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2 0 0 5 – 2 0 0 6 p r o g r e s s r e p o r t o n ALZHEIMER’S DISEASE

Journey

DISCOVERY

 to 

U.S. Department of 

Health and Human Services
ii 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease
progress report on alzheimer’s disease

2 0 0 5 – 2 0 0 6

National Institute on Aging

National Institutes of Health

U.S. Department of Health and Human Services
2 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

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 2005-2006 Progress Report 

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

NIA and other components of NIH, including:

• National Center for Complementary and Alternative Medicine (pages 29, 44)

• National Center for Research Resources (page 25)

• National Heart, Lung, and Blood Institute (pages 22, 23, 31, 33, 34, 44)

• National Institute of Biomedical Imaging and Bioengineering (pages 15, 36, 57)

• National Institute of Child Health and Human Development (page 29)

• National Institute of Mental Health (pages 30, 43, 50, 51, 52, 57)

• National Institute of Neurological Disorders and Stroke (pages 28, 51, 57)

• National Institute of Nursing Research (pages 52, 53, 57)

Additional AD research efforts also are supported by the National Cancer 

Institute, National Institute of Arthritis and Musculoskeletal and Skin 

Diseases, National Institute on Alcohol Abuse and Alcoholism, National 

Institute of Diabetes and Digestive and Kidney Diseases, National Institute 

of Environmental Health Sciences, National Center on Minority Health 

and Health Disparities, and the John E. Fogarty International Center.

In Remembrance

This Progress Report on Alzheimer’s Disease is dedicated to Leon Thal, M.D. 

(1944–2007), a leading AD researcher, exceptional scientist, consensus builder, 

caring and talented clinician, and wonderful human being of extraordinary wisdom 

and energy. Many, many people will deeply miss him.
2 0 0 5 – 2 0 0 6 2 0 0 5 – 2 0 0 6 progress report on progress report on alzheimer alzheimer’s disease s disease 3

PART 1 INTRODUCTION 5

5 Alzheimer’s Disease: A Looming 

National Crisis

6 AD Research: A National Priority

7 The 2005-2006 AD Progress Report: 

A Journey’s Tale

 8 A Brief Primer on AD

PART 2 AD RESEARCH ADVANCES: 

MANY PATHS TO THE GOAL 11

11 How Does AD Begin, and What Causes 

It to Progress?

 12 Beta-amyloid and Its Damaging 

Effects on Neurons

 16 New Developments in Tau

Research

 17 Cell Cycle: Bringing Life or Death?

 18 Vascular Dysfunction May be a 

Key Element in AD

 20 Learning More About Mild 

Cognitive Impairment

22 Can Lifestyle Interventions Slow the 

Disease Process?

 22 Lessons Learned from Couch Mice, 

Marathon Mice, and Men and 

Women Who Like to Walk

 26 A Healthy Diet May Be Important 

to Brain Health as Well as Body 

Health

 31 Managing Chronic Illness: 

A Possible Preventive Strategy 

for AD?

 36 Sophisticated Tools Help 

Investigators Learn More About 

Changes in the Brain

 38 How Do We Translate Scientific 

Discoveries Into Effective Treatments?

 38 The Emerging Field of AD 

Translational Research

 41 Putting Treatment Hypotheses to 

the Test in Clinical Trials

 44 A Closer Look at Two Aspects of 

AD Clinical Trials

PART 3 HOW WE’RE GETTING TO THE GOAL 47

47 NIA Initiatives for AD Research 

 47 Alzheimer’s Disease Centers

 48 National Alzheimer’s Coordinating 

Center

49 Major AD Research Initiatives

 49 Alzheimer’s Disease Genetics 

Initiative

 50 Alzheimer’s Disease Neuroimaging 

Initiative

 51 The Cognitive and Emotional 

Health Project

 52 Helping People with AD and Their 

Caregivers Cope

PART 4 OUTLOOK FOR THE FUTURE 55

PART 5 REFERENCES 59

CONTENTS
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Introduction
2 0 0 5 – 2 0 0 6 2 0 0 5 – 2 0 0 6 progress report on progress report on alzheimer alzheimer’s disease s disease 5

Alzheimer’s disease is an age-related, irreversible brain disorder that develops 

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

be mistaken for age-related memory change. 

These symptoms gradually lead to behavior 

and personality changes, a decline in cognitive abilities (such as decision-making and 

language skills), an inability to recognize family 

and friends, 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, called 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, although age-related brain and body 

changes can affect the development of dementia. 

Alzheimer’s Disease: 

A Looming National Crisis

For many older adults and their families, 

AD stands in the way of the “Golden Years.” 

And the impact of the disease doesn’t stop there, 

for it presents a major problem for our health 

care system and society as a whole as well:

AD is the most common cause of 

dementia among people age 65 and older. 

Scientists estimate that 4.5 million people in 

the U.S. currently have the disease, and 13.2 

million Americans will have AD by 2050 if 

current population trends continue and prevention is still not possible (Hebert et al., 2003). 

A 2005 Census Bureau report on aging 

in the U.S. notes that the population age 65 

and older is expected to double in size to about 

72 million within the next 25 years (He et al., 

2005). Moreover, the 85 and older age group 

is now the fastest growing segment of the 

population. This is important for AD because 

the prevalence of AD (the number of people 

with the disease at any one time) doubles for 

every 5-year age interval beyond age 65. One 

study shows that nearly half of all people age 

85 and older have AD (Evans et al., 1989). 

The number of AD caregivers—and 

their needs—can be expected to escalate rapidly 

as the population ages and as the number of 

people with AD grows. During their years of 

AD caregiving, spouses, relatives, and friends 

experience great emotional, physical, and 

financial stress. 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 growing number of people with 

AD and the costs associated with the disease 

put a heavy economic burden on society. The 

national direct and indirect costs of caring for 

AD patients are estimated to be as much as $100 

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PART1
6 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

billion a year (Ernst and Hay, 1994; Ernst 

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

commissioned by the Alzheimer’s Association 

and conducted by the Lewin Group provides 

a sobering picture of the impact of AD by 

projecting the future costs to Federal health 

programs of AD if current trends continue 

(Lewin Group, 2004). The study estimates 

that total Medicare spending on treating 

beneficiaries with AD will increase from $62 

billion in 2000 to $189 billion in 2015. By 

2050, Medicare will be spending more than 

$1 trillion on AD-related costs, or 4 out of 

every 10 dollars spent by the program. State 

and Federal Medicaid spending also will 

show large increases. The study estimates 

that this spending will increase from $19 

billion in 2000 to $118 billion in 2050.

AD Research: 

A National Priority 

Given our aging population, AD is a 

steadily increasing national health problem. 

This makes the disease an urgent research 

priority. Interventions that could delay or 

prevent 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 of caring for people with AD. 

Our knowledge about the origins and 

development of AD and about potential 

preventive and treatment strategies has 

progressed rapidly in recent years. The 

ultimate goal of reducing the individual 

and societal burden of this devastating 

disease is within our reach if we can:

 Improve diagnostic tools, such as neuropsychological tests, imaging tests, and •

biological markers, so that AD can be 

diagnosed accurately and early, and treatments can be monitored more effectively; 

 Develop better medicines and behavioral techniques to treat AD;

 Create improved strategies for caregiving 

and better coping mechanisms for 

caregivers; and

 Devise approaches that could delay the 

onset of AD or even prevent the disease. 

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Efforts to educate and inform people with AD, 

their families, the public, providers, and others 

interested in the disease are an important complement to NIA’s research initiatives in AD. 

The NIA Alzheimer’s Disease Education and 

Referral (ADEAR) Center (www.nia.nih.gov/

alzheimers) provides a variety of materials on AD, 

including information about caregiving, diagnosis 

and treatment, and results of research findings. 

For example, the online publication 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. Genes, Lifestyles, and Crossword 

Puzzles: Can Alzheimer’s Disease be Prevented?

summarizes the latest research findings on AD risk 

factors and potential prevention strategies. These 

booklets for the general public are available free 

of charge from the ADEAR Center.

ADEAR also maintains a database of AD clinical 

trials, develops recommended reading lists, and 

provides referrals to 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 (see p. 47 for more about the ADCs). 

Educating and 

Informing: Another 

Vital Mission
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The 2005-2006 AD Progress 

Report: A Journey’s Tale

Sometimes journeys are straightforward. Point B lies in a direct line some 

distance ahead of Point A. Other journeys 

are more circuitous—travelers must take 

many winding and intersecting paths, and 

even go around a few traffic circles to get 

from Point A to Point B. Scientific research 

in complex diseases like AD certainly falls 

into this latter category. Progress depends 

on the accumulation of results from many 

studies. Findings from one study add to 

or support findings from other studies. 

Unexpected findings can mean that investigators must head in a new direction. A 

promising track may suddenly become a 

scientific dead end, requiring researchers to 

rethink their original hypotheses. A possible 

intervention may have serious negative side 

effects in animals or humans, necessitating 

an alternative approach. Investigators may 

travel from laboratory “bench” to clinical 

“bedside” and back again before an intervention is thoroughly tested and refined. 

By following many pathways over the 

past 30 years, scientists have built a solid 

body of evidence about AD. Initially, 

research defined the major characteristics 

of AD, the course of the disease, and some 

aspects of its etiology (causal factors). As 

this knowledge base developed, scientists 

were able to design increasingly sophisticated studies to understand more about the 

early changes in the brain of a person with 

AD, and the many factors that contribute 

to the development of these pathologies, 

or damage caused by the disease. They 

also were able to expand into other areas 

of research. These research paths necessarily intersect and depend on each other:

Test tube and animal studies are 

revealing fundamental information about 

why, how, and when biological events 

•

occur in AD. They provide a major foundation for translational research (research 

that facilitates the two-way transfer of 

knowledge between basic scientific observations and clinical care and clinical trials; 

see p. 38 for more information). These 

studies also have increased our appreciation of the differences between species 

and the fact that findings in animals do 

not necessarily translate to humans. 

Epidemiologic studies in humans 

can show associations between basic 

characteristics and factors that are hypothesized to cause a disease. Epidemiologic 

studies are valuable because they pave the 

way for additional testing in clinical trials. 

Clinical trials test possible interventions suggested by test tube, animal, 

and epidemiologic studies. These trials 

can control variables known to be important, thereby lending greater certainty 

to conclusions about cause and effect 

(see p. 44 for more information). 

Findings from clinical trials feed back 

to suggest new pathways to explore in test 

tube, animal, and epidemiologic studies. 

Part 2 of the 2005-2006 Alzheimer’s 

Disease Progress Report describes recent 

milestones in this ongoing journey down 

the many paths of AD research. 

In addition to a map, journeys also 

require a means of transport. Part 3 describes 

NIH programs and initiatives that have nurtured the essential research infrastructure, 

allowing scientists to push forward the basic 

science, conduct essential observational and 

clinical studies, and begin to develop new 

drugs and other treatment approaches. 

Finally, travelers must plan ahead 

for future challenges as the journey 

unfolds. The final section of this 

report, Part 4, provides such an outlook for the future in AD research.

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8 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

A Brief Primer on AD 

The healthy human brain is made 

up of billions of different kinds of nerve 

cells (neurons) that are connected 

through a diverse array of chemical 

and electrical signals. A typical neuron 

has a nucleus in a cell body, an axon, 

and many dendrites. Neuronal function 

is supported by other kinds of cells 

called glial cells. 

The nucleus contains the cell’s 

genetic blueprint and helps regulate 

the cell’s activities in response to signals from outside and inside the cell. 

The axon transmits messages to other 

neurons. Dendrites receive messages 

from axons of other nerve cells or 

from specialized sense organs. 

The survival of neurons depends 

on the healthy functioning of several 

interdependent processes: 

Communication. When a 

neuron receives enough messages 

from surrounding cells, an electrical 

charge is generated that travels down 

to the end of the axon. Here, it triggers the release of special chemicals, 

called neurotransmitters, that move 

across a gap, called a synapse, to 

the dendrites of neighboring neurons. 

Scientists estimate that the typical 

neuron has up to 15,000 synapses. 

The neurotransmitters bind to specific 

receptor sites on the other dendrites, 

triggering chemical changes and 

building up new electrical charges. 

Metabolism. This process 

encompasses all the chemical reactions that take place in the cell. 

Efficient metabolism requires adequate blood circulation to supply 

the cells with oxygen and glucose, 

the brain’s major fuel. 

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Repair. Neurons are programmed to live a long time—even 

more than 100 years—so they must 

constantly maintain, repair, and 

remodel themselves. 

How Does AD Affect 

the Brain?

In healthy aging, most types of 

brain neurons are not lost in large 

numbers. In AD, however, many nerve 

cells stop functioning, lose connections 

with other nerve cells, and die because 

communication, metabolism, and repair 

are disrupted. 

At first, AD destroys neurons in 

parts of the brain that control memory, 

including the entorhinal cortex, the hippocampus, and related structures. AD 

later attacks the areas responsible for 

language and reasoning. Eventually, 

many other areas of the brain are damaged and the person becomes helpless 

and unresponsive to the outside world. 

What are the Main 

Characteristics of the 

Brain in AD?

Many changes take place in the 

brain of a person with AD. The three 

major characteristics that reflect the 

pathology caused by the disease are: 

Amyloid plaques. Plaques are 

found in the spaces between neurons. They consist of largely insoluble 

deposits of a protein fragment called 

beta-amyloid peptide, together with 

other proteins, remnants of neurons, 

degenerating dendrites and axons, 

glia, and other cellular material. 

Scientists used to think that plaques 

caused the damage to neurons seen 

•

•

in AD. Now, however, many think that 

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

(see p. 12 for more details on the 

plaque formation process).

Neurofibrillary tangles (NFTs).

NFTs, which are found inside 

neurons, are abnormal collections 

of a protein called tau. Healthy 

neurons are internally supported in 

part by structures called microtubules, 

which help guide nutrients and molecules from the cell body to the ends 

of the axon 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 the tau. As a result, tau disengages 

from the microtubules and begins to 

clump together with other threads of 

tau, eventually forming NFTs. When 

this happens, the microtubules disintegrate and the neuron’s transport 

system collapses. 

Loss of connections between 

cells and cell death. This feature of 

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

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

and eventually they die. As neuronal 

death spreads through the brain, 

affected regions begin to shrink in a 

process called brain atrophy. By the 

final stage of AD, damage is widespread and brain tissue has shrunk 

significantly.

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2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 9

What Causes AD?

In a very few families, people 

develop AD in their 30s, 40s, and 50s. 

These people have a mutation in one 

of three genes that they have inherited 

from a parent. We know that mutations in these genes cause AD in these 

“early-onset” cases. 

More than 90 percent of AD 

develops in people older than 65. This 

form of AD is called “late-onset” AD, 

and its development and pathology 

are very similar to that of early-onset 

AD. We don’t yet completely understand the causes of late-onset AD, 

but they probably include genetic, 

environmental, and lifestyle factors. 

The importance of these factors in 

increasing or decreasing the risk of 

developing AD differs from person to 

person. Scientists hope that what they 

learn about early-onset AD also can 

be applied to the late-onset form of 

the disease.

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? 

Research on how the brain changes 

normally as people age will help 

provide answers to this important 

question in AD. 

How is AD Diagnosed?

Clinicians today use a range of tools 

to diagnose “possible AD” (dementia 

could also be due to another condition) 

or “probable AD” (no other cause of 

dementia can be found). These tools 

include a medical history; physical 

exam; tests that measure memory, language skills, and other abilities related 

to brain functioning; and usually, brain 

scans. Knowledge about the clinical 

and behavioral characteristics of the 

disease also helps in diagnosing AD. 

In specialized research facilities, clinicians can now diagnose AD with 

up to 90 percent accuracy. At this 

time, however, AD can be diagnosed 

conclusively only by an autopsy of 

the brain of a person with dementia. 

Early, accurate diagnosis is crucial because it tells people not only 

whether they do or do not have AD 

but also whether they have something 

else instead, such as a stroke, tumor, 

Parkinson’s disease, or side effects 

of medications. It also helps families 

plan for the future while the person 

with AD can still participate in making 

decisions. Researchers are making 

progress in developing accurate diagnostic tests and techniques that may 

one day be used in general medical 

practice to detect the disease early, 

ideally even before symptoms emerge. 

How is AD Treated?

AD treatments are needed to control 

cognitive loss as well as behavioral and 

psychiatric problems that occur as AD 

progresses. Four FDA-approved medications are used to treat AD symptoms. Donepezil (Aricept), rivastigmine 

(Exelon), and galantamine (Reminyl) are 

prescribed to treat mild to moderate 

AD symptoms. Donepezil was recently 

approved to treat severe AD as well. 

These drugs act by stopping or slowing 

the action of acetylcholinesterase, an 

enzyme that breaks down acetylcholine (a neurotransmitter that helps in 

memory formation). The drugs maintain 

some patients’ abilities to carry out 

activities of daily living; may maintain 

some thinking, memory, or speaking 

skills; and can help with certain behavioral symptoms. However, they 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. This drug appears to 

work by regulating levels of glutamate, 

another neurotransmitter involved in 

memory function. Like the cholinesterase inhibitors, memantine will not 

stop or reverse AD. 

In addition to these medications, 

physicians use drug and non-drug 

approaches to treat behavioral and 

psychiatric problems. These problems 

include agitation, verbal and physical 

aggression, wandering, depression, 

sleep disturbances, and delusions. 
10 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

AD Research Advances:

Many Paths To The Goal
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 11

PART2

This section of the Progress Report describes some of the many paths that investigators 

are taking to the ultimate goal of discovering a 

cure for AD. These descriptions are organized 

around several major research questions:

 How does AD begin, and what causes it 

to progress?

 Can lifestyle interventions slow the disease 

process?

 How do we translate scientific discoveries 

into effective treatments?

How Does AD Begin, and 

What Causes it to Progress?

AD research has expanded greatly since 

the early days, when investigators focused 

on understanding the manifestations and 

natural progression of the disease. Findings 

from these studies, combined with advances 

in many scientific areas—imaging, genetic 

analysis, molecular and cellular biology, 

and development of highly sophisticated 

animal models, to name a few—have led 

to an explosion of knowledge about AD. 

We still have a lot to learn about the 

fundamental questions of AD pathology and 

etiology, however, and this continues to be a 

critical portion of the overall AD research portfolio. Learning more about the basic science is 

essential to understanding normal age-related 

change as well as how and why AD begins 

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•

and how it progresses over time. For example, 

we know that as AD develops, neurons go 

through a process from a healthy state to 

some loss of molecular 

efficiency, to a loss of 

synaptic function, to 

loss of synapses, and, 

ultimately, to cell death. 

We also know that the 

damage begins in the 

areas deep within the 

brain that control 

memory, including the 

entorhinal cortex, the 

hippocampus, and 

related structures. The 

damage then spreads to 

the cerebral cortex (the 

outer layer of neurons 

in the brain), and eventually to many other 

brain regions. But we 

don’t fully know how 

long this process takes or how much may be 

reversible. What event (or series of events) 

causes normal age-related change to become a 

disease? What normal pathways of molecular 

communication are disrupted during the early 

development of AD? How will understanding 

these pathways lead to the development of drugs 

to block them? At what points could other types 

of interventions, such as diet, exercise, social and 

intellectual stimulation, or other lifestyle factors, 

slow down the disease process? Answers to questions like these are essential not only because 

Healthy neuron

Dying neuron
12 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Pathway to Harm

they improve our overall knowledge about 

AD and other neurodegenerative diseases, 

but because they point to a range of strategies to treat or prevent AD. Some of these 

strategies are already being tested in animal 

studies and clinical trials. Recently, investigators made important headway in four 

main areas of basic AD research: betaamyloid and synapses, tau, the cell cycle, 

and vascular dysfunction.

Beta-amyloid and Its Damaging 

Effects on Neurons

Beta-amyloid has fascinated scientists 

for years. Long considered a key player in 

It’s a tale with terrific characters: 

elusive enzymes, a principal player 

protein whose ultimate character 

(hero or villain) depends on the location of a cut, and plaques that maybe 

aren’t the evildoers everyone thought 

they were. After painstaking research, 

many scientists in laboratories across 

the country have teased apart the 

biological clues provided by these 

characters. The result? A storyline 

that continues to evolve, some 

radically new thinking about betaamyloid and plaques, and several 

potentially promising new treatment 

approaches. 

The story starts with amyloid precursor protein (APP), a large protein 

that is thought to be important to the 

health of neurons. APP is embedded 

in the neuronal membrane, residing 

partly inside and outside the cell. At 

some point, APP is cut, or cleaved, 

into several fragments. For a long 

time, scientists were pretty certain 

that one or more enzymes (proteins 

that cause or speed up a chemical 

reaction) were responsible for this 

cleaving, but they weren’t able to 

identify them. Eventually, investigators identified the three cleaving 

enzymes, which they named alphasecretase, beta-secretase, and 

gamma-secretase. In a major breakthrough, scientists discovered that, 

depending on which enzyme does 

the cleaving and where the cleaving 

happens, APP processing can follow 

one of two pathways that have very 

different consequences.

In one, considered the usual 

pathway, alpha-secretase cleaves the 

APP molecule within the portion that 

has the potential to become betaamyloid. Cleaving at this site results 

in the release into the space outside 

the neuron of a fragment called 

sAPPα. This fragment may have 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 sequence. 

The smaller of the resulting fragments also is released, while the 

larger fragment remains within the 

Beta-amyloid: From APP to Plaques (But Not Always)

APP sticks through the neuron’s membrane. Beta-secretase cleaves APP at one end of the 

beta-amyloid peptide.
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 13

the development and progression of AD, 

it held its secrets closely. In the past several 

years, however, it has gradually begun to 

give up many of these secrets. Scientists 

have learned an enormous amount about 

how beta-amyloid plaques are formed and 

the toxic effects that these structures as 

well as the earlier forms of beta-amyloid 

have on neurons and synapses. These 

findings have opened up new avenues 

of investigation and new possibilities for 

therapeutic targets. Here are a few highlights from recent beta-amyloid work. 

neuron and is believed to enter the 

nucleus. No beta-amyloid is produced 

in this pathway.

In the second pathway, betasecretase cleaves the APP molecule 

at one end of the portion that 

has the potential to become betaamyloid, releasing a fragment called 

sAPPβ. Then, gamma-secretase 

cleaves the remaining fragment at 

the other end of the beta-amyloid 

sequence. Following its cleavage at 

both ends, a beta-amyloid peptide 

is released into the space outside 

the neuron. This pathway spells 

trouble for neurons because the 

beta-amyloid peptide begins to 

stick together with other similarly 

cleaved beta-amyloid peptides. 

These small, soluble beta-amyloid 

clumps are called Aß-derived diffusible ligands, or ADDLs. The number 

of individual beta-amyloid peptides 

within ADDLs varies, but collectively, they are called “oligomers.” 

It is likely that some oligomers 

are cleared from the brain. If they 

cannot be cleared from the brain, 

they clump together with more 

beta-amyloid peptides and other 

proteins and cellular material. As 

the process continues, these clumps 

grow larger, becoming increasingly 

insoluble entities called protofibrils 

and fibrils. Eventually they coalesce 

into the well-known plaques that 

are characteristic of AD. The rate at 

which beta-amyloid aggregates to 

form plaques is likely to be slowed 

by lowering the rate at which it is 

made or by increasing the rate at 

which it is degraded or physically 

removed from the brain.

Being able to spell out with 

greater clarity the sequence of 

steps from APP to beta-amyloid 

peptides to plaques has allowed 

scientists to think in new ways 

about these AD players. Many 

scientists now think that oligomers 

may be the most toxic culprit, not 

plaques. This thinking also has 

allowed investigators to pursue 

avenues of related research that 

may ultimately lead to new AD 

treatments. 

Gamma-secretase cleaves APP at the other end. Single beta-amyloid peptides clump into soluble 

oligomers. Eventually this clumping leads to 

plaques.
14 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Change in Amount Affects Neuronal Function

Based on recent evidence, some scientists think that oligomers harm neurons 

by attaching themselves to a receptor site 

on dendrites where messages are received 

(this site is called the post-synaptic membrane). When this happens, the synapses 

can’t function properly and can’t receive 

messages from other neurons. Unable to 

communicate, the neurons lose function 

and eventually die. In test tube studies and 

in animal studies with AD transgenic mice 

(mice that are genetically programmed to 

develop features of AD, such as amyloid 

plaques and memory problems), scientists 

at Rockefeller University explored how 

this disruptive process may occur (Snyder 

et al., 2005). First, the researchers found 

that applying beta-amyloid to neuronal 

cells in culture promoted the movement 

of NMDA receptors away from the cell 

surface and into the cell. Cell surface 

receptors are binding sites for neurotransmitters (see p. 8 for more on these 

chemical messengers) and are essential in 

cell-to-cell communication and function. 

NMDA receptors are necessary for signal 

transmission across synapses in response 

to the neurotransmitter glutamate. 

Thus, beta-amyloid reduces signal transmission across these synapses, which 

reduces synaptic plasticity. Synaptic 

plasticity, the term neuroscientists 

use to describe the inherent capacity 

of the synapse to alter its behavior 

in response to neural activity, is the 

basis for learning and memory. 

Next, the researchers examined the 

neurons of transgenic mice in tissue 

culture and found that they had reduced 

amounts of NMDA receptors on the 

surface of their neurons. When they 

reduced the production of beta-amyloid 

in these cultures, they found that NMDA 

receptor expression on the surface of 

neurons was restored. These findings are 

important because they show that the 

amount of beta-amyloid present affects 

the level of a key receptor, and that, in 

turn, interferes with the cell’s ability to 

function. These results suggest another 

way that beta-amyloid disrupts synaptic 

function and contributes to AD damage.

A Second Pathway Also 

Reduces Synaptic Plasticity

Another group of researchers, 

working at New York University School 

of Medicine, also focused on pathways 

involved in synaptic plasticity. These 

researchers hoped to discover a second 

pathway by which amyloid exerts its 

effects (Puzzo et al., 2005). In studies 

with transgenic mice, these investigators 

found that beta-amyloid also interferes 

with a particular molecular pathway, 

called the nitric oxide/cGMP/cAMPresponsive element-binding protein, or 

CREB, cascade. Beta-amyloid’s interference with this pathway suppressed 

synaptic plasticity in the hippocampus. 

The results from both of these synaptic 

plasticity studies suggest an approach to 

treating AD by blocking beta-amyloid’s 

effects on these particular molecules 

and cellular pathways. 

Function (or Dysfunction) Follows Form

Though many investigators these days 

are focusing on the early, oligomer, stage 

of beta-amyloid activity, other investigators remain interested in exploring the 

end product: beta-amyloid plaques. Some 

scientists now think that plaque formation 

actually may be a protective action by the 

brain to sequester beta-amyloid so that it 
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 15

cannot harm neurons, but a research team 

at Massachusetts General Hospital and 

Harvard Medical School has found that 

plaques may still have a damaging effect 

on synapses (Spires et al., 2005). In studies 

with AD transgenic mice, they discovered 

that plaques cause a change to the trajectory of dendrites. Plaques get in the way 

of a dendrite’s normal path and cause 

the dendrite to curve around the plaque. 

They also reduce the number of spines, or 

doorknob-shaped structures, that extend 

out from the dendrites and that are essential to signal transmission between neurons. 

These physical changes have damaging 

physiological effects because they disrupt 

synapse networks, which weakens neurons’ 

ability to communicate with each other. 

In recent years, scientists 

have learned a lot about 

gamma-secretase, one of the 

enzymes that cleave APP into 

fragments. They now know that 

it is composed of four proteins: 

presenilin, nicastrin, Aph-1, 

and Pen-2. Gamma-secretase 

cannot be active unless all four 

of these proteins are present. 

One of the gammasecretase components—

presenilin—has intrigued 

scientists for a long time, for 

another reason. 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, and the PS2 

gene on chromosome 1—are 

linked to the rare, early-onset 

form of AD. The APP gene is 

responsible for making APP, 

the precursor to beta-amyloid. 

PS1 and PS2 are responsible 

for making the presenilin protein. The fourth gene, APOE, 

affects the course of lateonset AD, depending on which 

allele, or variation, of the gene 

is inherited. (APOE-ε2 may 

provide some protection 

against AD, APOE-ε3 may 

play a neutral role in AD, and 

APOE-ε4 increases the risk 

of developing AD.)

A Massachusetts General 

Hospital team of researchers 

supported by the National 

Institute of Biomedical Imaging 

and Bioengineering (NIBIB) 

used a technique called 

fluorescence lifetime imaging 

microscopy to determine what 

effect mutations in the PS1 

gene might have on the activity 

of the presenilin protein and, 

by extension, on the progress 

of early-onset familial AD 

(Berezovska et al., 2005). This 

highly sophisticated imaging 

technique allows scientists to 

follow biochemical reactions 

in fluorescently-labeled 

molecules, thus imaging 

biochemical activity in 

specific cellular compartments 

of living cells. 

The researchers found 

that the mutation changed the 

spatial relationship of certain 

key molecules in the presenilin 

protein and also was associated with a consistent change 

in the configuration of the 

PS1-APP complex. They suggest that these changes may 

provide a molecular mechanism 

that underlies the pathology of 

early-onset AD across a wide 

range of PS1 mutations. 

Identifying exactly how PS1 

mutations cause early-onset AD 

may ultimately help investigators devise therapies to reduce 

the mutated gene’s effect on 

brain cells. 

Sophisticated New Imaging Technology 

Helps Scientists See Inside Living Cells
16 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

New Developments in Tau Research 

As mentioned earlier, one of the hallmarks of AD is the formation of NFTs, 

which consist largely of an abnormal form 

of tau. Long considered by many investigators to have a secondary role in AD, tau

has, in recent years, come into its own as 

a leading player in AD research. Findings 

from the past several years clearly show 

why tau is generating new excitement. 

NFTs are found in a variety of human 

diseases other than AD, including corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia 

and Parkinsonism linked to chromosome 

17 (FTDP-17). These diseases are called 

“tauopathies.” Even though no mutations 

have been found in the tau gene in AD, 

inherited mutations do occur in other 

tauopathies that can change the structure 

of the protein from normal to abnormal. 

Previously, only transgenic mice that 

had been bred to have mutated tau

demonstrated NFTs. Now, a research 

group at the Albert Einstein College 

of Medicine in New York, has developed a new mouse model of human AD 

(Andorfer et al., 2005). These “hTau” 

mice have non-mutant human tau protein 

and accumulate an excessive amount of 

an abnormal form of tau. They also form 

clumps of tau filaments in a regionspecific fashion that is similar to AD. 

This new mouse model will allow 

researchers to investigate the relationship between cell death, accumulation 

of altered tau, and the development of 

NFTs. This study also provides compelling evidence that neuronal death in AD 

may not result directly or primarily from 

NFT formation, but rather from disrupted 

axon transport (in other words, a loss of 

normal tau function). The scientists found 

that the presence of tau filaments did not 

directly correlate with death within individual cells. Instead, they found that it was 

associated with the appearance of cell-cycle 

molecules and the initiation of DNA synthesis, which suggests that cell death can 

occur independently of NFT formation. 

Possibly, the neurodegeneration occurring 

in the hTau mice may be at least partially 

due to abnormal, incomplete initiation of 

the cell-cycle process (see the following 

section for more on the cell-cycle process). 

In a second tau advance, scientists 

at the University of Minnesota Medical 

School were able to partially rescue 

memory function in a transgenic mouse 

model that had a form of a mutant tau

gene whose synthesis could be suppressed 

by a drug (SantaCruz et al., 2005). This 

meant that production of the mutant tau

could be precisely regulated. As the mice 

aged, they produced more mutant tau

and began to accumulate NFTs. Their 

neurons began to die, brain tissue shrank, 

and memory was lost. The researchers 

were able to stop the production of the 

mutant tau by giving the mice the drug 

that turned off the gene. Once the mutant 

gene was suppressed, the scientists found, 

much to their surprise, that not only did 
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 17

the memory loss stop, it actually was 

partially reversed. Even more striking, 

memory function improved even though 

NFTs formed from tau that had already 

been made continued to accumulate in 

the brains of the mice. The fact that 

memory function improved in mice 

carrying the mutant tau gene when 

the gene was turned off, despite continued NFT accumulation, implies that 

the processes that lead to memory loss 

and those that cause NFTs are separate. 

Perhaps NFTs do not invariably cause 

neuronal death, but an earlier, toxic 

form of abnormal tau does. Some investigators are suggesting that NFTs, like 

beta-amyloid plaques, may even be a 

protective response by the brain that is 

aimed at preventing abnormal tau from 

damaging the neuron (Tanzi, 2005). 

Tau studies are one of the most 

active areas of AD research, and, as with 

other areas of AD research, new findings are emerging all the time. Current 

and future studies in animal models are 

examining whether it might, in fact, be 

possible to “turn on and off’ the synthesis 

of abnormal, damaging tau and betaamyloid and exploring whether the brain 

could even regain some cognitive function once the disease process has begun. 

Cell Cycle: Bringing Life or Death?

Most cells in the body undergo a 

constant process of formation, maturation, and division—this is called the 

cell cycle and it’s an essential part 

of normal life and growth. Neurons 

are different, however. Once formed, 

they generally do not divide. Forcing 

a mature neuron to reenter the cell 

cycle and undergo cell division will 

cause it to die (Herrup et al., 2004).

Immunizing against the beta-amyloid peptide 

is a promising therapeutic approach (see p. 40 

for a description of current research in this area). 

Several studies have demonstrated in mouse 

models of AD that this approach, called “betaamyloid immunotherapy,” leads to a dramatic 

reduction in beta-amyloid deposition in the brain. 

The availability of new brain imaging techniques 

and mouse models that have both beta-amyloid 

and tau pathology has made it possible to tackle 

some key questions about the pathologic processes that may be alleviated by beta-amyloid 

immunotherapy and about how damage from 

beta-amyloid and tau relate to one another. 

Scientists from the University of California at 

Irvine injected anti-beta-amyloid antibodies in 

the brains of transgenic mice that develop both 

beta-amyloid deposits and NFTs. This treatment 

led to a rapid reduction of beta-amyloid deposits 

outside as well as inside neurons and reversed 

the early signs of tau pathology, namely accumulation of abnormal tau within neuronal bodies and 

dendrites (Oddo et al., 2004). When the antibeta-amyloid antibodies were removed, the 

beta-amyloid pathology re-emerged. This was 

followed by the reappearance of tau pathology. 

In a follow-up study, these investigators used 

anti-beta-amyloid antibodies to determine which 

aspect of beta-amyloid pathology coincides with 

early cognitive impairments in the same animal 

model. They found that clearance of beta-amyloid 

accumulations within the neurons was correlated 

with reverses in the early signs of cognitive 

dysfunction (Billings et al. 2005). 

These findings from animal models provide 

proof that beta-amyloid and tau pathology are 

linked in that levels of beta-amyloid deposits 

influence levels of NFTs. These findings also 

show that the accumulation of beta-amyloid 

within the neuron occurs before any apparent 

beta-amyloid deposits and coincides with early 

signs of cognitive impairment.

New Evidence Links 

Beta-Amyloid and Tau
18 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Based on findings from recent studies 

showing that the vulnerable neurons in 

AD brains contain proteins related to entry 

into the cell cycle, some researchers now 

hypothesize that the death of neurons in 

AD may be related to abnormal initiation 

of the cell cycle in these cells. Researchers 

at Case Western Reserve University, in 

Cleveland, Ohio, found that the cellcycle process was initiated in three 

different transgenic mouse models of 

AD in a pattern similar to that 

seen in human AD (Yang et 

al., 2006). Unlike human AD, 

though, the mouse neurons did 

not die. These results suggested to 

the research team that although 

cell-cycle events may be necessary 

to cause the death of neurons, 

they are not sufficient, and that 

a second, triggering, event may 

be needed to cause cell death. 

Another key finding of the study was 

that the cell-cycle process in these mice 

began before beta-amyloid plaques or 

NFTs began to accumulate, once more 

suggesting that earlier forms of betaamyloid may be the molecular trigger. 

Significantly, this cell-cycle process in 

these mouse models closely mimics that 

in humans with AD, thereby supporting 

the utility of these models in AD research, 

even in the absence of cell death or 

formation of NFTs.

Scientists at the Brigham and Women’s 

Hospital and Harvard Medical School 

have been pursuing a similar line of 

investigation by using Drosophila flies 

to study the impact of activating the 

cell-cycle process in neurodegenerative 

diseases, like AD, that feature abnormal 

deposits of tau protein (Khurana et al., 

2006). These researchers found that 

activating the cell-cycle process caused 

tau-induced neurodegeneration, and 

interfering with the process substantially reduced neurodegeneration. 

Vascular Dysfunction 

May be a Key Element in AD

Even though the brain makes up 

only 2 percent of the body’s mass, it 

receives 20 percent of the body’s blood 

flow. The blood delivers oxygen and 

glucose to neurons. Maintaining a constant and adequate blood flow in the 

brain is essential for neuronal survival 

and brain function, and decreased blood 

flow in parts of the brain affected by 

AD is an early feature of the disease. 

Recent research has focused on 

the many micro blood vessels that 

constitute a critical part of the brain’s 

blood supply. Two aspects of these 

capillaries are important in AD: 

 The brain’s ability to grow new 

micro vessels is diminished in AD.

 The brain uses the micro vessels to 

get rid of toxic beta-amyloid peptides. It appears that clearance of 

beta-amyloid across the blood-brain 

barrier (BBB) into the circulation is 

impaired in AD. The BBB is a protective barrier formed by the blood 

vessels of the brain to prevent large 

molecules from entering the brain.

For some time now, the study of the 

brain’s blood vessel system (vasculature) in 

the context of AD has been a productive 

line of inquiry. A scientific team at the 

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2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 19

University of Rochester Medical Center 

has proposed a “neurovascular hypothesis 

of AD,” which pulls together a decade’s 

worth of disparate research on the brain 

and its blood vessels (Zlokovic, 2005). 

This hypothesis states that faulty clearance 

of beta-amyloid peptides across 

the BBB, abnormal development of new micro vessels, and 

accelerated or abnormal aging 

of the brain’s blood vessel system 

could start a process that leads 

to BBB compromise, chemical 

imbalances in the neuronal environment, 

and synaptic and neuronal dysfunction. 

If it is true that diminished or abnormal 

functioning of the neurovascular system 

contributes substantially to AD, then 

a recent study by the University of 

Rochester team may go some of the way 

toward explaining the role of vasculature 

cells in the damage done by AD (Wu et 

al., 2005). This study focused on lipoprotein receptor-related protein 1 (LRP), 

a protein located in the endothelial cells 

that line the inside of brain micro vessels. 

LRP is responsible for transporting betaamyloid peptides out of the brain across 

the BBB into the body’s circulation. The 

endothelial cells in the brains of people 

with AD produce less LRP compared to 

healthy older people. As a result, clearance of beta-amyloid is impaired and the 

toxic peptide accumulates in the brain. 

Until now, scientists have not been able 

to understand why LRP production falls. 

The researchers approached this 

important question by comparing the 

pattern of expression of genes in endothelial cells isolated from brain tissue of 

people who had died of AD to the genetic 

expression pattern of endothelial cells 

isolated from brain tissue of cognitively 

healthy old and young people who had 

died of other causes. They found that 

the expression of a gene called MEOX2, 

which is known to be involved in the 

growth and development of brain micro 

vessels, was specifically reduced in AD. 

They also discovered that when the expression of this gene was stopped, a protein 

involved in endothelial cell death began 

to be produced. Using transgenic mice 

that express half the normal amount of 

MEOX2, the investigators discovered that 

when production of MEOX2 was reduced, 

the brain also was less able to grow new 

micro vessels in response to injury. When 

MEOX2 expression was reduced, the 

amount of LRP also was reduced, and 

the brain was not able to remove betaamyloid efficiently across the BBB. 

Clearly, much more work needs 

to be done to answer remaining questions about beta-amyloid, the cell-cycle 

process, tau, vascular dysfunction, 

and other factors that may promote or 

retard the AD process. However, these 

and other basic research studies are 

making an invaluable contribution to 

our understanding of AD, and they are 

opening promising new avenues in the 

search for AD therapeutic strategies. 

For some time now, the study of the brain’s 

blood vessel system in the context of AD has 

been a productive line of inquiry.
Learning More About Mild Cognitive Impairment

The best-known consequence of AD 

is memory loss, but this is not the only 

feature. A person with AD has other 

problems as well, including difficulties 

in processing and organizing information; problems with judgments and 

making decisions; personality changes; 

hallucinations, delusions, and other 

psychiatric problems; depression; loss 

of impulse control; perceptual-motor 

problems (for example, having trouble 

getting out of a chair); and physical 

problems that become pronounced 

as the disease nears its end.

As some people grow older, they 

develop memory problems greater 

than those expected for their age. But 

they do not experience the personality 

changes or have the cognitive or other 

problems that are characteristic of AD. 

Their condition, then, may not meet all 

the medically-defined criteria for AD. 

These people have a condition called 

mild cognitive impairment (MCI). 

People with MCI are a critically 

important group for research into 

the causes of AD because a higher 

percentage of them go on to develop 

AD compared to older people without 

these memory problems. It is not 

known whether all people with MCI 

will advance to AD. This puzzle has 

raised a number of questions for 

scientists. Is MCI an early stage of 

AD, or are they entirely separate 

conditions? Why and when does MCI 

sometimes, but not always, develop 

into AD? Do people with MCI who 

don’t go on to develop AD have some 

special protective characteristics? 

Can MCI be prevented or its progress 

delayed or interrupted?

These questions have created some 

obvious research objectives: 

 Define MCI and the relationship 

between MCI and AD

 Learn about the underlying causes 

and courses of MCI

Understand the pathology of MCI 

 Explore strategies that could prevent or delay MCI and AD

In recent years, investigators have 

made major progress in achieving 

these objectives. For example, scientists have developed a framework for 

understanding the causes and courses 

of MCI by defining subtypes of the 

condition based on cause (for example, 

degenerative, vascular, psychiatric, 

and medical), and on which aspects of 

cognition are predominantly affected. 

The subtype that features memory 

impairment most prominently is called 

MCI with memory loss, or “amnestic 

MCI.” This definition of MCI already 

has been widely used by research 

teams working on AD treatment strategies in clinical trials. Scientists working 

in ADCs have reported that about eight 

in 10 people who meet criteria for 

amnestic MCI progress to AD within 

6 years of diagnosis. The chart on the 

next page illustrates current thinking 

about the transition from healthy cognitive aging to amnestic MCI to AD. 

Individuals with other MCI subtypes 

may have prominent deficits in other 

cognitive functions, such as language 

skills or visuospatial ability (the ability 

to recognize objects and determine 

•

•

•

•

where they are in relation to each 

other, and to mentally rearrange 

them). Other degenerative diseases, 

such as frontotemporal dementia, 

dementia with Lewy bodies, and 

vascular dementia also can cause 

these symptoms (Petersen, 2005). The 

development of a clear description of 

these conditions and the elements and 

extent of cognitive function affected 

by amnestic MCI has been a major 

contribution to AD research, particularly 

to the conduct of clinical trials. 

Investigators pursuing many 

avenues of research have provided 

valuable additions to our storehouse 

of knowledge. Here are a few things 

we’ve recently learned about MCI:

Genetic risk factors appear to 

play a role in MCI as they do in AD:

Investigators at a number of 

research laboratories have found 

that people with MCI who also 

have the APOE-�4 allele progress 

to AD more rapidly than those 

without APOE-�4 (Fleisher et 

al., 2005; Petersen et al., 1995; 

Tschanz et al., 2006). 

In the recently completed 

3-year Memory Impairment Study, 

one of NIA’s Alzheimer’s Disease 

Cooperative Study (ADCS) clinical 

trials (see p. 44 for more on the 

ADCS), investigators compared the 

effectiveness of vitamin E, donepezil, and a placebo in delaying 

the onset of a diagnosis of AD in 

769 people with amnestic MCI 

(Petersen et al., 2005). In the 

subset of study participants who 

•

•

•

20 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease
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. For other participants, 

donepezil reduced risk of progressing to AD during the first 

12 months of the study, but this 

benefit disappeared by 18 months. 

Vitamin E did not appear to slow 

the progression to AD. 

Different brain regions appear 

to be activated in cognitively healthy 

people and those with MCI during 

certain types of cognitive activities. 

Using brain imaging techniques, 

University of Pittsburgh investigators 

participating in the Ginkgo Evaluation 

of Memory (GEM) trial were able to 

detect differences in an aspect of 

cognitive function called attentional 

control (Rosano et al., 2005). These 

changes are likely to be related 

to early cognitive impairment. (see 

p. 44 for more about the GEM trial). 

The rate of brain atrophy can 

predict cognitive impairment and 

dementia. Investigators compared 

magnetic resonance imaging (MRI) 

scans over time in the same individuals with either normal cognition 

or MCI (Jack et al., 2005). They found 

that higher brain atrophy rates predicted increased impairment and 

dementia.

Treatment with raloxifene 

(Evista), a selective estrogen receptor 

modulator used to treat osteoporosis, 

may reduce the risk of developing 

cognitive impairment and AD. The 

•

•

•

Multiple Outcomes of Raloxifene 

Evaluation (MORE) study was a prevention clinical trial conducted with 

nearly 5,400 postmenopausal women 

with osteoporosis (Yaffe et al., 2005). 

The women were divided into three 

groups: one group received a placebo, 

one group received 60 mg/day of the 

drug, and the third group received 

120 mg/day. After 3 years of treatment, there was no difference 

between the 60 mg/day group and 

the placebo group. However, women 

who took 120 mg/day had a statistically significantly lower risk of 

developing amnestic MCI and a somewhat lower risk of developing AD and 

any cognitive impairment than did 

the women who took the placebo. 

(See p. 42 for a description of a treatment clinical trial in which investigators are examining raloxifene’s effect 

in women who already have AD.)

In addition to conducting studies 

like these, investigators are using a 

variety of sophisticated tools to push 

the boundaries of knowledge about the 

very early stages of the AD process. 

Several of these tools are described in 

greater detail on p. 36. 

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

Total loss of 

independent 

function

Charting the Course of Healthy Aging, MCI, and AD

Healthy Aging Amnestic MCI Clinically Diagnosed AD 

Cognitive 

decline 

accelerates 

after AD 

diagnosis

Normal age-related 

memory loss

2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 21
22 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Can Lifestyle Interventions 

Slow the Disease Process? 

We now know that exercise, a healthy 

diet, and not smoking can help people stay 

healthy as they grow older. Research has 

shown that several chronic diseases and 

conditions that commonly affect people 

as they age—including diabetes, heart 

disease, stroke, and high blood pressure—are heavily influenced by lifestyle 

factors. Investigators are realizing that 

AD also may share some of these risk factors and have even begun to examine how 

lifestyle might contribute to the overall 

emotional health and cognitive abilities of older adults. A number of studies 

have shed light on this important topic.

Lessons Learned from Couch Mice, 

Marathon Mice, and Men and Women 

Who Like to Walk 

These days, exercise and physical 

activity are big buzz words. People are 

physically active—or know they should 

be—because they’ve heard the message: 

Exercise is good for everyone, whether 

we are young children or older adults. 

Exercise builds muscles, improves heart 

and lung function, helps prevent osteoporosis, and improves mood and overall 

well-being. Exercise is good for those who 

are already healthy, and it can improve 

the health of people with chronic conditions, including hypertension, diabetes, 

arthritis, obesity, and cardiovascular 

disease (Daniels, 2006; Klieman et al., 

2006; McDermott and Mernitz, 2006; 

Michael and Shaughnessy, 2006). 

So, it is not surprising that scientists 

began to think that if exercise benefited 

all parts of the body from the neck 

down, it surely must benefit the brain 

as well. They have conducted a number 

of epidemiologic studies to examine the 

associations between exercise, cognitive 

function, and risk of AD (Abbott 

et al., 2004; Larson et al., 2006), as well 

as a number of small clinical trials to 

assess the impact of exercise on cognitive function (Colcombe and Kramer, 

2003). Findings have been intriguing. 

Epidemiologic studies have examined 

whether exercise and physical activity 

are associated with beneficial effects on 

cognitive performance. For example, in 

an NIA-funded study, researchers at the 

Harvard School of Public Health analyzed 

data from almost 19,000 women aged 

70-81 who participated in the Nurses’ 

Health Study, a large study funded by the 

National Heart, Lung, and Blood Institute 

(NHLBI) in which nearly 122,000 nurses 

are asked questions every 2 years about 

their health, illnesses, diet, and lifestyles 

(Weuve et al., 2004). Comparing women 

at various levels of long-term (over several 

years) physical activity, they found that 

women at higher activity levels had better 

cognitive performance and reduced cognitive decline than women at lower activity 

levels. The cognitive benefit was similar to 

being about 3 years younger in age. And 

the association wasn’t confined only to the 

vigorous exercisers. Walking the equivalent 

of at least 11⁄2 hours per week at a 21-30 

minute-per-mile pace also was associated with better cognitive performance. 

Researchers at the University of Pittsburgh 

found similar results when they studied 

exercise patterns and cognitive function 
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 23

among rural residents in a relatively low 

socioeconomic area (Lytle et al., 2004). 

Other investigators have gone further 

and looked at the possible association of 

physical activity and risk of developing 

dementia among older adults (Abbott 

et al., 2004). Researchers at the Kuakini 

Medical Center in Hawaii examined data 

from the men in the Honolulu-Asia Aging 

Study (HAAS), a long-term epidemiologic study of stroke, neurodegenerative 

diseases, and aging in older JapaneseAmerican men (see p. 32 for other studies 

using HAAS data). The investigators 

found that walking less than a quarter of a 

mile every day was associated with almost 

twice the risk of developing dementia 

compared to walking more than two 

miles a day. A group of researchers from 

the Johns Hopkins University and the 

University of Pittsburgh examined this 

issue using data from older participants 

in the Cardiovascular Health Cognition 

Study (CHCS). The NIA-funded 

CHCS is an add-on study to NHLBI’s 

Cardiovascular Health Study (CHS). 

Since 1988, the CHS has examined 

risk factors for the development of heart 

disease and stroke in elderly adults. 

The Johns Hopkins and University 

of Pittsburgh investigators found that 

the highest energy expenditure and the 

greatest number of physical activities 

pursued were associated with a reduced 

risk of dementia, AD, and vascular 

dementia (Podewils et al., 2005). This 

association was stronger in people who 

did not have the APOE-ε4 allele than in 

people who did have it. These researchers 

speculate that the number of physical 

activities may be as important, or even 

more important, to risk of dementia than 

the frequency, duration, or intensity of the 

activities. A third group of researchers at 

the Group Health Cooperative in Seattle, 

Washington, followed older adults for 

6 years and found that regular exercise 

(defined in this study as 3 or more times 

a week) was associated with about onethird the risk of developing dementia as 

less frequent exercise (Larson et al.,

2006). Interestingly, 

they found that the 

greatest risk reduction 

occurred in those who 

were least physically 

fit at the beginning of 

the study.

These observational 

studies suggest that 

physical activity and 

exercise may protect 

the health of the brain 

in some way, especially

as physical activity and exercise were associated with cognitive health in each of the 

studies. However, other kinds of studies 

are needed to firm up these associations 

and clarify why exercise might reduce the 

risk of cognitive decline and dementia. 

Scientists have looked to studies with 

experimental animals for some of the 

answers. To date, several studies have shown 

positive effects of aerobic exercise on the 

structure and function of the brain in older 

animals. For example, in research with rats 

and mice, investigators have found that 

exercise increases the number of capillaries 

that supply blood to the brain and the 

number of connections between neuronal 

synapses. It also increases levels of brainderived neurotrophic factor (BDNF) in 

the hippocampus, the brain region most 

affected by AD. BDNF is a protein that 
24 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

supports the survival of existing neurons 

and encourages the development of new 

neurons. In a recent study with rats, 

researchers at the University of California 

at Irvine found that both daily exercise 

on a running wheel and exercise on alternate days increased BDNF levels and 

that BDNF levels remained elevated even 

after several days of rest (Berchtold et 

al., 2005). Moreover, animals that had 

exercised enough to raise BDNF levels 

and then had rested for a number of days 

needed only a brief return to exercise to 

increase BDNF to levels that would take a 

“couch potato” rat several weeks to reach. 

Using these clues, investigators have 

used animal studies to probe even more 

deeply into the relationships between 

physiological changes in the brain and 

effects on cognitive performance and 

progression of AD pathology. A group 

of researchers at the Salk Institute for 

Biological Studies in La Jolla, California, 

for example, wanted to see whether the 

age of the animal and the age at which 

You may have noticed in this 

section that we’ve always been 

careful to say that one thing is 

associated with another thing, 

rather than to use other words 

that might suggest a more 

definitive cause-and-effect

relationship. Why do the words 

matter? It’s because of the type 

of research we’re describing. 

In this section and in several 

others, we highlight findings 

from epidemiologic studies. 

This type of research compares 

the lifestyles, behaviors, and 

characteristics of groups of 

people. Scientists have used 

these studies to identify risk 

and protective factors for many 

types of diseases. For example, 

in the early days of heart disease research, epidemiologic 

studies were crucial to naming 

high-fat diets and smoking as 

major risk factors. 

However, epidemiologic 

studies are observational, gathering information about people 

who are going about their daily 

lives. Study participants follow 

many behaviors and practices. 

It’s difficult, therefore, to tease 

out the exact benefits or risks 

of one particular behavior 

from all the healthy or harmful 

behaviors followed by the 

participants. That’s why, in 

epidemiologic studies of AD, 

scientists restrict themselves 

to saying that a behavior is 

associated with AD, or not. The 

epidemiologic evidence linking 

a behavior and AD is, at best, 

suggestive, but we don’t know 

whether the behavior actually 

helps to cause or prevent AD. 

Other types of research—

test tube studies, studies in animals, and clinical trials—add to 

the findings from epidemiologic 

studies. Scientists use these 

to examine the same issue but 

in circumstances in which the 

various factors that might influence a result are controlled 

to a greater degree. This element of control allows them 

to be more certain about why 

they get the results they do. It 

also allows them to use more 

definitive words to describe 

their results. (To see what we 

mean, take a look at the animal 

studies described on these two 

pages and at Full-scale AD 

Treatment Clinical Trials on 

p. 42-43.) Of course, showing a 

cause-and-effect relationship in 

tissue culture or even in animal 

studies still does not mean that 

this result will be the same 

in humans. Clinical trials in 

humans are the gold standard 

for deciding whether a specific 

treatment actually prevents or 

delays AD. 

What’s the Difference Between an 

Association and Cause and Effect?
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 25

they began to exercise made a difference 

(van Praag et al., 2005). They found a 

beneficial effect even in mice that became 

active later in life—these mice learned 

and remembered a maze better than 

did old mice that weren’t exercisers. 

They also found that the older running mice also were able to form healthy 

new neurons at a similar rate to those 

of younger mice, suggesting that voluntary exercise can restore learning and 

neuronal formation in aged mice.

Two other research groups set out to 

test the effects of exercise and an enriched 

environment on the progression of AD 

pathology itself. One group, from the 

University of California at Irvine, divided 

transgenic AD mice into two groups—one 

had access to an exercise wheel and the 

other did not (Adlard et al., 2005). The 

scientists found that the exercising mice 

were better able to learn than the nonexercisers. Five months after the experiment began, the scientists examined the 

brains of the mice and found that the 

exercising mice also had significantly fewer 

beta-amyloid deposits in the hippocampus 

and cortex than did the non-exercisers. 

Using a different transgenic AD mouse 

model, researchers funded by NIA and the 

National Center for Research Resources 

found that mice living in an “enriched” 

environment that challenged them mentally as well as physically had significantly 

less beta-amyloid in the cortex and hippocampus compared to those housed in 

standard conditions (Lazarov et al., 2005). 

Upon further analysis, the University of 

Chicago investigators determined that 

long-term exposure to the enriched environment led to an increase in the brain’s 

capacity to degrade beta-amyloid and 

stimulated the expression of genes 

associated with learning and memory, cell 

survival, and generation of new neurons. 

All of these epidemiologic and animal 

studies have suggested that regular exercise may, indeed, have benefits from the 

neck up as well as the neck down. Further, 

they point to some possible reasons why 

these benefits exist. However, some major 

questions remain. For example, does a 

person have to be fit throughout life, 

or can physical activity late in life still 

help? How much does a person have to 

exercise to reap the benefits? How do the 

benefits change with a person’s level of 

fitness? How long do the positive effects 

last? Does exercise interact in some way 

with cognitively stimulating activities 

(such as doing games and puzzles or 

participating in social networks) to benefit the brain, and if so, how do those 

interactions work? Are sedentary people 

who later develop dementia and AD less 

active because they are already in the 

early stages of the disease, or is it the 

reverse—the dementia is partially due to 

a history of physical inactivity? Another 

avenue of research—clinical trials—is well 

suited to examine some of these questions and provide some concrete answers. 

NIA supports several clinical trials 

to explore issues related to exercise, cognitive function, and dementia risk: 

Aerobic exercise to improve executive function in sedentary older adults.

This trial is examining the impact of a 

6-month cardiovascular training program (walking briskly on a treadmill) 

on the ability of 80 older adults to 

carry out selected types of executive 

function tasks (for example, ability to 

block out irrelevant information and 

ability to switch easily from task to 

task) and on brain electrical activity. 

•
26 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Aerobic exercise to improve cognitive and brain function in sedentary older 

adults. This clinical trial is exploring the 

hypothesis that improvements in aerobic 

fitness in older adults will benefit cognitive function and brain structure and 

activity. One hundred and forty sedentary 

older adults will be enrolled in a 1-year 

aerobic fitness intervention (walking 

briskly on a treadmill) and assessed for 

changes in brain and cognitive function. 

Aerobic fitness to maintain or 

improve cognitive function in people 

with amnestic MCI. A small-scale 

12-week trial is examining the effect 

of an aerobic fitness program on cognitive function in 102 sedentary older 

adults with MCI. The investigators 

are studying the impact of exercise in 

delaying, arresting, or reversing the progression of age-related cognitive decline.

Combination of group exercise 

and health education to improve cognitive function in people with amnestic 

MCI. This trial of 170 sedentary older 

adults with MCI is testing a combined 

intervention of group exercise and 

a health promotion program over 36 

months. Individuals will be evaluated for 

the effectiveness of this intervention on 

cognitive, emotional, and physical function, as well as quality of life and rate 

of conversion from MCI to dementia. 

•

•

•

Because the research area of physical 

activity and cognitive function is so 

important, NIA also is considering 

adding a cognitive component to future 

exercise trials that ask questions about 

exercise effects on other body systems. 

Scientists hope that the results of these 

lines of research not only will answer 

questions about the cause and development of MCI and AD, but also will 

provide motivation for individuals to 

become and stay physically active to 

promote and preserve the health of 

their brains as well as their bodies. 

A Healthy Diet May Be Important to Brain 

Health as Well as Body Health 

A nutritious diet rich in fruits, vegetables, and whole grains and that is low in 

fat and added sugar can reduce the risks of 

many chronic conditions, including heart

disease, diabetes, obesity, 

and some forms of cancer. 

In recent years, investigators have used epidemiologic, animal, and test 

tube studies and clinical 

trials to explore whether 

diet can play a role in 

preserving cognitive function or even 

reducing risk of AD. 

A long-held theory about aging suggests that, over time, damage from free 

radicals (molecules that chemically react 

easily with other molecules) can build up 

in neurons, causing loss of function. This 

damage is called oxidative damage. The 

brain’s unique characteristics, including 

its high rate of metabolism and its longlived neurons, may make it particularly 

vulnerable to oxidative damage. Previous 

epidemiologic and laboratory studies have 

suggested that fruits and vegetables that 

are high in antioxidants might protect 

For more information about ongoing 

clinical trials described in the Progress 

Report, visit NIA’s ADEAR Center website.
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 27

the brain against this kind of damage. 

A group of Harvard Medical School 

researchers explored this possibility by 

examining data from more than 13,000 

Nurses’ Health Study participants aged 70 

and older (Kang et al., 2005). 

They found that the women 

who ate the most vegetables—especially green 

leafy vegetables (like 

spinach and romaine 

lettuce) and cruciferous 

vegetables (like broccoli 

and cauliflower)—experienced a slower rate 

of cognitive decline 

than did women who 

ate the least vegetables. The scientists 

were careful to account for other factors 

that might influence the results, such 

as use of vitamin supplements, physical 

activity, smoking and alcohol use, and 

educational attainment. Interestingly, fruit 

consumption did not appear to be associated with any change in cognitive ability. 

The scientists speculate that the abundant 

antioxidant and folate (a nutrient that 

appears to be important for proper neural 

activity and cognitive function) content 

of the green leafy and cruciferous vegetables was responsible for these results.

As with physical activity studies, 

these epidemiologic studies can only suggest associations between diet and cognitive performance. That’s why researchers 

have turned to animal studies to explore 

in greater detail possible diet and AD 

relationships. Dogs are a good model for 

this type of AD research because they 

can perform sophisticated and complex 

cognitive tests, their brains accumulate 

beta-amyloid plaques with age, and the 

degree of beta-amyloid deposition is 

related to the severity of cognitive decline. 

Investigators at the University of Toronto 

and the University of California at Irvine 

completed a 2-year study that 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 

and mitochondrial 

cofactors from vitamins E and C and fruit 

and vegetable extracts could 

reduce age-related cognitive 

decline (Milgram et al., 2004; 

Milgram et al., 2005). This 

study included both old and 

young dogs. Some received both the 

fortified food and enriched environment, 

some received one or the other enrichment, and some received neither. At the 

end of the first year, the researchers tested 

the dogs on two learning tasks. They 

found that antioxidant supplementation 

was effective only when it was combined 

with behavioral enrichment. The 2-year 

results, however, showed that the supplemented food by itself had a beneficial 

effect on the older dogs’ ability to perform 

the learning tasks, suggesting that the 

effects of the antioxidant supplementation became stronger over time. In both 

studies, the effects of the treatments were 

most evident in the dogs who received the 

dietary as well as the behavioral enrichment. In another similar study with 

dogs, these same researchers found that 

an antioxidant-enriched diet improved 

the performance of older dogs when 

they performed learning tests for the first 

time, but not on repeat tests, suggesting 
28 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

that the enriched diet was particularly 

helpful when the dogs had to process 

new information (Siwak et al., 2005).

Curcumin is the main ingredient of 

turmeric, a bright yellow spice used in 

curry. Scientists are extremely interested 

in this compound because it has powerful anti-inflammatory and antioxidant 

properties and can suppress the accumulation of beta-amyloid in brain tissue. 

In test tube and transgenic mice studies, 

a research group supported by NIA and 

the National Institute of Neurological 

Disorders and Stroke (NINDS) found 

that curcumin was able to cross the 

blood-brain barrier and bind directly to 

beta-amyloid peptides (Yang et al., 2005). 

These investigators, from the Greater Los 

Angeles Veterans Affairs Healthcare System, 

found that the curcumin actually had 

several different anti-amyloid properties. 

By binding to the beta-amyloid peptide, 

curcumin prevented the aggregation of the 

peptides into oligomers and inhibited the 

toxic effect of the oligomers (see p. 12 for 

more on the process by which beta-amyloid 

aggregates into oligomers and ultimately 

plaques). When fed to aged mice that 

had significant plaque accumulation, the 

curcumin was able to reduce amyloid 

levels and the overall amount of plaque. 

This research team also examined the 

effects of another dietary component—the 

omega-3 fatty acid called docosahexaenoic 

acid (DHA), which is found in abundance 

in some kinds of fish. DHA is a primary 

component of the membranes of nerve 

cells in the brain and is involved in 

multiple brain functions, including nerve 

cell communication. DHA is reduced 

in the brains of people with AD, and 

some evidence suggests that higher levels 

of DHA in the blood may be protective 

for dementia and AD (Schaefer et al., 

2006). In studies with transgenic mice, 

the researchers found that deficits in DHA 

can damage brain biochemistry, structure, 

and cognitive abilities (Calon et al., 2004). 

In contrast, a diet high in DHA reduced 

beta-amyloid and reduced the overall 

amount of plaque in the brain, especially 

in the hippocampus and parietal cortex, 

and reduced the amount of APP, the betaamyloid precursor protein (Lim et al., 

2005; Cole et al., 2005). 

Research teams at the University of 

Southern California, in Los Angeles, and 

the Mt. Sinai School of Medicine, in New 

York, also have used transgenic mice to 

investigate another possible link between 

diet and cognitive decline and AD. It is 

known that a calorie-restricted diet slows 

various aging processes in laboratory 

animals, so these investigators examined 

what effect calorie restriction might have 

on the AD process in transgenic mice. In 

one study, calorie restriction substantially 

decreased the accumulation and size of 

beta-amyloid plaques (Patel et al., 2005). 
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 29

It also reduced the activation of certain 

glial cells called astrocytes near betaamyloid plaques. Beta-amyloid plaques in 

the AD brain are usually surrounded by 

numerous activated astrocytes. The Mt. 

Sinai team found that a calorie-restricted 

diet also promoted the activity of alphasecretase, the enzyme involved in cleaving 

APP in a beneficial way. This prevented 

new beta-amyloid peptides from being 

formed and plaques from being deposited in brain tissue (Wang et al., 2005). 

These studies have provided 

intriguing hints about possible 

associations between various dietary 

elements, oxidative damage and 

inflammation in brain tissues, and 

AD pathology. To confirm these 

results, scientists have turned to 

clinical trials: 

Fish oil, alpha-lipoic acid, 

and AD. In test tube studies, fish oil and 

alpha-lipoic acid, a mitochondrial antioxidant, have been shown to decrease oxidative stress, inflammation, and lipid levels, 

making them candidates for therapies 

designed to slow the progression of AD. 

In this pilot clinical trial, investigators 

are assessing the effect of the fish oil and 

alpha-lipoic acid supplements on oxidative stress and cognition associated with 

disease progression. The research team 

also is closely monitoring the safety of the 

treatment. Enrollment of the 39 participants in this trial is complete, and data 

collection and analysis are ongoing. Pilot 

studies like this are used to collect initial 

data on the safety, effectiveness, and best 

dosage of a potential treatment. Results 

are used to design a full-scale clinical trial 

to assess the effects and potential benefits 

of the compound under investigation.

•

Vitamin E, Down syndrome, and 

AD. People with Down syndrome are 

vulnerable to a form of AD that is indistinguishable from late-onset AD. This 

multi-center trial will evaluate whether 

high-dose vitamin E, a cellular antioxidant, will slow the rate of cognitive and 

functional decline in 350 older people 

with Down syndrome, who are at very 

high risk of developing AD. Recruitment 

is ongoing. This trial is jointly sponsored 

by NIA, the National Institute of Child 

Health and Human Development, and 

the National Center for Complementary 

and Alternative Medicine (NCCAM).

Combination vitamin supplement in the treatment of AD in Down 

syndrome. In this 24-month trial, a highpotency supplement consisting of two 

cellular antioxidants (vitamins E and C) 

and a mitochondrial antioxidant (alphalipoic acid) has been tested in 60 people 

with Down syndrome and AD to assess 

safety and tolerability and to determine 

whether cognitive function improved with 

antioxidant supplementation. Enrollment 

for this trial is complete, and data collection and analysis are ongoing. 

•

•

Studies have provided intriguing 

hints about possible associations between 

various dietary elements, oxidative damage and 

inflammation in brain tissues, and AD pathology.
30 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Isoflavones and AD. This 6-month 

trial is examining the effects on cognitive 

functioning of soy isoflavones (a class of 

chemicals found in plants that act like 

estrogen in the body) in older adults with 

AD. The recent findings about increased 

health risks, including cognitive decline, 

• associated with hormone replacement 

therapy has increased interest in the 

potential of soy isoflavones as an alternative therapy. Preliminary findings 

suggest that these compounds may have 

cognitive benefits, but no data exist 

about AD-associated cognitive decline. 

Investigators plan to enroll 60 participants, 

and nearly half that number have already 

joined the trial.

Many news reports lately 

have touted the possible beneficial effects of moderate 

alcohol consumption, especially 

to prevent heart disease. These 

helpful qualities are due to 

the fact that alcohol reduces 

inflammatory proteins in the 

blood and increases levels of 

HDL (the “good” cholesterol).

A growing body of evidence 

is now suggesting that factors 

that play an important role in 

heart disease and stroke also 

may be important in AD. Could 

a glass of wine or beer help 

prevent AD, then?

Several epidemiologic studies 

have examined this question. 

They have found that moderate 

alcohol consumption was not 

associated with impaired cognitive function and actually is 

correlated with reduced risk 

of cognitive decline and AD 

(Bond et al., 2004; Evans and 

Bienias, 2005; Ganguli et al., 

2005; Luchsinger et al., 2004; 

Stampfer et al., 2005). As with 

heart disease, the beneficial 

effect of alcohol on cognitive 

abilities may occur because 

alcohol can reduce inflammatory 

proteins and increase HDL. 

Animal research also has 

linked certain compounds 

with beneficial effects on the 

brain. For example, a team of 

researchers at the North ShoreLong Island Jewish Institute for 

Medical Research supported by 

the National Institute of Mental 

Health (NIMH), found in testtube studies that resveratrol, a 

naturally occurring compound 

mainly found in grapes and 

red wine, markedly lowered 

the level of beta-amyloid in 

cells (Marambaud et al., 2005). 

Resveratrol did not inhibit the 

production of beta-amyloid, but 

rather promoted its degradation 

within the cell.

However, these findings 

come with lots of caveats. 

For one thing, we don’t know 

enough about alcohol’s effects 

on AD pathology to recommend 

it directly as a way to reduce 

cognitive decline or AD risk. For 

another, observational and epidemiologic research can reveal 

associations, but do not establish cause and effect. These 

limitations make it hard to say 

that the alcohol itself is responsible for reducing risk of cognitive decline. Many other factors 

about participants’ lifestyles 

and health also may play a role. 

Another complication is that 

the studies define “moderate” 

consumption differently, making 

it difficult to come to a definite 

conclusion about whether and 

how much alcohol may be 

beneficial. 

Finally, it’s important to 

remember that heavy alcohol 

consumption has wellestablished harmful effects, 

and older people can be 

more affected by alcohol 

than younger people. 

Emerging Evidence about Moderate Alcohol 

Consumption and Cognitive Function
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 31

As with other areas of research into 

lifestyle factors and AD, we have tantalizing hints about particular dietary components but few firm conclusions about 

diet as a whole and its relationship to 

cognitive decline and AD. One reason for 

this is the complexity of the diet. Because 

a person’s diet has numerous components 

and varies from day to day, researchers 

often must rely on supplements to isolate 

particular factors. Nutrient supplements 

on their own are not the same as nutrients within the context of whole foods, 

however, so caution is in order when 

applying these results to actual dietary 

patterns. Despite these limitations, findings to date about diet, cognitive decline, 

and AD are consistent with, and provide 

additional support for, current recommendations about the components of a 

nutritious and health-promoting diet.

Managing Chronic Illness: A Possible 

Preventive Strategy for AD? 

As we’ve seen with exercise and diet, 

evidence suggests that what may be good 

for the heart may be good for the brain. 

Moreover, metabolic changes that occur 

in a variety of chronic diseases of aging, 

such as heart disease, stroke, high blood 

pressure, and diabetes, may contribute 

to the development of AD, affect the 

severity of AD, or cause vascular dementia 

(Luchsinger et al., 2005; Curb, 2005). 

However, it has been difficult to 

untangle the association between AD 

and these chronic diseases. Scientists 

have offered several possible explanations. For example, many believe that 

atherosclerosis, which may or may not 

be clinically apparent as heart disease or 

stroke, may add to or accelerate cognitive 

decline in people who already have AD. 

Or, it is possible that metabolic changes 

related to chronic disease, such as elevated 

insulin levels in diabetes, may actually 

increase the amount of AD pathology that 

accumulates in brain tissue and directly 

contribute to the development of AD. 

Other possibilities or a combination 

of factors also may explain the associations. As we develop new strategies to 

treat AD, it will be important to know 

whether the metabolic changes related to 

chronic vascular disease actually increase 

the amount of AD pathology or whether 

they independently cause dementia.

These relationships need to be sorted 

out because heart disease and stroke 

are major causes of illness and death. 

Diabetes, high blood pressure, and other 

risk factors for these chronic diseases can, 

to a large extent, be modified by diet, 

exercise, and other lifestyle changes, so it 

is important to know whether reducing 

risks of or controlling diabetes and high 

blood pressure also may reduce AD risk. 

Heart Disease and Stroke

Currently, much of our knowledge 

about the associations between heart 

disease, stroke, cognitive decline, and 

dementia comes from epidemiologic 

studies. For example, the NHLBI’s 

Cardiovascular Health Study and NIA’s 

Cardiovascular Health Cognition Study 

have provided valuable data about the 

relationships between cardiovascular 

risk factors and AD because they include 

cognitive decline and dementia related to 

vascular disease as a key element of their 
32 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

design. In two recent analyses of CHS 

data, University of Pittsburgh investigators 

explored the relationships between cardiovascular disease and dementia. In the 

first study, the investigators showed that 

the risk of AD was 30 percent higher in 

people who had a history of cardiovascular 

disease other than stroke, compared with 

those without such a history (Newman 

et al., 2005). In the second study, investigators showed that vascular dementia 

and mixed dementia 

(vascular dementia 

and AD occurring 

simultaneously) 

account for a large 

proportion of new 

dementia cases 

(Kuller et al., 2005). 

An important result 

of the study was 

that it demonstrated 

the value of MRI 

as a diagnostic tool 

(see p. 50 for more 

on NIA’s Neuroimaging Initiative). 

Investigators working with HAAS 

data explored whether men with betaamyloid plaques and NFTs had an increased 

chance of crossing the threshold to clinical 

dementia if they also had cerebrovascular damage (Petrovitch et al., 2005). 

These Pacific Health Research Institute 

investigators found that, indeed, in men 

who had NFTs, dementia increased with 

increasing plaque density, particularly in 

the presence of cerebrovascular damage. 

This association was strongest in men 

who had the fewest plaques, suggesting 

that preventing cerebrovascular damage 

may be critically important in preserving 

cognitive abilities in older people.

As this area of research has blossomed, 

investigators have conducted studies 

of additional groups to explore associations between vascular disease and AD. 

For example, researchers from the Rush 

University Alzheimer’s Disease Center 

have included cerebrovascular disease 

measures when examining brain tissue 

samples from deceased participants of 

the Religious Orders Study, a long-term 

study of aging among members of 40 

religious communities (Bennett et al., 

2005). Consistent with other studies, 

participants who had amnestic MCI had 

evidence of intermediate levels of both 

AD and stroke damage in their brain 

tissue. They also had clinical symptoms 

that were in between those of people 

without cognitive impairment and those 

of people with dementia. 

Findings from these and other studies 

have provided sufficient evidence for NIA 

to support several clinical trials to investigate the association between heart disease 

risk and AD:

Simvastatin and AD progression. This 18-month Alzheimer’s Disease 

Cooperative Study trial, which began 

in 2003, is testing whether simvastatin 

(Zocor), a commonly prescribed 

cholesterol-lowering drug, can safely 

and effectively slow the rate of cognitive 

decline in people with mild to moderate 

AD. Data from some, but not all, epidemiologic studies suggest that high blood 

•
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 33

cholesterol levels are a risk for late-life 

cognitive decline and AD. In animal 

studies, high cholesterol levels increase 

AD plaques and affect cognition, and 

these effects are reversed by statin treatment. Nevertheless, few positive data 

about cognition have emerged to date 

from statin longitudinal studies or drug 

trials. The ADCS trial will be a rigorous 

test of the statin hypothesis in people 

who already have AD. The trial is being 

conducted in dozens of sites around the 

country, and the enrollment of 406 participants is complete. Data are now being 

collected and analyzed. Some participants 

receive 20 mg of simvastatin for 6 weeks 

and then 40 mg of the statin for the rest 

of the study period. Others receive a placebo during the entire study. Clinical 

trial staff are tracking changes in participants’ cognitive functioning by measuring a number of indicators, including 

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

Supplements to reduce homocysteine and slow the rate of cognitive 

decline. Previous studies have shown that 

elevated levels of the amino acid homocysteine are associated with both heart disease 

and AD and that high homocysteine levels 

make some neurons vulnerable to dysfunction and death. Homocysteine levels can 

be reduced by high-dose supplements of 

folate and vitamins B6 and B12. NIA is 

currently supporting an ADCS clinical trial 

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, which began in 2003, are divided 

into two groups: 60 percent of participants 

receive daily high-dose supplements (5 mg 

of folate, 25 mg of vitamin B6, and 1 mg 

of vitamin B12) and 40 percent receive a 

placebo. The research team has completed 

the enrollment of 400 participants, and 

data collection and analysis are ongoing.

Preventing cognitive decline in 

women. This trial is an add-on to two 

ongoing NHLBI clinical trials of chronic 

disease prevention in women—the 

Women’s Health Study (WHS) and the 

Women’s Antioxidant Cardiovascular 

Study (WACS). WHS tested low-dose 

aspirin and antioxidant supplementation 

in healthy women, and WACS tested 

antioxidant and folate supplements in 

women who already had heart disease. 

Scientists hypothesize that these agents 

also may prevent AD. The add-on trial 

is examining whether these treatments 

provided any protection against cognitive decline. Both WHS and WACS 

have been completed, and study investigators are analyzing study results.

Diabetes and AD 

The possible association of diabetes, 

insulin processing, and AD also is generating much interest among AD investigators. Type II diabetes mellitus is a major 

public health problem in the U.S. because 

it affects about one in five Americans 

older than 65 and has many serious 

•
34 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

health complications. A number of epidemiologic studies have suggested that 

people with diabetes have an increased risk 

of late-life cognitive problems, including 

MCI and AD, either as a direct result 

of high levels of blood sugar (hyperglycemia) or because of the conditions 

that are often associated with diabetes, 

namely high blood pressure, abnormal 

blood cholesterol levels, or too much 

insulin in the blood (Launer, 2005). 

Laboratory studies also have identified 

several pathways through which hyperglycemia can reduce neuronal viability 

(Launer, 2005). These include increases 

in oxidative stress, damage to endothelial 

and vascular function, and changes in gene 

transcription and expression in neurons. 

This evidence has spurred research 

on a variety of fronts, from epidemiologic 

studies, to test tube and animal studies, 

to clinical trials. The objective of these 

studies is to determine whether diabetes 

is a risk factor for cognitive decline, and 

if so, whether treatment for diabetes may 

help lower risk of cognitive decline or 

AD. NIA is currently funding several 

diabetes clinical trials to see whether 

treating one or other aspect of diabetes will 

affect cognitive health and AD progression:

ACCORD-MIND. This trial is 

an NIA-funded sub-study nested within 

NHLBI’s Action to Control Cardiovascular 

Risk in Diabetes (ACCORD) trial. 

ACCORD is aimed at evaluating whether 

intensive glucose, blood pressure, and 

lipid management can reduce cardiovascular disease in people with diabetes. 

ACCORD-MIND (ACCORD-Memory 

in Diabetes) will test whether these intensive interventions also can reduce the 

rates of cognitive decline and structural 

brain change in 2,800 

of the ACCORD study 

participants over a 4-year 

period. ACCORD-MIND 

participants will undergo 

periodic cognitive testing 

and MRI scans to assess 

change over time.

Glucose regulation and memory 

in AD. There is growing evidence suggesting that insulin’s role in the brain’s 

energy metabolism is not properly 

regulated in AD. Individuals with AD 

are at increased risk of insulin resistance 

(a condition in which muscle, fat, and liver 

cells are not able to use insulin properly; 

people who are insulin resistant are at 

high risk of developing diabetes). A key 

hypothesis that has emerged from work 

on diabetes and AD is that insulin resistance induces inflammation and elevations 

in free fatty acid levels, which interact 

with insulin-associated increases in 

damaging beta-amyloid. In this shortterm trial, researchers from the University 

•

•

NIA is currently funding several 

diabetes clinical trials to see whether 

treating diabetes will affect cognitive health 

and AD progression.
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 35

of Washington will test this hypothesis 

by examining the effects of induced and 

improved insulin resistance on cognition, beta-amyloid levels, and inflammation. They predict that inducing insulin 

resistance will increase beta-amyloid 

levels and inflammatory markers and 

will impair cognition, and that these 

effects will be greater for participants with 

AD and those who are overweight. The 

trial also will determine whether improved 

cognition after treatment with rosiglitazone (Avandia), a drug that has antiinflammatory properties and that improves 

the body’s ability to use insulin, will be 

associated with reduced levels of insulin, 

free fatty acids, and inflammation. The 

researchers hope that this study will provide valuable information about the mechanisms through which insulin resistance 

increases the risk of AD and about possible 

treatment approaches for reducing this risk.

Rosiglitazone and amnestic 

MCI. In this 18-month multi-center 

trial, researchers from the University of 

Washington also will test the effects of 

rosiglitazone on attention and memory 

skills in older adults with amnestic MCI. 

This trial will examine the effects of this 

medication on brain structures that support memory and other cognitive abilities, 

as well as on biological markers associated with inflammation, insulin resistance, and cardiovascular disease. Study 

participants will be divided into two 

groups—one group will receive 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 

biological markers in amnestic MCI.

Innovative insulin administration 

and cognitive function. A 4-month clinical 

trial is being conducted to examine the 

effects of administering a nasal-spray form 

of insulin on cognitive function, ability 

to carry out daily activities, glucose 

metabolism in the brain, and levels of 

beta-amyloid in people with AD. AD is 

associated with reduced levels of insulin 

in cerebrospinal fluid, and treatment 

with insulin has been shown to improve 

memory performance. However, insulin 

injections (a common way to administer insulin) can be problematic because 

they can sometimes result in hypoglycemia (low blood sugar). A nasal spray 

delivers insulin directly to the brain. 

Preliminary data on this alternative way 

to administer insulin show that people 

with AD improved their verbal memory 

and did not develop hypoglycemia. This 

clinical trial will provide useful data 

on the safety, feasibility, and potential efficacy of this innovative treatment 

approach, which investigators may use 

to plan future large-scale clinical trials. 

•
Sophisticated Tools Help Investigators Learn More About 

As people get older, changes occur 

in all parts of the body, including the 

brain. In the brain:

 Synapses become less efficient 

or are lost.

 Some neurons shrink, especially 

large ones in areas important 

to learning, memory, planning, 

and other complex mental activities. This translates into some 

shrinkage of brain volume over 

the course of years, even in 

healthy older people.

 Tangles develop inside certain 

neurons in particular brain regions 

and amyloid plaques develop in the 

spaces between some neurons.

 Damage by free radicals increases.

The impact of these changes differs among people as they age. Healthy 

older people may notice only a modest 

reduction in their ability to learn new 

things, retrieve information from 

memory, and plan and make decisions. 

Other people, however, experience 

much greater declines in their memory 

and cognitive abilities as they grow 

older because they are developing a 

neurodegenerative disease and these 

changes are occurring to a much 

greater extent. Understanding the difference between changes that occur 

with healthy aging and a neurodegenerative process is an important key to 

unlocking the secrets of AD. 

It is now clear that by the time 

the symptoms of amnestic MCI or AD 

become evident, the disease process 

is well underway—neurons have died, 

plaques and tangles have become 

abundant in different brain regions, and 

damage from inflammation and free 

•

•

•

•

radicals has greatly increased. Decades 

earlier, biological processes may have 

begun that predisposed the individual 

to develop AD or another neurodegenerative disease. As the previous 

sections of this report show, it is also 

increasingly clear that these biological 

processes are directed by a complex 

interaction of many factors, including 

genetic, lifestyle, and environmental 

influences.

If the disease process actually 

starts many years before it becomes 

evident, while a person still appears 

to be healthy, then it is imperative for 

researchers to learn as much as possible about its early stages so that they 

can identify those who may be at high 

risk and develop interventions to disrupt or prevent the disease. Advances 

in several key tools are helping scientists understand these early changes 

in the brain:

Neuroimaging. Increasingly 

sophisticated brain imaging techniques, especially MRI and positron 

emission tomography (PET) allow 

investigators not only to measure 

brain structure, volume, and activity 

but also to correlate changes in these 

measures with cognitive performance. These findings provide valuable insights into what happens in 

the brain as the disease progresses. 

For example, Massachusetts General 

Hospital researchers recently showed 

that people with MCI may compensate 

for the damage already done by the 

condition by activating a larger portion 

of particular brain regions when they 

are asked to do a cognitive task than 

do less impaired people (Dickerson et 

•

al., 2005). This increased activation 

may serve as a marker for impending 

clinical decline.

The NIBIB supports a broad portfolio 

of neuroimaging research, some of 

which is particularly relevant to AD. For 

example, cerebral amyloid angiopathy 

(CAA), the deposition of beta-amyloid 

in blood vessels in the brain, has been 

implicated as a common cause of 

hemorrhagic stroke and other forms 

of vascular disease. CAA also is frequently seen in AD. NIBIB-supported 

researchers at Massachusetts General 

Hospital are using low magnification 

imaging of brains from an AD mouse 

model to define the characteristics of 

CAA during disease progression and 

to develop a classification system 

correlating the severity of CAA deposition with the advancement of disease. 

This approach may enable clinicians 

to monitor the response to treatment 

more accurately (Domnitz et al., 2005).

Neuropsychological testing.

These tests, which measure delayed 

recall, verbal fluency, reasoning 

and decision-making abilities, and 

many other aspects of memory and 

cognition, are highly accurate in 

distinguishing between cognitively 

healthy people and those with mild 

AD, so long as differences caused 

by education, life experience, and 

age are adequately accounted for. 

They also are able to track changes 

in memory and cognitive function 

over time. These changes are the 

best way to differentiate between 

slow age-related changes and more 

rapid declines that are characteristic of amnestic MCI or AD. These 

•

36 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease
Changes in the Brain

capabilities make neuropsychological 

testing an essential tool for various 

purposes, including ensuring accurate diagnosis, measuring disease 

progression, and measuring response 

to treatments. Tests that may be 

practical for use in a doctor’s office, 

such as the AD-8, a brief 8-item 

questionnaire for caregivers, are 

being developed to differentiate those 

with very early clinical symptoms of 

dementia from adults with healthy 

cognition (Galvin et al., 2005).

Biomarkers. Techniques to 

measure specific components of 

blood, urine, and cerebrospinal fluid 

(CSF) are increasingly being tested in 

the laboratory. Understanding these 

biological markers—how they function and how, when, and why their 

levels change—will help investigators 

answer questions about the causes 

and early development of AD. They 

also will help scientists track changes 

in the brain and cognitive function 

over time and monitor response to 

treatments. 

Sensory studies also are 

adding to our knowledge of ways 

in which the body signals that a disease process may be unfolding. For 

example, problems with identifying 

smells occur early in the course of AD. 

Researchers at the New York State 

Psychiatric Institute and Columbia 

University have demonstrated that 

a short smell identification test was 

able to differentiate people with MCI 

and AD from those who were cognitively healthy (Tabert et al., 2005). 

Results also strongly predicted 

whether people with MCI would go 

•

•

on to develop AD. More recently, a 

research team at the University of 

Chicago has found that both visual 

and hearing impairment were associated with an increased risk of cognitive and functional decline over time 

in older women (Lin et al., 2004). 

Putting the Tools Together 

A New York University School of 

Medicine group recently conducted 

a longitudinal study of cognitively 

healthy people and those with MCI. 

This study, the first to combine data 

from memory testing, MRI scans, and 

CSF biomarkers, found that combining 

these different types of measures 

consistently improved diagnostic 

accuracy (de Léon et al., 2006). 

Compared to cognitively healthy 

people, those with MCI showed 

decreased memory performance, 

decreased hippocampal size, and 

increased CSF levels of tau and 

isoprostane, two substances known 

to be often abnormal in AD. Moreover, 

levels of isoprostane increased 

significantly over a 2-year time 

period. This elevation was associated 

with decreases in CSF beta-amyloid 

levels and decreased hippocampal 

volume, suggesting a progression 

of degeneration consistent with AD. 

Looking Toward the Future 

For the moment, these technologies are used primarily in experimental 

contexts but, some day, they could be 

used more widely in clinical settings as 

a diagnostic tool. The findings from the 

New York University School of Medicine 

study, for example, support the idea 

that an accurate, reliable, and possibly 

specific clinical diagnosis of AD in the 

MCI stage is a reasonable expectation. 

As these tools improve and become 

more widely available, they also could 

be used to predict and follow the 

course of AD and other neurodegenerative diseases as well as to explain 

similarities and differences among 

them. Another important application 

of these advances is in measuring 

response to treatments, which would 

be invaluable in clinical trials of new 

drugs. Some day, as the influence of 

diet, exercise, intellectual stimulation, 

and other lifestyle factors on AD risk 

is clarified, these tools may even be 

useful in tracking changes in risk that 

result from behavioral and lifestyle 

changes. (For more on how this might 

be done, see the Alzheimer’s Disease 

Neuroimaging Initiative described 

on p. 50.) 

2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 37
38 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

How Do We Translate 

Scientific Discoveries Into 

Effective Treatments?

Previous sections of this report have 

focused on the basic science research 

portfolio and on research into the lifestyle factors that increasingly appear to be 

related to the development, and possibly 

prevention, of AD. Findings from this 

growing body of knowledge have suggested a number of potential therapeutic 

targets, allowing investigators to intensify 

their hunt for AD treatments. Given the 

complex and long-term nature of the 

disease, it is unlikely that a “silver bullet” 

treatment will ever be possible. Rather, 

researchers hope to discover a range of 

drug and non-drug approaches that could 

be productively applied to delay the onset 

or slow the progress of AD or that could 

effectively treat AD symptoms. One focus 

of this area of research is the relatively 

new field of translational research. This 

work underpins the continuing emphasis 

on traditional treatment clinical trials.

The Emerging Field of AD 

Translational Research

Translational research is a multidisciplinary effort that creates a two-way 

bridge between basic science laboratory 

studies and clinical research. In essence, 

translational research provides a vital link 

between “bench” and “bedside,” allowing 

valuable knowledge from the laboratory 

to be quickly applied to potential new 

tests or interventions in the clinical setting. Translational research also serves as 

a crucial venue for collaboration between 

scientists who focus on understanding 

the cellular, molecular, and pathologic 

dimensions of disease and those who 

focus on treating people. These collaborations are essential to developing safe 

and effective treatments. Collaborative 

and training opportunities in translational research encourage scientists to 

identify and conduct research on neurobiological questions of clinical relevance, 

learn how to move knowledge gained 

from basic research into clinical studies, 

and appreciate how findings in clinical 

research inform and refine basic research. 

NIA’s Translational Initiative

NIA supports the flow of potentially 

useful therapeutic compounds from the 

test tube to treatment of people through 

the NIH Small Business Innovation 

Research (SBIR) and Small Business 

Technology Transfer (STRR) grant 

programs. These grants enable small 

businesses to explore the potential of 

compounds and other AD treatments. 

They also serve as a valuable link 

between laboratory work, clinical trials, 

and commercial development.

However, these programs alone are 

not sufficient to tap into and leverage 

the enormous potential of basic research 

in academic institutions that could possibly be “translated” into new therapies. 

As a result, in 2004, NIA launched a 

multi-component translational initiative to facilitate early drug discovery and 

drug development research by academic 

scientists and small biotechnology companies for treating and preventing AD, 

MCI, and age-related cognitive decline. 

This initiative provides small grants for 

early, exploratory drug discovery efforts 

and larger cooperative grants for various 

stages of preclinical drug development, 

in which new compounds are tested for 
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 39

safety and efficacy in test tube and animal 

studies before being tested in humans. The 

grants are awarded to investigators who 

have identified new compounds that need 

to be refined and characterized in relevant 

animal models in order to receive FDA’s 

Investigational New Drug (IND) approval. 

With these programs, NIA is broadening 

the range of potential treatments and 

expanding the number of therapeutic targets by investing relatively small amounts 

of money at critical steps of translational 

research that are traditionally not supported by the pharmaceutical industry. 

Undoubtedly, these are high-risk projects, but the compounds that successfully 

move through the translational process 

have high potential promise for patients. 

To facilitate this process further, NIA 

offers funding through its longstanding 

investigational new drug toxicology program for academic and small business 

investigators who have promising compounds to treat and/or prevent AD, MCI, 

or age-related cognitive decline, but lack 

the resources to perform the required 

safety studies in multiple animal species, 

which are necessary to obtain IND status. 

Finally, the translational initiative is 

complemented by a grant program that 

aims to support pilot clinical trials of promising compounds and non-pharmacologic 

interventions. This mechanism adds to 

NIA’s existing ADCS and clinical trials 

program. 

Basic Research Continues to Inform 

Translational Efforts

Basic research can make significant 

contributions to the pursuit of effective and safe therapies. Here are two 

examples that illustrate this contribution.

More Support for Beta-Secretase as a 

Therapeutic Target 

As we described earlier, beta-amyloid is 

produced as a result of the activity of two 

APP-cleaving enzymes: beta-secretase and 

gamma-secretase. Scientists have devoted 

considerable effort to devising strategies 

to inhibit the activities or suppress the 

production of these enzymes in hopes 

that this could reduce beta-amyloid 

production and, consequently, slow the 

progression of AD.

Recent discoveries have provided 

support for the validity of beta-secretase 

(also known as BACE1) as a therapeutic 

target. For example, scientists from the 

Salk Institute for Biological Studies in 

La Jolla, California, developed specially 

engineered RNA molecules known as 

“small interfering RNAs” (siRNAs), which 

were attached to a gene delivery system 

to silence the production of BACE1 in the 

brains of AD transgenic 

mice (Singer et al., 2005). 

Reducing BACE1 levels 

slowed the production 

of beta-amyloid peptides 

and amyloid plaques, 

and diminished the 

damage to neurons and 

synapses in the brains of 

these mice. Most importantly, the transgenic 

mice that received this gene therapy 

treatment had less difficulty in learning 

a task compared to their littermates 

that did not receive the treatment. 
40 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

The Search for Safer AD Immunotherapy

Immunizing people against disease 

has been a cornerstone of medical practice 

for decades. With this in mind, investigators wondered whether it might be possible to immunize people against AD by 

injecting them with beta-amyloid, which 

would cause their immune systems to 

make antibodies that lower the levels of 

brain amyloid (a technique called active 

immunization). Early animal studies, in 

which AD transgenic mice were actively 

immunized with a beta-amyloid peptide, 

were successful at decreasing the number 

of plaques and improving performance on 

memory tests. This led to a clinical trial 

in humans to test the safety and effectiveness of active immunization with the 

beta-amyloid immunogen (a substance 

designed to elicit an immune response). 

However, because about 6 percent of 

participants in the trial developed brain 

inflammation in response to the treatment, the trial was stopped. The adverse 

reaction was likely due to a T-cell reaction (part of the body’s immune response) 

against the beta-amyloid immunogen. 

Despite this setback, the interest in developing an AD vaccine remains high. 

The key issue in ongoing immunotherapy work is how to develop a vaccine 

that protects the brain against betaamyloid toxicity without promoting or 

worsening brain inflammation. To this 

end, researchers at Harvard Medical 

School tested alternative immunogens 

that contained only the first 15 amino 

acids of the beta-amyloid peptide but not 

the T-cell reactive sites of the full-length 

peptide (Maier et al., 2006). In trying this 

approach, the researchers hoped to avoid 

stimulating the harmful T-cell response. 

Immunizing non-transgenic mice with this 

short beta-amyloid peptide resulted in a 

high, non-inflammatory, anti-beta-amyloid 

antibody response. When AD transgenic 

mice were immunized with the same short 

peptide, they also produced significant 

numbers of non-inflammatory anti-betaamyloid antibodies. This was accompanied 

with a greatly reduced amyloid plaque load 

and improved learning compared to the 

control mice. These results are encouraging 

because they show that this novel immunogen approach may have promise for 

future AD vaccines.

Another approach that is garnering 

scientific interest is passive immunization. In this approach, instead of administering beta-amyloid directly, which then 

leads to antibody production, researchers 

administer anti-beta-amyloid antibodies. 

Several studies over the past few years 

have indicated that passively administered anti-beta-amyloid antibodies can 

effectively remove beta-amyloid peptides 

from the brain. Scientists at the University 

of South Florida carried out a passive 

immunotherapy trial in aged transgenic 

AD mice (Wilcock et al., 2004). Over 

5 months, the mice were given weekly 

injections of anti-beta-amyloid antibodies. This regimen resulted in complete 

reversal of learning and memory deficits in 

these mice 3 months after the beginning 

of treatment. At the end of the 5-month 

treatment, beta-amyloid deposits in the 

animals’ brains were dramatically reduced, 

indicating that even well-established 

amyloid deposits are susceptible to immunotherapy in these mice. However, the 

amount of beta-amyloid in the micro 

vessels of the treated mice was elevated 

and these vascular beta-amyloid deposits 

were sometimes associated with leakage 

of the micro vessels (microhemorrhages), 
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 41

presumably as a result of the betaamyloid being removed into the bloodstream. Because the cognitive benefits 

of the passive immunotherapy persisted 

in spite of the presence of vascular 

beta-amyloid and microhemorrhages, 

these data suggest that this promising 

approach needs to be further explored 

and modified to prevent the potential 

adverse events associated with 

microhemorrhages.

Putting Treatment Hypotheses to the 

Test in Clinical Trials

Previous sections of this report have 

described some of NIH’s ongoing pilot 

and full-scale AD clinical trials that are 

testing exercise, diet, and chronic disease 

intervention strategies (see pp. 25, 29, 

and 32). This section describes other 

treat-ment clinical trials, most of which 

are testing drugs for their effects on AD 

progression or on behavioral symptoms.

In the mid-1970s, scientists 

discovered that levels of the 

neurotransmitter acetylcholine 

fell sharply in the brains of 

people with AD. This was a 

crucial discovery, for it was one 

of the first pieces of evidence 

that definitively linked AD with 

biochemical changes in the 

brain. Investigators studied 

acetylcholine intensively and 

found that neurons in the hippocampus and cerebral cortex, 

areas heavily damaged in AD, 

depend on this neurotransmitter in the memory formation 

process. All but one of the 

currently approved medications 

used to treat AD are cholinesterase inhibitors. That is, they 

stop or slow the action of acetylcholinesterase, an enzyme 

that breaks down acetylcholine.

Because these medications don’t stop or reverse the 

disease process and appear 

to help patients for only a 

relatively short time, many 

scientists are working to 

develop alternative AD medications. For example, researchers 

at NIA’s Intramural Research 

Program have designed and 

synthesized a number of novel 

compounds that have proved 

useful in defining the role of an 

enzyme called butyrylcholinesterase (BChE), which is found 

in the brain (Greig et al., 2005). 

Like acetylcholinesterase, BChE 

inactivates the neurotransmitter 

acetylcholine, so the NIA investigators began to look for ways 

to disrupt the action of BChE. 

The investigators were able 

to develop potent, reversible, 

and brain-targeted BChE inhibitors. In rats, these compounds 

caused long-term inhibition of 

brain BChE and elevated extracellular acetylcholine levels, 

without inhibiting acetylcholinesterase. The scientists found 

that the rats showed improved 

performance on a maze test, 

which indicated improved 

cognitive performance. When 

the scientists examined brain 

tissue from the rats, they 

found that BChE inhibition 

augmented communication 

across synapses. In cultured 

human cells, inhibition of 

BChE led to reduced levels of 

APP and beta-amyloid peptide 

without affecting cell survival. 

Transgenic mice that overexpressed human mutant APP 

also were treated with the 

BChE inhibitors and they, too, 

showed lower beta-amyloid 

peptide brain levels compared 

to untreated mice. 

Though these results appear 

promising, much additional 

work needs to be done before 

the BChE inhibitors can be 

tested in people. As a first 

step in that process, the NIA 

investigators are conducting 

additional studies to define 

optimal concentrations of the 

BChE compounds for further 

preclinical characterization.

The Long and Winding Road to 

AD Treatment Medications
42 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Pilot MCI and AD Treatment Trials

Before beginning a full-scale clinical 

trial, investigators often conduct pilot 

clinical trials. The data gathered in these 

trials help scientists determine which 

interventions should go on to the next 

step. Here are a few of the current 

pilot clinical trials in MCI and AD: 

Nicotine skin patch and amnestic 

MCI. Some of the 60 non-smoking participants in this study are being given a 

nicotine patch and others a placebo patch. 

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 over a 1-year period 

to the participants with amnestic MCI. 

Study investigators also hope to determine 

whether nicotine can reduce memory loss 

and improve other cognitive symptoms 

over the longer term and whether it can 

help delay the progression of cognitive 

impairment and development of AD. 

Raloxifene and women with AD. 

This 12-month pilot trial will examine 

the effects of the osteoporosis drug, 

raloxifene, on cognitive function, ability 

to carry out daily activities, and biomarkers 

in older women with AD. In animal 

studies, raloxifene affects neuronal 

activity in ways that might be expected 

•

•

to improve cognitive function, and 

recent clinical data support the idea 

that this drug could lessen dementia 

symptoms in women with AD. 

Full-scale AD Treatment Clinical Trials

At the time of this report, the NIH 

is supporting more than 30 clinical 

trials of treatments for people with AD. 

Many of these are part of the Alzheimer’s 

Disease Cooperative Study. Here are 

highlights of a few of these trials. 

Divalproex sodium and agitation.

A previous ADCS clinical trial of divalproex sodium (Valproate), conducted in 

150 nursing home residents, was designed 

to see whether the medication could ease 

agitation in people with severe AD. In 

contrast to other trials, results from this 

multi-center trial did not show that divalproex sodium was helpful for people with 

severe AD. A trial currently underway is 

examining whether valproate therapy 

can delay or prevent agitation and psychosis in people with mild to moderate 

AD. Enrollment is nearly complete, 

with close to 300 people already participating. Researchers also are interested 

in seeing whether its possible neuroprotective properties have any effect on 

slowing the rate of cognitive decline. 

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 A 

performed better on memory tests than 

those on placebo. Investigators also are 

interested in huperzine A because it has 

•

•
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 43

antioxidant and neuroprotective properties 

that suggest it may be useful in treating 

AD. The study, which has enrolled 140 

of the 150 participants, is taking place in 

about 28 sites nationwide, and recruitment is ongoing. Participants are being 

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. 

Growth hormones and MCI.

Some data suggest that a particular set 

of growth hormones that work together 

has a significant beneficial effect on 

memory and reasoning ability. This hormonal group—growth hormone releasing 

hormone/growth hormone/insulin-like 

growth factor 1 (GHRH)—is also called 

the somatotrophic hormonal axis. This 

clinical trial is determining whether 

GHRH is beneficial for individuals with 

amnestic MCI. Investigators will examine 

the effects of GHRH on the cognitive 

function of 80 healthy older adults and 

80 older adults with amnestic MCI. 

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. In fact, 

depression in AD is increasingly recognized as a condition separate from major 

depression. NIMH-funded researchers at 

Johns Hopkins University have developed 

and published criteria for health care providers to use in diagnosing depression of 

Alzheimer’s disease (dAD) (Rosenberg et 

al., 2005). These criteria are broader than 

those used to diagnose major depression, 

and importantly, were developed with the 

help of AD caregivers. The researchers 

are conducting a clinical trial of dAD 

•

•

treatment and will validate the new diagnostic criteria as part of the trial. They 

have completed one clinical trial of the 

antidepressant medication sertraline 

(Zoloft) to examine the effects of antidepressant treatment on cognition and 

daily functioning, as well as on caregiver 

burden (Munro et al., 2004). Overall, 

results from the cognitive measures for 

the trial’s 44 participants indicate that 

neither improved mood nor use of sertraline was associated with cognitive 

changes over time in the participants. 

Further exploration of the data suggested that the cognitive abilities of 

women treated with sertraline improved, 

compared to women who did not receive 

treatment. In contrast, the cognitive 

abilities of men taking sertraline worsened compared to those not treated. 

Atypical antipsychotics to treat 

psychosis in AD. NIMH-funded investigators at the University of Southern 

California Keck School of Medicine 

recently published results from a clinical 

trial called the Clinical Antipsychotic 

Trials of Intervention Effectiveness 

(CATIE) (Schneider et al., 2006). This 

trial was designed to assess the effectiveness of atypical antipsychotic drugs for use 

in people with AD who experience hallucinations, delusions, agitation, or aggression. 

These symptoms are common in people 

with AD, and they can be very distressing 

to caregivers. The results from the trial 

showed no significant differences between 

the antipsychotic medications or placebo. 

Thus, the findings suggest a lack of significant clinical benefit of treatment with 

atypical antipsychotic medications in AD. 

•
A Closer Look at Two Aspects of AD Clinical Trials

As the Progress Report has shown, 

clinical trials are essential to continued 

progress in AD research. Clinical trials, 

which compare a potential new treatment with a standard treatment or 

with a placebo, are the primary way 

that researchers find out whether a 

promising treatment is safe and effective. Clinical trials also tell researchers 

which treatments are more effective 

than others. Some clinical trials focus 

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 focus on 

prevention strategies—using specific 

interventions or drugs to help people 

reduce the risk of developing AD in 

the future. Here’s a look at two critical 

aspects of clinical trials research.

Establishing the Infrastructure 

to Conduct Clinical Trials 

In 1991, NIA launched the 

Alzheimer’s Disease Cooperative Study 

(ADCS; http://adcs.ucsd.edu), a consortium of research sites around the 

country. The ADCS conducts clinical 

trials on compounds that are not 

generally of interest to large pharmaceutical companies. These include 

drugs that are off patent, drugs that are 

patented and marketed for another use 

but may be useful in treating cognitive and behavioral symptoms of AD, 

and novel compounds from individual 

investigators or small companies 

without adequate resources for 

clinical trials. Currently, the ADCS 

is supporting five clinical trials. 

The latest renewal of the ADCS in 

2006 will support new clinical trials 

to test drugs for their effectiveness in 

slowing the progression or treating the 

symptoms of AD, as well as to investigate new methods for conducting 

dementia research. Most of the new 

trials will focus on possible therapies 

aimed at affecting beta-amyloid and tau:

Docosahexaenoic Acid (DHA).

This trial will examine whether treatment with DHA will slow decline in AD. 

Observational studies associate high 

fish consumption with reduced risk of 

AD in people, and studies in mouse 

models of AD show that dietary DHA 

reduces brain levels of beta-amyloid, 

oxidative damage associated with 

beta-amyloid, and neurotoxicity (see 

p. 29 for more on this research). 

Intravenous Immunoglobulin 

(IVIg). Interest in passive immunization strategies against AD is growing 

(see p. 40 for more on these strategies). IVIg contains naturally-occurring 

antibodies against beta-amyloid, and 

preliminary studies have shown that 

IVIg may improve cognition. In addition, research has demonstrated that 

IVIg increased levels of anti-betaamyloid antibodies in plasma and 

promoted clearance of beta-amyloid 

from cerebrospinal fluid. The new 

ADCS trial will demonstrate whether 

IVIg is useful clinically for treating AD. 

Lithium. The biological activity 

of lithium, which has been shown 

in animal studies to block abnormal 

changes in tau, is of interest to ADCS 

investigators. They will undertake a pilot 

biomarker study to see whether the 

drug can lower tau and beta-amyloid 

levels in cerebrospinal fluid and be 

safely tolerated in older AD patients.

•

•

•

Innovative Ways to Recruit 

and Retain Participants

One of the major limitations in 

conducting trials in older adults is 

recruiting and retaining individuals 

who can effectively participate in 

lengthy evaluations in a specialized 

clinic setting. Many older people, 

particularly the very elderly, have 

physical, social, and health limitations 

that make it difficult for them to take 

part in research. Thus, NIA AD investigators are examining ways to make it 

easier for volunteers to participate in 

clinical research, and they are developing novel procedures and measures 

that can be administered at home or 

in other community settings:

The GEM trial. Extracts of leaves 

from the Ginkgo biloba tree are thought 

to have beneficial effects on brain 

function, especially those related to 

dementia and AD. This 10-year clinical 

trial, which began in 2000 and is cofunded by NCCAM, NHLBI, and NIA, 

is comparing ginkgo to placebo in 

people older than 75 who were cognitively healthy or who had MCI at 

the beginning of the trial (DeKosky et 

al., 2006). The study’s main goal is to 

determine whether ginkgo is helpful 

in preventing or delaying the onset of 

dementia, though researchers also are 

interested in assessing participants’ 

rate of cognitive and functional decline, 

the incidence of cardiovascular and 

cerebrovascular events, and causes of 

death. All participants have extensive 

neuropsychological evaluations at the 

beginning of the study. Each also has 

someone who has agreed to provide 

an independent assessment of the 

functional and cognitive abilities of the 

participant. Assessments are repeated 

•

44 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease
every 6 months. Significant cognitive 

decline at any visit leads to a repeat 

detailed neuropsychological assessment and a neurological and medical 

evaluation. Side effects and adverse 

events also are closely monitored. 

As with all clinical trials, recruitment was an important challenge. The 

researchers’ goal was to enroll about 

3,000 people age 75 and older at 

four sites in the U.S. (Fitzpatrick et al., 

2006). The investigators understood 

early on that recruiting participants in 

this age range would be difficult, and 

they carefully planned a systematic 

approach that included ways to collect 

data on the recruitment process. From 

the beginning, they tracked eligibility 

and refusal rates, which allowed for 

adjustments as needed. Study staff 

began their enrollment efforts by 

mailing 243,400 brochures about the 

study to potential participants. Followup phone calls to 14,603 households 

yielded 12,186 successful contacts. 

Out of these 12,186 people, 2,149 

people were ineligible to participate 

because of cognitive, medical, or other 

reasons. Of the remaining people, 

6,944 decided not to join. The end 

result was that 3,072 people enrolled 

in the study, a recruitment rate of about 

25 percent based on telephone contacts made, or about 1 percent based 

on the initial mailing. 

ADCS Prevention Instrument 

Project. Investigators are designing 

and developing new questionnaires and 

other instruments that can be used to 

evaluate individuals’ overall cognitive 

functioning, memory, ability to carry out 

activities of daily life, and quality of life. 

These instruments, which are mostly 

self-administered, can be completed in 

a less time-consuming and more costefficient manner than was possible 

with previous instruments. The aim of 

this project is to evaluate the effectiveness of these new tests in identifying 

change over time and conversion to 

MCI or AD in cognitively healthy elderly 

and to compare assessments completed in the clinic (the traditional inperson method) with those completed 

at home. The 4-year study simulates a 

primary prevention trial, a type of trial 

that aims to prevent the development 

of a disease. This study has enrolled 

644 healthy adults 75 years of age 

and older. Participants have been randomized to one of two groups, where 

baseline and follow-up assessments 

•

are completed at home or in the clinic. 

Results obtained from both venues are 

being analyzed to determine whether 

the home evaluations are equivalent to 

those done in the clinic. Data collection 

and analysis are continuing. 

Home-Based Assessment. This 

new ADCS study, conducted in people 

aged 75 and older, will further examine 

the development and use of homebased assessments. Three types of inhome assessment and data collection 

procedures are being examined: a) lowtechnology telephone assessment; b) a 

high-technology automated telephone 

assessment; and c) a high-technology 

computer assessment. Cognition, daily 

functioning, mood, and other factors will 

be evaluated in each of the methods. 

These innovative assessment and 

data collection methods will again be 

compared against traditional in-person 

methods. The findings from this study 

will provide information on how homebased assessments might be used 

in prevention trials. Such methods 

could significantly reduce the cost and 

increase the feasibility of participation 

in these long-term clinical trials. 

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2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 45

ADCS Study Sites in 2006
46 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

How We’re Getting To The Goal
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 47

PART3

As we noted at the beginning of this book, journeys require a means of transport. 

In this case, AD researchers need financial, 

technical, and scientific support to pursue their 

work. NIH has created and nurtured the essential research infrastructure that allows scientists 

to push the basic science forward, conduct 

epidemiologic and other clinical studies, and 

develop new drugs and therapeutic approaches. 

The advances and new knowledge that result are 

bringing us ever closer to a full understanding 

of the causes of this devastating disease and to 

effective prevention and treatment strategies. 

NIA Initiatives for AD Research

Several NIA initiatives provide critical 

venues through which investigators can conduct 

interdisciplinary and collaborative AD research.

Alzheimer’s Disease Centers 

The NIA-funded Alzheimer’s Disease 

Centers (ADCs) promote basic research, 

training and education, and technology transfer 

(www.nia.nih.gov/Alzheimers/). They also 

conduct multi-center and collaborative studies 

of diagnosis and treatment in AD, age-related 

neurodegenerative diseases, and normal aging. 

Many milestones in AD research in the 

U.S. since 1984 stem from research carried out 

at the ADCs. For example, ADC research has 

revealed much about 

the linkage and cloning 

of genes on chromosomes 1, 14, and 21 in 

early onset Alzheimer’s 

disease, chromosome 

17 in frontotemporal 

dementia, subsequent 

studies on processing 

of proteins coded by 

these genes, and the identification of the 

inherited risk factor for late-onset disease, 

APOE, on chromosome 19. Much of the work 

related to processing of proteins important 

for plaque and NFT formation, including the 

discovery of alpha synuclein in Lewy body 

dementia, and the recognition of the common 

properties of amyloids found in various 

neurodegenerative diseases, has been carried 

out in the ADCs. Recently, progranulin 

and the TDP43 protein were both discovered 

by ADC researchers and have contributed 

to our understanding of one type of frontotemporal dementia and motor neuron disease. 

Important studies that correlate pathologic 

changes in brain structure and function with 

preclinical and clinical evidence of disease 

are being conducted with people enrolled in 

ADC clinical studies. Complementary studies, 

such as imaging studies and autopsy evaluations, also are conducted at ADCs. In recent 
48 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

years, the centers have placed increasing 

emphasis on evaluating cognitive function in healthy aging and the transition 

to amnestic MCI and early dementia, as 

well as mixed dementias and overlapping 

dementia syndromes. Another growing 

focus for the ADCs is collaborative transcenter projects and collaborations with 

investigators outside the centers’ network. 

In addition to performing cutting 

edge research, the ADCs provide essential resources from which other research 

projects like the ADCS, the AD Genetics 

Initiative, and the AD Neuroimaging 

Initiative can draw (see the following sections for more on these initiatives). These 

resources include a cadre of researchers 

well versed in all aspects of AD, access to 

patient and family data, brain and other 

tissue samples, and molecular probes, as 

well as outreach programs that work with 

diverse groups, including minority and 

rural populations. 

National Alzheimer’s Coordinating Center

In 1999, NIA established the National 

Alzheimer’s Coordinating Center (NACC) 

so that data on patients from the ADCs 

could be pooled and shared (www.alz.

washington.edu). At the beginning, it 

was only possible to collect a minimum 

data set (MDS) with a limited number 

of variables. Eleven collaborative multicenter studies were funded by NACC 

and an additional seven collaborative 

investigator-initiated grants funded by 

NIA were linked to NACC and used 

data from the MDS. Between 1984 

and 2005, information on more than 

75,000 ADC study participants and 

neuropathological data on more than 

9,000 brains from autopsied participants were collected in the MDS. 

Much of this material is available for 

research by qualified scientists. 

Although the MDS collected the same 

data from all study participants, the centers did not collect the data in a standardized way, and the number of data points 

was limited. This prevented investigators 

from comparing data from one center 

to another. Standardized data collection 

allows data from multiple centers to be 

pooled, creating larger samples and the 

potential for more sophisticated and 

informative analyses than would be 

possible with data from only one center. 

The Uniform Data Set (UDS), which 

replaced the MDS in 2005, contains 

many more data elements and will be 

much more useful for research. The 

clinical task force designed the UDS 

initially for healthy participants and 

those with amnestic MCI and early AD, 

and is now developing new modules to 

collect data on participants with frontotemporal dementia, Lewy body dementia, 

and vascular dementia. More than 7,000 

individuals are now being evaluated using 

the UDS, and the data are available to 

qualified researchers through NACC.
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 49

Major AD Research 

Initiatives 

The NIA continues to support several 

major initiatives in which the clinical, 

genetic, imaging, and biological data 

and samples that are collected are being 

made widely available to qualified 

investigators through secure 

web-based systems. As a result, 

these initiatives have become 

a critical national and international resource for scientists 

who are interested in AD, other 

neurodegenerative diseases, 

healthy aging, and related topics.

Alzheimer’s Disease Genetics Initiative 

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. So far, scientists 

have discovered three mutations that cause 

the rare early-onset form of familial AD 

and one mutation that affects the risk of 

developing late-onset AD (see p. 15 for 

more on these genes). Scientists estimate 

that an additional four to seven risk factor 

genes exist for late-onset AD. Evidence 

uncovered by NIA investigators also suggests that variability in the genes that 

cause early-onset AD may increase the 

risk of developing late-onset AD (Myers 

et al., 2005; Singleton et al., 2004). 

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

scientists need many samples of genetic 

material if they are to continue making 

progress in identifying new risk factor 

genes, as well as identifying associated 

environmental factors and understanding 

the interactions of genes and the environment. These advances will ultimately 

allow investigators to identify people at 

high risk of developing AD and help 

them focus on new pathways that may 

be amenable to prevention or treatment. 

The goal of the NIA Genetics Initiative 

is to identify at least 1,000 families with 

members who have late-onset AD as well as 

unaffected family members, and encourage 

these individuals to provide blood samples 

and other clinical data for the initiative. 

More than 900 families already have been 

recruited but more are needed, so NIA is 

providing funding to the ADCs to help 

recruit the remaining participants. The 

NIA ADEAR Center is collaborating with 

the Alzheimer’s Association to develop 

media and community outreach programs 

to foster participation in the initiative 

among families who have two or more 

living members with late-onset AD. 

NIA initiatives have become a critical 

national and international resource for 

scientists who are interested in AD.
50 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

The Genetics Initiative collects blood 

samples and other clinical data from people 

with AD and their unaffected familiy members. This allows 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 risk factor genes, each 

of which may have relatively small effects 

on AD development. The National Cell 

Repository for AD 

(NCRAD), located 

at Indiana University, 

serves as the centralized repository for the 

initiative (http://ncrad.

iu.edu), providing 

DNA and cell lines 

to qualified investigators for genetics 

studies. In 2006, NIA 

opened the Genetics 

of Alzheimer’s Disease 

Data Storage Site at 

Washington University. Scientists who use 

NCRAD samples and data and AD geneticists funded by NIA are asked to submit 

published genetics data to the Storage 

Site for additional analysis by qualified 

investigators. An initial subset of cases has 

recently undergone a whole genome scan, 

and results are now available on the website. Many AD researchers also are taking 

advantage of a large sample repository 

and genetics database already developed 

by NIMH. Beginning in 2006, data from 

combined NIMH and NIA sample sets 

will be available through a unique data 

repository shared by the two Institutes. 

Alzheimer’s Disease 

Neuroimaging Initiative

NIA has launched the multi-year AD 

Neuroimaging Initiative, which will use 

serial MRI and PET scans to examine how 

brains change as MCI and AD progress. 

The project will follow approximately 

200 cognitively healthy individuals 

for 3 years, 400 people with MCI for 

3 years, and 200 people with early AD 

for 2 years. Funding for the initiative 

began in 2004 and enrollment of participants is nearly complete. 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, 

neuropsychological, and biological 

markers 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. Rigorous 

imaging and biomarker standards developed as a result of this initiative will help 

in early diagnosis and provide measures 

for the success of potential treatments. 

This would substantially increase the pace 

and decrease the cost of developing new 

treatments.
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 51

This initiative is a partnership 

among the NIA, university investigators, the pharmaceutical and imaging 

equipment industries, the FDA, and the 

NIH Foundation, with participation 

from the Alzheimer’s Association and 

the Institute for the Study of Aging. An 

important aspect of this initiative is that 

the clinical, imaging, and biological data 

collected will be shared and made available to all qualified scientific investigators 

for further analyses. For more information about the Neuroimaging Initiative, 

visit www.nia.nih.gov/Alzheimers. 

The Cognitive and Emotional 

Health Project

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 is yielding promising results in both animal and human 

studies, much remains to be discovered. 

These gaps in current knowledge spurred 

NIA, NINDS, and NIMH to jointly 

create the trans-NIH Cognitive and 

Emotional Health Project: The Healthy 

Brain. This initiative will spur advances 

in understanding changes in cognition 

and emotion in adulthood and what can 

be done to preserve and enhance positive 

outcomes—advances that are central to 

the missions of the participating Institutes. 

The overall goal of the Cognitive and 

Emotional Health 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. Project staff have completed a 

detailed evaluation of the scientific 

literature on factors involved in maintaining cognitive and emotional health in 

adults (Hendrie et al., 2006). The NIH 

Blueprint for Neuroscience Research has 

funded a 5-year effort to create the NIH 

Toolbox for Assessment of Neurological 

and Behavioral Function (www.neuroscienceblueprint.nih.gov). This effort 

will use state-of-the-art research and 

novel testing methods to develop an 

integrated set of measures of cognitive, 

emotional, and sensory health. These 

measures will be appropriate for use in 

large-scale studies and clinical trials. For 

more information on project activities 

currently underway to accomplish these 

goals, visit http://trans.nih.gov/CEHP. 
Helping People with AD and their Caregivers Cope

Perhaps one of the greatest costs 

of AD is the toll on families, caregivers, 

and friends. Investigators supported by 

NIA, NIMH, and the National Institute of 

Nursing Research (NINR) are exploring 

the emotional, psychological, and physical costs of caregiving and are investigating ways to ease the burden. Here 

are a few highlights of recent research.

Improving the Chances of 

Success in Assisted Living

Assisted living is a popular option 

for older adults, yet little is known 

about the impact of cognitive abilities, 

moods, and overall health on how well 

people in these facilities function. NIMH 

is supporting the Maryland Assisted 

Living Study to improve researchers’ 

knowledge about this important issue. 

A study team from the Johns Hopkins 

University School of Medicine has 

looked at 22 facilities to determine the 

prevalence, recognition, and treatment 

of dementia and other psychiatric 

disorders (Rosenblatt et al., 2004), 

and to examine factors that impair 

people’s ability to function well 

(Burdick et al., 2005).

In the first study, the Johns Hopkins 

team found that dementia and psychiatric disorders were common—nearly 

68 percent of the 198 participants 

had dementia and 26 percent had a 

psychiatric disorder—and that recognition and treatment were not as good 

as they could be. In the second study, 

the researchers found, not surprisingly, that cognitive difficulties, memory 

problems, depression, and poor overall 

health had a significantly negative 

impact on the residents’ ability to carry 

out their daily activities. Results from 

both of these studies may help assisted 

living facilities develop models of care 

that improve recognition of dementia 

and psychiatric disorders, incorporate 

key predictors of functional impairment, 

and improve resident care.

Helping People Express 

Care Preferences

All caregivers want to provide care 

that reflects the lifelong values and 

preferences of the person with AD. 

As the disease progresses and the 

person’s ability to form ideas and 

express thoughts diminishes, it 

becomes increasingly difficult to 

gauge these preferences. It is all the 

more important, therefore, to help 

people with AD and their families 

articulate these preferences early, 

when it is possible to discuss them 

and plan for the future.

NIMH-supported scientists at the 

Margaret Blenkner Research Institute, 

in Cleveland, Ohio, have developed 

and validated just such an approach 

(Whitlatch et al., 2005). The Values and 

Preferences Scale, a 24-item questionnaire that can be used in research or 

practice settings, was developed with 

the help and advice of practitioners, 

researchers, family caregivers, and 

people with cognitive impairment.

Finding Low-tech Solutions 

for Behavioral Symptoms 

Bathing can be one of the hardest 

aspects of AD caregiving because it 

often triggers agitation and aggression 

in the person with AD. A research group 

at the University of North Carolina 

developed and tested two methods of 

bathing—person-centered showering 

and a new type of in-bed bath with 

no-rinse soap called a towel-bath 

(Sloane et al., 2004). Agitation and 

aggression declined significantly with 

the new methods. Both methods also 

52 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease
improved skin condition and neither 

increased potentially harmful skin 

bacteria. Simple interventions like 

these can easily be learned and 

applied to improve the quality of life 

of the person with AD and ease the 

burden on family caregivers.

Researchers at Pennsylvania 

State University explored a different 

kind of solution. They tested different 

types of recreational activities to see 

which might be best at lessening 

agitation and passivity, two common 

problems among nursing home residents (Kolanowski et al., 2005). They 

compared activities that only matched 

residents’ interests, activities that only 

matched their skills, and activities that 

reflected both. Though all three types of 

activities lessened agitation and negativity, the interest-only and combined 

activities had the greatest positive 

effect. The authors suggest that these 

findings can help explain factors that 

produce behavioral symptoms and can 

help care facilities successfully tailor 

activities for residents with dementia.

Improving Support 

for Caregivers

Recent studies have contributed to 

a growing understanding not only of 

the burdens of caregiving, but of the 

wide range of physical and psychological reactions that caregivers have and 

to their diverse needs for support at 

various stages of caregiving. Resources 

for Enhancing Alzheimer’s Caregiver 

Health (REACH) is a long-term caregiver clinical trial supported jointly by 

NIA and NINR. Findings from Phase I 

of the project have clearly shown that 

social service and medical contacts 

and support interventions must be 

culturally appropriate and sensitive 

to the factors that influence (both 

positively and negatively) caregivers’ 

attitudes to their caregiving 

responsibilities. 

These findings have been applied 

to the second phase of the clinical 

trial, REACH II, and results have 

just been published (Belle et al., 

2006). The REACH II study included 

more than 600 Hispanic, white, and 

African-American dementia caregivers 

in five locations around the country. 

Caregivers within each ethnic/racial 

group were randomly assigned either 

to an intervention or a control group. 

Caregivers in the intervention group 

received intensive help with caregiving 

strategies through information sharing, 

instruction, role playing, problem 

solving, skills training, stress-management techniques and telephone 

support groups. Those in the control 

group received a packet of dementia 

education materials and two brief 

“check-in” telephone calls. 

After 6 months, improvements in 

overall quality of life were significant 

among the caregivers who took part 

in the intervention. Clinical depression 

also was significantly lower. 

Caregivers in the intervention group 

reported that taking part in the program 

helped them feel more confident in 

working with their loved one, made 

life easier for them, improved their 

caregiving ability, improved the care 

recipient’s life, and helped them 

keep their loved one at home. Many 

members of the control group said 

they also benefited from participating 

in the study, suggesting that even 

minimal support and attention can 

help caregivers.

Based on these results, investigators hope that the REACH approach 

can be used widely in the community, 

especially if the outcomes are replicated by others and the program is 

found to be cost-effective.

2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 53
54 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Outlook for the Future
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 55

Dementia is not new. Ancient Greeks and Romans wrote about it, and it even 

makes an appearance in Shakespeare. But 

it wasn’t until 1906 that Alois Alzheimer, a 

German scientist who pioneered investigations into various psychiatric disorders and 

brain diseases, first presented a case study of 

a 51-year old German woman, Auguste D., 

who had been admitted to the hospital in 

1903 with symptoms that included reduced 

comprehension and memory, an inability to 

speak or understand speech, disorientation, 

unpredictable behavior, and other behavioral 

and psychiatric problems. When Dr. Alzheimer 

conducted an autopsy of his patient, he had the 

benefit of the latest scientific technology—new 

techniques for staining brain tissues and greatly 

improved microscopes. These innovations 

allowed him to identify many globs of sticky 

proteins between neurons and tangled bundles 

of fibrils within cells throughout the cortex, or 

outer layer of neurons in her brain. Of course, 

these plaques and tangles are two characteristic 

features of the disease that now bears his name. 

We’ve come quite a long way since then. 

But, as this report shows, some things remain 

the same. Scientists are still pushing the bounds 

of technology to develop new methods and 

tools that can enhance their ability to learn 

about AD and other neurodegenerative diseases. Investigators are still combining dogged 

persistence with imagination and insight 

to improve their understanding of AD. 

With that increased knowledge, however, 

comes heightened sense of urgency. As our 

population ages and the number of people 

age 65 and older steadily 

climbs, the prevalence of 

AD and other neurodegenerative diseases, and 

the costs to families and 

society, will continue to 

rise. Our growing appreciation for the decadeslong developmental 

process of the disease and 

its complex nature means that we must devise 

multifaceted preventive and treatment strategies 

that begin early and continue throughout life.

As we said in the Introduction, good travelers 

plan for how they will meet future challenges 

as their journey unfolds. NIH has developed a 

number of resources that will help it meet these 

challenges in AD. For example, several NIH 

Roadmap (http://nihroadmap.nih.gov/) initiatives provide innovative infrastructure critical 

to discovery of the underlying causes and basic 

biological pathways associated with AD as well 

as numerous other diseases and conditions: 

The Molecular Libraries and Imaging 

Initiative offers biomedical researchers access 

to small molecules that can be used as chemical 

probes to explore the functions of genes, cells, 

and biochemical pathways in healthy aging 

and disease. 

The Building Blocks, Biological Pathways, 

and Networks Initiative supports exploration 

of the array of intricate and interconnected 

•

•

PART4
56 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

pathways that facilitate communication among genes, molecules, and cells; 

how these pathways are integrated in 

humans and other complex organisms; how disturbances in these pathways may lead to disease; and what 

might be done to restore disturbed 

pathways to their normal functions.

The Interdisciplinary Research 

Initiative is helping to address the complex 

challenges of AD research 

by encouraging and facilitating 

interaction among disciplines that 

is so critical to the study of a complex 

disease like AD and the development of 

research and therapeutic technologies. 

New reward systems and incentives are 

being developed to promote the work 

of multidisciplinary teams that bring 

together the expertise of neuroscientists, 

psychologists, social scientists, epidemiologists, geneticists, biologists, imaging specialists, biomedical engineers, and others 

to build synergy to find solutions for AD. 

•

The Re-Engineering the Clinical 

Research Enterprise Initiative is supporting work to find the best ways to 

foster broad community-based participation in clinical studies, including clinical 

trials. This emphasis is a critical shift for 

addressing the problems of illnesses like 

AD, which often require care within 

the home and in community settings. 

NIA also participates in the activities 

of the multi-Institute NIH Blueprint for 

Neurosciences Research. This 

effort provides a framework 

to enhance and fund cooperative activities and resources 

among 15 NIH Institutes 

and Centers to reduce the 

burden of nervous system 

disorders, including AD 

(Baughman RW et al., 2006). 

These NIH Institutes and 

Centers are working to make collaboration 

a day-to-day part of how NIH does neuroscience. By pooling resources and expertise, NIH can take advantage of economies 

of scale, confront challenges too large for 

any single Institute, and develop research 

tools and infrastructure that will serve 

the entire neuroscience community. 

Participants have built on existing 

programs to develop an inventory of 

neuroscience tools funded by NIH and 

other government agencies, enhance 

training in the neurobiology of disease 

for basic neuroscientists, and expand 

ongoing gene expression database efforts. 

Advances in the neurosciences and the 

emergence of powerful new technologies 

•

AD research efforts combine an 

accelerated search for causes, a vigorous 

assault on the effects of the disease, and an 

intensive effort to find ways to interrupt 

progression or delay onset.
2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease 57

will continue to provide new opportunities for Blueprint activities that will 

enhance the effectiveness and efficiency 

of AD and other research across NIH. 

Systematic development of genetically 

engineered mouse strains through the 

Blueprint will be of critical importance 

to AD research as will training in critical 

cross cutting areas such as neuroimaging and computational biology. 

NIA is also continuing to partner 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 early detection 

methods, and advance basic AD research. 

This initiative also is aimed at improving 

patient care strategies and developing 

approaches to lessen caregiver burdens.

Bringing the best scientific minds 

together to talk also helps NIA and other 

NIH Institutes and Centers chart a course 

for their future efforts in AD research. In 

October 2006, NIA, NINDS, NIMH, 

NIBIB, and NINR co-sponsored a conference called “AD: Setting the Research 

Agenda a Century after Auguste D.” 

Organizers chose this important centennial anniversary of Dr. Alzheimer’s first 

presentation on the disease to ask leading 

AD scientists to provide an overview of 

the status of current research from their 

particular perspective and to articulate 

the critical questions and issues that need 

to be addressed for continued progress 

in AD research. Recommendations from 

the presentations and the discussion 

sessions will help guide AD research plans 

and priorities over the next few years. 

Another important way AD research 

moves forward into the future is through 

collaboration between investigators from 

public and private sectors to maximize the 

quality and impact of research. As Part 3

of the Progress Report showed, there is a 

growing emphasis on developing standardized data collection systems and sharing 

data and biological samples with other 

qualified investigators in a timely fashion. 

As a result, NIH supports much of the 

basic research and development that is the 

foundation for new directions and clinical 

applications sponsored by the industry.

The multi-faceted, collaborative AD 

research effort described here combines an 

accelerated search for causes, a vigorous 

assault on the effects of the disease, and 

an intensive effort to find ways to interrupt progression or delay onset. This 

effort sustains the fight against AD and 

brings us closer to the day when we will 

be able to successfully manage or even 

prevent this terrible disease, which robs 

our older relatives and friends of their 

most precious possession—their minds. 
58 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

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64 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

Credits

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Special thanks to:

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For additional copies of this report or 

further information about Alzheimer’s 

disease, please contact:

Alzheimer’s Disease Education 

and Referral (ADEAR) Center

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www.nia.nih.gov/alzheimers

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visit www.nia.nih.gov.
66 2 0 0 5 – 2 0 0 6 progress report on alzheimer’s disease

U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Aging

NIH Publication Number: 06-6047

April 2007