Institute in Toronto, found that the number 

of patients who completed the treatment protocol 

did not differ between the two groups. Symptoms 

declined similarly in the two groups. However, the 

group treated with risperidone reported more side 

effects than the citalopram group. This trial suggests 

that antidepressants may be better tolerated and 

possibly safer than atypical antipsychotic medications 

in people with dementia. Before definitive conclusions 

can be made about treating behavioral and psychotic 

symptoms in people with AD, these findings need 

to be replicated in a larger group with a broader array 

of antidepressants and antipsychotic medications.

Managing agitation is a major priority in 

AD treatment, but nondrug options have limited 

effectiveness. Several drug options have been 

explored, but findings for anticonvulsants, antipsychotics, and cholinesterase inhibitors have been 

disappointing or associated with questionable riskto-benefit ratios. Better drug options are needed. 

Selective serotonin reuptake inhibitors show promise 

as a treatment for agitation in AD, based on 

evidence of a link between agitation and serotonin 

abnormalities in people with AD. Also encouraging 

are preliminary clinical data from a single-site trial 

in which the selective serotonin reuptake inhibitor 

citalopram proved superior to perphenazine (an antipsychotic drug) and a placebo. NIA and NIMH 

recently co-funded the Citalopram for Agitation in 

AD (CITAD) trial, which brings together investigators who have collaborated successfully in the 

ongoing Depression in Alzheimer’s Disease Study 

(DIADS-2) and the completed Clinical 

Antipsychotic Trials of Intervention Effectiveness–

Alzheimer’s Disease (CATIE–AD). CITAD will 

examine the efficacy and safety of citalopram as a 

treatment for clinically significant agitation in 200 

Ñ

Trial Name Principal Investigator Intervention Population

Exercise and Cognitive Training

SHARP-P (Seniors Health and 

Activity Research Program 

Pilot)

Mark Espeland Physical activity, 

cognitive training

People at risk of aMCI, 

ages 70-85

Other Trials

Antipsychotic Discontinuation in 

Alzheimer’s Disease

Dev Devanand Risperidone People with AD

CITAD (Citalopram for Agitation 

in AD)

Constantine Lyketsos Citalopram People with AD

Huperzine A in Alzheimer’s 

Disease

Paul Aisen Huperzine A People with AD

Phase II Trial of AAV-NGF Gene 

Delivery in Alzheimer’s Disease

Paul Aisen Nerve growth factor (NGF) 

gene delivery 

People with AD 

Pilot Phase II Study to Evaluate 

the Impact of Biomarkers of 

Resveratrol Treatment**

R. Scott Turner Resveratrol People with AD

Transdermal Nicotine Treatment 

of MCI

Paul Newhouse Nicotine patch People with aMCI 

TREA (Treatment Routes for 

Exploring Agitation)

Jiska Cohen-Mansfield TREA, a systematic 

approach to individualizing nonpharmacological interventions for 

people with dementia 

Nursing home 

residents with 

AD/dementia

Trial to Assess Biomarker 

Outcomes, Safety, and 

Tolerability of Lithium 

Carbonate**

Pierre Tariot Lithium People with AD

VALID (Valproate in Dementia)** Pierre Tariot Valproate People with AD 

NIA-Funded Clinical Trials ( c o n t i n u e d )

NOTE: For information about new and currently recruiting trials, visit www.nia.nih.gov/Alzheimers/

ResearchInformation/ClinicalTrials or www.ClinicalTrials.gov.

* As of October 2008.

** Alzheimer’s Disease Cooperative Study trial.

† NIA co-funded trials: GEM (National Center for Complementary and Alternative Medicine, lead institute); AREDS2 (National Eye Institute, 

lead institute).

‡ NIA-funded add-on trials: PREADVISE (add-on to National Cancer Institute’s SELECT trial); ACCORD-MIND (add-on to NHLBI’s ACCORD 

trial); KEEPS-CA (add-on to Kronos Longevity Research Institute’s KEEPS trial).

36 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 37
people with AD. The 9-week, eight-site trial also 

will investigate pharmacogenomic, genetic, and 

clinical predictors of response to citalopram therapy 

in outpatients and nursing-home and assisted-living 

residents. Using state-of-the-art clinical ratings and 

novel weekly caregiver telephone ratings, CITAD 

will examine the effects of citalopram on agitation, 

other neuropsychiatric symptoms, cognition, 

quality of life, and daily functioning. 

NIMH-supported investigators at the University of 

Southern California and the Veterans Administration 

Connecticut Health Care System conducted a costbenefit analysis of the use of atypical antipsychotic 

drugs to treat psychosis, agitation, and aggression 

in people with AD (Rosenheck et al., 2007). Using 

data from a large clinical trial on the effectiveness 

of treatment with antipsychotics, the investigators 

found that in some instances treatment with these 

drugs was no more effective than “watchful waiting,” 

which involves general medical management and 

support but no treatment with antipsychotics. They 

also found that drug treatment was significantly 

more expensive. 

Other investigators are exploring ways of 

managing psychiatric and behavioral problems 

through interventions that do not involve drugs.

An NIMH-supported study by researchers at 

Pennsylvania State University showed that adult 

day care services may help caregivers manage some 

behavioral and psychological symptoms, such as 

nighttime sleep disturbances (Femia et al., 2007). 

Scientists at the Research Institute on Aging 

of the Charles E. Smith Life Communities in 

Rockville, Maryland, developed and tested an algorithm for nursing home staff to use in providing 

individualized, non-drug interventions for residents 

with agitation (Cohen-Mansfield et al., 2007). 

The algorithm helped staff identify the type of 

Ñ

Ñ

Ñ

agitation and the particular needs of the resident. 

It also helped them design responses that reduced 

the resident’s agitation in a way that matched his 

or her cognitive, physical, and sensory abilities 

and lifelong habits and roles. Use of the algorithm 

significantly decreased agitation in the test group, 

and use of the individualized interventions 

increased residents’ pleasure and interest in life.

NINR supported a clinical trial, conducted 

by a research team at Rush University Medical 

Center, to test a skill-building intervention with 

a group of caregivers who were coping with 

severe behavioral symptoms in a family member 

with AD (Farran et al., 2007). Compared with a 

basic information and support intervention, the 

skill-building program more effectively reduced 

caregivers’ emotional distress. The reduced stress 

level persisted during an 18-month period.

NINR-supported researchers at the University 

of California San Francisco conducted a clinical 

trial that tested the effect of 1 hour of daily light 

therapy on the frequency and severity of disruptive 

behaviors in nursing home residents with AD 

(Dowling et al., 2007). Residents who received 

light therapy showed a small but statistically 

significant reduction in levels of agitation, 

depression, eating disorders, and abnormal 

motor behavior.

Many people who develop AD must eventually 

move from their homes or an assisted living facility 

to a nursing home where they can receive more 

intensive care. A major clinical goal is to maximize 

the person’s ability to function independently and 

to continue living in the least restrictive environment 

for as long as possible. A number of researchers 

are investigating ways to achieve this goal. 

Placing a loved one in a nursing home may 

relieve some of the burden of caregiving but does 

not necessarily reduce caregiver stress or emotional 

distress. Investigators at New York University School 

of Medicine tested the effects of an enhanced counseling and support program on nursing home 

Ñ

Ñ

Ñ

One of the best ways caregivers can help themselves is 

to become well informed about AD 

and to learn strategies for effective and flexible caregiving. The 

Alzheimer’s Disease Education and 

Referral (ADEAR) Center is an NIA 

service that provides the public—

including caregivers, people with 

AD, and health professionals—with 

AD information and resources. 

The ADEAR Center: 

Helping Caregivers Become Informed

ADEAR staff members answer 

telephone, email, and written 

requests and make referrals to 

local and national resources. In 

addition, the ADEAR Center offers 

information and publications for 

families, caregivers, and professionals on diagnosis, treatment, 

patient care, caregiver needs, longterm care, education and training, 

and research related to AD. 

The ADEAR website offers free, online 

publications in English and Spanish, 

email alerts, online Connections 

newsletter subscriptions, an AD 

clinical trials database, the AD 

Library database, and more. 

Alzheimer’s Disease Education 

and Referral (ADEAR) Center 

800-438-4380 (toll-free)

www.nia.nih.gov/Alzheimers

placement and caregiver health (Mittelman et al., 

2006; Mittelman et al., 2007). This program for 

AD caregivers consisted of six sessions of individual 

and family counseling, support group participation, 

and on-demand telephone counseling. Participants 

showed less of a decline in how they rated their 

own health over time than did other caregivers 

who did not participate in the program. Participants 

also were able to delay placing their loved ones in 

nursing homes by about 18 months. Researchers 

attributed these results to improved caregiver wellbeing, which was demonstrated by greater tolerance 

for the loved one’s memory and behavior problems, 

improved satisfaction with the support provided by 

family and friends, and fewer symptoms of depression. 

In an ongoing NIMH-supported study, investigators at Johns Hopkins University followed 

198 people for 18 months to estimate the 

association between dementia and the length of 

time in an assisted living facility before death or 

placement in a nursing home (Lyketsos et al., 2007). 

Preliminary findings showed that the length of 

residence for people with dementia was, on average, 

209 days shorter than for other residents. The 

researchers found that a lack of treatment for 

dementia and the presence of other serious medical 

conditions predicted the shorter stays of residents 

with dementia. To a lesser extent, impairments 

in mobility and limited participation in activities 

at the assisted living facility also played a role.

Ñ

38 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 39
AD and to identify people at the greatest 

genetic risk of cognitive decline or AD. 

Understanding Disease Progression 

Findings from the Alzheimer’s Disease Neuroimaging Initiative reported over the next few years 

will likely indicate which combinations of clinical, 

neuropsychological, imaging, and biomarker tests 

best predict who will progress from aMCI to 

AD and how this progression occurs. Improved 

knowledge in this area also will help accelerate 

and refine the conduct of clinical trials. A 

greater understanding of disease progression will 

eventually allow clinicians to start therapies much 

earlier in the disease process, when changes in 

the brain associated with AD are still minimal. 

Making the Most of Translational 

Research and Clinical Trials

Translational initiatives and federally supported 

clinical trials should provide important new 

approaches for AD prevention and treatment 

because they will ensure that researchers with 

promising therapies have opportunities to 

develop them. Many compounds that test 

well in animal models and that have a sound 

theoretical basis fail in clinical trials because of 

safety or efficacy problems. It is important to 

understand why this happens. Many different 

therapeutic targets must be pursued besides 

the obvious ones of beta-amyloid and tau.

By funding clinical trials, NIA also hopes 

to provide the necessary foundation for 

private industry or NIH to support “follow-up” 

clinical studies of the most promising leads.

Cultivating Research 

Infrastructure and Resources

NIH will continue to provide the framework 

through which investigators can conduct 

interdisciplinary and collaborative AD research. 

For example, in 1999, NIA established the 

National Alzheimer’s Coordinating Center 

(NACC) (www.alz.washington.edu) so that 

data on healthy people and patients from the 

Alzheimer’s Disease Centers could be pooled 

and shared. By 2005, information on more 

than 75,000 Alzheimer’s Disease Center study 

participants and neuropathologic data on more 

than 9,000 brains from autopsied participants 

had been collected. Much of this material is 

After 30 years of intensive study, momentum  in AD research is palpable. Today, scientists 

are increasingly optimistic about the promise of 

AD research. Initially, they focused on defining 

the major characteristics of the disease, its course, 

and aspects of its etiology. Since then, they have 

built an enormous base of knowledge about AD 

and the many factors that contribute to the damage 

it causes to the brain and body. Researchers are 

now beginning to apply that knowledge to treatment and prevention strategies. To sustain this 

momentum, NIH is moving ahead on a number 

of fronts, described in the sections below.

Improving Basic Understanding

Research must continue to refine the mechanistic 

understanding of AD. Though we understand 

much about the disease, important gaps in 

knowledge remain. Basic research is central to 

the search for effective new therapies because it 

allows scientists to understand better the normal 

biology of the aging brain and what goes wrong 

in a disease like AD. One promising area of 

basic research involves studies to learn more 

about the molecular basis of cognition and how 

it changes with age. Another area of interest 

is how the brain adapts to injury. Researchers 

know that the brain is a remarkably adaptive 

organ, and they want to learn more about the 

components that are important to adaptability, 

the molecular basis of cognitive reserve, and 

whether strategies to build cognitive reserve can 

prevent or delay the negative consequences of 

AD pathology. The Cognitive Aging Summit 

sponsored by NIA and the McKnight Brain 

Research Foundation in Washington, D.C., in 

October 2007 helped identify topics in these areas 

of basic research that are most likely to bear fruit.

Identifying Genetic 

Causes and Risk Factors

With the establishment of the Alzheimer’s Disease 

Genetics Initiative and the Alzheimer’s Disease 

Genetics Consortium, scientists hope to learn 

considerably more about the major risk-factor 

genes for late-onset AD and for cognitive decline. 

Understanding more about the genetics of cognitive decline and AD will shed light on how much 

genetic risk they share. Knowing the risk-factor 

genes will help to pinpoint new pathways 

that contribute to the early development of 

 for the

Outlook

Future

40 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E | 41
available for research by qualified scientists. 

In 2006, NACC launched the Alzheimer’s 

Disease Center Uniform Data Set (UDS), a system 

that improved upon a previous data collection 

system by standardizing data collection across 

research sites. Initially developed to gather information on healthy participants and those with 

aMCI and early AD, the UDS has since expanded 

to collect data on participants with frontotemporal 

dementia, Lewy body dementia, and vascular 

dementia. More than 15,000 individuals are now 

being evaluated using the UDS. Data are available 

to qualified researchers through NACC.

Workshops and meetings, such as the AD 

Planning Meeting held in October 2006 and the 

Cognitive Aging Summit held in October 2007, 

provide an opportunity for experts to gather and 

assess basic, translational, and clinical research 

efforts and to assess future strategies for maximizing public investment. 

NIA and other NIH Institutes and Centers 

that conduct research on AD collaborate with many 

others to push the boundaries of our knowledge 

about this disease. For example, the Institutes work 

with the Foundation for the National Institutes of 

Health to identify appropriate funding opportunities 

with private industry. NIA collaborates with private 

foundations, such as the Alzheimer’s Association 

and the Alzheimer’s Drug Discovery Foundation, 

on specific initiatives. NIA has worked with both 

organizations on the Alzheimer’s Disease Neuroimaging Initiative through the Foundation for the 

National Institutes of Health and with the AD 

Discovery Foundation on translational research 

projects. NIH scientists also work with colleagues 

at the Centers for Disease Control and Prevention, 

the FDA, and other Federal agencies to ensure 

expeditious efforts to find the best combinations 

of behavioral and drug interventions for AD and 

age-related cognitive decline.

Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, 

Aggarwal NT, Shah RC, Wilson RS. Neuropathology 

of older persons without cognitive impairment from 

two community-based studies. Neurology 2006a;

66(12):1837-1844.

Bennett DA, Schneider JA, Tang Y, Arnold SE, Wilson RS. 

The effect of social networks on the relation between 

Alzheimer’s disease pathology and level of cognitive 

function in old people: a longitudinal cohort study. 

Lancet Neurology 2006b;5(5):406-412.

Blacker D, Lee H, Muzikansky A, Martin EC, Tanzi R, 

McArdle JJ, Moss M, Albert M. Neuropsychological 

measures in normal individuals that predict subsequent 

cognitive decline. Archives of Neurology 2007;64(6):862-871.

Blackwell T, Yaffe K, Ancoli-Israel S, Schneider JL, 

Cauley JA, Hillier TA, Fink HA, Stone KL. Poor sleep 

is associated with impaired cognitive function in older 

women: the study of osteoporotic fractures. The Journals 

of Gerontology. Series A, Biological Sciences and Medical 

Sciences 2006;61(4):405-410.

Buchman AS, Boyle PA, Wilson RS, Tang Y, Bennett DA. 

Frailty is associated with incident Alzheimer’s disease and 

cognitive decline in the elderly. Psychosomatic Medicine 

2007;69(5):483-489. 

Caselli RJ, Reiman EM, Locke DE, Hutton ML, 

Hentz JG, Hoffman-Snyder C, Woodruff BK, 

Alexander GE, Osborne D. Cognitive domain decline 

in healthy apolipoprotein E epsilon4 homozygotes 

before the diagnosis of mild cognitive impairment. 

Archives of Neurology 2007;64(9):1306-1311.

Cohen E, Bieschke J, Perciavalle RM, Kelly JW, Dillin A. 

Opposing activities protect against age-onset proteotoxicity. 

Science 2006;313(5793):1604-1610.

Cohen-Mansfield J, Libin A, Marx M. Nonpharmacological 

treatment of agitation: a controlled trial of systematic 

individualized intervention. The Journals of Gerontology.

Series A, Biological Sciences and Medical Sciences 2007;

62(8):908-916.

Colcombe SJ, Erickson KI, Scalf PE, Kim JS, Prakash R, 

McAuley E, Elavsky S, Marquez DX, Hu L, Kramer AF. 

Aerobic exercise training increases brain volume in aging 

humans. The Journals of Gerontology. Series A, Biological 

Sciences and Medical Sciences 2006;61(11):1166-1170.

Damjanovic AK, Yang Y, Glaser R, Kiecolt-Glaser JK, 

Nguyen H, Laskowski B, Zou Y, Beversdorf DQ, Weng N. 

Accelerated telomere erosion is associated with a declining 

immune function of caregivers of Alzheimer’s disease 

patients. Journal of Immunology 2007;179(6):4249-4254.

DeCarli C, Frisoni GB, Clark CM, Harvey D, 

Grundman M, Petersen RC, Thal LJ, Jin S, Jack CR, 

Scheltens P, Alzheimer’s Disease Cooperative Study 

Group. Qualitative estimates of medial temporal lobe 

atrophy as a predictor of progression from mild 

cognitive impairment to dementia. Archives of Neurology 

2007;64(1):108-115.

Devanand DP, Pradhaban G, Liu X, Khandji A, 

De Santi S, Segal S, Rusinek H, Pelton GH, Honig LS, 

Mayeux R, Stern Y, Tabert MH, de Leon MJ. Hippocampal 

and entorhinal atrophy in mild cognitive impairment: 

prediction of Alzheimer disease. Neurology 2007;

68(11):828-836.

Dowling GA, Graf CL, Hubbard EM, Luxenberg JS. 

Light treatment for neuropsychiatric behaviors in 

Alzheimer’s disease. Western Journal of Nursing 

Research 2007;29(8):961-975.

Erickson KI, Colcombe SJ, Wadhwa R, Bherer L, 

Peterson MS, Scalf PE, Kim JS, Alvarado M, Kramer AF. 

Training-induced functional activation changes in dualtask processing: an fMRI study. Cerebral Cortex

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Evans DA, Scherr PA, Cook NR, Albert MS, 

Funkenstein HH, Smith LA, Hebert LE, Wetle TT, 

Branch LG, Chown M, Hennekens CH, Taylor JO. 

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r e f e r e n c e s

Conclusion

The theme of the 2007 Alzheimer’s Disease Progress 

Report is “Discovery and Hope.” It’s a fitting 

description for, during 2007, AD researchers 

continued to push the boundaries of knowledge 

through discoveries on a number of fronts—basic 

and genetics research on the fundamental nature 

of the disease and its relationship to normal aging; 

epidemiologic studies on associations between 

AD risk, lifestyle factors, and chronic disease; 

studies on early physiologic changes that signal 

AD development; translational research studies; 

clinical trials; and studies to help caregivers. 

These discoveries are fostering hope that our 

richer understanding of the disease (and our growing 

appreciation of its complexities) are leading to the 

development of improved techniques for diagnosing 

AD early and accurately and to the identification 

of a range of potential therapeutic targets. There 

is also new hope for the development of effective 

strategies for helping caregivers cope and even for 

the identification of possible factors that may 

reduce AD risk.

At the same time, we cannot forget that AD 

remains an urgent health problem for our Nation 

and that we still have much to learn about the 

disease. Our task is to build on these recent 

discoveries through continued support for multidisciplinary, collaborative AD research so that its 

potential will become a reality for millions of 

older adults.

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Image Credits

The National Institute on Aging extends sincere appreciation to Brian J. Bacskai, Ph.D., and 

his optical imaging lab at Massachusetts General Hospital/Harvard Medical School for providing the 

Alzheimer’s disease microscopy images shown throughout the 2007 Progress Report on Alzheimer’s Disease. 

Images from Dr. Bacskai’s lab are shown on the front, inside front, inside back, and back covers; 

title page; and pages 2, 4, 5, 6, 10, 11, 14, 18, 21, 26, 29, 32, 40, 41, and 42.

Thanks also to the following individuals and institutions for other images included in this report: 

Pascale N. Lacor, Ph.D., Northwestern University – Front cover (center)

Getty Images – Front cover (left)

University of Pittsburgh – Inside front cover (top)

Stacy Jannis, Jannis Productions – Pages 9, 17

Corbis – Back cover (left)

Laboratory of Neuro Imaging, University of California Los Angeles – Back cover (top right)

48 | 2OO7 P R O G R E S S R E P O R T on A L Z H E I M E R ’ S D I S E A S E
U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Aging

NIH Publication Number: 08-6430

November 2008