Discoveries,

Insights

New

New

U.S. Department of 

Health and Human Services

PROGRESS REPORT ON 

ALZHEIMER’S DISEASE

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National Institute on Aging

National Institutes of Health

U.S. Department of Health and Human Services

P R O G R E SS R E P O R T O N A L Z H E I M E R ’ S 
Advances Research

at NIH

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The National Institute on Aging (NIA), part of the Federal Government’s National Institutes of Health (NIH), has primary 

responsibility for basic 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 2004-2005 Progress Report on 

Alzheimer’s Disease summarizes recent AD research conducted or supported by NIA and 

other components of NIH, including:

■ National Cancer Institute (pages 43, 62)

■ National Center for Complementary and Alternative Medicine (page 62)

■ National Center for Research Resources (pages 14, 16)

■ National Heart, Lung, and Blood Institute (page 50)

■ National Institute of Biomedical Imaging and Bioengineering (page 26)

■ National Institute of Child Health and Human Development (pages 18, 31, 44)

■ National Institute of Diabetes and Digestive and Kidney Diseases (pages 25, 52)

■ National Institute of Environmental Health Sciences (page 24)

■ National Institute of Mental Health (pages 16, 25, 39, 41, 47, 58, 62, 63, 67, 71)

■ National Institute of Neurological Disorders and Stroke (pages 23, 24, 30, 31, 38, 67, 71)

■ National Institute of Nursing Research (pages 62, 63, 64, 65, 67)

AD research efforts also are supported by the National Institute of Arthritis and 

Musculoskeletal and Skin Diseases, National Institute on Alcohol Abuse and Alcoholism, 

National Institute of Dental and Craniofacial Research, National Institute of Deafness 

and Other Communication Disorders, National Human Genome Research Institute, 

National Center on Minority Health and Health Disparities, John E. Fogarty International 

Center, the NIH Office of the Director, and the NIH Roadmap Initiative.
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Contents

PART 1 Introduction 1

 1 The Impact of AD

 2 AD: An Urgent National 

Research Priority

PART 2 Knowledge and 

Understanding Continue to Grow 5

6 What are the Main Characteristics 

of the Brain in AD?

 6 Amyloid Plaques

 7 Neurofibrillary Tangles 

 7 Loss of Connections Between 

Cells and Cell Death

7 What Causes AD? 

9 What Do We Know About 

Diagnosing AD? 

11 How Is AD Treated Today?

PART 3 2004-2005 AD 

Research Advances: New 

Discoveries, New Insights 13

13 What Happens in the Brain to Cause 

the Transformation From Healthy 

Aging to AD?

 14 New Thinking About Cognitive 

Reserve

 18 Mild Cognitive Impairment

 20 The Journey from Healthy Aging 

to AD: Damage in the Brain

 38 The Brain Protects Itself

40 Can Certain Factors Protect 

Against or Increase Risk of AD?

 41 New Discoveries About 

AD Genetics

 47 Lifestyle and Dietary Patterns

 49 Vascular Disease and AD

 52 Diabetes and AD

55 What Can be Done to Slow 

the Progression of AD or Lessen 

its Effects?

 57 Clinical Trials 

 62 Improving Support for 

Caregivers

PART 4 Outlook for the 

Future 67

67 Providing a Planning Framework

 67 Supporting a Collaborative 

Research Infrastructure

68 Facilitating Innovation for the Future

PART 5 References 73
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Alzheimer’s disease is an age-related and irreversible brain disorder that develops 

over a period of years. Initially, people experience memory loss and confusion. These 

symptoms gradually lead to behavior and 

personality changes, a decline in other cognitive abilities (such as thinking, decisionmaking, and language skills), and ultimately 

to a severe loss of mental function. These 

losses are related to the breakdown of the 

connections between certain nerve cells in 

the brain and the eventual death of many 

of these cells. AD is one of a group of disorders, termed dementias, that are characterized by cognitive and behavioral problems. 

The course of this disease varies from 

person to person, as does the rate of decline. 

In most people with AD, symptoms first 

appear after age 65. Although the risk of 

developing AD increases with age, AD and 

dementia symptoms are not part of normal 

aging. AD and other dementing disorders 

are caused by diseases that affect the brain. 

The Impact of AD 

AD is the most common cause of 

dementia among people age 65 and older. 

It presents a major health problem for 

the United States because of its enormous impact on individuals, families, the 

health care system, and society as a whole. 

Scientists estimate that 4.5 million people 

currently have the disease, and the prevalence (the number of people with the disease 

at any one time) doubles for every 5-year 

age group beyond age 65. 

These numbers are significant now 

and will become even more so in the 

future because of dramatic increases in 

life expectancy since the turn of the century. Researchers estimate that by 2050, 

13.2 million Americans will have AD if 

current population trends continue and 

no preventive treatments become available 

(Hebert et al., 2003). Approximately 

4 million Americans are age 85 years or 

older, and this age group is one of the fastest 

growing segments of the population. It is 

also the group with the highest risk of AD. 

The U.S. Census Bureau estimates that 

nearly 19 million Americans will be age 85 

and older by the year 2050. Some experts 

who study population trends suggest that 

the number could be even greater. This 

trend is not only apparent in the U.S. but 

also worldwide. As more and more people 

live longer, the number of people affected 

by diseases of aging, including AD, will 

continue to grow. For example, one study 

showed that nearly half of all people age 

85 and older have some form of dementia 

(Evans et al., 1989). 

These prevalence trends translate 

into a huge impact on people with the 

disease, their families and friends, and 

caregivers. Slightly more than half of 

AD patients receive care at home, while 

the remainder are cared for in a variety 

of health care institutions. During 

their years of AD caregiving, spouses, 

relatives, and friends experience emotional, physical, and financial stress. 

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They watch their loved ones become more 

and more forgetful, frustrated, and confused. Eventually, the person with AD 

does not even recognize his or her nearest 

and dearest relatives and friends. 

Caregivers—most of whom are 

women—must juggle child care, 

jobs, and other responsibilities 

along with caring for relatives 

with AD who cannot function on their own. As the 

disease runs its course and 

the abilities of people with 

AD steadily decline, family 

members face difficult decisions about the long-term care 

of their loved ones. Frequently, 

they turn to assisted living facilities, 

then nursing homes, for care and support. The number of caregivers—and their 

needs—can be expected to escalate rapidly 

as the population ages and as the number 

of people with AD grows. 

The increasing number of people with 

AD and the costs associated with the disease mean that AD puts a heavy economic 

burden on society. The annual national 

direct and indirect costs of caring for AD 

patients have been estimated to be as much 

as $100 billion (Ernst and Hay, 1994; Ernst 

et al., 1997; Huang et al., 1988).

AD: An Urgent National 

Research Priority 

Given our aging population, the 

magnitude of AD as a national health 

problem is steadily increasing. This makes 

the disease an urgent research priority. 

Interventions that could delay the onset 

of AD would have an enormous positive 

public health impact because they would 

greatly reduce the number of people with 

the disease. This in turn would reduce the 

personal and financial costs associated with 

caring for them. 

AD research supported by the Federal 

Government is divided into three broad, 

overlapping areas: causes/risk factors, diagnosis, and treatment/caregiving. Research 

into the basic biology of the aging nervous 

system is critical to understanding what 

goes wrong in the brain of a person with 

AD. Understanding how nerve cells lose 

their ability to function and communicate with each other and the reasons why 

some nerve cells die and others do not is a 

central part of scientific efforts to discover 

what causes AD. Assessing factors that 

may increase or decrease risk of developing AD is a growing component of 

this research effort.

Many researchers are also looking for 

better ways to diagnose AD in the early 

stages and to identify the earliest brain 

changes that could indicate that the AD 

process has begun. Investigators are striving 

to identify markers of early dementia, 

improve ways to test patient function, 

improve neuroimaging technologies, 

and enhance case-finding and sampling 

methods for population studies.

Other researchers are working to 

discover and develop interventions that 

may help treat symptoms, slow the progress 

of AD, delay its onset, or even prevent the 

disease. Many of these interventions are 

now being tested in clinical trials. Finally, 

scientists and many health care professionals 

are seeking better ways to help people with 

AD and their caregivers cope with the 
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decline in mental and physical abilities and 

the problem behaviors that accompany 

the disease. 

An important complement to the 

National Institutes of Health’s (NIH) 

research initiatives in AD are its efforts to 

educate and inform people with AD, their 

families, the public, providers, and others 

interested in the disease. The National 

Institute on Aging (NIA) Alzheimer’s

Disease Education and 

Referral (ADEAR) Center 

(www.alzheimers.org) provides a variety of materials 

on AD, including information about caregiving, diagnosis and treatment, and 

results of research findings.

For example, NIA’s booklet for the general public, Alzheimer’s Disease: Unraveling 

the Mystery, uses illustrations and text to 

explain AD, highlight ongoing research, 

and describe efforts to support caregivers 

of people with AD. Another booklet 

for lay audiences, Genes, Lifestyles, and 

Crossword Puzzles: Can Alzheimer’s Disease 

be Prevented?, summarizes the latest research 

findings on AD risk factors and potential prevention strategies. The ADEAR 

Center also maintains a database of AD 

clinical trials, develops recommended 

reading lists, and provides referrals to 

local AD resources. In addition, all of 

the NIA-supported Alzheimer’s Disease 

Centers (ADCs) have education and 

information programs that work locally 

to disseminate information about AD. 

We now know a lot about AD—what 

it is, who can get it, how it develops, and 

what course it follows. We also have made 

significant progress in the critical area of 

early diagnosis and have some promising 

leads on possible treatments. All of the 

research has deepened our understanding 

of this devastating disease. It also has 

expanded our knowledge about other 

late-life neurodegenerative diseases, brain 

function in healthy older people, and ways 

in which to minimize normal age-related 

cognitive decline. 

The 2004-2005 Progress Report on 

Alzheimer’s Disease describes this important 

research effort. It begins with a description 

of our current knowledge about AD. This 

provides the foundation for the next section, 

which highlights recent studies supported 

by NIA and other NIH Institutes. The 

report closes with a section called “Outlook 

for the Future,” which takes a look at some 

exciting AD research initiatives. These 

initiatives are designed to accelerate laboratory and clinical research and collaboration across the Federal Government and in 

association with the private sector so that 

research findings can be translated expeditiously into real advances for patients, 

families, and caregivers. 

Interventions that could delay the onset 

of AD would have an enormous positive public 

health impact.
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Part 2

 K N O W L E D G E A N D U N D E R S T A N D I N G 

 C O N T I N U E T O G R O W

I

n healthy aging, nerve cells (neurons) in 

the brain are not lost in large numbers. 

In AD, however, many nerve cells stop 

functioning, lose connections with other 

nerve cells, and die. At first, AD destroys 

neurons in parts of the brain that control 

memory, including the entorhinal cortex 

and the hippocampus (structures in the 

brain that help form and store shortterm memories) and related structures. As 

nerve cells in these structures stop working 

properly, short-term memory fails, and a 

person’s ability to do easy and familiar tasks 

can begin to decline. AD later attacks the 

cerebral cortex (the outer layer of neurons in 

the brain), particularly the areas responsible 

for language and reasoning. At this point, 

AD begins to take away language skills 

and changes a person’s ability to make 

judgments. Personality changes also may 

occur. Emotional outbursts and disturbing 

behaviors, such as wandering, begin to 

happen and can become more frequent as 

the disease progresses. Eventually, many 

other areas of the brain are damaged and the 

person with AD becomes bedridden, helpless, and unresponsive to the outside world.

The brain is essential to our survival. With the help of motor and 

sensory nerves throughout the body, 

it integrates, regulates, initiates, 

and helps control the body’s functions. The brain governs thinking, 

personality, moods, the senses, 

and physical action. We can speak, 

move, remember, and feel emotions 

and physical sensations because of 

the complex interplay of chemical 

and electrical processes that takes 

place in our brains. The brain and 

the rest of the nervous system also 

regulate body functions that happen 

automatically, such as breathing and 

digesting food.

The healthy human brain is made 

up of billions of neurons that share 

information with one another through 

a diverse array of biological and 

chemical signals. A typical neuron 

has a cell body, an axon, and many 

dendrites, all surrounded by a cell 

membrane. The nucleus, which is 

found inside the cell body and contains genes composed of deoxyribonucleic acid (DNA), helps to regulate 

the cell’s activities in response to 

signals from outside and inside the 

cell. The axon, which extends from 

the cell body, transmits messages to 

other neurons, sometimes over very 

long distances. Dendrites, which 

also branch out from the cell body, 

receive messages from axons of 

other nerve cells or from specialized 

sense organs. Axons and dendrites 

collectively are called neurites. 

Neurons are surrounded by glial 

cells, which 

support and 

nourish them. 

Neurons generally communicate with each other 

and with sense organs by producing 

and releasing special chemicals 

called neurotransmitters. As a 

neuron receives messages from the 

dendrites of surrounding cells, an 

electrical charge (nerve impulse) 

builds up within the cell. This 

charge travels down the axon until it 

reaches the end. Here, it triggers the 

release of the neurotransmitters that 

move from the axon across a gap, 

called a synapse, between it and 

the dendrites or cell bodies of other 

neurons. Scientists estimate that 

Structure and Function of the Brain

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(continued on page 6)
What are the Main 

Characteristics of the 

Brain in AD?

The brain in AD has three major characteristics that contribute to the pathology, 

or damage, of the disease. Though scientists 

have known about these characteristics for 

many years, recent research has revealed 

much about their nature and their possible 

roles in the development of AD.

Amyloid Plaques

Plaques are found in the spaces between 

the brain’s nerve cells. They were first discovered by Alois Alzheimer nearly 100 

years ago, in 1906. They consist of largely 

insoluble (cannot be dissolved) deposits 

of a protein peptide, or fragment, called 

beta-amyloid, together with other proteins, 

remnants of neurons, non-nerve cells 

such as microglia (cells that surround and 

digest damaged cells or foreign substances), 

and other glial cells, such as astrocytes 

(see p. 36 for more on these cells). 

Beta-amyloid is snipped, or cleaved, from a 

larger protein called amyloid precursor protein (APP). APP is associated with the cell 

membrane, but its normal function in the 

cell is not yet fully known. In AD, plaques 

develop first in areas of the brain used for 

memory and other cognitive functions.

Most people develop some plaques in 

their brain tissue as they age. However, the 

AD brain has many more plaques in certain 

brain regions. For many years, scientists 

thought that these structures might cause all 

the damage to neurons that is seen in AD. 

However, that concept has evolved considerably in the past few years. Many scientists 

now think that beta-amyloid clusters at an 

earlier stage in the plaque development 

process—called Aβ-derived diffusible 

ligands, or ADDLs (also known as soluble 

oligomers)—may be a major culprit. Many 

also think that plaques are a late-stage attempt 

by the brain to get harmful beta-amyloid 

away from neurons (see p. 20 for more on 

this rapidly developing area of research).

Structure and Function continued

a typical neuron has up to 15,000 

synapses. Neurotransmitters bind to 

specific receptor sites on cell bodies 

and the receiving end of dendrites 

of adjacent nerve cells. In this way, 

signals travel between neurons in 

a fraction of a second. Millions of 

signals continuously flash through 

the brain.

Groups of neurons in the brain 

have specific jobs. For example, 

some neurons are involved in 

thinking, learning, remembering, and 

planning. Others are responsible 

for vision or hearing, regulating the 

body’s biological clock, or managing 

the many other tasks that keep the 

human body functioning.

The survival of neurons in the 

brain depends on the healthy 

functioning of several processes 

all working in harmony. These 

processes are communication, 

metabolism, and repair. The first 

process, communication between 

neurons, depends on the integrity 

of the neuron and its synapses, 

as well as the production of 

neurotransmitters. 

The second process is metabolism, or all the chemical reactions 

that take place in the cell. Some of 

these reactions break down substances, which releases energy. 

Other reactions involve building 

complex substances that the cell 

needs to function out of simple 

“building block” molecules. Efficient 

metabolism requires adequate blood 

circulation to supply the cells with 

oxygen and glucose (a sugar), the 

brain’s major fuel. 

The third process is repair. Unlike 

most other body cells, most neurons 

are already formed at birth. Neurons 

are programmed to live a long 

time—even more than 100 years. In 

an adult, when neurons die because 

of disease or injury, they are usually 

not replaced, although we now know 

that new neurons can be generated 

in several areas of the brain. To prevent their own death, living neurons 

must constantly maintain, repair, 

and remodel themselves. 

Research shows that the damage 

seen in AD involves changes in 

all three of these neuronal processes: communication, metabolism, 

and repair.

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Neurofibrillary Tangles

The second hallmark of AD pathology, 

also found by Alois Alzheimer, consists of 

abnormal collections of twisted protein 

threads found inside nerve cells. The chief 

component of these structures, called neurofibrillary tangles, is a protein called tau. 

Healthy neurons are internally supported 

in part by structures called microtubules, 

which help transport nutrients and other 

cellular components from the body of 

the cell down to the ends of the axon and 

back. 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 tau. As a result of this “phosphorylation” 

process, tau disengages from the microtubules and begins to aggregate with other 

threads of tau. Ultimately, these tau threads 

become enmeshed with one another, 

forming tangles. When this happens, the 

microtubules disintegrate and the neuron’s 

transport system collapses (see p. 29 for 

more on this active area of research). This 

may result first in malfunctions in 

communication between neurons and 

later in the death of the cells.

Loss of Connections Between 

Cells and Cell Death

The third major pathological feature 

of AD, only described in the past 30 years, 

is the gradual loss of connections between 

neurons. This process damages neurons to 

the point that they cannot function properly. Eventually, they die. As the death of 

neurons 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?

In a very few families, about half of 

the children of a parent with AD develop 

the disease in their 30s, 40s, and 50s. These 

people have inherited mutations in one of 

three genes. (See p. 41 for more about the 

genetic aspects of AD.) So, in these “earlyonset” cases, we know exactly what causes AD. 

However, the vast majority of AD 

cases—more than 90 percent—develop in 

people older than 65. This form of AD is 

called “late-onset” AD. We don’t yet completely understand the causes of late-onset 

AD, but they probably include a mix of 

genetic, environmental, and lifestyle factors. The importance of these factors in 

increasing or decreasing the risk of developing the disease may differ from person 

to person.

Healthy brain

AD brain
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The Main Characteristics of AD
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Although many questions about the 

players and steps involved in the causes and 

development of AD have been answered, our 

knowledge still has some surprising gaps. For 

example, we don’t yet fully understand the 

normal function of several key players, such as 

APP. Certainly a better knowledge of normal 

function would give us clues about the causes 

of AD. 

Perhaps the greatest mystery is why AD 

largely strikes the elderly. Why does it take 

30 to 50 years for people to develop signs of 

the disease, even those individuals who are 

born with disease-causing mutations? One 

possibility is that the environment of the 

aging brain is subtly different from that of 

the young brain. We may need to understand 

more about how the brain changes normally 

as we age before we can fully understand AD. 

Scientists supported by the NIH are 

working in laboratories and research institutions all across the U.S. and in other countries 

to assemble the many bits of new knowledge 

that, combined with our existing understanding, will some day explain this complex 

biological puzzle. 

What Do We Know About 

Diagnosing AD?

AD can be diagnosed conclusively only 

by examining in an autopsy the brain of a 

person with dementia to determine whether 

the plaques and tangles in certain brain 

regions are characteristic of AD. However, 

clinicians use a range of tools to diagnose 

“possible AD” (dementia can also be due 

to another condition) or “probable AD” 

(no other cause of dementia can be found) 

in a living person who is having difficulties with memory or other mental functions. 

These tools include a medical history; physical 

exam; tests that measure memory, language 

skills, and other abilities related to changes in 

brain function; and sometimes, brain scans. 
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Much is known about the clinical and 

behavioral characteristics of the disease, 

and this also helps in diagnosing AD. The 

diagnostic process is crucial in identifying 

AD accurately as well as in ruling out 

other conditions that might be causing 

cognitive problems or dementia, such as 

stroke, tumors, Parkinson’s disease (PD), or 

side effects of medications. In many older 

people, AD co-exists with other conditions, 

such as cerebrovascular disease, that may 

also cause dementia.

An early, accurate diagnosis of AD is 

especially important to people with AD 

and their families because it helps them 

plan for the future and pursue care options 

while the person with AD can still take 

part in making decisions. Researchers are 

making progress in developing accurate 

diagnostic tests and techniques. In specialized research facilities, clinicians can now 

diagnose AD with up to 90 percent accuracy. Scientists are working on methods to 

improve the ability of clinicians to make 

accurate diagnoses of AD even earlier in 

the disease process. These advances are providing important insights into the initial 

changes that occur in the brain of a person 

with AD even before a clinical diagnosis is 

made. For example, the newest neuropsychological diagnostic tests for AD, which 

measure delayed recall, verbal fluency, and 

overall cognitive status, are highly accurate in distinguishing between cognitively 

healthy individuals and people with mild 

AD. Various neuroimaging techniques, such 

as positron emission tomography (PET) 

scanning and magnetic resonance imaging 

(MRI) also are being used in the laboratory 

to track early changes that may indicate AD 

(see p. 16 for more on neuroimaging).

Insights from ongoing studies will help 

scientists understand the natural history 

of AD and the ways in which changes in 

A Recent Study 

Sheds Light on 

Length of Survival 

After a Diagnosis 

of AD

After a diagnosis of AD, one of the first 

things that the patient and family want 

to know is how long the person may be 

expected to live with the disease. However, 

until a recent study conducted by scientists 

at the University of Washington and the 

Group Health Cooperative (GHC) in Seattle, 

little information was available on this vitally 

important question (Larson et al., 2004).

During the study period—1987 to 1996—

the GHC, a health maintenance organization, 

had about 23,000 members age 60 and older. 

At the start of the study, 521 members of this 

group were newly diagnosed with AD. Not 

surprisingly, the scientists found that people 

with AD had a significantly decreased survival 

compared with the average life expectancy of 

the U.S. population. For example, men had a 

median survival of 4.2 years from their initial 

diagnosis, and women had a median survival 

of 5.7 years.

Men had poorer survival across all age 

groups compared to women. The life expectancy of 70-year-old men with AD was 

4.4 years compared to 9.3 years for the U.S. 

population. Survival for 70-year-old women 

with AD was shortened to 8.0 years compared to 15.7 years for the U.S. population. 

For men age 85, survival was 3.3 years compared to 4.7 years for the U.S. population. 

Survival for women at age 85 was 3.9 years 

compared to 5.9 years for the U.S. population.

Other factors, including severity of cognitive impairment, decreased ability to carry out 

daily activities, history of falls, and chronic 

illnesses such as diabetes and heart disease, 

further shortened the lifespans of people 

with AD.
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memory and other cognitive functions differ 

in normal aging, AD, and other dementias. 

This knowledge will help clinicians diagnose 

AD earlier and more accurately and also will 

help researchers pinpoint changes that could 

be targets for drug therapy. 

How Is AD Treated Today?

For those who already suffer from the 

effects of AD, the most immediate need is 

for treatments to control cognitive loss as 

well as problem behaviors, such as verbal and 

physical aggression, agitation, wandering, 

depression, sleep disturbances, and delusions. Treatments are needed that work on 

many people with AD, remain effective for a 

long time, ease a broad range of symptoms, 

improve a person’s cognitive function and 

ability to carry out activities of daily living, 

and have no serious side effects. Eventually, 

scientists hope to develop treatments that 

attack earlier AD processes, preventing the 

disease from progressing and damaging 

cognitive function and quality of life.

The U.S. Food and Drug Administration 

(FDA) has approved five medications to 

treat AD symptoms, though only four are 

used today. The first drug to be approved, 

tacrine (Cognex), has been replaced by 

three other drugs—donepezil (Aricept), 

rivastigmine (Exelon), and galantamine 

(Razadyne, previously known as Reminyl). 

These three drugs, which are prescribed 

to treat mild to moderate AD symptoms, 

act by stopping or slowing the action of 

acetylcholinesterase, an enzyme that breaks 

down acetylcholine. Acetylcholine, a neurotransmitter that is critically important in 

the process of forming memories, is used 

by many neurons in the hippocampus and 

cerebral cortex—regions devastated by AD. 

These drugs improve some patients’ abilities to carry out activities of daily living; 

may improve certain thinking, memory, 

or speaking skills; and can help with 

certain behavioral symptoms. However, 

these medications will not stop or reverse 

AD and appear to help patients only for 

months to a few years.

The newest AD medication is memantine (Namenda), which is prescribed to treat 

moderate to severe AD symptoms (Reisberg 

et al., 2003; Tariot et al., 2004). This drug 

appears to work by lowering glutamate 

levels in the brain. Glutamate is another 

neurotransmitter involved in memory function, but high levels may damage neurons. 

Like the cholinesterase inhibitors, memantine will not stop or reverse AD. In addition to these medications, physicians use a 

number of drug and non-drug approaches 

to treat the behavioral and psychiatric problems that occur frequently as AD progresses. 

Helping people with AD live their daily 

lives and maintain their cognitive abilities 

is one of the most important goals of AD 

treatment research. Many investigators are 

working to develop new and better treatments to preserve these critical functions 

for as long as possible. Other investigators 

are working to improve the quality of life 

for people with AD and caregivers through 

research on behavioral management techniques and caregiver skills. 

One of the primary characteristics of 

the NIH AD research effort over the past 

25 years has been support for a wide range 

of studies conducted by a large and multidisciplinary cadre of researchers. All of these 

studies have contributed to the solid base 

of knowledge that exists today. The accelerating pace of discovery in AD research 

continues to expand this base, and it is 

pointing scientists in new and productive 

research directions. It is also helping investigators ask better questions about the issues 

that are still unclear. 
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During the past 2 years, scientists supported by NIH have made advances 

in a number of areas important to AD. This 

section of the Progress Report focuses on 

recent research that has attempted to answer 

three key questions:

 What happens in the brain to cause 

the transformation from healthy aging 

to AD?

 Can certain factors protect against or 

increase the risk of AD?

 What can be done to slow the progression of AD or lessen its effects?

These questions are important because 

they focus on the central issues of AD: 

What occurs during the very first steps of 

the disease process, what might we do to 

prevent AD, and what can be done once 

the disease process has started? They can be 

asked only because of the knowledge that 

has accumulated through past research. 

Answers to these questions are emerging, 

and they hold the key to future prevention, 

treatment, and caregiving strategies.

What Happens in the 

Brain to Cause the 

Transformation From 

Healthy Aging to AD?

As people age, changes occur in all parts 

of the body, including the brain:

 Some neurons shrink, especially large 

ones in areas important to learning, 

memory, planning, and other complex 

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mental activities. This translates into 

some shrinkage of brain volume over 

the course of years, even in healthy 

older people (Resnick et al., 2003).

 Tangles develop inside neurons and 

plaques develop in the spaces between 

neurons.

 Damage by free radicals increases 

(free radicals, also called reactive oxygen 

species, are a kind of molecule that 

reacts easily with other molecules; see 

p. 32 for more on free radicals).

The impact of these changes differs 

among people as they age. Some older 

people may notice only a modest reduction 

in their ability to learn new things, retrieve 

information from memory, and plan and 

make decisions. Their performance on 

complex tasks of attention, learning, and 

memory may decline. However, if given 

enough time, they may ultimately score 

as well on the task as a younger person. 

Other people, however, experience much 

greater declines in these cognitive abilities 

as they grow older. Understanding the 

differences between healthy aging and a 

neurodegenerative process is an important 

key to unlocking the secrets of AD. 

Long ago, before we knew much about 

AD, many people thought that “senile 

dementia” was just a part of aging. Now, 

of course, we know that AD is a distinct 

disease that affects the brain. Several recent 

studies and reviews of the scientific literature have provided some evidence that 

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Part 3

 2 0 0 4 - 2 0 0 5 A D R E S E A R C H A D V A N C E S : 

 N E W D I S C O V E R I E S, N E W I N S I G H T S
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cognitive decline with age and AD are, in 

some respects, separate entities that follow 

different pathways as they evolve. For 

example, an investigator from Washington 

University in St. Louis recently published 

a review of a vast array of data on memory 

and executive function (the cognitive 

abilities involved in planning, organizing, 

and decision-making) in aging and AD 

(Buckner, 2004). The review suggested that 

factors that influence executive function 

more commonly falter with normal aging. 

In contrast, factors that influence long-term 

memory function are more impaired in AD. 

Some of the changes that can take place in 

normal aging may not necessarily be the 

cause of AD. In a more direct assessment of 

this idea, this investigator and colleagues at 

Washington University used MRI to measure volumes of the hippocampal region and 

the white matter region between the two 

hemispheres of the brain in 150 people 

aged 18 to 93 years (Head et al., 2005). 

They found that early-stage AD did not 

make age-associated reductions in the white 

matter region worse. They also found that 

early-stage AD was characterized by significant reductions in hippocampal volume, 

whereas age alone was associated with only 

mild reductions in hippocampal volume. 

These results suggest that AD manifests 

itself early and significantly in the area of 

the brain encompassing the hippocampus, 

whereas normal aging affects the white 

matter connecting the front regions of the 

brain. These frontal white matter reductions 

may underlie the executive function difficulties that are common in normal aging.

Columbia University scientists funded 

by the National Center for Research 

Resources (NCRR) and NIA, in collaboration with researchers at the California 

National Primate Research Center, conducted neuroimaging studies in older monkeys and rats to distinguish the effects of 

healthy aging and AD on the structure of 

the brain (Small et al., 2004). The selection 

of the animals for this study was important 

because neither monkeys nor rats naturally 

develop AD. They found that the brain 

region known as the dentate gyrus (a region 

within the hippocampus) was changed by 

aging in both species. However, AD predominantly affected a different region of 

the hippocampus, thus indicating that some 

processes affecting normal aging and AD 

may be distinct.

New Thinking About 

Cognitive Reserve

Two questions have fascinated investigators for years: 

 Why do some people remain cognitively healthy all their lives while others 

develop dementia?

 Why do some people remain cognitively 

healthy even though examination of 

their brain tissue after death shows significant deposits of plaques and tangles? 

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One possible explanation revolves 

around the concept of “cognitive reserve.” 

Reserve refers to the brain’s ability to 

operate effectively even when function is 

disrupted and to the amount of damage 

that the brain can sustain before the 

damage is clinically apparent. Individual 

variability in reserve may reflect genetic 

differences or differences in life experiences, such as education, occupational 

experience, or leisure activities. 

Lifelong engagement in activities that 

help to build and maintain cognitive reserve 

is generally beneficial to health and may 

even help keep people cognitively healthy 

as they age. A number of research teams 

are looking intensively at these activities. 

For example, new information from the 

Religious Orders Study, a long-term study 

of aging among members of 40 religious 

communities, has revealed that years of 

formal education may modify the relationship between level of cognitive functioning 

and AD pathology (Bennett et al., 2003). 

After comparing participants’ brain tissue 

after their deaths and the results of earlier 

cognitive function tests, study investigators at the Rush University Medical Center 

ADC in Chicago, found that the density 

of plaques in the brain tissue was linked to 

cognitive function. This relationship was 

modified by the number of years of education the person had received, such that 

a person with a higher level of education 

retained a higher level of cognitive function 

even in the presence of AD damage to 

the brain.

In another study, scientists from 

Columbia University periodically tested the 

memory performance of 136 cognitively 

healthy older people over the course of 

5 years (Manly et al., 2003). The scientists accounted for the participants’ age at 

the beginning of the study and their years 

of education. They found that participants with low levels of literacy (a proxy 

for quality of education) had a steeper 

decline in their ability to remember a 

word list immediately after seeing it, 

as well as after a delay, as compared to 

those with a higher literacy level. These 

findings suggest that literacy may be an 

important measure of cognitive reserve, 

or even that literacy itself builds cognitive reserve, protecting against memory 

decline in older people without dementia. 

Rush ADC investigators from the 

Chicago Health and Aging Project (CHAP), 

an epidemiologic study of AD risk factors in a racially diverse urban population, 

looked at the issue of cognitive reserve 

from a slightly different angle (Barnes et 

al., 2004). They wondered whether an 

important life experience, such as the level 
of engagement in social networks of family 

and friends, could be related to changes 

in cognitive function. The 6,102 AfricanAmericans and whites in the study participated in up to three interviews over the 

course of about 5 years. The researchers 

found that more social networks and a 

higher level of social engagement were associated with a higher initial level of cognitive 

function. These factors also were related 

to a reduced rate of cognitive decline over 

time. Additional research is clearly necessary 

to sort out cause and effect. Does increased 

involvement with social networks increase 

cognitive reserve, or are people who later 

develop dementia less involved because they 

are already in the early stages of AD, before 

symptoms are evident?

Findings from recent studies suggest that 

the brain has an inherent ability to cope 

with age- and disease-associated changes. 

Use of Neuroimaging, Biomarkers, and Other Indicators to 

Recent advances continue to 

demonstrate the current and potential 

value of neuroimaging techniques, 

biological markers, and sensitive 

oral and written tests of changes in 

memory, language skills, and cognitive function. These techniques help 

investigators understand the events 

unfolding in specific regions of the 

brain in the very early stages of AD. 

They also can be used to identify 

people who are at risk of AD even 

before they develop the symptoms of 

the disease. They may even become 

a valuable means for assessing the 

effectiveness of potential therapeutic 

strategies. Two recent developments 

demonstrate the growing importance 

of all these efforts to AD research:

NIA has launched a multiyear effort that will combine data 

from serial MRI and PET scans with 

clinical, neuropsychological, and biomarker data to examine how brains 

change as mild cognitive impairment (MCI) and AD progress. See 

p. 18 for more information on MCI 

and p. 68 for more on the NIA AD 

Neuroimaging Initiative.

In September 2004, the Centers 

for Medicare and Medicaid Services 

(CMS) approved Medicare coverage 

for PET scans for some beneficiaries 

whose clinical exams cannot distinguish between possible AD and 

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another cause of dementia. For more 

information on Medicare coverage, 

see www.cms.hhs.gov.

Investigators are using these 

techniques in a variety of ways. For 

example, a recent study attempted 

to develop a more precise diagnostic 

marker for the progression of AD. 

Investigators from the New York 

University School of Medicine used 

serial MRIs in cognitively healthy and 

AD participants to calculate the rate 

of volume loss within the entire brain 

and within the medial temporal lobe, 

the region that is particularly affected 

early in the course of AD (Rusinek et 

al., 2004). The investigators found that 

the rate of atrophy within the medial 

temporal lobe derived from the serial 

MRIs was indeed a useful marker 

because it allowed them to classify the 

two groups of participants correctly 

more than 90 percent of the time.

Researchers from Rush University 

Medical Center in Chicago used 

MRIs to assess the predictive value 

of volume changes on an even more 

detailed level (deToledo-Morrell et 

al., 2004). Twenty-seven participants 

with MCI received an MRI scan at the 

beginning of the study and an annual 

scan for 3 years after that. During that 

time, 10 of the participants developed 

AD. The volumes of two brain structures within the medial temporal lobe 

that are known to be involved very early 

on in the course of AD— the entorhinal 

cortex and the hippocampus—were 

compared to determine which region 

could best differentiate those who 

would convert to AD from those who 

would not. Although changes in both 

regions independently predicted conversion, changes in the entorhinal 

cortex more accurately predicted the 

change to AD. 

Scientists also are developing 

highly sophisticated computer and 

analytic tools to help them understand what neuroimaging observations mean. Investigators from the 

University of California at Los Angeles 

funded by the NCRR and the National 

Institute of Mental Health (NIMH) 

have developed a series of computer 

algorithms that they used to compare 

AD brain images across individuals 

and over time (Thompson et al., 2003). 

These algorithms allowed the scientists to describe more fully the loss of 

neurons that is typical of AD and the 

characteristic manner in which this 

loss spreads through the brain. 

Other investigators are trying to 

discover whether certain substances 

in the blood or cerebrospinal fluid 

(CSF) could reflect early changes 

in the brain associated with AD. 

Understanding these “biomarkers”—

what they are, how they function, 

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It may attempt to compensate for these 

changes through various mechanisms, such 

as the use of alternate brain networks to 

bypass those that are not functioning or the 

use of new cognitive strategies (Buckner, 

2004). A number of scientists are exploring 

these compensatory mechanisms. For 

example, researchers at Columbia University 

examined whether engaging in various intellectual, social, and physical activities, such as 

gardening, reading, traveling, and going to 

the movies, might enhance cognitive reserve 

(Scarmeas et al., 2003). Cognitively healthy 

older people and people with early AD were 

scanned for blood flow in the brain using 

PET. The researchers found that study 

participants with AD who had a higher 

leisure activity score also had prominent deficits in cerebral blood flow, despite being at 

the same level of clinical disease. Those participants who had engaged in more lifestyle 

activities before disease onset were able to 

Define and Understand Early Brain Changes

and how and when their levels 

change—will help investigators 

answer questions about the cause 

and early development of AD and 

may lead one day to the identification 

of targets for treatments to delay or 

prevent the onset of the disease. For 

example, scientists at the University 

of Pennsylvania ADC in Philadelphia 

assessed levels of tau and betaamyloid in the CSF of 106 people with 

dementia, 4 people diagnosed with 

AD but without dementia, and 69 cognitively healthy people (Clark et al., 

2003). The study team found that 

the elevated levels of tau and betaamyloid in the CSF were associated in many participants with AD 

pathology and were helpful in 

distinguishing AD from other 

types of dementia. 

A second biomarker study, conducted at the New York University 

School of Medicine Center for Brain 

Health, used MRIs as well as CSF 

levels of tau to identify the earliest 

clinically detectable evidence for AD 

brain changes in cognitively healthy 

people and those with MCI (de Leon 

et al., 2004). The researchers found 

that levels of one specific form of tau

were highly correlated with reductions 

in hippocampal volume measured 

by MRI, and that using CSF and MRI 

measures together improved their 

ability to distinguish between normal 

cognition and MCI. They also found 

that it was not possible to use the tau

level to measure AD progression, but 

that these changes could be tracked 

with another biomarker, isoprostane. It 

may be that a panel of biomarkers will 

prove to be the most useful for accurate diagnosis and tracking over time.

Finally, recent developments in 

neuropsychological tests are demonstrating their utility as a valuable and 

complementary tool that clinicians 

can use to define and understand 

early changes in AD. For example, 

University of Pittsburgh researchers 

were interested in seeing whether 

individuals who were ultimately diagnosed with AD showed evidence of 

cognitive impairment in the years 

before dementia symptoms began 

(Saxton et al., 2004). The study, part 

of the longstanding Cardiovascular 

Health Study, included 693 people 

living in the community (see p. 50 for 

more AD-related studies from the 

Cardiovascular Health Study). The 

participants completed a series of 

neuropsychological tests in 1991 and 

1992 and then were tested every year 

for the next 8 years. Seventy-two 

people were ultimately diagnosed 

with AD. Of these, 24 were diagnosed 

1.5 to 3.4 years after the initial round 

of testing, 20 were diagnosed 3.5 to 

5 years after testing, and 28 were 

diagnosed 5.1 to 8.1 years after 

testing. The research team found 

that participants who were ultimately 

diagnosed with AD had poorer scores 

on the initial neuropsychological tests 

than did participants who remained 

cognitively healthy. Although individuals who were diagnosed after the 

shortest period of time performed the 

most poorly on the initial tests, cognitive impairment was detected even in 

those who did not develop AD until 

5 to 8 years later. 

NIA researchers have pursued this 

idea even more specifically by comparing the predictive value of scores 

on two different neuropsychological 

tests—the Benton Visual Retention 

Test (BVRT), which measures visual 

memory, and the WAIS-vocabulary 

test, which measures verbal memory 

(Kawas et al., 2003). The study, which 

involved participants in the Baltimore 

Longitudinal Study of Aging, revealed 

that those who scored six or more 

errors on the BVRT had approximately twice the risk of developing 

AD than did subjects with zero to 

five errors. More importantly, BVRT 

results even as many as 15 years 

before AD diagnosis were still predictive. In contrast, scores on the 

vocabulary test were not associated 

with the risk of AD.

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sustain more pathology, as shown by greater 

cerebral blood flow deficits. 

Another approach to understanding 

compensatory mechanisms comes from 

Down syndrome (DS) and AD PET scan 

studies. National Institute of Child 

Health and Human Development 

(NICHD)-funded researchers 

at the University of California 

at Irvine tested a hypothesis 

that dementia starts in the 

same places in the brain 

in both DS and AD and 

progresses through similar 

patterns of change. Data 

from the scans, which track 

glucose use by cells in particular brain regions, allowed 

the researchers to measure and 

compare brain activity in adults with 

DS who did not have dementia, adults 

with AD, and cognitively healthy adults 

(Haier et al., 2003). The researchers found 

that, compared to the healthy adults, both 

those with DS and those with AD exhibited lower brain activity in one particular 

region of the brain (the posterior cingulate). 

However, when the researchers looked at 

another area of the brain—the inferior temporal/entorhinal cortex (the area known to 

be the site of the earliest brain damage in 

AD)—the participants with DS had higher 

brain activity while those with AD had 

lower activity compared to the healthy participants. The researchers believe that those 

with DS were in the very early stages of 

developing dementia and that their elevated 

brain activity levels represent an attempt by 

damaged neurons to work harder to maintain function. They also suggest that this 

compensatory response may eventually fail 

and the brain activity rates decrease, leading 

to degeneration of the neurons and the first 

clinical signs of dementia. 

Understanding that AD is a process 

that develops over many years and is the 

result of many factors creates opportunities 

for early interventions that may prevent 

or delay the onset of the disease. It may 

be that because of the physical properties 

of a person’s brain and his or her genetic 

makeup and life experiences, the person 

is able to tolerate and adapt to a certain 

amount of change and damage that occurs 

to the brain during aging. This tolerance level differs from person to person 

depending on cognitive reserve and other 

factors. At some point in the life of some 

people, the balance may tip in favor of a 

disease process. For others, the balance may 

remain in favor of healthy aging. Learning 

about the earliest developments in the disease process will help researchers understand 

this complex, lifelong balancing act.

Mild Cognitive Impairment

As some people grow older, they develop 

memory problems greater than those 

expected for their age. However, these problems do not necessarily meet all the accepted 

criteria for AD. These people have a condition called mild cognitive impairment. 

Because many, but not all, people with 

MCI progress to AD, scientists debate 

whether MCI is an early stage of AD, an 

entirely distinct condition, or a multifaceted 

condition in which AD is one of several 

potential causes. To help settle this question, scientists hope to learn more about 

the underlying causes and courses of MCI. 

They have defined subtypes of MCI based 

on cause (for example, degenerative, vascular, psychiatric [especially depression], 

and medical), and on which aspects of 

cognition are predominantly affected. 
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The subtype that features memory impairment most prominently is called MCI with 

memory loss, or “amnestic MCI,” and is the 

subtype likely to lead to AD. Individuals 

with other MCI subtypes may have prominent deficits in other cognitive functions, 

such as language skills or visuospatial ability. 

These types of dementia can be caused by 

other degenerative diseases, such as frontotemporal dementia and dementia with 

Lewy bodies, or by other conditions such 

as vascular dementia (Petersen, 2005a).

Being able to describe the essential 

characteristics of MCI is another important step in understanding this condition. 

Investigators at the Alzheimer’s Disease 

Cooperative Study (ADCS; see p. 57 for 

more information) have done just that in a 

recent study (Grundman et al., 2004). The 

research team compared participants with 

amnestic MCI to individuals with AD and 

determined that the people with this type 

of MCI had impaired memory but that 

other elements of cognitive function were 

not affected. The people with amnestic 

MCI achieved test scores between healthy 

people and those with AD on cognitive and 

functional tests. Of the 214 participants 

with this type of MCI who progressed to 

dementia, 212 were classified as having AD 

after 3 years of follow-up (Petersen et al., 

2005b). By so clearly describing this population in terms of the elements and extent 

of cognitive function affected by amnestic 

MCI, the study team has made a major 

contribution to a vital component of AD 

research—clinical trials. Their definition 

of amnestic MCI has already been widely 

used by other research teams working on 

AD treatment strategies.

Using Different 

Kinds of MCI Studies

to Full Advantage

Scientists conduct clinic-based and 

community-based studies of MCI, knowing 

that the goals and the constraints of both 

are different. Clinic-based studies can use 

a greater number and array of assessment 

tools, including specialized imaging techniques, and they can gather rich data on 

potential causes based on expert clinical 

judgment. However, they typically involve 

smaller numbers of highly selected participants who volunteer or are selected for 

the studies. 

Community-based epidemiological studies 

provide valuable complementary information because they involve large numbers of 

participants who exhibit the variety of health 

conditions that are typical of the general 

population. For example, the Monongahela 

Valley Independent Elders Survey (MoVIES) 

study, conducted by a University of Pittsburgh 

School of Medicine team, revealed that the 

prevalence of MCI in this community-based 

sample was 3 to 4 percent among persons 

who were, on average, about 75 years old. 

The study also found that many people with 

MCI did not progress to dementia and some 

even reverted to normal cognitive functioning. 

The researchers concluded that MCI may be 

much more heterogeneous than previously 

thought and suggested that the condition 

represents more than just a precursor to 

AD (Ganguli et al., 2004).

Understanding the multiple, potentially 

overlapping, causes of MCI and its relationship to dementia and AD will require clear, 

reliable definitions and reliable long-term 

data that come from both of these types of 

studies—the community-based studies of 

“regular folks” as well as the carefully controlled studies of selected participants.
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In an effort to understand the effects of 

memory problems on cognitive function, 

researchers have examined what happens 

in specific brain regions of individuals with 

memory complaints when these regions 

are activated during memory tasks. A 

group of investigators from Massachusetts 

General Hospital conducted a type of MRI 

called “functional MRI” (fMRI), which 

measures brain activity, in 32 older individuals with memory complaints who did 

not have dementia (Dickerson et al., 2004). 

Participants performed several cognitive 

tasks during and after the fMRI. Several 

activated regions within the medial temporal lobe of each participant were identified, and the investigators measured the 

degree of activation in those regions during 

the tests. They found that greater activation of the hippocampal regions was correlated with better memory performance. 

They suggest increased activation in people 

with memory complaints could predict 

impending clinical decline. Paradoxically, 

participants who had a greater degree of 

cognitive impairment recruited a larger 

extent of particular portions of the hippocampal region during the successful 

cognitive tasks than did less impaired 

participants. This was also true for those 

whose cognitive abilities declined over 

the 2.5 years of the study. The researchers 

hypothesize that the increased activation of 

these brain regions reflects a compensatory 

response to accumulating neuronal damage 

and is itself a marker of that damage.

The Journey from Healthy Aging 

to AD: Damage in the Brain

Since the earliest days of AD research, 

investigators have focused on the basic 

disease process in the brain—on trying to 

understand exactly what happens in neurons to damage and ultimately kill them. In 

the last several years, scientists have made 

enormous progress in characterizing the 

individual players in this process, describing 

their activities, and determining the exact 

steps in the disease process. These advances 

mean that scientists are increasingly able 

to move away from studies of these players 

in isolation and focus on their complex 

relationships and how their effects on each 

other affect the development of AD. This 

section of the Progress Report describes a 

number of significant advances in this area. 

New Discoveries About Beta-amyloid 

and Plaque Formation 

Recent studies have dramatically 

improved scientists’ understanding of how 

beta-amyloid plaques are formed. These 

Birth 40 60 80 Death

Life Course

AD brain 

changes start 

decades before 

symptoms 

show

Amnestic MCI: 

memory problems; 

other cognitive 

functions OK; 

brain compensates 

for changes

Cognitive 

decline 

accelerates 

after AD 

diagnosis

Total loss of 

independent 

function

Charting the Course of Healthy Aging, MCI, and AD

Healthy Aging Amnestic MCI Clinically Diagnosed AD 
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discoveries have fundamentally changed 

how scientists think about this critical component of AD pathology. 

APP, the starting point for beta-amyloid 

plaques, is one of many proteins associated 

with cell membranes, the lipid barrier that 

encloses the cell. As it is being made inside 

the cell, APP becomes embedded in the 

neuron’s membrane, 4/5 on the outside and 

1/5 on the inside, like a toothpick stuck in 

an orange. While APP is embedded in the 

cell membrane, certain enzymes (proteins 

that cause or speed up 

a chemical reaction) 

cleave it into discrete 

fragments. Several years 

ago, scientists identified 

the enzymes responsible for cleaving APP into these peptides. 

These enzymes are called alpha-secretase 

(α-secretase), beta-secretase (β-secretase), 

and gamma-secretase (γ-secretase). In a 

major breakthrough, scientists then discovered that, depending on which enzyme does 

the cleaving and the segment of APP within 

which the cleaving occurs, APP processing 

can follow one of two pathways that have 

very different consequences (see illustration 

on p. 22). 

In one pathway, alpha-secretase cleaves 

the APP molecule within the portion that 

has the potential to become beta-amyloid. 

Cleaving at this site results in the release 

from the neuron of a fragment called 

sAPPα. This fragment has beneficial properties, such as promoting neuronal growth 

and survival. The remaining APP fragment, 

still tethered in the neuron’s membrane, is 

then cleaved by gamma-secretase at the end 

of the beta-amyloid segment. The smaller 

of the resulting fragments also is released 

into the space outside the neuron, while the 

larger fragment remains within the neuron 

and interacts with factors in the nucleus.

In the second pathway, beta-secretase 

cleaves the APP molecule at one end of 

the beta-amyloid peptide, releasing a fragment called sAPPβfrom the cell. Gammasecretase then cleaves the resulting fragment 

at the other end of the beta-amyloid peptide. Following its cleavage at both ends, 

the beta-amyloid peptide is released into 

the space outside the neuron and begins 

to stick to other peptides of beta-amyloid. 

These small, soluble clumps of two, three, 

four, or even up to a dozen beta-amyloid 

peptides are called ADDLs. The number 

of individual beta-amyloid peptides within 

ADDLs varies, but collectively, they are 

referred to as oligomers. It is likely that 

some oligomers may be cleared from the 

brain. Those that cannot be cleared clump 

together with more beta-amyloid peptides 

and other proteins and cellular material. 

As the process continues, these oligomers 

grow larger, becoming increasingly insoluble entities called protofibrils and fibrils. 

Eventually these entities coalesce into the 

well-known plaques that are characteristic 

of AD. 

Until recently, scientists thought that 

fibrils and plaques were somehow responsible for all the neuronal damage and death 

in AD. Now, new evidence suggests that the 

formation of plaques may actually be a kind 

of clearance mechanism that the brain uses 

to get harmful beta-amyloid clumps away 

from neurons. 

In a major breakthrough, scientists discovered that 

APP processing can follow one of two pathways that 

have very different consequences.
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Two Pathways...Different Outcomes

Gamma-secretase cleaves the 

remaining fragment. The smaller 

portion is released into the 

space outside the neuron; the 

larger stays within the neuron.

Pathway to Harm

Pathway to Healthy Aging

Beta-secretase cleaves APP 

at one end of the beta-amyloid 

peptide; sAPP is released into 

the space outside the neuron.

As it is being made, APP sticks through the 

neuron’s membrane, partly inside and partly 

outside the cell.

Alpha-secretase cleaves the APP 

molecule within the portion that 

would have formed beta-amyloid. 

sAPPα is released into the space 

outside the neuron.

Gamma-secretase cleaves 

APP at the other end of the 

beta-amyloid peptide, releasing 

it into the space outside the 

neuron. The other fragment 

stays within the neuron.
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Researchers also are increasingly convinced that oligomers that are not cleared 

from the brain and that do not become 

part of a plaque may be one of the neurondamaging culprits. A research team at 

Northwestern University has even suggested 

how oligomers damage neurons and cause the 

memory loss that features so prominently in 

AD (Cleary et al., 2005; Lacor et al., 2004). 

Working with cell cultures and tissue extracts 

taken from AD and rat brains, the scientists 

found that some oligomers attach themselves 

to the synapses located on neurites (the structures that branch out from the cell body; 

see the Structure and Function of the Brain 

sidebar on p. 5). When this happens, the synapses are not able to function properly and 

therefore cannot receive messages from other 

neurons. Unable to communicate, the neuron 

ultimately ceases to function and dies. As this 

destructive process accelerates, essential cognitive operations, such as memory formation 

and retrieval, are disrupted. 

University of California at San Francisco 

investigators funded by the National Institute 

of Neurological Disorders and Stroke 

(NINDS), NIA, and other research institutions are contributing to this understanding 

through their studies of an enzyme called 

fyn kinase, which is thought to increase the 

susceptibility of neurons to beta-amyloid toxicity. In their studies with transgenic mice, 

the investigators found that fyn kinases were 

necessary for the toxic effects of beta-amyloid 

on neuronal synapses and contributed to premature death in the mice, but they were not 

involved in all elements of the pathologic 

process in neurons (Chin et al., 2004).

This expanding knowledge about the 

stages of plaque formation and the toxicity 

of molecules formed at each stage is giving 

scientists new therapeutic targets. For 

example, because toxic forms of beta-amyloid 

build up most rapidly when they are at high 

Single beta-amyloid peptides clump into soluble oligomers. Some oligomers attach to neurites, disrupting synapse function. Some oligomers clump together with other 

cellular material, forming increasingly insoluble fibrils. 

Eventually this clumping process leads to the insoluble 

plaques that are found in abundance in AD.

Key Questions Remain

Even though scientists have deciphered 

the steps in the APP cleaving process, they are 

still working to answer three key questions: 

 Why is one pathway taken rather than 

the other in any single cleaving of APP? 

 Why, in some people, is one pathway 

consistently favored over the other through 

the course of many years? 

 What is the relative toxicity of oligomers, 

fibrils, and plaques? 

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concentrations in the brain, one strategy is 

to investigate whether high levels of betaamyloid in the brain might be partly due 

to how rapidly these molecules are removed 

from brain tissue into the blood stream 

through the blood-brain barrier. Several 

groups are trying to understand which 

receptors on the surface of cells at the 

blood-brain barrier are responsible for this 

transport and whether their ability to move 

beta-amyloid in and out of the brain might 

be related to AD pathology. 

One research team based at the 

University of Rochester Medical Center 

is working on receptors that remove betaamyloid from the brain (Deane et al., 

2004). A receptor called low-density lipoprotein receptor-related protein (LRP) was 

previously found to be primarily responsible for this task. The new studies show 

that LRP binds to beta-amyloid at the 

blood-brain barrier. Interestingly, LRP’s 

efficiency in clearing beta-amyloid from 

the brain into the blood was greatest for 

the most soluble form of normal betaamyloid. In contrast, mutated forms (such 

as one found in a Dutch family where 

mutated beta-amyloid accumulated around 

blood vessels) and less soluble forms of 

normal beta-amyloid were cleared from 

the brain much less rapidly. However, at 

high concentrations, all forms of betaamyloid directly caused an increased rate 

of LRP breakdown, reducing the ability of 

LRP to clear beta-amyloid from the brain. 

Together, these results indicate that preserving LRP activity at the blood-brain 

barrier may be an important component 

of strategies to remove beta-amyloid from 

the brain. 

A receptor called p75NTR also is coming 

under scientific scrutiny. Among other 

actions, p75NTR makes many kinds of neurons more susceptible to beta-amyloid. 

In a recent study funded by NINDS and 

other organizations, a research team from 

the University of Rochester studied the 

effects of beta amyloid on p75NTR levels 

in cell cultures of human neurons. They 

expected that increasing p75NTR would 

make the neurons more susceptible to betaamyloid. Instead, they found that exposure 

to beta-amyloid increased p75NTR activity in 

the neurons and that the increased activity 

actually protected the cells, even when 

cells were exposed to levels of beta-amyloid 

2,500 times higher than those usually found 

in people with AD (Zhang et al., 2003). 

These findings open the door to future 

studies to examine the possibility that activating the p75NTR receptor may be a useful 

strategy for treating AD in humans.

Scientists funded by the National 

Institute of Environmental Health Sciences, 

NIA, and the Wisconsin Distinguished 

Rath Graduate Fellowship in Medicine 

have investigated another protein that 

may be protective because it binds betaamyloid (Stein et al., 2004). This research 

team, from the University of Wisconsin at 

Madison, studied why transgenic mice that 

had defective genes from people with earlyonset AD inserted into their DNA had high 

levels of beta-amyloid deposits but did not 

exhibit any neurodegenerative symptoms. 

Further investigations led the research team 

to discover that these mice were producing 

high levels of transthyretin, a carrier of the 

thyroid hormone thryroxine. When the 

mice were given antibodies that prevented 

transthyretin from interacting with the 

beta-amyloid protein, the mice showed 

an increased level of brain cell death. Cell 

culture studies of human brain cells treated 
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with transthyretin and beta-amyloid showed 

minimal amounts of cell death while betaamyloid alone caused significant cell death. 

These studies indicated that transthyretin 

can block the progression of AD in this 

mouse model by inhibiting the effects of 

beta-amyloid protein. Although we do not 

yet know whether transthyretin protects 

against beta-amyloid in humans, this discovery suggests that it may be possible to 

develop a drug that increases the production 

of transthyretin and thus protects people at 

risk of AD, possibly including those who 

are at higher genetic risk of developing the 

disease. The findings also may improve 

the detection of environmental agents that 

may play a role in the development of AD 

by allowing scientists to determine which 

of these agents upsets the balance between 

transthyretin and beta-amyloid proteins.

Avenues of beta-amyloid research 

involving new pathways are proving to be 

rich ground for discovery. The possibility 

that blocking the production of betaamyloid in the brain might prevent the 

development of AD is one such avenue. 

NIMH- and NIA-funded scientists at the 

Howard Hughes Medical Institute and the 

University of Pennsylvania built on previous 

research suggesting that an enzyme called 

glycogen synthase kinase-3 alpha (GSK-3α) 

may be crucial to the development of AD 

because inhibiting the action of GSK-3α 

also inhibits the formation of beta-amyloid 

plaques and neurofibrillary tangles. In the 

new study, the investigators examined the 

potential of the mood-stabilizing medication lithium to inhibit GSK-3α and minimize the biological changes leading to AD 

(Phiel et al., 2003). The researchers first 

showed that lithium inhibited GSK-3α in 

cultured cells, reducing the production of 

beta-amyloid. Then, they demonstrated that 

administering therapeutic doses of lithium 

to transgenic mice markedly reduced the 

accumulation of beta-amyloid in the mouse 

brains. These results appear promising 

and are opening new lines of investigation 

about the association of lithium and AD. 

Building a Better 

Structural Model for 

Beta-amyloid

Researchers at the National Institute of 

Diabetes and Digestive and Kidney Diseases 

(NIDDK) have used the latest in sophisticated 

microscopes and solid-state nuclear MRI 

technology to construct a molecular model 

of a beta-amyloid fibril (Antzutkin et al., 2002; 

Antzutkin et al., 2003; Petkova et al., 2004). 

This model has provided many insights into 

the molecular interactions that drive fibril formation. For example, beta-amyloid peptides 

of slightly different lengths appear to have the 

same physical structure even though one is 

associated with AD and the other is not. The 

researchers speculate that the difference in 

solubility and the speed of fibril formation, 

rather than the difference in structure, are 

responsible for the difference in toxicity. 

The researchers also found that a specific 

segment of the full length beta-amyloid protein associated with early-onset AD mutations 

has a loop or bend in it. This structural feature 

may have some importance in the plaque formation process. 

These studies point up the complexity of 

beta-amyloid and the importance of understanding its structure and the interactions of 

its various parts. Expanding knowledge in this 

area may reveal much about the mechanisms 

underlying the development of AD. 
For example, it may be useful to investigate whether patients who have taken 

lithium for bipolar disorder show a lower 

incidence of AD. However, even if lithium 

does prove to be useful as an AD intervention, its known side effects, such as nausea, 

fatigue, and hand tremor, particularly in 

older patients, may require the development 

of new agents that provide the therapeutic 

effects without the negative side effects. 

New Discoveries About Presenilin 

At the same time that researchers are 

making new discoveries about beta-amyloid 

oligomers, they are gaining insight into 

another crucial AD player—presenilin. 

Presenilin is an essential component of the 

gamma-secretase enzyme responsible for 

cleaving APP to form beta-amyloid. Certain 

mutations in the presenilin genes (PS1 

and PS2) cause the most common type of 

familial early-onset AD (FAD). Most of the 

research on the effect of presenilin mutations on AD has focused on their effects on 

the gamma-secretase enzyme complex. 

Gamma-secretase is an example of an 

enzyme whose biological activity depends 

on several proteins working together in a 

complex. To understand how this important enzyme functions, we need to know 

what other proteins it contains besides 

presenilin. Knowing the additional protein components will allow us to answer 

important questions about how it works, 

Building a Better Mouse Model for AD...

and Better Imaging Equipment to See AD Pathology

Research in animals has always 

been a vital part of understanding 

any disease process, including AD, 

and mice and rats have been the 

mainstay of animal research for 

decades. Researchers have recently 

developed better small animal 

models for AD along with highly 

sophisticated imaging systems to 

look at brain changes. 

University of California at Irvine 

researchers recently developed 

an entirely new breed of mice that 

exhibit the hallmarks of AD as they 

age (Oddo et al., 2003). These mice 

contain two mutated genes that 

cause early-onset AD and a mutated 

tau gene that causes another form of 

dementia. Using these “triple transgenic” mice, the scientists were able 

to demonstrate, for the first time, a 

chronology of cellular and functional 

impairments consistent with those 

seen in AD. They found that disruption 

of normal synaptic functions and the 

presence of abnormal beta-amyloid 

in the spaces between neurons preceded the formation of plaques and 

tangles. This transgenic mouse model 

holds great promise as a means to 

understand the pathologic process in 

AD more completely and as a tool for 

testing future diagnostic and therapeutic strategies.

In complementary research, two 

teams of investigators funded by 

the National Institute of Biomedical 

Imaging and Bioengineering have 

made several advances in imaging 

systems that may alter the way scientists study and visualize biochemical 

processes in small animals. Imaging 

systems like these also help to lay 

the groundwork for future progress 

in human brain imaging.

 Scientists at Washington 

University and Massachusetts 

General Hospital have refined a light 

microscope-based technique called 

multiphoton microscopy. Using this 

■

technique over a period of months, 

they can image microscopic structures in the brains of living mice that 

develop AD-like plaques (Skoch et 

al., 2005). A subset of neurons in the 

brains of these mice has been engineered to express an imaging agent 

called yellow fluorescent protein. A 

near-infrared laser is used to excite 

this imaging agent. The resolution of 

this technique is several orders of 

magnitude higher than existing techniques, such as PET or MRI. 

 University of Pennsylvania 

researchers have developed methods 

to improve the speed, sensitivity, and 

resolution of another kind of imaging 

technology, called single photon 

emission computed tomography 

(SPECT) technology (Acton and Kung, 

2003). These improvements allow 

investigators to take advantage of 

existing SPECT machines to better 

visualize biochemical processes in 

living mouse models of AD.

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what proteins besides APP it may cleave, 

and how its activity can be altered. A group 

of Harvard Medical School investigators 

used mass spectroscopy, a highly sensitive 

analytical technique that can identify and 

quantify both known and unknown compounds, to isolate and characterize gammasecretase (Fraering et al., 2004). Using this 

technique, the researchers determined that 

the gamma-secretase complex contains 

three other proteins in addition to presenilin—nicastrin, Aph-1, and Pen-2—and 

that all four proteins must be present for 

gamma-secretase activity. In addition, the 

researchers found that increased production 

of beta-amyloid, or production of a slightly 

longer form of beta-amyloid that was more 

prone to aggregate into toxic products, 

could be modified by several factors that 

influence the structure of the gammasecretase components. These factors include 

the lipid composition of the cell membrane 

and a number of well-characterized gammasecretase inhibitors. These results provide 

important clues to possible therapeutic 

strategies for lowering the production of 

toxic beta-amyloid by modulating gammasecretase activity. 

Researchers are now showing that the 

presenilin proteins appear to be involved in 

a number of other nervous system functions 

as well. Examples are clearance of proteins 

no longer required by the cell, neurogenesis 

(the generation of new neurons), and cell 

signaling. Some of these other functions 

of presenilins are likely to be important 

in brain aging and development of AD 

and perhaps in other neurodegenerative 

diseases as well. 

A team of scientists from the Mt. 

Sinai School of Medicine, in New York, 

is exploring the possibility that presenilins normally play an important role in 

preventing other typical AD pathologies, 

including changes to tau and cell death 

(Baki et al., 2004). Using cells taken from 

transgenic mice with both normal and 

mutated PS1 genes, the researchers found 

evidence suggesting that PS1 normally 

activates a cell signaling pathway called 

PI3K/Akt. This pathway blocks cell death 

and inhibits tau phosphorylation. It 

also appears that AD mutations in PS1 

may promote AD pathology by inhibiting 

the PI3K/Akt pathway. The researchers 

hypothesized that inadequate activation of 

PI3K/Akt signaling and impaired transmission of survival signals due to familial 

PS1 AD mutations (or the loss of normal 

presenilin function) could contribute to 

AD pathology independent of PS1’s role in 

cleaving APP.

Other studies have focused on a newlydiscovered effect of presenilin mutations 

on one of the two main “garbage disposal” 

systems of the cell, the lysosome. Neurons 

contain a large number of these structures, 

which eliminate most of the damaged or 
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Exploring Commonalities in the Transformation from 

Healthy Aging to Neurodegenerative Disease

For some time, scientists have 

realized that a number of devastating 

diseases—such as AD, dementia 

with Lewy bodies, frontotemporal 

dementia, Parkinson’s disease, 

Huntington’s disease, and prion 

diseases—are characterized by 

aggregations of abnormally folded 

proteins. In AD, the abnormal proteins are beta-amyloid and tau; in PD, 

it’s synuclein; and in frontotemporal 

dementia, it’s tau. Scientists think, 

therefore, that the pathological process in these diseases must share 

some characteristics, though these 

overlaps are not fully understood. 

For example, research in the 

past 2 years on beta-amyloid aggregates has provided evidence that 

the actual structure of oligomers 

may help to explain the pathology 

seen in these diseases. In one 

series of experiments, scientists at 

the University of California at Irvine 

made an antibody in rabbits that 

specifically recognizes soluble betaamyloid oligomers. The antibody 

failed to recognize soluble lowermolecular weight and fibrillar forms 

of this peptide (Kayed et al., 2003). 

This antibody also reacted with a 

variety of soluble protein oligomers 

that are involved in other neurodegenerative diseases, regardless of 

their specific amino acid sequence. 

Importantly, this particular antibody 

blocked the toxicity of these oligomers on cells in culture, including 

that of beta-amyloid oligomers. 

These results suggest that many 

types of soluble oligomers contain a 

common structural feature, independent of their amino acid sequence, 

and that the toxicity and pathogenesis of these oligomers may be mediated by a common mechanism. 

Scientists also know that many 

neurodegenerative diseases have 

some clinical characteristics in 

common. For example, some people 

with AD have trouble moving, the 

most obvious symptom of PD. Many 

of those with PD also have dementia. 

Sleep-wake disorders, delusions, 

psychiatric disturbances, and 

memory loss occur in all of these 

diseases. Finally, it is clear that all 

of these diseases develop over 

many years and occur as a result 

of complex interactions of genes, 

lifestyle and environmental factors, 

and factors affecting all parts of the 

body (such as hormonal changes). 

One way of looking at this constellation of disease pathologies, 

manifestations, and classifications 

is shown below. It recognizes that 

complex and interactive biological 

processes over time result in a group 

of early symptoms that signal that 

some kind of disease is beginning 

to manifest itself. The result may 

be any one of a number of diseases 

that has unique characteristics as 

well as shared characteristics with 

other diseases.

By investigating these diseases 

individually and together, scientists 

hope to shed light on their causes 

and, possibly, on future common 

treatment and prevention strategies.

Neurodegenerative 

Diseases*

AD/PD

DLB

PDD

AD

MID

ALS

FTD

PD

Early Symptoms

Tremor

Memory loss

 Executive function 

problems

Movement problems

Gait and balance problems

Sleep-wake disorders

Hallucinations

 Delusions

 Rigidity

* AD = Alzheimer’s disease, AD/PD = AD with parkinsonism, ALS = amyotrophic lateral sclerosis, DLB = dementia with Lewy bodies, 

FTD = frontotemporal dementia, MID = multi-infarct dementia (also known as vascular dementia), PD = Parkinson’s disease, 

PDD = Parkinson’s disease with dementia 

Adapted from an Emory University illustration 

Lifetime 

Influences

Genes

Environment

Systemic 

factors

Damaging Processes 

Occurring Before 

Symptoms Appear

Amyloid plaques

Synuclein deposits

Tau tangles

Other abnormal 

protein deposits

Nutritional compromise

Hormonal changes

Reduced oxygen 

flow to tissues

Toxic processes
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abnormal proteins that can accumulate 

in age-related neurodegenerative diseases. 

Researchers from the Mailman Research 

Center, McLean Hospital, Belmont, 

Massachusetts, found that presenilin gene 

mutations induce more severe damage to 

lysosomal systems in the brains of people 

dying with FAD than that seen in brains 

of individuals with the more common 

late-onset AD (Cataldo et al., 2004). This 

difference was also seen in PS1 transgenic 

mouse models of the disease. Some of the 

lysosomal pathology seemed to be in reaction to the presence of beta-amyloid, and 

some occurred independently. These results 

indicate that presenilin mutations can compromise the major garbage disposal systems 

of the cell and cause a loss of normal 

neuronal function. 

In another twist to the garbage disposal 

story, a University of Pennsylvania team 

of scientists showed that removing the 

presenilin genes altogether in transgenic 

mice also interfered with the cell’s lysosomes (Wilson et al., 2004). The investigators showed that the faulty lysosomes in 

these mice contained very high levels of 

two proteins, alpha- and beta-synuclein. 

This is an important finding because the 

abnormal accumulation and aggregation of 

alpha-synuclein has been implicated in several neurodegenerative diseases, including 

Parkinson’s disease. The effects were not 

due to loss of the gamma-secretase activity 

itself, but seemed more likely to be due to 

an effect on calcium metabolism within the 

cells that lacked PS proteins. Thus, aberrant 

accumulation of alpha- and beta-synuclein 

in degradative organelles are novel features 

of neurons that lack PS1, and similar 

events may promote the formation of 

clumps of alpha-synuclein found in several 

neurodegenerative diseases. 

New Discoveries About 

Tangles and Tau

Even though scientists have agreed for 

years that plaques and tangles are two of 

the major features of AD, they’ve disagreed 

about the relative importance of each. The 

development of the mouse model of AD 

that exhibits all the major characteristics 

of the disease (see p. 26 for more on this 

mouse model) has given scientists further 

insights into plaques and tangles, their 

interrelationships, and the roles that both 

beta-amyloid and abnormal tau play in 

damaging normal neuronal function. 

When scientists at the University of 

California at Irvine placed a beta-amyloid 

antibody into the hippocampus of one 

side of the brains of a group of triple transgenic mice in an immunotherapy study, 

they were not surprised to see that betaamyloid deposits were partially removed 

from the spaces outside the neurons 

(Oddo et al., 2004). Intriguingly, they 

also found that beta-amyloid levels inside 

neurons also appeared to be reduced. 

However, a most important lead for the 

further understanding of AD pathology 
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came from the unexpected finding that 

this beta-amyloid immunotherapy also 

resulted in the clearance of abnormal 

tau from the cell body and dendrites of 

hippocampal neurons of these animals. 

No tau was cleared from hippocampal 

neurons on the side of the brain without 

the antibody. Reduction of abnormal tau

following anti-beta-amyloid treatment 

suggests a direct interaction between these 

two hallmarks of AD. Furthermore, it suggests that a hierarchy exists—the abnormal 

beta-amyloid appears first, followed by 

abnormal tau. 

A recent study supported by NINDS, 

NIA, and other organizations also explored 

the association between beta-amyloid and 

tau (Gamblin et al., 2003). A team of 

Northwestern University researchers used 

test tube studies to demonstrate that certain enzymes called caspases can break the 

tau protein into segments when they are in 

neurons that have already been treated with 

beta-amyloid. The resulting segments have a 

greater tendency to form damaging tangles 

than does normal tau. These findings help 

expand our understanding of the functional 

relationship between beta-amyloid and tau

and suggest that the caspases, which are well 

known for their involvement in cell death 

pathways, also may be involved.

Recent studies have examined other 

aspects of tangles and tau, and they also 

are helping to explain tau’s role in the AD 

process. For example, some scientists think 

that the misfolded shape of the highly phosphorylated tau in the neuron increases its 

tendency to form neurofibrillary tangles 

and encourages the loss of stabilization 

of microtubules. Studies have shown that 

the molecular chaperones Hsp90 and 

Hsp70 (proteins that protect cells from the 

adverse effects of protein misfolding and 

aggregation), stabilize tau’s normal shape, 

reduce tau’s abnormal phosphorylation 

and aggregation, and restore its binding 

to microtubules (Dou et al., 2003). This 

research, which was funded by NIA, the 

Alzheimer’s Association, and the Ellison 

Foundation, has implications not only for 

AD and diseases caused by tau mutations 

(such as FTD and parkinsonism linked to 

chromosome 17), but also for other neurodegenerative diseases, such as Huntington’s 

disease and prion diseases that are characterized by abnormal aggregates of other types 

of protein. 

Scientists have known for years that 

tau is important in maintaining microtubule integrity and, therefore, their ability 

to transport materials and organelles, such 

as mitochondria, between the cell body of 

the neuron and the synapse. However, only 

more recently has it become clear that the 

level of tau and normal phosphorylation 

might also regulate the actual transport 

of materials down intact microtubules. As 

with other neuronal systems, a delicate 

balance must be maintained for optimal 

function. A research team at the New 

York State Institute for Basic Research in 

Developmental Disabilities investigated how 

high levels of tau actually inhibit axonal 

transport from the cell body to the synapse 

(Tatebayashi et al., 2004). They found that 

the enzyme called GSK3β, which is regulated by the PS1 gene, also phosphorylates 

tau under normal conditions. This phosphorylation does not alter tau’s ability to 

bind to microtubules, but it appears to be 

required for normal axonal transport in 
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cells. These findings raise the possibility 

that the physiological phosphorylation of 

tau by GSK3β also may be involved in 

regulating organelle transport. Supporting 

the idea that either too much or too little 

of a protein like GSK3β might adversely 

affect neuronal function, NICHDfunded researchers from the University of 

Connecticut Health Center found that 

another function of PS1 is to maintain 

physiological levels of GSK3β (Pigino et 

al., 2003). When the gene for PS1 was 

eliminated, GSK3β activity increased. This 

caused a critical transport protein to fall 

off the microtubules, causing a decrease in 

axonal transport. The investigators then 

inserted a PS1 gene containing a mutation 

called M146V, which causes a very aggressive early-onset form of FAD and got the 

same effect.

In the last several years, researchers have 

actually begun to test a potential therapy 

for the loss of neuronal function that occurs 

when microtubules disintegrate and tau

filaments begin to form tangles. In studies 

funded by NINDS, several other NIH 

Institutes, and the Institute for the Study 

of Aging, a research team at the University 

of Kansas showed that beta-amyloid toxicity can be reduced by pretreating tissue 

culture cells with agents that stabilize 

microtubules, such as taxol, a drug used in 

cancer treatment (Li et al., 2003a). These 

agents seem to work by indirectly inhibiting 

an enzyme that abnormally phosphorylates 

tau. The researchers then generated taxollike compounds that, unlike taxol, can 

cross the blood-brain barrier and showed a 

likely positive effect of these drugs in combating beta-amyloid toxicity in adult mice. 

Working in the same area, a team of scientists from the University of Pennsylvania 

School of Medicine treated transgenic 

mice that develop AD-like tangles with 

a drug that binds microtubules—in effect, 

substituting for the tau that should normally be there (Zhang et al., 2005). The 

investigators found that after 12 weekly

treatments, the drug restored microtubule 

function, increased the number of stable 

microtubules, and lessened motor impairments in the mice. These findings open the 

way for additional studies to explore the 

therapeutic potential of drugs that offset 

the effects of beta-amyloid toxicity and loss 

of microtubules.

New Discoveries About 

Mitochondria

Mitochondria are critically important 

structures in all cells, including neurons. 

They are the power plants for the cell, 

providing the energy a cell needs to move, 

divide, and carry on its functions. A mitochondrion has a smooth outer membrane 

and an inner membrane that forms many 

folds. On these folds, glucose combines 

with oxygen to produce ATP, the cell’s 

primary energy source.
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AD researchers have thought for some 

time that damage to or mutations of mitochondria could play a role in the early 

development of AD because they lead in 

several ways to the death of the cell through 

a process called apoptosis (Beal, 2000; 

Melov, 2004). Damage to mitochondria 

also leads to a rapid increase in the formation of free radicals, which are highly reactive oxygen molecules that can build up in 

neurons over time. If unchecked, the buildup of these molecules can cause oxidative 

stress, which damages other cellular molecules such as proteins, lipids, and nucleic 

acids. Oxidative stress and mitochondrial 

dysfunction have been implicated in several 

neurodegenerative diseases, including AD.

Several research teams have recently 

expanded our understanding of mitochondria, free radicals, and oxidative stress. For 

example, Columbia University scientists 

observed that in AD brains, beta-amyloid 

is bound to a protein called Aβ -binding 

alcohol dehydrogenase (ABAD), which is 

an integral part of mitochondria (Lustbader 

et al., 2004). Studies in AD transgenic 

mice show that the binding of betaamyloid peptides to ABAD prevents the 

normal function of ABAD and leads to 

enhanced production of free radicals followed by increased apoptosis. When 

the investigators developed transgenic 

mice that overproduced ABAD as well 

as developed plaques, they observed 

increased oxidative damage in their brains. 

Cognitive tests showed that these mice 

had impaired memory compared to AD 

transgenic littermates that had normal 

levels of ABAD. If these findings are 

borne out in additional studies, blocking 

the interaction between ABAD and betaamyloid could be a possible target for 

future therapeutic strategies in AD.

A research team from the Buck Institute 

for Age Research, in Novato, California, 

took advantage of the availability of genetic 

models of oxidative stress as well as other 

technologies to explore the impact of mitochondrial oxidative stress on the activity 

of individual mitochondrial enzymes 

(Hinerfeld et al., 2004). For this research, 

they used mice deficient in a key antioxidant enzyme known as superoxide dismutase type 2 (SOD2). These mice suffer a 

loss of neurons in particular brain regions. 

The investigators found that certain parts 

of the mitochondrial molecular machinery 

that produces energy are more vulnerable 

to oxidative stress than are others. Most 

important from a therapeutic standpoint 

was the finding that an antioxidant compound was able to prevent the damage of 

the mitochondrial enzymes, and in doing 

so, restored some of the neuronal loss 

caused by the oxidative stress. 

NIA researchers have tracked the 

declines in synapse activity and neuronal 

energy consumption that occurs during the 

evolution of the AD process (Rapoport, 

2003). They found that changes in the 

structure and function of synapses resulting 

from AD pathology reduce neuronal energy 

demand and lead to potentially reversible 

decreases in energy production within the 

mitochondria. PET scans showed that, at 

this early stage in the disease process, the 

synapses can almost be normally activated 

in response to stimulation. As the disease 

progresses, however, tangles with abnormally phosphorylated tau accumulate 

within the neuron to the point that they 

disrupt microtubules and axonal transport. Mitochondria are prevented from 

traveling along the axon between the cell 
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body and the synapse. The resulting severe 

energy depletion at the synapse and other 

pathology leads to the death of the neuron. 

If these findings are confirmed by further 

research, strategies to maintain neuronal 

energy metabolism during the early stages 

of the disease process may be a potential 

therapeutic goal.

Other research teams have focused on 

genetic aspects of mitochondria’s role in 

AD. Mitochondria possess their own DNA, 

distinct from the DNA in the cell’s nucleus. 

Although the amount of DNA in a mitochondrion is very small compared to that 

in the nucleus, mutations in it can have 

deleterious effects. Researchers from Cornell 

University Medical College set out to test 

whether people with AD have mutations 

in mitochondrial DNA (Coskun et al., 

2004). They found several mutations in the 

part of mitochondrial DNA that controls 

the activity of mitochondrial genes. These 

genetic changes could be found in more 

than half of the AD brains examined but in 

none of the brains from cognitively healthy 

individuals of the same age. These ADspecific mutations in mitochondrial DNA 

could underlie the mitochondrial failure to 

produce sufficient energy for proper functioning of neurons, which, in turn, can 

result in loss of communication between 

neurons. These investigators speculate that 

the accumulation of these mutations might 

be a significant and contributing factor to 

the development and progression of AD.

Finally, a research group from Oregon 

Health and Sciences University compared 

the expression of mitochondrial genes from 

the brains of cognitively healthy individuals 

and brains from people at early- or latestage AD (Manczak et al., 2004). They 

found AD-related changes in the patterns 

by which certain genes are expressed. These 

genes encode the proteins that make up the 

three major components of mitochondria’s 

energy-producing machinery. These findings suggest that the ability of the mitochondria to produce energy is compromised 

in AD and that the mitochondria inside the 

surviving neurons are trying to compensate 

for the brain’s loss of energy resources. 

New Discoveries About Other 

Processes that Contribute to 

Neuronal Damage

Over the last several years, knowledge 

has grown about several other related areas 

that appear to play an important role in AD. 

Cell Death. An area that is generating 

increasing scientific interest is abnormal 

cell death caused by disruptions in the 

normal function of key structures in neurons. For example, a proteasome is a large 

structure, which, along with lysosomes, 

is responsible for chopping up misfolded 

or damaged proteins so that the cell can 

dispose of them. This critical system protects cells from the toxicity of damaged 

proteins. Increasing evidence suggests that 

disruptions to proteasome activity occur in 

normal aging as well as in many neurodegenerative conditions, including AD, PD, 

and Huntington’s disease. The inhibition 

of proteasome activity causes many and 

diverse effects on cells, including cell death, 

and recent studies suggest that proteasome 

inhibition may contribute to some diseaserelated mitochondrial changes. A research 

team from the University of Kentucky 

explored the effects of chronic, low-level 

proteasome inhibition on cell function by 

looking at changes in the activity of a large 

number of genes. These changes are called 

“gene expression” (Ding et al., 2004). 
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Players on the AD Stage: Putting It All Together
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The researchers found that a limited 

number of genes changed their level of 

expression in cells in which proteasome 

action was inhibited, and the affected genes 

were those involved in cell cycle events, 

inflammatory processes, calcium control, and 

protein degradation. Alterations in these cell 

processes have been implicated in normal 

aging and neurodegenerative diseases.

Another type of cell death is the process 

called apoptosis. Some evidence suggests that 

cell death in AD occurs through this process. 

Sometimes, apoptosis involves mitochondria. 

Other times, the process can be activated by 

membrane receptors, such as tumor necrosis 

factor receptor (TNFR). Studies have shown 

that components of a TNFR-1 pathway were 

elevated in AD brain tissue, while cellular 

inhibitors of this pathway were decreased. 

One, called TRADD, binds to the TNFR-1 

receptor, causing cell death. Another, called 

DENN/MADD, binds to the TNFR-1 

receptor and prevents cell death. Researchers 

at the University of Southern California Keck 

School of Medicine recently found a reduction in DENN/MADD and an increase in 

TRADD in the hippocampus of brains from 

people with AD compared to tissue from 

cognitively healthy people (Del Villar and 

Miller, 2004). Similar changes were seen in 

neurons treated with beta-amyloid and in cortical tissue from transgenic mice that develop 

AD-like disease. These changes, which may 

be caused by inflammation or oxidative stress, 

may be responsible for increased apoptosis in 

the AD brain.

Inflammation. A dynamic and complex 

biological process, inflammation affects 

cells and tissues all through the body. This 

process occurs in response to many types 

of injuries or abnormal situations. In some 

cases, the inflammation reaction occurs as 

part of a healing process, such as when the 

body reacts to a simple scrape on the skin. 
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In other cases, inflammation is a central 

characteristic of a disease process, such 

as in rheumatoid arthritis. Inflammation 

occurs in the AD brain as well, and many 

scientists are examining its role in the 

development and progression of the disease. They don’t necessarily agree on its 

significance—some scientists think that 

inflammation is part of a vicious cycle 

that is harmful to neurons. Others think 

that aspects of inflammation may be valuable to the brain by counteracting the 

detrimental aspects of the AD process. 

Recent inflammation-related research 

has focused on two kinds of glial cells: 

astrocytes and microglia. These cells have 

the capacity to move toward and respond 

to sites of injury. Beta-amyloid plaques in 

the AD brain are surrounded by numerous 

activated astrocytes and microglia. In fact, 

the presence of large numbers of activated 

astrocytes surrounding sites of brain injury 

is one of the earliest manifestations of AD. 

Scientists speculate that this event could 

occur in response to degenerating synapses 

and neurons and to the accumulation of 

beta-amyloid plaques. 

A collaborative team of researchers from 

Columbia University, Stanford University, 

and the Gladstone Institute of Neurological 

Disease in San Francisco demonstrated 

that astrocytes isolated from adult mouse 

brains can degrade and remove betaamyloid peptides (Wyss-Coray et al., 

2003). This finding from tissue culture 

was a surprise because in AD brains, astrocytes surrounding beta-amyloid deposits 

seem incapable of removing beta-amyloid. 

Discovering ways to stimulate the ability 

of astrocytes to clear beta-amyloid may be 

a fruitful strategy for reducing the toxicity 

and neurodegeneration associated with 

plaques and their earlier-stage aggregates.

Other investigators are exploring strategies for stimulating microglia. Like astrocytes, most of the evidence to date shows 

that microglia can engulf and remove 

beta-amyloid aggregates in tissue culture, 

but they fail to do so in living brains. 

Identifying the molecular details of this 

“phagocytic” activity is crucial if scientists 

are to develop microglia that will successfully engulf and remove beta-amyloid 

aggregates from the brain. Researchers 

from Cleveland’s Case Western Reserve 

University School of Medicine used both 

pharmacological and genetic approaches 

to discover in tissue culture that betaamyloid fibrils are engulfed by a receptor 

composed of several proteins on the surface 

of microglia. This receptor is entirely different from the typical phagocytic receptors (Bamberger et al., 2003). When each 

of the receptor components was blocked, 

the microglia lost the capacity to degrade 

beta-amyloid (Koenigsknecht and Landreth, 

2004). These findings pave the way for 

researchers to find out why the plaqueassociated microglia in living brain tissue 

are unable to remove the beta-amyloid 
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deposits effectively, despite their physical 

association with the plaques. 

Other scientists have found that 

microglia also may be responsible for some 

of the damaging processes that occur in the 

AD brain. Microglia are rapidly activated 

in the presence of aggregated beta-amyloid 

and are responsible for the strong inflammatory response that can encourage the 

neurodegenerative changes observed in AD. 

Deciphering the molecular mechanism by 

which fibrillar beta-amyloid activates this 

inflammatory response may suggest future 

therapeutic targets. In trying to address 

this problem, scientists from Massachusetts 

General Hospital put beta-amyloid into the 

brains of normal mice and mice that were 

deficient in a particular cell surface protein 

called CD36 (El Khoury et al., 2003). The 

researchers found that far fewer microglia 

were recruited to the beta-amyloid site in 

CD36-deficient mice compared to normal 

mice. In addition, microglia isolated from 

CD36 mice could not produce certain toxic 

molecules in response to aggregated betaamyloid, which precluded the ability of 

these molecules to harm neurons. 

In an effort to understand how to 

regulate the negative effects of microglia, 

Stanford University scientists found that a 

growth factor, TGF-β, which regulates cell 

survival and inflammation throughout the 

body, has a key role in maintaining neuronal 

integrity and regulating microglial activity 

(Brionne et al., 2003). The researchers found 

that the brains of mice that are deficient in 

TGF-β have widespread neuronal degeneration and microgliosis, a process characterized 

by the presence of numerous microglia that 

have the capacity to harm neurons. They 

also examined transgenic mice that overproduced TGF-β in their brains and found 

that overproduction of TGF-β protected 

against various forms of brain injury. This 

finding is highly significant in light of the 

fact that humans have large variations in the 

levels of TGF-β in the brain.

Other researchers have been investigating additional factors that may influence brain injury caused by beta-amyloid. 

A team of scientists at the University of 

California at Irvine developed transgenic 

mice that lack a protein called C1q. This 

protein is involved in the complement cascade, a precise series of events that takes 

place during the body’s immune response; 

inflammation is part of this response. The 

researchers bred these C1q-deficient mice 

with transgenic mice that develop amyloid 

plaques and found that the offspring that 

develop plaques in the absence of C1q 

do not exhibit the intense inflammatory 

response in the brain tissue as mice that 

have C1q (Fonesca et al., 2004). The C1qdeficient mice also showed a slower loss of 

markers of neuronal communication as the 

plaque pathology developed. These findings 

suggest that C1q is part of the molecular 

signaling that leads to the deterioration of 

neurons in the presence of beta-amyloid 

aggregates. 

Epidemiologic studies have suggested 

that long-term use of non-steroidal antiinflammatory drugs (NSAIDs), such as 

naproxen, ibuprofen, and indomethacin, 

are associated with a decreased risk of AD. 

These studies provide another avenue of 

research suggesting that an inflammatory 

process may be involved in AD. However, 

previous laboratory research by a group 

of scientists from the Mayo Clinic in 

Jacksonville, Florida, showed that some 

NSAIDs could lower beta-amyloid production, hinting that this mode of action, 
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rather than an inflammatory pathway, 

might be responsible for the possible protective effect of some NSAIDs. To further 

investigate this connection, the Mayo Clinic 

researchers used cell cultures and an AD 

transgenic mouse model to study the effects 

of a number of common NSAIDs on betaamyloid production (Eriksen et al., 2003). 

After screening 20 widely-used NSAIDs, the 

scientists found that 8 effectively reduced 

beta-amyloid levels both in the cell cultures 

and in the mouse models. Moreover, this 

action occurred through a different mechanism than that usually associated with most 

NSAIDs. The investigators suggest that some 

NSAIDs could act to delay the development 

of AD by inhibiting gamma-secretase, and 

that it might be useful to screen other types 

of agents for their effect on this key process 

in AD neuropathology. So far, no clinical 

trial has shown a beneficial effect of NSAIDs 

on AD prevention or progression.

The Brain Protects Itself

Until recently, scientists thought that 

the brain’s ability to repair itself after injury 

or neurodegeneration was limited or nonexistent. In the past several years, however, 

with new discoveries about brain anatomy 

and function and the emerging concept of 

cognitive reserve, scientists are changing 

that view. 

One exciting recent development is 

the discovery that the brain can, in fact, 

generate new neurons in a process called 

neurogenesis. In the adult, this process 

occurs in two areas of the brain, the hippocampus and the subventricular zone, 

and possibly in others as well. These brain 

areas contain special cells called stem cells, 

which can divide and migrate to other 

areas of the brain under certain conditions. 

These adult neural stem cells can make 

new neurons and glial cells. This discovery 

raises the prospect that neural stem cells 

could be harnessed to replace dying cells or 

to repair damaged cells and neural circuits 

in the aging or diseased brain. 

Many researchers are studying the 

fundamental biology of neurogenesis and 

how it may be linked to AD. For example, 

NIA-funded researchers recently examined whether abnormalities in neural stem 

cells might contribute to human disorders 

of learning and memory, including AD 

(Haughey et al., 2002). If neurogenesis is 

impaired in AD, then it may be possible 

to develop therapeutic approaches that 

enhance neurogenesis. The investigators 

wanted to determine whether stem cell proliferation, survival, and differentiation were 

impaired in transgenic mice that developed 

a form of FAD. They also wanted to assess 

the effects of beta-amyloid on stem cell 

survival and neuronal differentiation. They 

found that proliferation and survival of 

the stem cells in a certain region of the 

hippocampus was reduced in the mice. 

They also found that beta-amyloid impaired 

proliferation and neuronal differentiation 

of human and mouse stem cells, and 

promoted apoptosis of the cells. 

Presenilin mutations also have been 

shown to reduce neurogenesis from stem 

cells in the brain. Mt. Sinai School of 

Medicine scientists discovered that the PS1 

mutation that causes the most severe and 

earliest form of FAD had a major inhibitory 

effect on the survival of newly-formed 

neuronal cells from stem cells in mutated 

PS1 transgenic mice compared with 

transgenic mice that contained the normal 

PS1 gene (Wen et al., 2004). This could 

have implications for the physiological 

functioning of the hippocampus in FAD. 

In contrast to the impaired neurogenesis 

caused by PS1 mutations in other transgenic mouse models of AD, the NINDS- 
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and NIA-supported work of researchers at 

the Buck Institute for Age Research showed 

that neurogenesis is actually enhanced in 

the hippocampus of people with AD as well 

as in a transgenic mouse model with two 

APP mutations that cause FAD (Jin et al., 

2004). It is possible that different forms 

of AD mutations have different effects on 

brain neurogenesis and that neurogenesis 

may be an important mechanism the brain 

uses to try and repair the early effects of 

AD. Enhancing neurogenesis could be an 

effective therapeutic strategy. 

Other basic science 

studies conducted by NIAfunded researchers have 

focused on a protein called 

Notch, which resides on 

the surface of neural stem 

cells. Previous studies have 

shown that Notch controls 

the process of neurogenesis. When the gene 

for Notch is disabled in mice, the development of their brains is severely abnormal 

and they die in the womb. A similar abnormality in brain development occurs when 

the PS1 gene is disabled. Mutations in 

PS1 cause FAD, suggesting a link between 

Notch and AD. NIA-funded scientists 

designed experiments using transgenic mice 

to determine whether Notch is involved in 

learning and memory (Wang et al., 2004). 

These mice, which had reduced levels of 

Notch, exhibited impaired communication 

at synapses between hippocampal neurons 

that are critical for learning and memory. 

When a protein that activated Notch was 

applied to the hippocampus, communication at the synapses was enhanced. These 

findings suggest an important role for 

Notch in synaptic function associated with 

learning and memory processes, and it may 

be a new target for therapeutic interventions to improve learning and memory.

Scientists also are beginning to look 

at other regulators of neural stem cell 

biology, especially as they influence aging 

and neurodegenerative diseases like AD. 

For example, NIMH- and NIA-funded 

investigators at the Washington University 

School of Medicine in St. Louis found that 

transgenic mice had a decreased capacity to 

generate new neurons in the hippocampus 

and this decrease was greatest when they 

were under stress from being housed in 

isolation (Dong et al., 2004). These deficits also were associated with deficits in 

contextual memory, which is the aspect 

of memory related to experiences such as 

recognizing physical surroundings. Greater 

amounts of plaques also were deposited in 

the stressed mice compared to unstressed 

mice. However, an antidepressant medication that increases cell proliferation in 

normal mice also increased cell proliferation and improved contextual memory in 

the stressed transgenic mice. These results 

suggest that this AD mouse model has an 

impaired ability to generate new cells in the 

hippocampus and that this impairment can 

be modulated by stress and certain drugs.

A number of important questions are 

being asked about the role of neurogenesis in counteracting the effects of neurodegenerative damage. In an effort to find 

answers, a Mt. Sinai School of Medicine 

One exciting recent development is the discovery 

that the brain can generate new neurons in a process 

called neurogenesis.
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research team studied whether injuries to 

the entorhinal cortex, which has direct connections to the hippocampus, affected the 

ability of mice to generate new neurons 

from stem cells in the hippocampus (Gama 

Sosa et al., 2004). The development of 

new neurons and their survival was studied 

for several weeks after the injury. Results 

showed that the number of new neurons 

that were formed in the days immediately 

after the injury did not increase. However, 

6 weeks later, the number of new neurons 

had almost doubled. This transgenic mouse 

shows promise as a model for studying the 

molecular events affecting neurogenesis in 

the hippocampus. 

Researchers also continue to be very 

interested in examining the potential of 

neurotrophic factors, which are proteins 

that stimulate neuronal survival and 

growth, to prevent or treat neurodegenerative disorders. The problem has been 

how to deliver these proteins to the brain 

because they do not readily cross the 

blood-brain barrier. Another challenge is 

how to specifically target them to degenerating neurons to avoid unwanted side 

effects. Gene therapy offers one approach. 

Recently, a group of researchers from 

the Salk Institute for Biological Studies 

in La Jolla, California, developed a gene 

delivery system to carry the human neprilysin gene, which makes an enzyme that 

degrades beta-amyloid (Marr et al., 2003). 

The team put the neprilysin delivery 

system into brain areas containing betaamyloid plaques in APP transgenic mice. 

The production of neprilysin appeared to 

increase degradation or reduce the growth 

of existing plaques. The amount of plaque 

was reduced to less than half that found in 

untreated areas. This study suggests that 

boosting normal, protective processes in 

the nervous system might 

help prevent or treat degenerative events associated 

with AD, and this strategy 

provides a new way of 

potentially interfering with 

the disease process. 

Can Certain Factors 

Protect Against or Increase 

Risk of AD?

We’ve known for some time that certain 

genetic and nongenetic factors can increase 

the risk of developing AD. Recent evidence 

has suggested that other factors may actually 

help to reduce AD risk (see p. 14 for more 

on one of these factors—cognitive reserve). 

The combined weight of these advances is 

making scientists eager to understand how 

these risk and protective factors balance each 

other over the course of a lifetime. They 

also want to know more about the types of 

interventions that may be useful in changing 

this balance in the direction of healthy aging 

and the times in the life cycle at which these 

interventions might be most effective. 

Ideas about what these risk and protective factors might be are derived from 

a variety of different types of studies, 

including genetics studies, studies of individual lifestyles and behavioral patterns, and 

studies of large groups or populations. 

Findings from these studies are important 

because they point the way to potential 

therapeutic approaches that might be worth 

investigating in controlled clinical trials. If 

Scientists are eager to understand how risk 

and protective factors balance each other over the 

course of a lifetime.
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confirmed in trials, they may suggest ways 

that people can change their lifestyles or 

environments to reduce risk. The genetics 

studies, in particular, will help identify 

pathways that affect the development or 

progression of AD. They also will help 

researchers develop new animal models to 

understand early events in the disease, as 

well as identify potential targets for treatment and prevention. 

New Discoveries About 

AD Genetics

Genetic studies of complex neurodegenerative diseases such as AD have 

focused on two key issues—whether a gene 

might influence a person’s overall risk of 

developing a disease and whether a gene 

might influence some particular aspect of 

a person’s risk, such as the age at which the 

disease begins (“age at onset”). To date, only 

four of the approximately 30,000 genes in 

the human genetic map (the “genome”) 

have been conclusively shown to affect AD 

development. Mutations in three genes—

the APP gene found on chromosome 21, 

the PS1 gene on chromosome 14, or the 

PS2 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 code for proteins that are 

components of enzymes that play an important part in cleaving APP to form betaamyloid. Presenilin gene mutations promote 

the breakdown of APP, leading to increased 

production of harmful beta-amyloid. 

A fourth gene on chromosome 19 

encodes a protein called apolipoprotein E 

(ApoE). ApoE carries lipids in the bloodstream and is important in clearing lipids 

from the blood. APOE, the gene that 

encodes ApoE, has three common forms, 

or alleles—ε2,ε3, andε4. Theε4 allele 

is a risk factor gene for the common lateonset AD. Theε2 allele may provide some 

protection against AD andε3 is thought to 

play a neutral role. 

Scientists estimate that an additional 

four to seven risk factor genes exist for 

late-onset AD. A study from researchers at 

Massachusetts General Hospital, who are 

participating in NIMH’s Alzheimer Disease 

Genetics Initiative and who are also supported by NIA funding, is shedding light 

on these genes. The researchers screened 

the entire genomes of a large number of 

families with AD using 382 genetic markers 

and complex statistical analysis to identify 

regions of the genome that were associated 

with AD and might contain additional 

susceptibility genes (Blacker et al., 2003). 

The study identified 12 additional chromosomal regions that might be linked to 

AD. Some of these regions will probably be 

found not to contribute to AD. However, 

other regions may well harbor genuine AD 

susceptibility genes, particularly the regions 

that yielded strong statistical evidence 

during the genome analysis. Even though it 

will be difficult to identify and characterize 

the genes in these chromosomal regions, the 

results will greatly facilitate the development 

of strategies for AD treatment, early intervention, and prevention. 

Another team of researchers examined 

genetic associations with AD in a different 

population. This Boston University School 

of Medicine team worked with a population in Wadi Ara, an Arab community in 

northern Israel that has an unusually high 

prevalence of AD (Farrer et al., 2003). A 

genomic scan conducted on people from 

this community with and without AD 

revealed markers with significant AD allelic 

association on chromosomes 2, 9, 10, and 

12. The researchers then analyzed the distribution of allele frequencies to narrow 
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the potential regions on these chromosomes where the genes might be found. 

The unique characteristics of the Wadi 

Ara populations and the fact that findings 

from this analysis replicate those from other 

genome scans may help scientists more rapidly identify AD risk factor genes on these 

chromosomes. 

Other studies have shown that a region 

on chromosome 10 is likely to harbor at 

least one AD risk factor gene and several 

research teams have made advances in 

this area. For example, scientists from the 

Karolinska Institute in Stockholm, Sweden, 

examined a stretch of genetic material on 

chromosome 10 that contains the insulin 

degrading enzyme (IDE) gene (Prince et al., 

2003). This enzyme is of interest because 

it also degrades beta-amyloid. Genetically 

engineered mice that do not have the IDE 

gene develop high insulin levels, glucose 

intolerance, and increased brain levels of 

beta-amyloid (see p. 52 for more on the 

links between AD, insulin, and diabetes). 

The scientists compared genetic material 

from people with and without AD to assess 

the IDE gene and two other close-by genes. 

They were interested in finding differences 

between individuals at a single point in the 

genetic code (these points are called SNPs) 

and in stretches of DNA that are inherited 

in common among groups of people (these 

stretches of DNA are called haplotypes). 

Results strongly indicated that this region 

contains alleles and haplotypes that confer 

AD risk. These findings provide substantial 

evidence that genetic variation within or 

extremely close to IDE affects both disease 

risk and traits related to the severity of the 

disease. The study also indicated that an 

analysis of this type can be an effective way 

to assess genetic variation in complex diseases like AD.

Investigators from the Veterans Affairs 

Puget Sound Health Care System, in 

Seattle, explored the connection between 

IDE and APOE status in a study with cognitively healthy older people and those with 

AD (Craft et al., 2003). The scientists gave 

participants infusions of insulin at five different levels and then measured cognitive 

performance and APP levels in the blood 

2 hours later. The results supported a role 

for insulin in normal memory function 

and on APP levels and suggested that the 

APOE-ε4 allele interacts with insulin to 

affect APP levels. This team of investigators explored these relationships further 

in a second study (Cook et al., 2003). In 

light of the possible association of IDE with 

late-onset AD and the evidence that APOE 

status may affect insulin metabolism, they 

hypothesized that the expression of the IDE 

gene may be altered in people with AD. 

To test this hypothesis, they measured the 

expression of IDE in hippocampal tissue 

from the brains of individuals who were 

cognitively healthy and others who had 

AD. They found that the hippocampal 

IDE protein was reduced by about half in 

those with AD who carried the APOE-ε4 

allele compared to the participants with AD 

who did not carry the APOE-ε4 allele or 

to cognitively healthy participants. These 

findings show that reduced IDE expression is associated with APOE-ε4 and suggest that IDE may interact with APOE-ε4

status to affect beta-amyloid metabolism. 

Consistent with these findings, scientists at 

the University of California at Los Angeles 

found that deficient insulin signaling correlated with reduced IDE in the brains of 

people with AD, as well as in the brains 

of a mouse model of AD. The authors 

hypothesize that enhancing the effects of 
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insulin in the brain may reduce amyloid 

accumulation and is a promising strategy 

to pursue against AD (Zhao et al., 2004). 

Studies of chromosome 10 also are 

allowing scientists to explore another 

intriguing aspect of AD—age of onset. A 

research team at Duke University Medical 

Center began their study by focusing on 

a region of chromosome 10 that earlier 

studies suggested contained an area that 

influenced age of onset for both AD and 

Parkinson’s disease (Li et al., 2003b). 

This chromosomal region contains a large 

number of genes, however, so the investigators established a novel approach called 

“genomic convergence,” which allowed 

them to reduce and prioritize the number 

of candidate genes in the chromosome 10 

region. By combining three independent 

but complementary lines of evidence, the 

team found four genes that mapped to a 

region of chromosome 10 that appeared 

to be important to the age of onset. These 

genes were expressed differently in people 

with and without AD. Though these findings are potentially valuable, additional 

studies must be conducted to determine 

whether, in fact, these genes do affect age 

of onset.

Other scientists have focused on chromosomes 12 and 19. In one study, conducted 

collaboratively by scientists from NIA and 

Celera Diagnostics of Alameda, California, 

the researchers examined regions of chromosomes 12 and 19 from three separate sample 

sets that included people with and without 

AD (Li et al., 2004). The researchers found 

that SNPs in the glyceraldehyde 3 phosphate dehydrogenase (GAPD) gene family 

were significantly associated with AD risk in 

all three sample sets. They also found that 

some GAPD SNPs on chromosome 12 were 

associated with an age of onset of 75 years 

and older, whereas some GAPD SNPs on 

chromosome 19 were associated with an age 

of onset of less than 75 years. Individually, 

the GAPD SNPs made different contributions to AD risk in each of the sample sets, 

and the investigators speculate that variants 

in functionally similar genes may account for 

this heterogeneity of AD risk.

Finally, knowledge gained from studying 

Down syndrome is revealing much about 

chromosome 21 and its possible role in AD. 

Most people have two copies of chromosome 21, but people with DS have three. 

Therefore, they have an extra copy of 

the APP gene. Every individual with DS 

who survives into his or her third decade 

develops the signature brain pathology of 

AD, although the location and distribution 

of these features are much more variable 

than in traditional AD. Research conducted 

by National Cancer Institute (NCI)-funded 

scientists demonstrates that those who survive into adulthood with DS also have a 

substantially increased risk of death from a 

number of causes, including cancer (Hill et 

al., 2003).
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In recent years, DS has become a “natural model” for studying how AD develops 

and progresses. For example, several teams 

of scientists funded by the NICHD have 

attempted to find the genes on chromosome 21 that contribute to the development 

of dementia in individuals with DS and to 

understand the implications of these changes 

for the level of gene expression on normal 

brain development and maturation. At least 

10 genes on chromosome 21 are involved in 

brain structure or function, but investigators 

have implicated only three of these genes to 

date in DS. Researchers at the University of 

Arkansas for Medical Sciences, Little Rock; 

the University of Connecticut, Farmington; 

and the Instituto de Médica in Córdoba, 

Argentina, are studying various aspects of 

these alterations in gene expression and the 

pathways these genes influence. Findings 

from these studies will help them understand why dendrites develop abnormally in 

infants with DS and will help them learn 

more about amyloid plaque formation and 

neuronal decline and death in middle-aged 

people with DS. 

The University of Arkansas researchers 

discovered that in adults with DS, neuronal loss is dramatic and the plaques that 

develop are consistent with those found 

in AD (Mrak and Griffin, 2004). The 

researchers were able to demonstrate that 

two chromosome 21-based gene products—APP and S100B—are involved in 

these neuronal changes. S100B, which is 

over-expressed throughout the lifetime of 

people with DS, has been implicated in 

beta-amyloid plaque formation and correlates with the AD pathology that people 

with DS begin to experience as young 

adults. They also found that a protein 

called IL-1 (an inflammatory protein), 

which is not found on chromosome 21, 

is also over-expressed throughout life in 

people with DS. IL-1 increases expression 

of APP and S100B and drives numerous 

processes that contribute to the development of late-onset and DS-related AD. 

Another genetics area of great interest 

to investigators is APOE-ε4, the risk factor 

gene found on chromosome 19. A number 

of recent studies have shed additional light 

on the role of this APOE allele in AD. For 

example, studies using PET scans have 

found that people with AD have abnormally low rates of glucose metabolism in 

certain areas of the cerebral cortex (the outer 

layer of neurons in the brain that controls 

conscious thought, mental activity, and 

voluntary movement, and that processes 

sensory information from the outside 

world). Building on earlier PET studies 

that showed that cognitively healthy older 

carriers of the APOE-ε4 allele had abnormally low rates of glucose metabolism in 

those same brain regions, investigators at 

the Banner Good Samaritan Medical Center 

in Phoenix, Arizona, examined whether 

this was true for relatively young adults as 

well (Reiman et al., 2004). The investigators performed PET and MRI scans and 

conducted neuropsychological tests on 

24 healthy participants, 12 of whom were 

APOE-ε4 carriers and 12 were not. The 

two groups did not differ significantly in 

gender, age, educational level, neuropsychological test scores, or other characteristics. 

Results of this study were consistent with 

previous studies in that the researchers 

found that APOE-ε4 carriers had abnormally low rates of glucose metabolism in 

the selected brain regions. This study is 

important because it documents the earliest 

brain changes yet seen in living persons at 

risk of AD. These results also provide evidence that AD-like changes in the brains of 

APOE-ε4 carriers can occur in cognitively 
healthy young adults. Tracking brain and 

cognitive changes over time will be necessary to determine how this pattern of ADlike brain changes relates to the likelihood 

that APOE-ε4 carriers will develop AD at 

a later age. If these functional brain changes 

are eventually validated as an early predictor 

of AD, very early intervention and treatment will become a possibility.

Another study from the same group compared memory decline and new learning in 

APOE-ε4 carriers and noncarriers aged 48 to 

77 over a 2-year period. These investigators 

and colleagues from several other research 

sites in Arizona found that APOE-ε4

carriers aged 60 and older showed a decline 

in new learning as compared with noncarriers 

(Baxter et al., 2003). No difference in cognitive performance was seen in those younger 

than 60 years old. These findings suggest 

that repeat testing of new learning over time 

may be a sensitive measure for detecting early 

cognitive changes in older people who are at 

increased risk of AD.

In a follow-up study with a larger group 

of participants and a longer study period, 

the Arizona researchers examined whether 

Identifying changes in the activity 

level of genes in the brain over an 

organism’s lifespan may implicate 

genes that protect brain health, as 

well as those that contribute to agerelated brain disorders. Similarly, 

gene expression related to critical 

behaviors, such as learning and 

memory, which change with normal 

aging and age-related disorders, 

might point to sites for possible 

therapeutic interventions. One way 

to look for gene expression that 

changes with age and with cognitive impairment is to use a powerful new technology called a gene 

microarray analysis. In this type of 

analysis, thousands of genes are 

quickly screened to detect expression changes in cells or pieces of 

tissue. Two recent gene microarray 

studies show the potential of this 

technology.

In the first study, Harvard Medical 

School investigators conducted a 

gene microarray analysis of one 

brain region—the frontal cortex—

from individuals ranging in age from 

26 to 106 (Lu et al., 2004). The profile 

showed that a set of genes with 

reduced expression after age 40 

could be identified. These genes play 

key roles in the healthy functioning 

of synapses, neuronal transport, and 

mitochondrial function. In the older 

individuals, the investigators also 

found increased expression of genes 

that mediate stress responses, 

inflammatory or immune responses, 

antioxidants, and DNA repair. In particular, they found that DNA damage 

to the regulatory regions of certain 

genes was markedly increased in the 

cortex by age 40 and was prominent 

by age 70. The regulatory regions 

of the same genes were selectively 

damaged by oxidative stress in 

human neurons in tissue culture. 

In the second study, scientists at 

the University of Kentucky College 

of Medicine grappled with a fundamental challenge posed by gene 

microarray studies—how to analyze 

the enormous amounts of data gathered in order to obtain useful and 

reliable information. The investigators used a sophisticated, statistical 

approach to validate data on gene 

expression patterns in rat hippocampal 

tissue (Blalock et al., 2004). 

Based on the pattern of changes 

in gene activity related to aging and 

cognition revealed by the microarray 

analysis, the investigators were able 

to suggest a model of brain aging in 

which loss of neuronal processes and 

other changes in nerve cells fuel brain 

inflammation, eventually leading to 

impaired neuronal function and cognition. Again, most of the gene expression changes became apparent in 

mid-life, at a time when cognition was 

not impaired, suggesting that changes 

in gene activity in the brain in early 

adulthood might initiate cellular or 

biological changes that could lead to 

functional changes later in life. 

As more microarray studies 

of aging and AD are published, 

common features of gene expression changes will be found. Insights 

from these studies will advance our 

understanding of the molecular basis 

of normal brain aging and may point 

to ways in which people can make 

the most of their brain function to 

enhance healthy aging.

Gene Analysis Provides a Window on Very Early 

Brain Changes That Could Signal AD Development 

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memory loss could be detected in carriers 

of APOE-ε4 before the onset of amnestic 

MCI (Caselli et al., 2004). The cognitive abilities of a group of 212 cognitively 

healthy middle-aged to older adults were 

evaluated over approximately 33 months. 

In this study, the investigators did find 

that APOE-ε4 carriers older than age 50 

showed a modest decline in a number of 

memory skills compared to noncarriers of 

the same age, but they detected no differences in language, spatial skills, or executive functioning. As with the other studies, 

the authors emphasize that more work 

is needed before the relationship, if any, 

between memory decline and MCI or AD 

can be determined.

Other investigators have looked at the 

occurrence of APOE-ε4 across a number 

of neurodegenerative diseases. A research 

team from the Mayo Clinic in Rochester, 

Minnesota, and Jacksonville, Florida, and 

the London School of Hygiene, assessed 

whether the presence of the APOE-ε4

allele influenced the frequency of AD-like 

pathology in dementia with Lewy bodies, 

frontotemporal degeneration, progressive 

supranuclear palsy, corticobasal degeneration, and multiple system atrophy (Josephs 

et al., 2004). They found that this allele 

strongly influenced the occurrence of ADlike damage in these diseases, particularly 

in dementia with Lewy bodies and multiple 

system atrophy. Further study is needed to 

find out why APOE-ε4 appears to have a 

larger effect in these diseases than in others.

A group of investigators from the 

Cache County Study has reported on 

recent genetic findings about whether 

AD is an inevitable consequence of aging 

(Khachaturian et al., 2004). The Cache 

County Study, a long-term study of 5,000 

people in Cache County, Utah, provides a 

unique perspective on AD because the participating population is one of the longest 

lived in the United States. It includes about 

700 individuals older than 85 and almost 

250 who are 90 years old and older. This 

aspect of the study allowed the investigators 

to explore one AD puzzle: 

We know that the risk of 

AD increases with age, but 

we don’t know much about 

the proportion of people 

who would be likely to get 

AD over an extended lifetime, say 100 years, or about the effect of 

APOE-ε4 over that time period. Using 

several types of analytic models, these 

investigators set out to estimate the risk 

of developing AD as a function of age and 

number of APOE-ε4 alleles. The models 

estimated that 28 percent of individuals 

would not develop AD over any reasonable life expectancy. They confirmed that 

AD onset is accelerated in individuals with 

one, and especially two, APOE-ε4 alleles, 

but did not see any meaningful difference 

in lifetime risk of developing AD related to 

number of APOE-ε4 alleles. The authors 

concluded that this population contains 

individuals who are not susceptible to 

developing AD at an advanced age, regardless of which APOE allele they may carry. 

Discovering the genetic or environmental 

factors that are responsible for this resilience 

is clearly a high priority for future research.

Finally, scientists have used a genetics 

approach to examine late-life depression, a 

condition that is often associated with cognitive impairment and is a risk factor for 

Discovering the genetic or environmental 

factors responsible for AD is clearly a high priority 

for future research.
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the development of dementia and AD. 

To determine whether the presence of 

APOE-ε4 could explain the linkage of 

this form of depression with dementia, 

University of Pittsburgh investigators 

funded by NIMH and NIA analyzed how 

frequently the different forms of APOE 

occurred in patients with depression compared to healthy older adults and people 

with AD (Butters et al., 2003). As expected, 

APOE-ε4 occurred more frequently in individuals with AD. However, the frequency 

of APOE-ε4 was not higher in those with 

depression compared to the healthy study 

participants. APOE-ε4 frequency also did 

not differ among depressed participants 

with and without accompanying cognitive impairment. Unexpectedly, the onset 

of depression occurred at a younger age for 

APOE-ε4 carriers compared to noncarriers. 

These results indicate that APOE-ε4 is 

associated with the age of onset of late-life 

depression, but not cognitive functioning 

in that condition. Further studies will be 

required to elucidate the avenues through 

which late-life depression may contribute 

to the onset of AD. 

Lifestyle and Dietary Patterns

The possible impact of environmental 

and lifestyle factors, such as intellectually 

stimulating activities, physical activity, and 

diet, on AD risk is becoming an increased 

focus of research. A number of studies over 

the past few years have provided intriguing 

hints that these factors may be linked to a 

reduced risk of AD, and they are consistent 

with what we know about other benefits 

associated with health-promoting behaviors 

throughout life. It is important to note, 

however, that these factors have been identified in observational and animal studies, 

and at present, they are only associated with 

changes in AD risk. Only further research, 

including clinical trials, will reveal whether, 

in fact, these factors can help prevent AD.

Recent studies have looked at these 

environmental and lifestyle issues from 

various aspects. For example, researchers 

from the Rush ADC found reduced 

AD risk among participants in 

a Chicago Health and Aging 

Project study who consumed 

fish frequently and whose 

diet was high in unsaturated, unhydrogenated 

fats (Morris et al., 2003a; 

Morris et al., 2003b). In 

this CHAP study, complete dietary intake and 

disease diagnosis data were 

available on 815 people, and 

the length of follow-up between 

dietary assessment and clinical evaluation 

was about 2.3 years. CHAP investigators 

found that participants who consumed 

one or more fish meals per week had a 60 

percent reduced risk of AD compared to 

participants who seldom or never ate fish. 

People whose diets were higher in polyunsaturated and vegetable fats also had a 

reduced AD risk compared to those whose 

fat intake was predominantly saturated 

fats. Though these studies support other 

research showing health benefits related to 

fish and unsaturated fat consumption and 

provide some intriguing hints about AD, 

the authors caution that further studies are 

needed before dietary recommendations can 

be made based on a relationship to AD risk.

In another study, NIA-funded 

researchers used data from the HonoluluAsia Aging Study to find out whether 

certain dietary antioxidant intakes could 

reduce oxidative stress and thereby reduce 

dementia risk (Laurin et al., 2004). This 

study of approximately 3,700 JapaneseAmericans focused on possible relationships 

between vascular factors—such as blood 
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pressure, blood cholesterol, and inflammation—and the later development of 

dementias such as AD. The team found no 

association between risk of dementia and 

mid-life intakes of antioxidants such as vitamins E and C and beta-carotene.

A considerable amount of research also 

has been devoted to examining the role 

of educational attainment on AD risk. 

One recent study, conducted by investigators at Harvard Medical School, used data 

from the long-term Nurses’ Health Study 

of 16,596 older female registered nurses 

to assess the relationship of educational 

attainment, husband’s education, household income, and childhood socioeconomic 

status to cognitive function and decline 

(Lee et al., 2003). The study participants 

had an initial cognitive assessment in the 

late 1990s and a second assessment about 

2 years later. The investigators found that 

women with a graduate degree had substantially decreased odds of a low initial 

cognitive score and of cognitive decline over 

the 2 years compared to women with less 

education. The other measures of socioeconomic status considered in this study had 

little, if any, relation to cognitive function 

or decline in later life.

In the past few years, several research 

groups have attempted to link participation in leisure activities with a lower risk 

of dementia. However, the exact relationship remains unclear. Scientists do not 

know whether increased participation in 

leisure activities lowers the risk of dementia 

or whether people who later develop 

dementia participate less in leisure activities because they are already in the early 

phase of dementia, before symptoms are 

evident. Investigators from the Albert 

Einstein College of Medicine in New York 

City explored this issue in a group of 469 

cognitively healthy people who were older 

than age 75 and still living in the community (Verghese et al., 2003). Over a period 

of about 5 years, 124 people developed 

dementia. Based on a statistical analysis, 

the investigators concluded that participation in leisure activities was associated 

with a reduced risk of dementia, even after 

adjusting for participants’ initial cognitive 

status and after excluding participants with 

possible preclinical dementia. Controlled 

clinical trials are needed to explore this issue 

further and assess the protective effect of 

leisure activities on the risk of dementia.

In addition to these studies, which suggest an association between particular lifestyle factors and actual AD risk reduction, 

other research provides indirect indications 

that lifestyle factors may be related in some 

way to AD risk. For example, a recent collaborative study by investigators at the 
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University of Toronto and the University 

of California at Irvine assessed whether 

long-term treatment with a combination 

of “behavioral enrichment” (extra attention 

and lots of training and stimulation) and a 

diet rich in antioxidants, including vitamins 

E and C, and fruit and vegetable extracts 

could reduce age-related cognitive decline 

in dogs (Milgram et al., 2004). Dogs are a 

good model for studying AD because they 

can perform sophisticated and complex 

cognitive behaviors, their brains accumulate beta-amyloid plaques with age, and the 

degree of beta-amyloid deposition is related 

to the severity of cognitive decline. This 

study included both old and young dogs. 

Some received the fortified food and the 

enriched environment, some received one 

or the other enrichment, and some received 

neither. At the end of a year, the researchers 

tested the dogs on two learning tasks. Not 

surprisingly, the researchers found that the 

old dogs performed less well than the

young dogs. However, 

the performance of the 

old dogs was improved 

by the fortified food 

and behavioral enrichment. The effects of 

the treatments were 

most evident in the

dogs who received both interventions.

Accumulating evidence also suggests 

that being physically active may benefit 

more than just our hearts and waistlines. 

Research in animals has shown that aspects 

of both brain function and cognitive 

function improve with physical exercise. 

Several studies in aging adults have shown 

similar results. One study, conducted by 

researchers at the University of Illinois at 

Urbana-Champaign, used a form of MRI 

to measure changes in brain activity in 

healthy adults aged 58 to 78 before and 

after a 6-month program of brisk walking 

(Colcombe et al., 2004). The researchers 

found that the function of neurons in key 

parts of the brain increased along with 

improvements in the participants’ cardiovascular fitness. Compared to a physically 

inactive group, the walkers were able to 

pay attention better and focus more clearly 

on goals while disregarding unimportant 

information. Scientists working in this 

area speculate that physical activity may be 

beneficial because it may improve blood 

flow to the brain. Another possibility under 

investigation is that physical activity triggers 

cellular mechanisms that protect the brain 

from damage and promote its repair.

Vascular Disease and AD

In recent years, a number of studies 

have suggested that vascular diseases—heart 

disease and stroke—may contribute to the 

development of AD, the severity of AD 

dementia, or the development of multiinfarct dementia (a type of dementia that 

results from multiple strokes). If this is true, 

it may have great scientific importance for 

two reasons. First, it may help investigators 

understand the origins of AD by encouraging them to focus attention on particular 

aspects of damage to the brain, such as 

microscopic strokes. Second, new avenues 

for preventive or delaying strategies may be 

possible if it becomes clear that modifiable 

risk factors for vascular disease (such as high 

cholesterol and high blood pressure) also are 

risk factors of AD or of degree of dementia. 

Accumulating evidence suggests that being 

physically active may benefit more than just our 

hearts and waistlines. 
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Recently, five research teams working in 

separate large-scale epidemiologic studies 

explored whether vascular disease affects the 

likelihood of developing AD:

Using data from the Washington 

Heights-Inwood Columbia Aging Project, 

a study of aging and dementia in New York 

City that includes 1,766 Medicare recipients, investigators found that the risk of AD 

was 60 percent higher in individuals with a 

history of stroke compared with individuals 

without such a history (Honig et al., 2003). 

The risk of AD was particularly great if 

hypertension, type II diabetes, or heart 

disease also was present.

Boston University School of Medicine 

researchers working on the long-standing 

Framingham Study studied a group 

that had not had a stroke and did not 

have dementia (Ivan et al., 2004). The 

researchers found that those participants 

who went on to have a nonfatal stroke 

were twice as likely to develop dementia 

as those who did not experience a stroke. 

This finding underscores the importance of 

stroke prevention in reducing the possible 

risk of dementia.

A group of scientists analyzed data 

from the University of Washington/Group 

Health Cooperative Alzheimer’s Disease 

Patient Registry and found that people 

with the same level of cognitive decline in 

AD who also had vascular damage had less 

severe AD pathology in brain tissue than 

those with AD alone (Riekse et al., 2004). 

These findings suggest that cerebrovascular 

disease may act to increase the severity 

of the cognitive impairment in people 

with AD.

An analysis of data from the 

Honolulu-Asia Aging Study showed 

that high blood pressure during mid-life 

increased the risk of dementia later in life. 

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■

■

Study participants who had high diastolic 

blood pressure, but who were never treated 

for hypertension, had an increased risk of 

atrophy in the hippocampal region of the 

brain (Korf et al., 2004). The authors suggest that early treatment of hypertension 

may reduce this risk.

Finally, researchers at the Rush ADC 

and Rush Institute for Healthy Aging in 

Chicago, conducted a long-term clinical 

and pathology study as part of the ongoing 

Religious Orders Study (Schneider et al., 

2004). These scientists found that brain 

infarction (a stroke occurring in blood vessels in the brain) and AD pathology each 

contributed to an increased likelihood of 

dementia. In particular, the odds of developing dementia increased nearly three-fold 

if evidence of one or more brain infarctions was present. Brain infarctions and AD 

pathology contributed jointly to a greater 

risk of developing dementia than would be 

indicated by either condition alone.

Since 1988, the National Heart, 

Lung, and Blood Institute has funded the 

Cardiovascular Health Study (CHS), a 

long-term study of risk factors for the development and progression of coronary heart 

disease (CHD) and stroke in elderly adults. 

This study has provided valuable data about 

the relationships between cardiovascular risk 

factors and AD, and it includes cognitive 

decline and dementia related to vascular 

disease as a key element of its design. One 

of the distinguishing features of the study 

has been add-on components funded by 

other NIH Institutes, including NIA. These 

add-ons have provided a cost-effective 

opportunity for investigators to use existing 

study populations to explore issues that 

were not part of the original study design. 

In the past 2 years, CHS study investigators 

from the University of Washington and the 

University of Pittsburgh have made several 

advances important to AD research. These 

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studies have laid the groundwork for future 

examinations of the interactions between 

cerebrovascular risk factors, AD, MCI, 

and dementia:

The researchers have developed a 

methodology for conducting long-term 

dementia evaluations (Lopez et al., 2003a). 

In 1991, they conducted MRIs on approximately 3,600 CHS participants. This large 

and diverse study population is a particular 

strength of the CHS. This same group of 

participants received cognitive function evaluations every year thereafter, 

and, from 1998 to 2000, 

they also were evaluated 

for dementia through 

detailed neurological and 

neuropsychological exams. 

Not only was this the largest-ever 

study of dementia to include cognitive testing, MRI, and examination of 

genetic markers, but it provides a methodology that other researchers can use 

to study dementia in large groups. 

The investigators assessed the incidence of dementia, vascular dementia, and 

AD across the CHS population who had 

received the MRIs (Fitzpatrick et al., 2004). 

There was no indication of sex or racial differences, but strong associations with education and APOE-ε4 status were apparent. 

Compared with results from other studies, 

the incidence of vascular dementia was 

higher than expected. 

Investigators found that particular 

measures of cognitive function, APOE-ε4 

status, and brain tissue characteristics as 

seen on MRI were strong predictors of both 

dementia and AD in the CHS population 

(Kuller et al., 2003). 

The research team found that 22 percent of the participants aged 75 or older 

had amnestic MCI. Most of these people 

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■

■

had other health problems as well, which 

affected their cognitive function (Lopez et 

al., 2003b). The research team also discovered that the people who developed this 

form of MCI were more likely to suffer 

from depression, be African-American, have 

a relatively low educational level, carry the 

APOE-ε4 allele, or have cerebrovascular 

disease (Lopez et al., 2003c). Presence of 

the APOE-ε4 allele was linked only to 

amnestic MCI. Though these findings are 

intriguing, additional research is necessary 

to determine exactly how these factors are 

associated with MCI risk. 

In collaboration with NIA researchers, 

a group of scientists at the University of 

California at San Francisco took a somewhat different look at vascular risk factors 

and the risk of cognitive decline (Yaffe et 

al., 2004a). These researchers wanted to 

determine whether an earlier stage of the 

cardiovascular disease process—metabolic 

syndrome—increased the risk of cognitive 

decline. Metabolic syndrome, a constellation of factors that increases heart disease 

risk, includes abdominal obesity, high 

triglyceride levels, low HDL (“good 

cholesterol”) levels, high blood pressure, 

and insulin resistance (an impaired ability 

to use insulin). The researchers also wanted 

to see whether vascular inflammation—

another heart disease risk factor—modified 

possible associations between metabolic 

syndrome and cognitive decline. The 

investigators worked with participants of 

The Cardiovascular Health Study has provided 

valuable data about the relationships between 

cardiovascular risk factors and AD.
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the Health, Aging, and Body Composition 

study, a 1997 to 2002 study of 3,075 older 

adults living in Memphis and Pittsburgh. 

The researchers found that those participants with metabolic syndrome had an 

increased risk of cognitive impairment and 

decline, even adjusting for other demographic and lifestyle factors. The increased 

risk of cognitive impairment was seen primarily in participants who had high levels 

of inflammation markers in their blood. 

This suggests that at least some of the 

increased risk associated with metabolic syndrome is caused by inflammation. Though 

these results are consistent with the findings 

of other studies, further research is clearly 

needed to determine whether reducing risk 

factors for cardiovascular disease or lowering 

inflammation can reduce the risk of cognitive impairment in older adults.

Another aspect of heart disease risk 

that has been of continuing interest to 

both heart disease and AD researchers is 

homocysteine. Previous epidemiologic 

studies have shown that elevated levels 

of this amino acid, which is a risk factor 

for heart disease, are associated with an 

increased risk of developing AD. Basic 

science studies have shown that high 

homocysteine levels make some neurons 

vulnerable to dysfunction and death and 

that an enzyme called betaine-homocysteine methyltransferase (BHMT) may play 

a major role in regulating homocysteine 

levels in the blood. However, little is known 

about the properties of BHMT and the 

extent to which genetic variations in the 

enzyme might contribute to abnormally 

high levels of homocysteine. University of 

Illinois scientists funded by NIDDK have 

been trying to fill these knowledge gaps 

and recently found that BHMT functions 

only when it is in a certain structural form 

(Szegedi and Garrow, 2004). Additional 

studies will help to clarify the relationship 

between BHMT structure and function.

Diabetes and AD

The possible association of diabetes, 

insulin, and AD also is garnering increasing 

attention. Type II diabetes mellitus is a 

serious public health problem in the U.S. 

The condition affects about one in five 

people over age 65 and has been associated with a variety of adverse health effects. 

Evidence from a number of epidemiologic 

studies suggests a possible link between 

diabetes and cognitive impairment, and 

this has spurred researchers to examine this 

link on many levels, from test tube investigations to population studies. The idea 

behind this area of research is to determine 

whether or not diabetes is a risk factor 

for cognitive decline, and if so, whether 

therapies for diabetes may help lower risk 

of cognitive decline or AD. 

One way that researchers are looking at 

the association between diabetes, cognitive 

problems, and AD is through epidemiologic studies. Recent long-term studies have 

linked diabetes to cognitive function in four 

distinct populations: Catholic nuns, priests, 

and brothers older than 55; female registered nurses aged 70 to 81; postmenopausal 

women with osteoporosis; and whites aged 

42 to 89 years old and living in the community. In the first of these studies, conducted by investigators at the Rush ADC, 

participants of the Religious Orders Study 

underwent annual assessments of five cognitive “systems” that are commonly affected 

by aging, dementia, and AD (Arvanitakis et 

al., 2004). Over the 5.5-year study period, 

151 people were diagnosed with AD, 

including 31 who had diabetes. An analysis 

of the study data revealed that the risk of 

developing AD was 65 percent higher in 

people with diabetes than in those who did 
not have diabetes. The study also showed 

that diabetes appears to affect different 

cognitive systems differently, with the area 

of perceptual speed (the speed with which 

simple comparisons can be made) being 

most affected.

In the second study, investigators from 

the Harvard School of Public Health, 

working with participants in the Nurses’ 

Health Study, found that women with 

diabetes performed worse on a range of 

cognitive tests than did women without diabetes (Logroscino et al., 2004). The odds of 

cognitive difficulties were particularly high 

for those women who had had diabetes for 

a long time. Interestingly, women who were 

taking oral diabetes medications performed 

as well on the cognitive performance tests 

as did women without diabetes.

Researchers from the University of 

California at San Francisco investigated 

As we now know, the gammasecretase enzyme complex is 

essential to APP metabolism and 

the formation of beta-amyloid (see 

p. 26 for more on gamma-secretase). 

However, new studies are showing 

that the milieu and place where the 

gamma-secretase functions may be 

just as important. 

APP is cleaved in cholesterolrich domains, also called “lipid 

rafts,” which are found in the cell 

membrane of the neuron (Vetrivel et 

al., 2004). This fact is central to the 

thesis that cholesterol and ApoE (the 

principal cholesterol carrier in the 

brain and major risk factor for earlyand late-onset AD) have direct roles 

in AD pathology. 

Scientists are now speculating 

about whether disturbances in 

brain cholesterol could contribute 

to AD development and progression. Though knowledge in this area 

is growing, many questions remain 

about how cholesterol affects the 

processing of APP and formation 

of beta-amyloid.

Research in this area began 

with a study that showed that betaamyloid deposits increased in the 

hippocampal neurons of rabbits 

fed a cholesterol-rich diet for 

2 months. Since then, other studies 

using cells in culture and transgenic mice and guinea pigs, have 

confirmed and extended those 

experiments. Complementing this 

work, other studies showed that 

when AD transgenic mice were 

given a certain statin drug, not only 

did their blood cholesterol levels 

decrease, but levels of toxic betaamyloid in the brain were significantly reduced (Petanceska et al., 

2003). Importantly, two other studies 

pointed to a decreased incidence of 

AD and dementia in individuals with 

coronary artery disease who were 

treated with statins. Clinical trials 

testing statins in AD progression are 

underway, and those results should 

allow for definitive recommendations 

concerning the use of statins against 

AD (see p. 57 for more about one 

such trial). 

Basic research is being conducted to answer a key question: 

How does cholesterol alter betaamyloid production? Recent work 

by a team of NIA investigators may 

provide some clues. These experiments measured amounts of different 

lipids in brain cells from people with 

AD and healthy older people. The 

investigators found much higher 

levels of cholesterol in the brain 

cells from the people with AD. They 

also found a lipid called ceramide 

specifically in brain regions important for learning and memory. These 

lipid abnormalities were associated 

with increased damage to nerve 

cells caused by free radicals (Cutler 

et al., 2004). 

When the investigators exposed 

other neurons to beta-amyloid, similar 

increases in cholesterol and ceramide 

occurred. The lipid abnormalities 

were prevented, and the neurons 

were protected from beta-amyloid 

toxicity when they were treated with 

the antioxidant vitamin E or a drug 

called ISP-1, which prevents the 

accumulation of ceramide. 

These findings suggest a sequence 

of events that causes degeneration 

of nerve cells in AD: Beta-amyloid 

induces oxidative stress, resulting 

in disturbed ceramide and cholesterol metabolism. This disturbance, 

in turn, triggers a neurodegenerative cascade that leads to clinical 

disease. Although additional studies 

are clearly needed, these findings 

also suggest that diets and drugs 

that target lipid abnormalities may 

someday help in preventing and 

treating AD. 

Intriguing New Evidence about Lipids, 

Cholesterol, and AD

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whether diabetes and impaired fasting 

glucose (IFG, an indicator of increased 

diabetes risk) were linked to cognitive function (Yaffe et al., 2004b). The data for the 

study came from the Multiple Outcomes 

of Raloxifene Evaluation (MORE), a longterm osteoporosis study of more than 7,000 

women between the ages of 31 and 80 (see 

p. 61 for information on MORE). The 

investigators found that the cognitive abilities of women with IFG were lower than 

those of women with normal blood glucose 

levels but higher than those with diabetes. 

They also found a higher risk of developing 

cognitive impairment among the women 

with IFG or diabetes than among the 

women with normal blood glucose levels.

Another University of California at 

San Francisco team of researchers examined the change in cognitive performance 

over a 4-year period among older adults 

participating in a study called the Rancho 

Bernardo Study (Kanaya et al., 2004). 

Participants, who were divided into three 

groups—normal glucose tolerance, impaired 

glucose tolerance, and diabetic—were given 

three different cognitive tests at the beginning of the study and again 4 years later. 

The researchers found that scores on all 

three cognitive function tests did not differ 

across the groups at the beginning of the 

study, but that the women with diabetes 

had a more rapid decline in performance on 

the verbal fluency test over the study period 

compared with women in either of the 

other two groups.

These findings are complemented by 

additional epidemiologic research conducted 

by researchers from the Mt. Sinai School 

of Medicine and Israel’s Tel Aviv University 

and Sheba Medical Center (Schnaider Beeri 

et al., 2004). These investigators, working 

with more than 10,000 male participants in 

the Israeli Ischemic Heart Disease study, also 

found evidence of diabetes as a risk factor 

for dementia. In contrast to other studies, 

however, these researchers linked diabetes in 

midlife to dementia that emerged more than 

35 years later in very old members of the 

study group. 

An analysis of data from the HonoluluAsia Aging Study provides intriguing 

evidence about the possible associations 

between insulin levels and dementia risk 

(Peila et al., 2004). These data showed that 

increasing levels of insulin in the blood 

were associated with an increased risk of 

dementia. Too-high insulin levels can be 

controlled through dietary changes and 

increased physical activity, so this may be 

a modifiable risk factor if future research 

confirms these findings.

Other researchers, such as one team 

from New York University School of 

Medicine, are studying diabetes and cognition through studies with animals and 

small numbers of individuals (Convit et al., 

2003). We know that age is a risk factor for 

both impaired cognition and impaired glucose metabolism, and a relationship between 

these deficits is suspected. It is not clear, 

however, how poor glucose metabolism may 

exert its effect on memory function. One 
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possibility is through the hippocampus, the 

brain structure that is important for learning 

and memory and is one of the earliest 

regions damaged by AD. Rodent studies 

have shown that during performance of a 

memory task, the hippocampus is activated, 

and hippocampal glucose levels drop in specific locations depending on the difficulty of 

the task. In older rodents, the drop in hippocampal glucose levels is more profound 

and lasts longer, perhaps forming a basis 

for impairments in memory performance 

seen in some older animals. Because of this 

vulnerability, subtle metabolic insults may 

lead to damage and volume loss. Using these 

findings as a starting point, the New York 

University investigators conducted memory 

tests with 30 nondiabetic middle-aged 

and older individuals who did not have 

dementia. Simultaneously, they administered 

a glucose tolerance test to measure the participants’ ability to regulate glucose. The 

size of the hippocampus and other brain 

regions was measured with MRI. A decreased 

ability to regulate glucose was associated with 

decreased general cognitive performance, 

memory impairments, and atrophy of the 

hippocampus. This association was not 

related to the participants’ ages. The investigators also found no association between the 

volume of other brain regions and glucose 

regulation. They concluded that a decreased 

ability to regulate glucose is associated with 

modest impairments of memory and that 

the impairments may be the result of a direct 

impact of poor glucose metabolism on brain 

structures important for memory. Based on 

these findings, the researchers suggest that 

memory deficits among older people with 

poorer glucose tolerance may be caused by 

an inability to compensate for the drops in 

hippocampal glucose levels that normally 

occur with activation of brain circuits during 

performance of a memory task. Perhaps 

better lifetime management of blood sugar 

may help maintain memory function in old 

age and perhaps even reduce the risk of hippocampal damage. 

What Can be Done to Slow 

the Progression of AD or 

Lessen its Effects?

The research advances described in the 

two previous sections of this report have 

vastly increased our understanding of brain 

function, the transformation from healthy 

aging to AD, and the factors that influence 

the development of AD. These findings 

have opened doors to a range of potential 

therapeutic approaches being investigated in 

various ways by NIA, other NIH Institutes, 

other research institutions, and private 

industry. Studies are underway on dozens 

of compounds and strategies to:

 Help people with AD maintain cognitive 

function over the short-term;

 Treat AD-associated behavioral and 

neuropsychiatric symptoms; 

Slow the progression of the disease; and

Prevent AD.

As this report has shown, AD research 

has progressed to a point where scientists 

are increasingly able to think about how 

they can intervene to treat AD or perhaps 

even to prevent it. They think about the 

importance of timing—when is it best to 

intervene and what interventions are most 

appropriate at what time? For example, a 

physician would certainly provide different 

treatments to a patient who is having a 

stroke than to a patient who is seemingly 

healthy but at higher risk of having a stroke 

at some point in the future. AD develops 

over the course of years or decades, and a 

person’s brain is affected well before any 

symptoms are evident. It may be that one 

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Recent Findings About Reproductive Hormones, 

Cognitive Health, and AD: An Illustration of the 

Scientific Process at Work

AD research advances over the 

past three decades would not have 

been possible without the various 

threads of scientific inquiry supported by NIH. These threads include 

population studies, basic research in 

laboratories, and studies in animals. 

Findings from these types of studies 

lay the foundation for clinical trials, 

in which interventions are tested for 

safety and effectiveness. 

Sometimes, the process is 

straightforward—observations 

from population studies prompt 

researchers to investigate further 

in laboratory studies with tissue samples and laboratory animals. Positive 

findings from these studies lead to 

several rounds of testing in humans. 

At the end, an effective drug may 

come on the market.

Other times, the process is less 

straightforward—scientists experience setbacks at one stage or 

another and have to “return to the 

drawing board” to rethink their 

hypotheses or methods. Though 

these setbacks can be discouraging, 

they also are useful because they 

often raise issues that ultimately 

lead researchers down entirely 

new and fruitful scientific paths. 

Recent research that has explored 

associations between reproductive 

hormones and AD provides a good 

illustration of the scientific process 

at work.

Estrogen is a hormone produced 

by a woman’s ovaries during her 

childbearing years. It has widespread effects in the brain and 

affects neurotransmitter systems and 

brain regions involved in learning 

and memory. Over the past 25 years, 

laboratory and animal studies and 

observational studies in populations have suggested that estrogen 

has positive effects on cognitive 

function. These findings led to two 

large clinical trials. The Women’s 

Health Initiative Memory Study 

(WHIMS) began in 1995 and was 

designed to study whether hormone 

therapy would decrease the risk 

of developing dementia in older 

women, years after menopause. As 

a sub-study of the Women’s Health 

Initiative (WHI), it was stopped 

when scientists found that WHI participants on hormone therapy were 

at increased risk of heart attacks, 

breast cancer, strokes, and blood 

clots, compared to participants on 

placebo. Women taking the hormone 

treatments also had twice the risk of 

dementia, rather than a decreased 

risk, as hoped. 

Despite this setback, a number 

of NIA studies continue to support 

the idea that estrogen may have a 

positive effect on the brain and is 

one avenue for maintaining healthy 

cognitive function. As scientists plan 

research to explore this issue further, 

they are asking many questions to 

guide their new thinking:

Timing: When in a woman’s life 

is it best to begin hormone therapy? 

How long should it be used?

Administration: Should it be taken 

continuously over time or in ways 

that more closely mirror natural hormone fluctuations? Should high or 

low doses be taken? What is the best 

way to deliver the hormones—a pill 

or a patch?

Type: Can equine estrogen formulations be used in future studies or 

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should only human estrogen 

be used?

Researchers at NIA and others 

funded by NIA also have been 

exploring some preliminary findings 

about possible associations between 

testosterone levels in older men and 

AD risk. In the first observational study 

of its kind, investigators assessed the 

testosterone levels of 574 men, ages 

32 to 87, who were participating in the 

Baltimore Longitudinal Study of Aging. 

Based on physical, neurological, and 

neuropsychological exams, 54 of the 

574 men were diagnosed with AD 

(Moffat et al., 2004).

The research team found that 

for every 50 percent increase in the 

levels of testosterone freely circulating in the bloodstream, there 

was about a 26 percent decrease in 

the risk of developing AD. Although 

overall free testosterone levels fell 

over time, these levels dropped more 

precipitously in those men who later 

developed AD. In fact, at the end of 

the study, men who were diagnosed 

with AD, on average, had about half 

the levels of circulating free testosterone as men who didn’t develop 

the disease. In some cases, the 

drop-offs in free testosterone levels 

associated with AD were detected 

up to a decade before diagnosis.

Study authors speculate that circulating free testosterone may have 

a broad range of influences on the 

aging brain, but they also emphasize that these are early days yet. 

Considerable additional study is 

necessary before firm conclusions 

can be drawn about any possible role 

of testosterone in the development of 

certain types of memory loss and AD.

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kind of intervention with a particular compound or approach may be most effective if 

it is applied well before any symptoms are 

evident. Other interventions may be most 

appropriate for use after AD is established. 

Investigators are working to develop an 

array of options from which clinicians can 

choose. For example, developing new and 

better drugs and broadening the range of 

nondrug therapeutic approaches are critically important for those who already have 

AD because of the long-term nature of the 

disease and its high emotional and physical 

toll. Slowing the progress of the disease and 

alleviating psychiatric and behavioral problems could do much to delay or prevent 

institutionalization, maintain the dignity 

of people with AD, reduce physical and 

emotional stress on caregivers, and reduce 

the financial costs associated with the disease. Finding ways to prevent the disease 

altogether is an increasingly urgent priority 

because of the enormous impact of AD on 

our society. Scientists use clinical trials to 

pursue all of these goals.

Clinical Trials

Clinical trials, which compare a 

potential new treatment with a standard 

treatment or with a placebo, are the only 

way to determine whether a drug, other 

compound, or nondrug approach is effective. These complex and expensive studies 

involve hundreds or even thousands of 

people and are often conducted over a 

long period of time. Some clinical trials are 

focused on treatment strategies—helping 

people with AD preserve cognitive function for as long as possible, for example, or 

helping people with behavioral or psychiatric problems associated with AD. Other 

clinical trials are focused on prevention

strategies—using specific compounds to 

help people reduce the risk of developing 

AD in the future. The sections that follow 

describe some of NIH’s AD treatment and 

prevention clinical trials. Recruitment is 

ongoing for a number of these trials. For 

more information about the clinical trials 

described here and other trials, visit NIA’s 

ADEAR Center website. 

AD Treatment Clinical Trials

The NIH is currently supporting 22 

clinical trials of treatments for people who 

already have AD. Many of these are conducted as part of the Alzheimer’s Disease 

Cooperative Study, an NIA-supported 

national consortium of more than 50 

research sites that conduct clinical trials 

for both cognitive and behavioral symptoms 

of AD. Here are highlights of just a few 

of these trials. 

Divalproex sodium and agitation. An 

ADCS clinical trial of divalproex sodium 

(Valproate), conducted among 150 nursing 

home residents, was designed to see 

whether this medication could ease agitation in people with severe AD. Data from 

this study are being analyzed and results 

should be available before the end of 2005. 

A second trial that has recently begun will 

examine whether divalproex sodium can 

delay or prevent agitation and psychosis 

in individuals with mild to moderate AD. 

Researchers are also interested in seeing 

whether its possible neuroprotective properties have any effect on slowing the rate of 

cognitive decline. 

Simvastatin and AD progression. This 

18-month ADCS trial, which began in 

2003, is testing whether simvastatin (Zocor), 

a commonly prescribed cholesterol-lowering 

drug, can safely and effectively slow the rate 

of disease progression in people with mild to 

moderate AD. Data from epidemiologic and 

animal studies indicate that high cholesterol 

levels increase the risk of AD and that statin 
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drugs specifically may help reduce this 

risk. The trial, which is being conducted 

in about 40 sites nationwide, will enroll 

400 participants. To date, 350 people have 

been enrolled and recruitment of participants continues. Some participants will 

receive 20 mg of simvastatin for 6 weeks 

and then 40 mg of the statin for the rest 

of the study period. Others will receive a 

placebo during the entire study. Clinical 

trial staff are tracking changes in participants’ cognitive health by measuring 

a number of indicators, including mental 

status, functional ability, behavioral disturbances, and quality of life. 

Huperzine A and cognitive function.

This ADCS trial is evaluating whether 

huperzine A, a natural cholinesterase inhibitor derived from the Chinese herb, Huperzia 

serrata, can slow the progression of cognitive 

decline in people with mild to moderate 

AD. A number of small, randomized controlled trials in China have indicated that 

people with AD who were treated with 

huperzine performed better on memory tests 

than those on placebo. Investigators also are 

interested in huperzine because it has antioxidant and neuroprotective properties that 

suggest it may be useful in treating AD. The 

study, which will enroll 150 participants, is 

taking place at about 20 sites nationwide, 

and recruitment is ongoing. Participants 

will be randomly assigned to three equal 

groups—two groups will receive varying 

amounts of huperzine A every day and the 

third group will receive a placebo. All participants will receive huperzine A during the 

last 8 weeks of the 24-week trial. 

Supplements to reduce homocysteine 

and slow the rate of cognitive decline.

High homocysteine levels are associated 

with increased AD risk. Levels of this 

amino acid can be reduced by high-dose 

supplements of folate and vitamins B6 and 

B12. This ADCS clinical trial, which began 

in 2003, is designed to determine whether 

reduction of homocysteine levels with 

high-dose supplements of folate, vitamin 

B6, and vitamin B12 will slow the rate 

of cognitive decline in older adults with 

AD. Participants in this clinical trial were 

divided into two groups: 60 percent of participants will receive daily high-dose supplements (5 mg of folate, 25 mg of vitamin 

B6, 1 mg of vitamin B12) and 40 percent 

will receive a placebo. Enrollment of the 

400 participants has been completed. 

Sertraline to treat depression in AD.

Major depression affects approximately 

25 percent of people who have AD, so 

finding effective ways to treat this condition is an important priority for AD 

research. NIMH-funded researchers at 

Johns Hopkins University are conducting a 

clinical trial to assess the efficacy and safety 

of the antidepressant medication sertraline 

(Zoloft) for the treatment of major depression in AD (Lyketsos et al., 2003). The 

trial is still ongoing, but preliminary results 

from 44 participants indicate that sertraline 

reduced depressive symptoms in 84 percent 

of those treated. In contrast, depressive 

symptoms were reduced in 35 percent of 

those treated with a placebo. Participants 

taking sertraline also experienced a lessening 

of behavioral disturbances, such as apathy, 

anxiety, or irritability, and improvements 

in activities of daily living, such as bathing, 

dressing, and feeding. Their cognitive 

functions did not improve, however. The 

research team is continuing this trial with 

other groups of people with AD in hopes 

that similar treatment with antidepressant 

medication can benefit those with milder 

depression or with differing profiles of 

depressive symptoms.
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Atypical antipsychotics to treat psychosis in AD. NIMH-funded investigators 

at the University of Southern California 

Keck School of Medicine have recently 

completed a clinical trial called the Clinical 

Antipsychotic Trials of Intervention 

Effectiveness (CATIE) (Schneider et al., 

2003). This trial was designed to assess the 

effectiveness of atypical antipsychotic drugs 

for use in people with AD who experience 

hallucinations, delusions, or agitation. These 

symptoms are very common in people with 

AD, and they can be very distressing to caregivers. The trial ended in October 2004, and 

publication of results is underway.

AD Pilot Treatment Trials

Before beginning a full-scale clinical 

trial, NIH Institutes often conduct pilot 

clinical trials to collect initial data on the 

safety, effectiveness, and best dosage of a 

potential treatment. These data help the 

Institutes determine which interventions 

should go to the next step. Here are highlights of a few current pilot clinical trials 

in AD: 

Combination vitamin supplement 

in the treatment of AD in Down syndrome. This high-potency supplement 

consists of two cellular antioxidants 

(vitamins E and C) and a mitochondrial 

antioxidant (alpha-lipoic acid). The aims 

of this 24-month intervention trial are 

to determine whether cognitive function 

improves with antioxidant supplementation 

and to determine its safety and tolerability. 

Nicotine skin patch and amnestic MCI.

Some of the 60 participants in this study 

will be given the nicotine patch and others 

a placebo patch. Research has suggested 

that one of the causes of memory disorders 

may be a reduction in the neurotransmitter 

acetylcholine. Acetylcholine is critically 

important in the process of forming memories, and nicotine imitates many of the 

actions of acetylcholine. Preliminary studies 

have suggested that short-term administration of nicotine appears to improve memory 

in patients with mild memory loss and early 

AD. Furthermore, nicotine administration 

appears to have significant neuroprotective 

effects, and it may have positive influences 

on APP processing. The primary goal of this 

pilot trial is to demonstrate whether the nicotine patch is safe to administer to the nonsmoking amnestic MCI participants over a 

1-year period. Study investigators also hope 

to determine whether nicotine can improve 

memory loss symptoms over the longer term 

and whether it can help delay the progression of memory loss symptoms. 

Rosiglitazone and amnestic MCI. This 

18-month clinical trial will test whether 

rosiglitazone (Avandia), a drug that has 

anti-inflammatory properties and that 

improves sensitivity to insulin, can improve 

memory in people who have amnestic MCI. 

Epidemiologic studies indicate that people 

with insulin resistance are at increased risk 

for both MCI and AD. Insulin resistance 

also is associated with inflammation, which 
may increase AD risk through several mechanisms. These findings provide the rationale 

for this novel treatment strategy. Study participants will be divided into two groups—

one group will receive the rosiglitazone, the 

other a placebo. 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. This 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 biomarkers in MCI 

with memory loss.

AD Prevention Trials 

NIH is currently conducting seven 

AD prevention clinical trials. Although 

two of these trials have been suspended, 

investigators are still periodically assessing 

the participants’ health. 

People With Early AD Can Still Learn

The extent to which people with 

early-stage AD can learn new information and use it to perform daily 

tasks is not clear, and this is an area 

of vital importance to people with 

AD and their families. 

Cognitive rehabilitation strategies have been shown to improve 

performance on memory and other 

cognitive measures in other brain 

disorders, such as traumatic brain 

injury and stroke, and some of 

these same techniques have shown 

promise in their ability to enhance 

learning in people with AD. However, 

until now, no systematically applied 

cognitive rehabilitation program for 

people with AD has incorporated 

all the techniques available. 

In a clinical trial at the University of Miami Medical Center/Mt. 

Sinai Medical Center, in Miami 

Beach, 44 people with AD were 

randomly assigned into two groups 

(Loewenstein et al., 2004). All 

participants in the study were 

taking donepezil (Aricept) or similar 

medications. The 25 people in a 

“cognitive rehabilitation” (CR) group 

participated in two 45-minute sessions weekly for a total of 24 sessions. During these sessions, they 

learned face-name recognition 

techniques, such as associating a 

prominent facial feature with a name. 

To enhance time and place orientation, CR participants were given 

memory notebooks and encouraged 

to record appointments, medication 

schedules, and contact information 

for relatives, friends, and doctors. 

They also were taught effective ways 

to make change for a purchase and 

were asked to use a calculator to 

balance a checkbook after paying 

three bills. In addition, they learned 

to click a mouse button in response 

to yellow boxes that randomly 

appeared on a computer screen. This 

technique was designed to improve 

attention span and cognitive processing speed. Finally, the CR group 

was asked to manipulate objects, 

such as a key, as though they were 

using them. Participants and their 

caregivers were encouraged to practice all of these techniques at home. 

The 19 participants in a control 

“mental stimulation” (MS) group 

played computer games that required 

memory, concentration, and problemsolving skills. In addition, participants 

in this group were asked to discuss 

various topics, such as describing 

the neighborhood in which they 

grew up. They also were asked to do 

crossword puzzles, word scrambles, 

and other “homework” assignments. 

At the end of the study, those in 

the CR group showed, on average, 

significantly improved ability to 

associate faces and names, had 

faster mental processing speeds, 

were better oriented to time and 

place, and were better able to make 

correct change for purchases than 

those in the MS group. However, 

neither group showed memory 

improvement for manipulating 

objects or balancing a checkbook. 

The improvements were still evident 3 months after the cognitive 

training ended. 

This promising study suggests 

that some people with early cognitive impairment can still be taught to 

recall important information and to 

perform daily tasks better. It is the 

first trial to combine several specific 

cognitive memory techniques into 

a single rehabilitation program for 

those who are mildly impaired with 

AD. The study shows that people 

with early AD can learn, and that 

learning can be enhanced by using 

specific cognitive rehabilitation 

strategies. Thus, people with AD 

can be helped to remain engaged 

in daily activities and retain a connection to family, friends, and the 

world around them for a longer 

period of time. 

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Some prevention trials are exploring the 

potential of drugs and other compounds 

that already have been tested as treatments in people with established AD. 

Even when results have indicated that the 

compounds are not effective treatments for 

people who already have AD, enough laboratory, animal, and epidemiologic evidence 

exists to suggest that they may still have a 

potentially useful preventive function. Here 

are highlights from a few AD prevention 

studies.

The Multiple Outcomes of Raloxifene 

Evaluation. This clinical trial, conducted 

with nearly 5,400 postmenopausal women 

with osteoporosis, was designed to determine whether treatment with raloxifene 

(Evista), a selective estrogen receptor 

modulator (SERM) that is used to treat 

osteoporosis, affects the risk of developing 

AD and cognitive impairment (Yaffe et al., 

2005). The women were divided into three 

groups: one group received a placebo, one 

group received 60 mg of the drug every 

day, and the third group received 120 mg 

daily. After 3 years of treatment, the 60 mg 

group and the placebo group did not differ. 

However, women who took 120 mg had a 

statistically significantly lower risk of developing MCI and a somewhat lower risk of 

developing AD and any cognitive impairment than did the women who took the 

placebo. Additional clinical trials are 

needed to confirm these results.

The Memory Impairment Study. Over 

the course of 3 years, this study compared 

the effectiveness of vitamin E, donepezil 

(Aricept), and a placebo in delaying the 

onset of a diagnosis of AD in 769 people 

with amnestic MCI. Results indicated 

that participants taking donepezil were at 

reduced risk of progressing to AD during 

the first 12 months of the study, but 

this benefit disappeared by 18 months 

(Petersen et al., 2005b). However, in 

the subset of patients who carried the 

APOE-ε4 allele, donepezil appeared to 

decrease the risk of progression to a diagnosis of AD for the full 36 months of the 

study. Vitamin E did not appear to slow the 

progression to AD. The investigators are 

conducting additional analyses to determine 

why donepezil’s effect dropped off over 

time and to assess the practical and clinical 

implications of this complex study. 

 This landmark MCI trial, which took 

place in 69 sites in the U.S. and Canada, 

represents a major advance in clinical trial 

methodology, as it demonstrated that 

investigators could use standardized criteria 

in a multi-center trial to define and differentiate individuals with amnestic MCI, 

healthy people, and those with AD. Future 

clinical trials in people with this type of 

MCI should be instrumental in research to 

detect, treat, and delay AD (Grundman 

et al., 2004). 

NSAIDs and inflammation. Some 

epidemiologic studies have suggested that 

NSAIDs might help slow the progression 

of AD, but clinical trials thus far have not 

demonstrated a benefit from these drugs. 

A clinical trial studying two of these drugs, 

rofecoxib (Vioxx) and naproxen (Aleve) 

showed that they did not delay the progression of AD in people who already have the 

disease. Treatment in another trial, testing 

whether the NSAIDs celecoxib (Celebrex) 

and naproxen could prevent AD in healthy 

older people at risk of the disease, was suspended after some participants showed indications of increased cardiovascular risk with 

long-term use of these drugs. Investigators 

are examining data about possible cardiovascular risk and continue to assess the 

participants’ health periodically. However, 
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researchers are continuing to look for ways 

to test how other anti-inflammatory drugs 

might affect the development or progression 

of AD.

The Prevention of Alzheimer’s 

Disease with Vitamin E and Selenium 

(PREADVISE) trial. This trial is NIA’s 

add-on to NCI’s Selenium and Vitamin E 

Cancer Prevention Trial (SELECT), which 

is evaluating whether taking selenium and/

or vitamin E supplements can prevent prostate cancer in healthy men older than 60. 

PREADVISE is evaluating whether these 

agents can help prevent memory loss and 

dementia, such as that found in AD. Studies 

show that increased oxidative stress may 

damage brain cells and is linked with AD. 

Animal and tissue culture studies of vitamin 

E and selenium suggest that they can protect 

brain cells from oxidative damage. 

Ginkgo biloba. Extracts of leaves 

from the ginkgo tree are thought to have 

beneficial effects on brain function, especially those related to dementia and AD. 

NIA is co-funding a National Center for 

Complementary and Alternative Medicine 

prevention trial comparing ginkgo to placebo in more than 3,000 people older than 

70 who are cognitively healthy at the beginning of the trial. The study’s results should 

indicate whether ginkgo is helpful in preventing or delaying the onset of dementia. 

As part of this trial, University of Pittsburgh 

investigators have used brain imaging techniques to determine whether cognitively 

healthy individuals and those with amnestic 

MCI show any differences in activation in 

specific parts of the brain that are normally 

related to an aspect of cognitive function 

called attentional control (Rosano et al., 

2005). They have been able to detect 

differences in activation in these brain 

regions between the two groups, and these 

changes are likely to be related to early 

changes in cognitive impairment. 

Improving Support for Caregivers 

Although much of NIH’s AD research 

effort is focused on the causes, characteristics, diagnosis, and treatment of AD, 

researchers never lose sight of the enormous personal and emotional toll exacted 

by AD on those with the disease as well 

as their families, friends, and caregivers. 

Investigators supported by several Institutes, 

including NIA, NIMH, and the National 

Institute of Nursing Research (NINR) are 

exploring the emotional, psychological, and 

physical costs of caregiving, and they are 

investigating ways to ease the burden. 

For example, it is well established that 

AD caregivers often experience stress, 

anxiety, depression, and other mental health 

problems as a result of the continuing and 

demanding nature of AD care. This chronic 

stress is known to have detrimental affects 

on caregivers’ physical health. A research 

team at the University of California at 

San Diego explored this issue by assessing 

whether different emotional symptoms 

had different physical effects (von Kanel 

et al., 2004). 

Working with a group of 48 older 

participants, the researchers found that 

although stress-associated depression and 

anxiety both raised the level of certain molecules in the blood that are associated with 

increased coronary risk, anxiety appeared 

to have a stronger effect than depressive 

symptoms. Having a more nuanced understanding of the effects of caregiving stress 

may inform the development of interventions to help caregivers cope with the daily 

stresses of caring for a loved one with AD.
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A recent study, conducted by NINRfunded researchers at the University of 

Texas Health Science Center in San 

Antonio explored another aspect of caregiving stress by examining how male 

and female caregivers respond differently 

to the emotional and biological stresses 

of caregiving (Thompson et al., 2004). 

The researchers found that although the 

two groups of caregivers did not differ 

in the number of distressing caregiving 

experiences, men reported a lower sense 

of burden and a lower level of perceived 

stress than women. In addition, men had 

lower scores for depression, anxiety, anger, 

and physical symptoms, and higher scores 

for relaxation, social functioning, mental 

health, role performance, and sense of 

coherence. These findings point out the 

need for tailored caregiving support interventions that take caregivers’ individual 

characteristics into account.

The emotional and psychological costs 

of caregiving are amenable to interventions, 

according to a recent study conducted by 

New York University School of Medicine 

scientists funded by NIA and NIMH 

(Mittelman et al., 2004). This study was 

conducted as part of the NYU-Spouse 

Caregiver Intervention Study, the longest 

study devoted to interventions that improve the mental 

health and well-being of AD 

caregivers. The Caregiver Core 

of the New York University 

ADC provided the infrastructure for this study. A total of 

406 caregivers were enrolled 

in the study over its 17-year 

duration, and were divided 

into two groups. Half the 

caregivers, the control group, 

received counseling upon 

request. The other half, the 

enhanced treatment group, 

were given three additional types of counseling: two sessions of individual counseling, four sessions of family counseling, 

and weekly meetings with a support group 

of fellow caregivers. A key feature of the 

enhanced group was that each member was 

served by a single counselor for the duration of the study. After one year, nearly 

30 percent of caregivers in the enhanced 

treatment group had symptoms of clinical 

depression, compared with more than 

45 percent of those in the control group. 

Three years later, caregivers who received 

the enhanced care still had fewer symptoms 

of depression, on average, than those in the 

control group. This was true even for caregivers whose spouses moved to a nursing 

home or died, both of which are known 

to be highly stressful events for caregivers. 

Interestingly, many of the effects of the 

enhanced treatment were not felt immediately. The two groups of caregivers did 

not begin to show significant differences 

in their depression symptoms until a year 

after they enrolled in the study. The effects 

appeared to last for about 5 years; after that 

time, the level of depression in the control 
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and intervention groups became the same. 

The researchers note that the use of multiple types of coordinated therapy was one 

of the most important factors in decreasing 

depression among caregivers. Another 

important aspect of the study was that the 

counseling was tailored to the particular 

coping challenges that each caregiver and 

family were dealing with. These findings 

have important clinical implications because 

they offer evidence that the distress and 

depression experienced by family caregivers 

can be effectively eased and that the benefits 

can be sustained over a long period of time.

Up to now, research on family caregiving has generally focused on assessing 

the demands of providing care at home 

and developing interventions to reduce 

those burdens. Recently, an NIA/NINRfunded team of nurse researchers at the 

Rush University College of Nursing interviewed more than 170 caregivers to explore 

their concerns and identify best caregiving 

practices (Farran et al., 2003; Farran et 

al., 2004). Most caregivers said that they 

felt stressed as they responded to changes, 

reevaluated their life goals and lifestyle, 

adapted to new roles, and faced competing 

demands from other family members, work, 

and outside responsibilities. Many caregivers 

admitted frustration about the limitations 

that caregiving placed on their own lives. 

The most sensitive and skillful caregivers 

learned to read the emotional and physical 

cues of the person with AD and understand 

the sequences that often led to inappropriate behaviors, and they responded to the 

needs of the person in a variety of creative 

ways. They also maintained their flexibility 

in the face of many demands, educated 

themselves about the disease and practical 

strategies, used their available resources, 

involved other family members and friends, 

and balanced the needs of the patient with 

their own needs. These findings could lead 

to the development of interventions to help 

caregivers cope with their stress and develop 

new caregiving skills. 

In an effort to reduce the overall stress 

levels of caring for a person with AD at 

home, University of Minnesota researchers 

funded by NINR developed an innovative 

intervention that focused on changes in the 

home environment (Gerdner et al., 2002). 

Nurses taught care plans that emphasized 

changes in the home environment that 

would enhance safety, compensate for the 

cognitive decline of the person with AD, 

and reduce confusing stimuli. The impact 

of the intervention on the frequency of 

problem behaviors in care recipients and the 

home caregivers’ reactions to these behaviors 

were then assessed. This psychoeducational 

intervention improved responses to the care 

recipient’s memory and behavioral problems 

by both spouse and nonspouse caregivers. 

More recently, some researchers have 

begun to focus on learning about transitions into and out of the caregiving role. A 

study conducted by University of Pittsburgh 
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scientists explored this issue by examining 

the experiences of caregivers when they 

place a relative into a nursing home or other 

care institution (Schulz et al., 2004). In 

particular, this study looked at the forces 

leading to the institutionalization, the frequency and types of contact among caregivers and their relatives, and the psychiatric 

and physical health status of caregivers after 

placement. Caregivers included in this study 

were enrolled in the NIA/NINR jointlyfunded Resources for Enhancing Alzheimer’s 

Caregiver Health (REACH) study, a multisite clinical trial that is testing the feasibility 

of various psychosocial interventions and 

their impact on the health and well-being 

of family caregivers. The study found that 

many caregivers who placed their relative 

in care reported depressive symptoms and 

anxiety to be as high as when they were 

in-home caregivers. In addition, caregivers 

who said that providing help to their relative 

made them feel useful, needed, appreciated, 

and important were less likely to institutionalize their relative than were caregivers who 

did not report these feelings. The authors 

note that bereavement studies have shown 

that caregivers do recover after the death of 

their loved one, but the benefits to the caregiver of placing a relative into a care setting 

appear to be less positive, possibly because 

the caregiving role is not wholly relinquished 

after placement. Clearly, it is important 

to remember that caregivers are at risk for 

adverse health outcomes not only while 

providing care at home, but also after their 

loved one has been placed into a care setting. 

REACH has recently published findings from a number of other caregiver 

studies as well:

An assessment of the burdens of endof-life AD care and the caregivers’ response 

to the death showed how time-consuming 

and difficult this phase of caregiving can 

■

be (Schulz et al., 2003). University of 

Pittsburgh investigators found that many 

participating caregivers were assessed as 

being at risk of clinical depression before 

the person’s death, but that these numbers 

dropped significantly within a year after 

the death.

An exploration of caregiving practices among African-American and white 

caregivers by scientists at the University of 

Alabama revealed that a majority of AfricanAmerican caregivers were caring for a parent 

or other nonspouse family member, whereas 

most white participants were caring for 

their spouses (Roff et al., 2004). AfricanAmerican caregivers also were younger 

and had a lower family income than the 

whites. Interestingly, the African-American 

caregivers reported finding more positive 

aspects to caregiving, had lower anxiety, a 

higher degree of religious faith, and were 

less bothered by the behavior of the person 

with AD than were whites. Examining the 

positive aspects of caregiving may provide 

useful lessons and new strategies for all 

caregivers.

A 6-month follow-up evaluation 

of nine different REACH interventions 

involving more than 1,000 caregivers 

showed that the interventions were successful in helping lessen the perceived 

burden felt by caregivers, though only one 

intervention significantly reduced caregiver 

depression (Gitlin et al., 2003). One clear 

lesson from this evaluation, conducted by 

investigators at Thomas Jefferson University 

in Philadelphia, is that caregiver interventions need to target multiple aspects of caregiving and be tailored to the characteristics 

and circumstances of the caregiver. 

■

■
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Part 4

 O U T L O O K F O R T H E F U T U R E

Research in AD continues to move forward rapidly, bringing us ever closer 

to a full understanding of the causes of 

this devastating disease and to effective prevention and treatment strategies. 

Findings from basic science are unlocking 

the secrets of the disease process at a 

molecular level, involving beta-amyloid, 

presenilins, tau, and mitochondria, to name 

just a few. Findings from other types of 

studies are providing insights about possible risk and protective factors and ways 

to help caregivers cope as the disease takes 

hold in a loved one. Knowledge from 

these studies is giving scientists and clinicians increasing hope about the potential 

for new therapeutic agents and strategies. 

Realizing these hopes for the future, 

however, requires action on a number of 

complementary fronts. In the past several 

years, the NIA, along with other NIH 

Institutes and Centers, the Alzheimer’s 

Association, the Institute for the Study 

of Aging, and additional organizations, 

have launched several major initiatives to 

create and nurture the essential research 

infrastructure that will help NIH move 

from basic science to fully developed 

drugs and therapeutic approaches that 

can be tested in clinical trials and ultimately used to help people with AD. 

Providing a Planning 

Framework

Two of these initiatives provide a critical 

framework for overall planning and support 

for AD and broader neurosciences research.

NIA has partnered with NIMH, 

NINDS, and NINR in the AD Prevention 

Initiative, which is designed to invigorate 

discovery and testing of new treatments, 

identify risk and protective factors, enhance 

methods of early detection and diagnosis, 

and advance basic science to understand 

AD. The Initiative also endeavors to 

improve patient care strategies and alleviate 

caregiver burden. 

NIA is an active member of the 

newly-established multi-institute NIH 

Blueprint for Neurosciences Research. This 

effort provides a framework to enhance 

cooperative activities among 15 NIH 

Institutes and Centers to reduce the burden 

of nervous system disorders, including AD. 

Supporting a Collaborative 

Research Infrastructure

Two other initiatives provide venues 

and mechanisms for interdisciplinary 

and collaborative research on AD 

development and progression.

■

■
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Many milestones in AD research in 

the U.S. since 1984 stem from resources 

provided by the Alzheimer’s Disease 

Centers. NIA currently funds 32 ADCs 

around the country. Imaging, pathology, 

and clinical studies conducted in the ADCs 

are allowing investigators to correlate 

changes in brain structure and function 

with clinical evidence of disease. In recent 

years, the Centers have placed increasing 

emphasis on evaluating cognitive function 

in healthy aging and the transition to MCI 

and early dementia as well as mixed dementias and overlapping dementia syndromes. 

Another growing focus for the ADCs is 

collaborative trans-Center projects and collaborations with investigators outside the 

Centers’ network. 

■ In 1999, NIA established the 

National Alzheimer’s Coordinating Center 

(NACC) to provide a mechanism whereby 

data on patients from all of the ADCs could 

be pooled and shared. Eleven collaborative 

multi-Center studies have been funded by 

NACC and seven other collaborative investigator-initiated grants have been funded 

and are linked to NACC. The NACC now 

has information on more than 73,000 ADC 

study participants enrolled since 1984 and 

neuropathological data on 9,400 brains 

from participants autopsied in the ADCs. 

The data are accessible to Center scientists 

through NACC’s website. NACC is now 

including more long-term data on ADC 

study participants and is working to define 

and standardize the clinical data elements 

that will be collected. This uniform data set 

became operational in September 2005. It is 

hoped that this effort will lead to better and 

more extensive research projects using standardized data collected from all Centers. 

New procedures have been adopted for 

widening access to the NACC database 

by non-Center scientists wishing to use 

the data. 

Facilitating Innovation 

for the Future

An additional five efforts focus on 

particular aspects of AD or brain research, 

including neuroimaging, genetics, drug 

development and clinical trials, techniques 

for evaluating change over time in cognitive functioning, and healthy brain aging:

NIA has launched a multi-year AD 

Neuroimaging Initiative, which will use 

serial MRI and PET scans to examine how 

brains change as amnestic MCI and AD 

progress. The scans and other data and 

■

■
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biological samples from the Neuroimaging 

Initiative will be collected at about 60 clinical sites based in universities throughout 

the U.S. and Canada. The project will 

follow approximately 200 cognitively 

healthy individuals for 3 years, 400 people 

with amnestic MCI for 3 years, and 200 

people with early AD for 2 years. Planning 

for the many interrelated facets of this initiative has been moving forward rapidly and 

enrollment has begun. By using MRI and 

PET scans at regularly scheduled intervals, 

investigators hope to learn 

when and where in the 

brain degeneration occurs as 

memory problems develop. 

Scientists will correlate 

this imaging information 

with clinical and neuropsychological assessments, 

and biomarkers from blood, cerebrospinal 

fluid, and urine samples collected at intervals from individuals in the study. Potential 

markers include levels of beta-amyloid and 

tau, indicators of inflammation, and measures of oxidative stress. NIA hopes the 

Neuroimaging Initiative will help create 

rigorous imaging and biomarker standards 

that will aid in early diagnosis and provide 

the yardstick by which the success of future 

treatments can be measured. This would 

substantially increase the pace and decrease 

the cost of developing new treatments.

This landmark Initiative is a publicprivate partnership among government, 

industry, foundations, voluntary organizations, and academia. An important 

aspect of this Initiative is that the clinical, 

imaging, and biological data collected 

will be made available to qualified scientific investigators for further analysis. This 

emphasis on sharing data and resources 

across research institutions will have an 

important beneficial impact on future 

research because it means that larger databases of information and samples of participants will be available. This expanded 

data will help increase the statistical power 

of studies and allow for analyses of small 

subpopulations and infrequent outcomes 

that wouldn’t be possible otherwise. 

Through the Alzheimer’s Disease 

Cooperative Study—the Federal government’s major mechanism for funding AD 

clinical trials—another NIA initiative is 

focused on a critical “nuts and bolts” aspect 

of prevention clinical trials. The Prevention 

Instrument Project is developing sensitive 

and more effective methods for evaluating 

change over time in cognitively healthy 

elderly. Investigators involved in this project 

are focused on designing, developing, and 

testing new questionnaires and other instruments that can be used to test individuals in 

a number of areas, such as overall cognitive 

functioning, memory, ability to carry out 

activities of daily life, and quality of life. 

This study is comparing the results of evaluation instruments filled out by participants 

at home versus those done in the clinic to 

determine whether the home evaluations are 

equivalent to the clinic evaluations. If this 

proves to be the case, this innovation could 

■

Sharing data and resources across research 

institutions will have an important beneficial 

impact on future research.
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go far to reduce clinic visits and burden 

on participants and families, simplify and 

reduce the cost of clinical trials, and make 

recruitment and retention easier.

As AD genetics research has intensified, it has become increasingly clear 

that scientists need many more samples 

of genetic material if they are to continue 

making progress. NIA’s Genetics Initiative

is aiming to identify at least 1,000 families 

with members who have late-onset AD as 

well as unaffected family members, and is 

encouraging these individuals to provide 

blood samples and clinical data. The blood 

samples will allow investigators to create 

and maintain “immortalized” cell lines—

cells that are continuously regenerated in 

the laboratory. These cell lines are crucial 

for the exhaustive DNA analysis studies 

needed to identify additional risk factor 

genes. The National Cell Repository for AD 

(NCRAD), located at Indiana University, 

serves as the centralized DNA and cell line 

repository for the Initiative. 

■

Many families already have been 

recruited but more are needed. NIA has 

provided funding to the ADCs to help 

recruit additional study participants, and 

the ADEAR Center is collaborating with 

the Alzheimer’s Association to develop 

media and community outreach programs 

to foster participation in this Initiative. 

Results will allow scientists to find new 

pathways affected in AD and help clinicians 

accurately identify and counsel people at 

high risk of developing the disease. Results 

also will help investigators recruit susceptible individuals into clinical trials, which 

will reduce the number of participants 

necessary and the cost and complexity of 

trials. Shorter trials with fewer participants 

will allow investigators to be more effective in identifying and 

testing promising treatments 

emerging from basic science 

and translational studies. 

It also will contribute to 

future prevention strategies. 

NIA’s new 

Translational and Drug 

Testing Initiative aims to 

encourage researchers to 

move from purely basic research on AD 

and associated disorders into translational 

research and drug testing in clinical trials. 

This program is intended to expand the 

potential range of therapies that can be 

tested against AD and other aging-related 

diseases and age-related cognitive decline. 

The initiative provides small grants for 

research early in the drug development 

process and larger cooperative grants to 

move drugs through development up to 

approval by the FDA for clinical testing. 

Another component of the Translational 

■

Shorter trials with fewer participants will allow 

investigators to be more effective in identifying 

and testing promising treatments emerging from 

basic science and translational studies.
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Initiative is the longstanding Investigational 

New Drug Toxicology program, which provides toxicology services to academic and 

small business investigators who believe they 

have promising compounds to treat or prevent AD but lack the resources to perform 

the required toxicology studies. This initiative also funds pilot clinical trials (see p. 59 

for more on pilot clinical trials) as well as 

the ADCS and other clinical trials. 

NIA, NINDS, and NIMH have 

joined efforts to launch the Cognitive and 

Emotional Health Project: The Healthy 

Brain, a new trans-NIH initiative. A large 

number of people are at substantial risk for 

cognitive impairment from many causes 

as they age. The same is true for emotional disorders. Although research into 

biological mechanisms and environmental 

and social effects are yielding promising 

results in animal and human studies, much 

remains to be discovered. Advances in 

understanding the positive and negative 

changes in cognition and emotion in adulthood, and what can be done to preserve 

and enhance positive outcomes, is central to 

the missions of the participating Institutes. 

The goal of the Healthy Brain Project is to 

assess the state of longitudinal and epidemiologic research on demographic, social, 

and biologic determinants of cognitive and 

emotional health in aging adults, and to 

accelerate identification of ways to maintain 

cognitive and emotional health. The Project 

also is examining the pathways by which 

cognitive and emotional health may influence each other. 

■

 As this report has shown, our knowledge about the many dimensions of AD is 

advancing rapidly, and the results of the 

initiatives described here will certainly accelerate new scientific 

discoveries. As we celebrate 

our scientific successes, 

however, we do not 

forget that AD remains 

an urgent problem for 

our Nation. Our challenge is to continue 

building upon the 

events and experiences 

of the past and present 

to create a brighter future 

in which the potential for 

successfully managing AD or 

even preventing it can become 

a reality for our older loved ones.
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Part 5

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P R O G R E S S R E P O R T O N A L Z H E I M E R ’ S D I S E A S E 2 0 0 4 – 2 0 0 5 

Credits

Writer

Anne Brown Rodgers

Computer Illustrations

Stacy Jannis, Rebekah Fredenburg

Jannis Productions

Medical Illustration

Christy Krames

Page 7

Illustration Advisor

D. Stephen Snyder, Ph.D.

NIA Neuroscience and Neuropsychology 

of Aging Program

Editors

Patricia D. Lynch and Karen M. Pocinki

NIA Office of Communications and Public Liaison

Design

Kristin Deuel Duffy, Jeffrey Dever

Dever Designs

Project Coordinator

David M. Burton

Johnson, Bassin & Shaw, Inc.

Special thanks to:

Marcelle Morrison-Bogorad, Ph.D. and the staff 

of the NIA Neuroscience and Neuropsychology of 

Aging Program, and the staff of the NIA Intramural 

Research Program of the Gerontology Research 

Center

Photography 

Cover, top – Stockbyte 

Cover, bottom; back cover, top; page 43 – 

Digital Vision

Inside front cover, center right; pages ii, 2, 48, 54, 

71, 72 – Photodisc

Inside front cover, top and bottom left; inside back 

cover, top; back cover, middle; pages iii, iv, 18, 36, 

47, 63 – Photos.com

Inside back cover – Rubberball

Back cover, bottom left – Blue Moon

Page 4 – John Foxx

Pages 12, 15, 68 – Brand X Pictures

Pages 14, 64 – Marty Katz

Page 59 – Rick Brady

Page 66 – Blend Images 
For additional copies of this report or 

further information about Alzheimer’s 

disease, please contact:

Alzheimer’s Disease Education 

and Referral (ADEAR) Center

Phone: 1-800-438-4380

Web: www.alzheimers.org

For more information about the 

National Institute on Aging, please 

visit www.nia.nih.gov.
U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Aging

NIH Publication Number: 05-5724

November 2005