U.S. Department of 

Health and Human Services

DISEASE

ALZHEIMER’S

A Deeper Understanding

P R O G R E S S R E P O RT

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T he National Institute on Aging (NIA), part of the 

Federal Government’s National Institutes of Health 

(NIH) at the U.S. Department of Health and Human 

Services, has primary responsibility for basic, clinical, behavioral, and social research in Alzheimer’s disease, aimed at 

finding ways to treat and, ultimately, prevent this disease. The 

Institute’s Alzheimer’s disease research program is integral to 

its mission, which is to enhance the health and well-being of 

older people. This 2010 Progress Report on Alzheimer’s 

Disease summarizes recent Alzheimer’s research conducted or 

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

 Eunice Kennedy Shriver National Institute of Child 

Health and Human Development (NICHD)—pages 22, 23, 

32, and 47

 National Cancer Institute (NCI)—pages 21, 27, 34, 36, 37, 

and 47

 National Center for Complementary and Alternative 

Medicine (NCCAM)—page 37

 National Center for Research Resources (NCRR)—

pages 18, 19, 21, 22, 23, 24, 25, 28, 31, 35, 36, 38, and 39

 National Eye Institute (NEI)—page 28

 National Heart, Lung, and Blood Institute (NHLBI)—

pages 17, 18, 19, 21, 24, 28, 30, 31, 32, 39, and 56

 National Human Genome Research Institute (NHGRI)—

pages 21 and 24

 National Institute of Allergy and Infectious Diseases 

(NIAID)—pages 19, 20, and 36

 National Institute of Arthritis and Musculoskeletal and Skin 

Diseases (NIAMS)—pages 17, 30, and 31

 National Institute of Biomedical Imaging and 

Bioengineering (NIBIB)—pages 22, 23, and 39

 National Institute of Diabetes and Digestive and Kidney 

Diseases (NIDDK)—pages 20, 25, and 32

 National Institute of Environmental Health Sciences 

(NIEHS)—pages 17, 32, 40, and 59

 National Institute of General Medical Sciences (NIGMS)—

pages 28 and 37

 National Institute of Mental Health (NIMH)—pages 17, 18, 

19, 21, 22, 26, 28, 31, 33, 35, 36, 37, 39, 40, 41, 46, 47, 

56, and 58

 National Institute of Neurological Disorders and Stroke 

(NINDS)—pages 18, 20, 21, 22, 25, 26, 27, 28, 30, 36, 37, 

38, 39, 40, 41, and 61

 National Institute of Nursing Research (NINR)—pages 17, 

56, and 57

 National Institute on Alcohol Abuse and Alcoholism 

(NIAAA)—page 32 

 National Institute on Deafness and Other Communication 

Disorders (NIDCD)—pages 28 and 42

 National Institute on Drug Abuse (NIDA)—pages 22, 26, 

and 27

 National Library of Medicine (NLM)—page 39

Alzheimer’s disease research efforts also are supported by the 

NIH Common Fund. 

Page 13: Stacy Jannis, Jannis Productions

Page 28: Mark P. Mattson, Ph.D., and Dong Liu, Ph.D., Intramural Research Program, NIA 

Page 39: Paul Aisen, M.D., Alzheimer’s Disease Cooperative Study, University of California, San Diego

Image Credits

 2 2010 Progress Report on Alzheimer’s Disease
Introduction ............................................5

Executive Summary ........................8

A Brief Primer on 

Alzheimer’s Disease and 

the Brain .................................................. 11

2O1O Research Advances ........ 15

 Estimating the Extent of 

 Alzheimer’s Disease ........................ 15

 Estimating How Many 

 People Have MCI .....................................16 

 Dementia Incidence 

 Among the “Oldest Old” ...........................17

 Discovering the Genes Behind 

 Alzheimer’s Disease ........................ 17

 Large Studies Revealing Genetics 

 of Alzheimer’s Disease ..............................19

 Gene Expression Studies Reveal 

 Proteins Involved in Disorder .....................19

 Imaging the Genetics of Alzheimer’s ..........22

 Cognitive Decline and the 

 APOE Gene ..............................................23

 Animal Studies Describe 

 Roles of ApoE4 Protein ............................23

 Genetic Counseling and 

 Coping with Alzheimer’s ............................24

 Understanding the Biology of 

 Alzheimer’s Disease ....................25

 Investigating Changes in Brain Tissue .......25

 Brain Amyloid: Is It Ever Benign? ..............26

 Imaging “Normal” Brain Aging ...................26

 Cellular Changes in 

 Alzheimer’s Disease ..................................27

 Determining Risk Factors 

 for Alzheimer’s and 

 Cognitive Decline ..................................29

 Links Between Cardiovascular 

Disease and Cognitive Decline ..................30

 Physical Frailty and 

 Cognitive Decline .....................................30

 Exercise and Maintaining 

 Cognitive Health .......................................30

 The Role of Diet in Maintaining 

 Cognitive Health .......................................31

 Obesity and Risk for 

 Cognitive Decline .....................................32

 Vitamin D and Brain Health 

 As We Age ...............................................32

 Caregiver Stress and 

 Cognitive Health .......................................33

 Aging Animals, Stress, 

 and Cognition ..........................................33

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 Developing 

New Treatments ...........................33

 Beta-Amyloid Directed Therapies ..............34

 Identifying New Therapeutic Targets ..........35

 Testing of Therapeutic Candidates ............36

 Advances in Detecting 

Alzheimer’s Disease .....................38

 CSF Biomarkers and 

 Risk Assessment, Diagnosis .....................39

 Imaging the Living Brain ...........................40

 Developing New Cognitive Tests ...............41

 Fluctuating Symptoms in 

 Alzheimer’s Disease ..................................41

 Sensory Changes .....................................42

 Motor Changes ........................................42

 Testing Therapies to 

 Treat, Delay, or Prevent

 Alzheimer’s Disease ..............................43

 NIA Programs Support Clinical Trials .........43

 NIA-Funded Clinical Trials .........................44

 Reports from Recently 

 Completed Clinical Trials ...........................45

 Advancing Support 

for Caregivers ...............................56

 Factors in Caregiving and Mortality ...........56

 Reducing Caregiver Stress ........................56

 REACH-ing Out to Caregivers ...................57

 Support for Patient/Caregiver Pairs ...........57

 Examining Social and 

 Economic Risk Factors .................59

 Advancing the Future 

of Alzheimer’s Research: 

NIA Research Infrastructure 

and Initiatives .................................60

References .......................................65

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 4 2010 Progress Report on Alzheimer’s Disease
Introduction

A lzheimer’s disease is an age-related brain disorder that gradually destroys a person’s ability to 

remember, think, learn, and carry out even the 

simplest of tasks. Alzheimer’s is a type of dementia, a 

broad term for diseases and conditions that damage brain 

cells and, over time, impair brain function. Alzheimer’s is 

associated with the breakdown of connections between 

brain cells, or neurons, and their eventual death. 

Typically diagnosed in people age 60 and older, in 

rare cases the disease can occur in people in their 30s 

and 40s. The first clinical signs of Alzheimer’s disease 

include memory loss or other cognitive problems, such 

as trouble with language or decision making. As cognition continues to decline, people may also experience 

disturbing changes in personality and behavior. In the 

final stage of Alzheimer’s dementia, people lose the ability to recognize family and friends and become totally 

dependent on others for their daily care. Ultimately, 

Alzheimer’s is a terminal illness.

Research shows that Alzheimer’s causes changes in the 

brain years and even decades before the first symptoms 

appear, so even those who seem free of the disease today 

may be at risk. The fight against Alzheimer’s is urgent 

because, without a cure or more effective treatment, it 

will grow increasingly prevalent as the population ages. 

This report from the National Institute on Aging (NIA), 

part of the National Institutes of Health (NIH), focuses 

on the scientists waging that fight, who work each day 

toward better treatments and, ultimately, prevention of 

Alzheimer’s disease. Their efforts are dedicated to a future 

free of this devastating disorder. This report details some 

of their progress toward that goal. 

Baby Boomers and the 

Risk for Alzheimer’s 

Today, an estimated 2.4 million to 5.1 million people in 

the United States may have Alzheimer’s disease. While 

estimates of the number of people with the disorder 

vary, few would dispute the urgent need to find ways 

to prevent, delay, and treat this age-related disease—

especially in light of America’s aging population. The 

U.S. Census Bureau estimates that the 65-and-older 

population will double to about 72 million during the 

next 20 years. In fact, in January 2011, America reached 

a significant milepost when the oldest “baby boomers” 

turned 65. This trend toward an aging population is 

accompanied by a sobering reality: studies have shown 

that the number of people with Alzheimer’s doubles for 

every 5-year interval past age 65. And the ranks of the 

very elderly, those 85 years and older and at the highest 

risk for Alzheimer’s, are expected to triple by 2050. 

To fully appreciate the impact of Alzheimer’s disease 

in America, one must understand its enormous personal 

and societal costs. Family, friends, and caregivers of 

people with Alzheimer’s experience emotional, physical, 

and financial stress as they watch a loved one become 

increasingly forgetful, frustrated, confused, and lost as 

the disease progresses. Families struggle to care for loved 

ones at home but often face difficult decisions about 

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 5 2010 Progress Report on Alzheimer’s Disease
daily, short-term, and long-term care. Frequently, people 

with Alzheimer’s disease rely on assisted living facilities, 

then nursing homes, for care and support. 

Unless more effective interventions are developed, 

the number of people living with the disease could 

escalate significantly, along with the need to support 

them and their caregivers. That is why researchers 

and clinicians are devoting their time and talent to 

developing the interventions needed to help people 

with Alzheimer’s, those at risk for the disease, and the 

many caregivers on the frontlines of support. 

In January 2011, Congress passed and President 

Barack Obama signed into law the National 

Alzheimer’s Project Act (NAPA). The legislation 

mandates the establishment of a national strategy 

to oversee, coordinate, and advance Alzheimer’s 

disease research, care, and services. Under the new 

law, the Secretary of Health and Human Services is 

charged with leading a national project to: 

 Create and maintain a national plan to 

overcome Alzheimer’s disease

 Share information and coordinate research and 

services across the Federal Government

 Accelerate the development of treatments to 

prevent, halt, or reverse the course of Alzheimer’s 

 Improve the early diagnosis and the care and 

treatment of people with Alzheimer’s

 Include racial and ethnic minorities in the plan 

with an aim to decrease health disparities associated with research, treatment, and services

 Coordinate with international entities in the 

global fight against Alzheimer’s disease

A National Plan to Advance Alzheimer’s 

Research, Care, and Services

NIH-Supported Research on 

Alzheimer’s Disease

Dr. Alois Alzheimer first described Alzheimer’s disease 

more than 100 years ago. But it was not until the 1970s 

that researchers began to question the commonly held 

belief that dementia—or senility, as it was then known—

was a normal part of aging. Since then, the scientists 

The law established a public-private Advisory 

Council on Alzheimer’s Research, Care, and 

Services, made up of Federal and non-Federal 

experts and advocates. The Advisory Council is 

charged with advising the Secretary in preparing a 

formal national plan—to be updated annually—to 

prioritize Federal efforts in research, clinical care, 

and support services. 

The Council comprises 12 Federal agencies, 

including the Centers for Disease Control and 

Prevention, Administration on Aging, Department 

of Veterans Affairs, and Food and Drug 

Administration. The National Institutes of Health is 

represented by NIA, which leads the nation’s 

Alzheimer’s disease research program. The Council 

also has a dozen non-Federal members representing Alzheimer’s disease advocacy groups, caregivers, healthcare providers, and others. The Advisory 

Council met for the first time in September 2011. 

For more information, please visit the NAPA 

Web site at http://aspe.hhs.gov/daltcp/napa/index.

shtml. To view the NAPA law, go to www.gpo.gov/

fdsys/pkg/PLAW-111publ375/pdf/PLAW111publ375.pdf

 6 2010 Progress Report on Alzheimer’s Disease
and clinicians who have dedicated their lives to finding 

the causes of and possible treatments for Alzheimer’s 

disease have greatly advanced our understanding of the 

disorder. The NIA leads this effort and, with its sister 

institutes at the NIH, funds and oversees a productive 

research program into the basic biology of the disease 

and the factors that influence its development and progression.

The NIH research portfolio covers a broad array of 

scientific disciplines and seeks to answer complex questions: What are the causes of Alzheimer’s disease? How 

can it be diagnosed early and accurately? How might it 

be treated? How could it be delayed or even prevented? 

Over the past quarter century, scientific advances have 

deepened our insights into this complex disease. While 

we have much to learn, it is notable that the pace of 

translational research—which takes laboratory knowledge into the clinical arena—is accelerating. International 

collaborations are also leading to important discoveries 

as scientists collect and share the data needed to tease 

out the genetic variants that may play a role in developing Alzheimer’s, and identify and standardize imaging 

and biomarker measures to better understand the disease’s earliest brain changes.

Over the pastquarter century, 

scientific advances have deepened our insights into this 

complex disease.

 7 2010 Progress Report on Alzheimer’s Disease
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Executive Summary

A Deeper Understanding of 

Alzheimer’s Disease 

The NIH conducts and supports a balanced program of 

research that investigates the biological, translational, 

clinical, behavioral, and societal aspects of Alzheimer’s 

disease, all aimed at improving care, delaying the onset 

of Alzheimer’s disease, and, ultimately, preventing it 

entirely. Over the past 30 years, since the realization in 

the late 1970s that Alzheimer’s is a distinct disease associated with aging, this research has provided new 

insights and led to improved scientific methods and 

tools that are helping to unravel the complexities of 

Alzheimer’s disease and cognitive decline. In recent 

years, these technologies have allowed researchers to process and analyze vast amounts of data, to look inside the 

living brain to find Alzheimer’s-related changes, and to 

develop tests that detect disease onset and progression in 

blood and other biological samples. 

Advances in the Biology 

Underlying Alzheimer’s

While two of the hallmarks of Alzheimer’s—abnormal levels of amyloid and tau proteins in the brain—have been 

known for a century, new research is exploring a number 

of other Alzheimer’s-related changes in the brain. Scientists 

are using imaging to get a clearer picture of the loss of 

metabolism and connectivity between brain regions, for 

example. Disruption in the normal functioning of mitochondria—the cell’s energy source—is another fruitful area 

of research. Researchers are also looking at calcium imbalances in the cell to tease out what goes awry in brains that 

may eventually lead to Alzheimer’s disease. (See Understanding 

the Biology of Alzheimer’s Disease, page 25.)

Collaborative Studies Reveal 

Genetics of Alzheimer’s

International teams of researchers are working together 

on genome-wide association studies (GWAS) to identify 

gene variants that may play a role in the timing of the 

onset and progression of Alzheimer’s disease. In 2010, 

NIA-funded researchers analyzed brain scans and GWAS 

data to identify several genes associated with Alzheimer’srelated changes in the brain. GWAS enabled a study 

of how mutated genes regulate proteins, such as betaamyloid, that may play a role in risk for Alzheimer’s. An 

NIA-led consortium also advanced our understanding of 

Alzheimer’s in a GWAS using DNA data from tens of 

thousands of volunteers. (See Large Studies Revealing 

Genetics of Alzheimer’s Disease, page 19.) 

 8 2010 Progress Report on Alzheimer’s Disease
Revised guidelines for measuring Alzheimer’s disease progression from presymptomatic stages 

through dementia reflect our growing understanding of the full course of the disease and its underlying pathology. These new guidelines are primarily 

directed at testing and validating new concepts in 

research, but they also update ways for clinicians 

to assess patient complaints about memory loss 

and other cognitive changes. Expert panels convened by the NIA and Alzheimer’s Association 

began meeting in 2009 to update the clinical diagnostic criteria for the disease. Completed in April 

2011, the National Institute on Aging/Alzheimer’s 

Association Diagnostic Guidelines for Alzheimer’s 

Disease established a new paradigm for diagnosing and researching the disorder. 

The original diagnostic criteria, developed 27 

years ago, described what we now know are the 

later stages of Alzheimer’s, when symptoms of 

dementia are already evident. The updated guidelines cover the full spectrum of Alzheimer’s as it 

New Guidelines Set for Staging, 

Diagnosing Alzheimer’s

gradually develops over many years, from the earliest preclinical stages in which symptoms are not 

evident, to mild cognitive impairment, to dementia 

due to Alzheimer’s pathology. Importantly, the new 

guidelines address the use, primarily in a research 

setting, of brain imaging and blood and cerebrospinal fluid biomarkers that may help diagnose 

Alzheimer’s disease at earlier stages. The guidelines are intentionally flexible to allow for changes 

that could come from emerging technologies and 

further advances in our understanding of biomarkers and the disease process itself.

For more on the revised guidelines, go to 

www.nia.nih.gov/research/dn/alzheimersdiagnostic-guidelines.

View a short interview of 

NIA’s Dr. Creighton Phelps on the updated 

Alzheimer’s disease diagnostic guidelines.

 9 2010 Progress Report on Alzheimer’s Disease
Identifying Promising 

Targets for Therapies

Drugs are under development to clear away or reduce the 

damage thought to be caused by the abnormal accumulation of tau and amyloid proteins in the brain. Other 

therapeutic targets being researched include compounds 

such as the SIRT1 and STEP61 enzymes, and substances 

being tested in animals, such as rapamycin and resveratrol. 

(See Developing New Treatments, page 33.)

Detecting and Diagnosing Alzheimer’s

Researchers announced new findings about the relationship between changes in cerebrospinal biomarkers connected to shrinkage in specific brain regions—a pattern 

that may be an early warning sign of Alzheimer’s. They 

are also exploring how changes in the sense of smell, 

ability to walk, and other behaviors might signal disease 

onset. These are just a few ways researchers and clinicians are seeking to identify the earliest signs of 

Alzheimer’s in the brain in order to develop effective 

interventions. (See Advances in Detecting Alzheimer’s 

Disease, page 38.)

Can Lifestyle Factors Delay or 

Prevent Alzheimer’s?

Researchers are exploring several lifestyle factors, from 

diet and exercise to stress, that may influence age-related 

cognition and risk for Alzheimer’s. In addition to learning more about the connection between heart function 

and brain health, they are also shedding light on whether 

the disease mechanisms that play a role in physical frailty 

also play a role in Alzheimer’s. It is possible that reducing 

high cholesterol, diabetes, and smoking may also 

reduce the risk of cognitive decline and Alzheimer’s. 

(See Determining Risk Factors for Alzheimer’s and 

Cognitive Decline, page 29.) 

Testing Therapies in Clinical Trials 

A wide array of clinical trials investigating ways to prevent Alzheimer’s and cognitive decline are underway. 

Recently reported results are both promising (a pilot 

study showed the use of an insulin nasal spray may 

improve cognition) and disappointing (the largest trial to 

date testing cholesterol-lowering statins showed they did 

not improve cognition in people with Alzheimer’s). (See

Testing Therapies to Treat, Delay, or Prevent Alzheimer’s,

page 43; this section includes a list of ongoing trials and 

a video on the topic.)

Revised guidelines for measuring Alzheimer’s 

disease progression from presymptomatic stages through 

dementia reflect our growing understanding of 

the full course of the disease and its underlying pathology.

 10 2010 Progress Report on Alzheimer’s Disease
 The healthy human brain is 

made up of tens of billions of 

neurons that act as information messengers, transmitting and 

receiving information via chemical and 

electrical signals. Glial cells and the 

brain’s rich supply of blood vessels help 

support and regulate these important 

activities. Most neurons have three 

parts: a cell body, an axon, and many 

dendrites. The cell body contains the 

nucleus, the cell’s genetic blueprint that 

directs and regulates the cell’s activities. 

The axon, a cable-like structure extending from one end of the neuron, transmits messages. Dendrites, branch-like 

structures radiating from the other end 

of the neuron, receive messages.

The function and survival of neurons 

depends on several key biological processes:

● Communication—When one neuron 

receives messages from another, the cell 

body generates an electrical charge that 

travels to the end of the axon. Chemicals 

called neurotransmitters are released and 

move across a tiny gap, or synapse, to 

the dendrites of neighboring neurons. 

The neurotransmitters bind, or lock into, 

specific receptor sites, or keyholes, on 

the dendrites. This action triggers a 

chemical or electrical charge that either 

stimulates or inhibits the neighboring 

neuron’s activity. Scientists estimate that 

one neuron may have as many as 7,000 

synaptic connections to other neurons.

A Brief Primer

Alzheimer’s Disease

Brain

on

and the

● Metabolism—This process encompasses all chemical reactions that take 

place in the cell to maintain life. These 

reactions require chemical energy in the 

form of oxygen and glucose, which is 

supplied by blood circulating through 

the brain. The brain consumes up to 20 

percent of the energy used by the 

human body, more than any other 

organ, and has one of the richest blood 

supplies of any organ.

● Learning, memory, and repair—

Unlike many short-lived cells in the 

body, neurons have evolved to live a 

long time—more than 100 years in 

humans—so they must constantly 

maintain and repair themselves. Neurons 

also continuously remodel themselves—

especially as we learn new things—by 

breaking down synaptic connections 

with one neighboring neuron and forming new ones with the same cell or even 

a different neighbor. Research shows 

that a few brain regions may actually 

generate new neurons, even as we 

grow older. 

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View a short video showing the progression of 

Alzheimer’s disease in the brain.

 11 2010 Progress Report on Alzheimer’s Disease
How Does Alzheimer’s 

Disease Affect the Brain? 

While the brain may shrink to some 

degree in healthy aging, it does not lose 

neurons in large numbers. In Alzheimer’s 

disease, however, damage is widespread 

as many neurons stop functioning, lose 

connections with other neurons, and die. 

The disease disrupts processes vital to 

neurons and their networks, including 

communication, metabolism, and repair.

At first, Alzheimer’s disease typically 

destroys neurons and their connections 

in parts of the brain involved in memory, 

including the entorhinal cortex and the 

hippocampus. It later affects areas in 

the cerebral cortex responsible for language and reasoning. Eventually, many 

other areas of the brain are damaged, 

and a person with Alzheimer’s becomes 

helpless and unresponsive to the outside world.

What Are the 

Main Characteristics of 

the Brain with 

Alzheimer’s Disease?

Many changes take place in the brain of 

a person with Alzheimer’s disease. Some 

of these changes can be observed under 

the microscope after death. The three 

abnormalities most evident in the brains 

of people who have died with the 

disorder are:

● Amyloid plaques. Found in the 

spaces between neurons, plaques consist predominantly of abnormal deposits 

of a protein fragment called beta-amyloid. 

Plaques form when pieces of a protein 

called amyloid precursor protein (APP) 

begin to stick together. Plaques also 

contain other proteins, remnants of 

degenerating neurons, and other cellular 

material. Scientists used to think that 

amyloid plaques were the primary cause 

of the damage to neurons seen in 

Alzheimer’s. Now, however, many think 

that other, unclumped forms of betaamyloid, seen earlier in the plaque formation process, may be the major 

culprits. Scientists have not yet determined if plaques are a cause or a 

byproduct of Alzheimer’s disease.

● Neurofibrillary tangles. Found 

inside neurons, neurofibrillary tangles 

are abnormal, insoluble clumps 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 end of the axon. Researchers 

believe that tau binds to and stabilizes 

microtubules. In Alzheimer’s disease, 

however, tau undergoes abnormal 

chemical changes that cause it to 

detach from microtubules and stick to 

other threads of tau, eventually forming 

neurofibrillary tangles. The tangles 

cause the network of microtubules to 

disintegrate, and the neuron’s transport 

system collapses. As with beta-amyloid, 

some scientists think that other, smaller 

forms of abnormal tau may cause the 

most damage to neurons.

● Loss of neuronal connections and 

cell death. In Alzheimer’s disease, the 

synaptic connections between certain 

groups of neurons stop functioning and 

begin to degenerate. This degeneration 

may be due to abnormal deposits of 

beta-amyloid and tau. When neurons 

lose their connections, they cannot 

function properly and eventually die. As 

neuronal injury and death spread 

through the brain, connections between 

networks of neurons break down, and 

affected regions begin to shrink in a 

process called brain atrophy. By the 

final stage of Alzheimer’s, damage is 

widespread, and brain tissue has shrunk 

significantly.

What Causes 

Alzheimer’s Disease?

In some rare cases, people develop 

Alzheimer’s in their late 30s, 40s, or 50s. 

This form of the disease, called “earlyonset dominantly-inherited” Alzheimer’s 

disease, often runs in families and is 

caused by a mutation in one of three 

genes that a person has inherited from 

a parent. An NIA-funded clinical study is 

underway to identify the sequence of 

brain changes in this form of early-onset 

Alzheimer’s, even before symptoms 

appear. (See the DIAN study under NIA 

Research Infrastructure and Initiatives, 

page 63.) 

More than 90 percent of Alzheimer’s 

cases occur in people age 60 and older. 

The development and progression of 

this “late-onset” form of the disease are 

very similar to those of the early-onset 

form of the disorder. The causes of lateonset Alzheimer’s are not yet known, 

but they are believed to include a combination of genetic, environmental, and 

lifestyle factors. The importance of any 

one of these factors in increasing or 

decreasing the risk of developing 

 12 2010 Progress Report on Alzheimer’s Disease
Alzheimer’s differs from person to 

person—even between twins. 

Much basic research in Alzheimer’s 

disease has focused on the genes that 

cause early-onset of the disease, and 

how mutations in these genes disrupt 

cellular function and lead to disease. 

Scientists hope that what they learn 

about early-onset Alzheimer’s disease 

can be applied to the late-onset form of 

the disease.

Perhaps the greatest mystery is why 

Alzheimer’s disease largely strikes people of advanced age. The single best 

known risk factor for Alzheimer’s is age, 

and studies show that the prevalence of 

the disease dramatically increases after 

age 80. Research on how the brain 

changes normally as people age will 

help explain Alzheimer’s prevalence in 

older adults.

How Is Alzheimer’s 

Disease Diagnosed? 

Clinicians use a number of tools to 

diagnose “possible Alzheimer’s dementia” (dementia that could be due to 

another condition) or “probable 

Alzheimer’s dementia” (no other cause 

of dementia can be found). Some 

people with memory problems may 

have mild cognitive impairment (MCI), a 

condition that may lead to Alzheimer’s 

disease. People with MCI have more 

memory problems than normal for people their age, but their symptoms are 

not as severe as those seen in 

Alzheimer’s. Importantly, not all people 

with MCI go on to develop Alzheimer’s 

disease, and some may even recover 

from MCI and regain their normal cognition. This recovery may happen if the 

MCI is due to a medicine’s side effect or 

temporary depression, for example.

Tools for diagnosing probable 

Alzheimer’s disease include a medical 

history, a physical exam, and tests—

preferably over time—that measure 

memory, language skills, and other abilities related to brain functioning. Information provided by family members or 

other caregivers about changes in a 

person’s day-to-day function and 

behavior also help in diagnosis. Currently, 

a definitive diagnosis of Alzheimer’s can 

be made only after a brain is autopsied 

after death. However, in specialized 

research facilities such as the NIA’s network of 29 Alzheimer’s Disease Centers, 

clinicians may also use brain scans and 

biomarkers in blood and cerebrospinal 

fluid to help diagnose Alzheimer’s 

dementia in people who may or may 

not be participating in a clinical trial. 

Early, accurate diagnosis is crucial 

because it tells people whether they 

have Alzheimer’s or whether their symptoms are caused by something else. 

Stroke, tumor, Parkinson’s disease, 

sleep disturbances, or side effects of 

medications are all known to affect cognitive function and memory, and some 

of these conditions are reversible. When 

Alzheimer’s is diagnosed, knowing early 

on can help families plan for the future 

while the person with the disorder can 

still participate in making decisions. 

Researchers are developing tests using 

biomarkers to detect the disease before 

memory loss or cognitive impairment is 

evident. One day these tests could be 

used in general medical practice.

How Is Alzheimer’s 

Disease Treated?

Only a few medications have been 

approved by the U.S. Food and Drug 

Administration to help control the cognitive loss that characterizes Alzheimer’s 

disease. Donepezil (Aricept®), rivastigmine (Exelon®), and galantamine 

(Razadyne®, formerly known as 

Healthy neuron Dying neuron

 13 2010 Progress Report on Alzheimer’s Disease
Reminyl®) are prescribed to treat mild to 

moderate Alzheimer’s symptoms. 

Donepezil also is approved to treat 

severe Alzheimer’s. 

These drugs act by stopping or 

slowing the action of acetylcholinesterase, an enzyme that breaks down 

acetylcholine (a neurotransmitter that 

helps in memory formation). They maintain some patients’ abilities to carry out 

everyday activities and may slow down 

symptoms related to thinking, memory, 

or speaking skills. They also may help 

with certain behavioral symptoms. 

However, they do not stop or reverse 

the underlying disease process and help 

some patients only for months to a 

couple of years.

Another type of medication, memantine (Namenda®), is prescribed to treat 

moderate to severe Alzheimer’s symptoms. This drug appears to work by 

blocking receptors for glutamate, another 

neurotransmitter involved in memory 

function. Studies in animals suggest that 

memantine may have disease-modifying 

effects, although this effect has not yet 

been demonstrated in humans. 

In addition to these medications, 

physicians may use other drugs and 

nondrug approaches to treat behavioral 

and psychiatric problems associated 

with Alzheimer’s. These problems 

include agitation, verbal and physical 

aggression, wandering, depression, 

sleep disturbances, and delusions. (It is 

important to note that since no drugs 

are specifically approved by the U.S. 

Food and Drug Administration to treat 

behavioral or psychiatric symptoms in 

dementia, this practice constitutes “offlabel” usage.)

Efforts to educate and inform people with 

Alzheimer’s, their families, the public, providers, 

and others interested in the disease complement 

NIH’s research initiatives. The NIA Alzheimer’s 

Disease Education and Referral (ADEAR) Center 

provides free information and publications for 

families, caregivers, and professionals on 

research, diagnosis, treatment, patient care, 

caregiver needs, long-term care, and education 

and training related to Alzheimer’s. For example, 

the publication Alzheimer’s Disease: Unraveling 

the Mystery explains the disease, highlights 

ongoing research, and describes efforts to support caregivers of people with the disease. An 

animated companion video brings to life the latest knowledge about Alzheimer’s and the brain. 

Other ADEAR Center publications include 

Caring for a Person with Alzheimer’s Disease: 

NIA’s ADEAR Center Offers Free 

Alzheimer’s Information and Resources

Your Easy-to-Use Guide from the National 

Institute on Aging, which provides caregiving 

information and advice. ADEAR fact sheets 

cover a variety of topics, including basic information, Alzheimer’s genetics, and participating in 

clinical trials and studies. Many ADEAR publications also are available in Spanish. 

ADEAR staff members answer telephone, 

email, and written requests and can suggest 

local and national resources. In addition, the 

ADEAR Center Web site offers email alerts, an 

Alzheimer’s clinical trials database, and the 

Alzheimer’s Disease Library database. 

To read and order these publications, view the 

video, and take advantage of many other resources, 

visit the ADEAR Center at www.nia.nih.gov/

alzheimers or call the Center toll-free at 

1-800-438-4380. 

 14 2010 Progress Report on Alzheimer’s Disease
omarkers

imaging clinical risk beta

biomarkers

alpha

Research Advances

The NIA/NIH scientific portfolio for Alzheimer’s disease covers a wide range of 

disciplines and research programs. Research conducted and supported by NIH is 

deepening our understanding of this complex neurodegenerative disorder. This 

research will help researchers develop new and more effective strategies for delaying 

and ultimately preventing Alzheimer’s and cognitive impairment. 

Highlights of studies in 2010 focus on:

1 Estimating the Extent of Alzheimer’s Disease

2 Discovering the Genes Behind Alzheimer’s Disease

3 Understanding the Biology of Alzheimer’s Disease

4 Determining Risk Factors for Alzheimer’s and 

Cognitive Decline

5 Developing New Treatments

6 Advances in Detecting Alzheimer’s Disease

7 Testing Therapies to Treat, Delay, or Prevent 

Alzheimer’s Disease

8 Advancing Support for Caregivers

9 Examining Social and Economic Risk Factors

1 Estimating the Extent 

of Alzheimer’s Disease

New and effective ways to prevent, delay, and 

treat Alzheimer’s disease are urgently needed. Today, as 

many as 5.1 million Americans have the disorder, and its 

financial and societal burden on individuals and society 

is expected to rise along with the number of older adults. 

Preparing for this challenge from a public health 

standpoint requires a clear grasp of the numbers 

involved—how many people are currently affected by 

Alzheimer’s, how prevalence may vary in different socioeconomic groups, and likely future trends. Researchers 

focused on the epidemiology of Alzheimer’s disease—or 

the study of disease in a population setting—met in 

2009 to examine the best way to measure prevalence. 

Researchers attending the NIA Workshop on 

Prevalence and Trends considered current peer-reviewed 

estimates of Alzheimer’s prevalence (between 2.4 to 5.1 

million people in the United States). They wanted to 

understand why estimates vary and whether the higher 

2O1O

 15 2010 Progress Report on Alzheimer’s Disease
and lower estimates are useful indicators of the scope of 

Alzheimer’s disease (Anderson and Brayne, eds., 2011). 

They determined that the higher prevalence figure 

of 5.1 million primarily includes people with mild 

Alzheimer’s disease who still function fairly normally. 

This figure would prove useful, for example, in determining the size of the market for an effective therapy 

that targets the early stages of the disease. The lower figure of 2.4 million includes people who have moderate to 

severe Alzheimer’s disease and who depend on others for 

help with daily living. This estimate could be useful in 

public health planning for more intense resource needs 

in Alzheimer’s caregiving. 

Estimating How Many People Have MCI 

Mild cognitive impairment, or MCI, is now widely 

accepted as a possible precursor stage in Alzheimer’s 

disease when symptoms of memory loss are first noticeable. Partly because people with MCI continue to function fairly normally, it remains unclear how common 

the condition is in the aging population. However, 

obtaining estimates for MCI prevalence is important for 

two reasons. First, while people with MCI do not always 

develop Alzheimer’s, they are at greater risk. Second, 

although people with MCI require less care from their 

families and health professionals than do people with 

Alzheimer’s dementia, there are costs associated with the 

condition. Scientists increasingly believe that developing 

and testing early interventions in people with MCI may 

be one way to find effective treatments that delay or prevent the symptoms of Alzheimer’s disease. 

Past estimates of MCI prevalence have come mostly 

from clinic-based studies. These data may be influenced 

by the fact that people who come to the clinic may difEpidemiology is the scientific discipline that investigates the distribution of disease in human populations. The basic measures are “prevalence” and 

“incidence.” Prevalence, a measure of disease burden, is a count of the number of people with the 

disease in a given population at a specific point in 

time. Prevalence can also be represented as a proportion, or percentage. Incidence pertains to the 

number of people who acquire the disease during 

a given interval of time, such as a year. Usually 

presented as a rate, incidence is a direct measure 

of disease risk—higher incidence implies higher 

risk (Ganguli and Kukull, 2010; Brayne et al., 2011).

Estimates of the prevalence and incidence of 

Alzheimer’s disease depend on how broadly or 

narrowly the condition is defined. Current estimates 

can be considered low in the sense that only 

Prevalence versus incidence—

what do the numbers mean?

people with clinically obvious disease are included. 

In particular, higher estimates in the general population tend to come from studies that embrace a 

broader range of the disease spectrum, from mild 

to severe cases of Alzheimer’s disease. 

 Epidemiology is also concerned with identifying determinants or predictors of future disease. 

Some predictors of Alzheimer’s disease may in fact 

be early signs or markers of the disease. Others 

are independent risk factors, such as a lifestyle 

factor whose presence or absence is associated 

with a reduced or increased likelihood that the disease process will commence. The risk factors 

associated with Alzheimer’s and cognitive impairment from epidemiological studies are of most 

interest as they can uncover potential targets for 

interventional studies. 

 16 2010 Progress Report on Alzheimer’s Disease
fer from those who don’t, for example, by being more 

aware of their cognitive problems or better able to afford 

care. For that reason, Mayo Clinic-Rochester researchers 

undertook a “community-based” study of MCI prevalence in Olmsted County, MN, in which they randomly 

recruited participants (Petersen et al., 2010). Some 16 

percent of the nearly 2,000 participants, age 70 to 89, 

were affected by MCI, the study showed. Among this 

group, amnestic MCI, in which memory loss is the most 

prominent feature and the risk for transitioning to 

Alzheimer’s dementia is greater, occurred 2.3 times more 

frequently than nonamnestic MCI. MCI prevalence was 

higher in men than women. It was also higher in people 

who had never married and in those who carried one or 

two copies of the APOEε4 allele, a known genetic risk 

factor for late-onset Alzheimer’s disease. However, prevalence was lower in those with more years of education.

In another community-based study, University of 

Pittsburgh researchers used three comparable sets of 

diagnostic criteria to measure MCI prevalence within a 

single population (Ganguli et al., 2010). They studied 

2,036 people age 65 or older living in small towns in 

western Pennsylvania. The prevalence of MCI varied, 

from 18 percent to 36 percent, depending on the 

measurement used. The researchers noted that the lower 

figure was calculated using a combination of functional 

and neuropsychological assessments, while the higher 

figure employed only neuropsychological assessment. 

The results of this study indicate that accurate comparison of MCI prevalence in different populations requires 

researchers to agree on a single set of criteria. 

Dementia Incidence Among 

the “Oldest Old”

Previous research tells us that dementia incidence, or the 

rate of occurrence of new cases, increases exponentially 

among people age 65 and 90, doubling approximately 

every 5 years. Scientists do not know if this doubling 

continues after age 90, but the answer to this question is 

critical because the “oldest old,” people over age 85, are 

the fastest growing segment of the U.S. population. 

Their numbers are expected to grow from 5.5 million to 

19 million by 2050. 

Researchers at the University of California, Irvine, 

investigated rates of dementia onset in the advanced 

elderly (Corrada et al., 2010). Studying 330 cognitively 

normal participants age 90 and older living in a southern California retirement community, they found that 

dementia incidence climbed steadily in this group after 

age 90. Rates ranged from 13 percent new cases per year 

among those age 90-94 to 41 percent per year in the 

100-plus age group, and they continued to almost 

double with every 5 years of age. Rates of dementia were 

similar for men and women. Interestingly, preliminary 

analyses showed no association of dementia in this 

90-plus population with risk factors identified in 

younger age groups, such as history of stroke, heart 

disease, or the presence of the APOEε4 allele.

Additional references:

Hebert LE et al. (2010) Change in risk of Alzheimer disease 

over time. Rush University Medical Center. Supported by NIA, 

NIEHS, NHLBI, and NINR.

Borson S et al. (2009) Comorbidity in aging and dementia: 

scales differ, and the difference matters. University of 

Washington, Seattle. Supported by NIA and NIMH.

2Discovering the 

Genes Behind 

Alzheimer’s Disease

Age is the best known risk factor for cognitive decline 

and Alzheimer’s disease. Age aside, some groups of 

people appear to be more vulnerable than others. To test 

new treatments to prevent or delay the onset of the disorder, it will be essential to identify people who are at 

high risk of Alzheimer’s disease but do not show signs of 

cognitive impairment. This way, interventions can be 

targeted to those most likely to benefit. Research on 

Alzheimer’s risk factors is offering new insights into the 

genetics and underlying biology of the disorder beyond 

the amyloid hypothesis, suggesting new mechanisms and 

possible targets for drug development. 

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 17 2010 Progress Report on Alzheimer’s Disease
We know that rare, early-onset familial Alzheimer’s disease 

runs in specific families. But children with a parent with the 

more common, sporadic form of the disease—called lateonset Alzheimer’s—often share an understandable concern 

about their risk for developing the disease. Indeed, while age 

is the most common risk factor for late-onset Alzheimer’s, 

having one or both parents with the disorder comes second. 

Researchers study the adult children of parents with lateonset Alzheimer’s because they have a higher risk of developing 

the disease. Following these participants before they may develop clinical symptoms of Alzheimer’s increases the chances of 

identifying relevant biological signs (biomarkers) of the disease. 

Scientists are looking at biomarkers in cerebrospinal fluid (CSF) 

and blood and tracking brain changes through neuroimaging. 

Teams at Boston University, New York University School of 

Medicine, and William S. Middleton Memorial Veterans 

Hospital in Madison, WI, used a variety of measures to see if 

they could detect early signs of brain degeneration in cognitively normal study participants with an average age of 57 to 

61. They found that children who had a parent with late-onset 

Alzheimer’s were more likely than those without an Alzheimer’s 

parent to show Alzheimer’s-associated changes on brain 

scans and in two biomarkers (Mosconi, Rinne et al., 2010). 

In the New York study, the adult children of parents with 

late-onset Alzheimer’s, particularly those with affected mothers, 

had higher levels of amyloid deposition in certain brain regions 

vulnerable to Alzheimer’s compared with those without a parental history (Mosconi, Berti, et al., 2010). The Boston University 

group found that children of parents with late-onset Alzheimer’s 

who were APOEε4-positive also scored lower on memory tests 

(Debette et al., 2009). Their memory performance was poor for 

their age, and they had a higher rate of brain atrophy.

Alzheimer’s disease is more common in people whose 

mothers had the disease than in those whose fathers had it. 

Researchers found evidence of this possible “maternal effect” 

Children of Parents with Late-Onset Alzheimer’s: 

Who’s at Risk?

in cognitively normal adult children of parents with late-onset 

Alzheimer’s. A University of Kansas group found that cognitively normal adults (average age 74) whose mothers had lateonset Alzheimer’s were more likely to show Alzheimer’s-like 

patterns of brain shrinkage than those whose fathers had the 

disease (Honea et al., 2010). In the studies of middle-aged 

adults described above, people with a maternal history of lateonset Alzheimer’s were also more likely to show Alzheimer’slike brain and CSF biomarker changes as well as reduced 

memory-test performance. In fact, in some tests, people 

whose fathers had late-onset Alzheimer’s did not differ significantly from people who did not have a parent with Alzheimer’s. 

Scientists cite some possible explanations for these findings. One has to do with the phenomenon of genetic “imprinting.” People inherit two copies of their genes—one from their 

mother and one from their father. Usually, both copies of each 

gene are active, or “turned on.” But in less than 1 percent of 

genes, the copy from the father is “turned off” while the copy 

from the mother is active. While Alzheimer’s disease is not 

linked to the female, or X, chromosome, there may be genes 

on the X chromosome contributing to neuronal vulnerability 

and dementia risk. Lastly, we inherit mitochondria—the part of 

each cell that converts food into chemicals that power the 

cell—exclusively from our mothers. If a mother passes on the 

genetic code for faulty mitochondrial function, her children 

could be at increased risk for late-onset Alzheimer’s. 

Additional references:

Mosconi L et al. (2010) Oxidative stress and amyloid-beta 

pathology in normal individuals with a maternal history of 

Alzheimer’s. New York University School of Medicine. Supported 

by NIA and NCRR.

Bendlin BB et al. (2010) White matter is altered with parental 

history of Alzheimer’s disease. William S. Middleton Memorial 

Veterans Hospital. Supported by NIA and NIMH.

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 18 2010 Progress Report on Alzheimer’s Disease
Large Studies Revealing Genetics of 

Alzheimer’s Disease

After age, inheritance is the biggest risk factor associated 

with Alzheimer’s disease. Efforts to identify genes that 

play a role have gathered considerable momentum during 

the past 2 years, thanks primarily to several GWAS 

involving investigators around the world. Those studies 

resulted in the identification of the first candidate genetic 

risk factors for late-onset Alzheimer’s to be discovered 

since 1992, when APOEε4 was first associated with the 

disease. In 2010, these recent successes were confirmed 

and expanded when studies identified additional candidate genes emerging from even larger-scale analyses. 

Other new candidate Alzheimer’s risk genes have emerged 

from studies combining brain imaging and genetics.

WHAT IS GENE 

EXPRESSION?

In gene expression, the 

information encoded in a 

gene is switched on at a 

certain time to direct the 

assembly of a specific 

protein. Proteins are required 

for the structure, function, 

and regulation of cells, 

tissues, and organs. 

WHAT IS A GENOME? 

Every human being is 

unique, in part because we 

each carry a unique genome. 

The genome is the complete 

set of DNA (deoxyribonucleic 

acid), the chemical compound 

that resides within each cell 

and contains the instructions 

necessary to build cells and 

direct their activities. The 

genomes of any two humans 

are 99 percent alike, but 

the 1 percent of variation is 

critical. It is this variation that 

creates differences among 

individuals in eye, skin, hair 

color, and the shapes of our 

bodies and faces. Genetic 

variation also contributes to 

individual differences in 

internal physiology, including 

the risk of developing certain 

diseases.

Gene Expression Studies Reveal 

Proteins Involved in Disorder

In some cases, a disease-causing mutation may lie not 

within a gene itself, but in a nearby region of DNA that 

regulates gene expression (see What is gene expression?). 

Researchers at the Mayo Clinic, Rochester, MN, looked 

for mutations affecting the expression activity of 12 candidate Alzheimer’s disease genes (Zou et al., 2010). In a 

GWAS examining postmortem brain tissue from 200 

people who had Alzheimer’s dementia, they looked for 

gene variants associated with individual differences in 

gene expression levels. They identified three singlenucleotide polymorphisms (see What is a SNP?, page 22)

associated with increased expression of the insulin 

degrading enzyme (IDE) gene, which reduce levels of 

beta-amyloid proteins in the brain. Consistent with that 

biological role, GWAS analysis of more than 4,500 samples from people with Alzheimer’s and those free of the 

disorder showed one of the IDE-linked SNPs to be 

associated with reduced risk of the disorder.

Genes involved in specific cellular processes 

(sugar metabolism, for example) tend to be 

switched on and off together in groups. In one 

study, University of California, Los Angeles, 

researchers identified “modules,” or clusters of 

genes likely to be involved in similar cellular processes (Miller JA et al., 2010). In the genomes of 

humans and mice, the researchers identified and 

then compared the organization of gene modules in 

 19 2010 Progress Report on Alzheimer’s Disease
Individual risk for developing the common, 

late-onset form of Alzheimer’s disease is 

believed to be influenced by variations in 

specific genes. Scientists hunt for those 

genes by comparing the genomes (see 

What is a genome?, page 19) of people 

who develop the disease with those of 

people who do not. However, it has 

become increasingly clear that while many 

genes influence the risk of late-onset 

Alzheimer’s, most of them (other than 

APOE) increase risk by only a small percent. Such genes are elusive quarry: 

finding them requires searching through 

millions of bits of DNA in samples 

obtained from thousands of people. 

Recent technological breakthroughs 

have made such genome-wide association studies (GWAS) possible. In GWAS, 

DNA samples are placed on tiny chips 

and scanned on automated laboratory 

machines, which can rapidly analyze 

large numbers of samples at specific 

sites within the genome known to show 

high levels of variability in humans. To 

accelerate the use of this large-scale 

How Genome-wide Association Studies Advance Research

the two species. Some modules are very similar in mice 

and humans—for example, modules that regulate energy 

metabolism include pretty much the same groups of genes. 

The researchers then looked for modules that differed significantly in humans versus mice. They identified one that was both unique to humans and included 

genes known to be turned on or off in Alzheimer’s disease. This module contained not only known Alzheimer’srelevant genes, but also genes not previously suspected 

to be involved in the disorder. These newly uncovered 

genes may therefore be “team players” in the disease process, including genes involved in protecting the brain’s 

white matter. The finding is particularly intriguing given 

increasing evidence that degeneration of white matter 

occurs in specific brain regions. (Also see Kuczynski et 

al., 2010)

Additional references:

Lipinski MM et al. (2010) Genome-wide analysis reveals 

mechanisms modulating autophagy in normal brain aging and in 

Alzheimer’s disease. Harvard Medical School. Supported by NIA, 

NIAID, NIDDK, and NINDS.

Thambisetty M et al. (2010) Association of plasma clusterin 

concentration with severity, pathology, and progression in 

Alzheimer disease. King’s College, London. Supported by NIA.

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technology for the study of late-onset 

Alzheimer’s, the NIA in 2009 established 

the Alzheimer’s Disease Genetic 

Consortium (ADGC). The ADGC also 

supports collaborations—worldwide—

among Alzheimer’s disease genetics 

researchers to promote the sharing of 

technical and data resources.

The idea propelling GWAS is that 

power lies in numbers—not only in bits 

of DNA analyzed per study participant, 

but also in the number of participants 

per study. ADGC-led GWAS published in 

2009 included up to 4,000 people with 

Alzheimer’s disease and 8,000 controls, 

leading to the discovery of three new 

 20 2010 Progress Report on Alzheimer’s Disease
late-onset Alzheimer’s disease risk-factor 

genes (PICALM, CLU, and CR1). Numbers 

of participants are crucial to the discovery 

of still more Alzheimer’s risk-factor genes. 

ADGC researchers analyzed three different sets of DNA data obtained from 

56,000 study participants and found 

variations in an additional four genes 

(CD2AP, MS4A4/MS4A6E, EPHA1, and 

CD33) to be associated with greater risk 

of Alzheimer’s disease. In that study, the 

largest to date, the ADGC confirmed four 

genes—CR1, CLU, BIN1, and PICALM—

that were discovered in earlier GWAS 

completed in 2009 and 2010.

 More challenges remain: finding 

other risk-factor genes for late-onset 

Alzheimer’s and making sense of the 

most recent GWAS discoveries. GWAS 

discoveries reveal associations between 

specific single-nucleotide polymorphisms and disease risk, and scientists 

can make educated guesses about 

which gene is associated with a particular SNP. However, additional analyses are 

required to confirm those guesses. 

Then, the real work begins. Having 

established that a particular gene 

increases risk for developing Alzheimer’s, 

scientists study that gene (and the protein 

it encodes) in cultured cells and animal 

models to understand its function and 

how disruption of that function might 

lead to disease.

Fortunately, we already know about 

the functions of the newly discovered 

genes, and subsets of them appear to 

be involved in common biological pathways, such as lipid processing, immune 

responses, and cell membrane function 

and maintenance. GWAS discoveries 

are providing not only new genes to 

study, but also broader insights into 

what biological processes are likely to 

be disrupted in Alzheimer’s disease. 

Additional references:

Jones L et al. (2010) Genetic evidence 

implicates the immune system and cholesterol metabolism in the aetiology of 

Alzheimer’s disease. Cardiff University 

School of Medicine, Cardiff, UK. 

Supported by NIA.

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Jun G et al. (2010) Meta-analysis 

confirms CR1, CLU, and PICALM as 

Alzheimer disease risk loci and reveals 

interactions with APOE genotypes. 

University of Pennsylvania School of 

Medicine. Supported by NIA, NINDS, 

NCRR, NHLBI, NHGRI, and NIMH.

Lambert JC et al. (2010) The 

CALHM1 P86L polymorphism is a 

genetic modifier of age at onset in 

Alzheimer’s disease: a meta-analysis study. 

Institut Pasteur de Lille, Lille, France. 

Supported by NIA and NINDS.

Naj AC et al. (2010) Dementia 

revealed: novel chromosome 6 locus for 

late-onset Alzheimer disease provides 

genetic evidence for folate-pathway 

abnormalities. University of Miami 

School of Medicine. Supported by NIA 

and NINDS.

Naj AC et al. (2011) Common variants 

at MS4A4/MS4A6E, CD2AP, CD33, and 

EPHA1 are associated with late-onset 

Alzheimer’s disease. University of Miami 

John P. Hussman Institute for Human 

Genomics. Supported by NIA, NHGRI, 

NCI, NIMH, NCRR, and NINDS.

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How Genome-wide Association Studies Advance Research (continued)

 21 2010 Progress Report on Alzheimer’s Disease
Imaging the Genetics of Alzheimer’s

The structure of the human brain is thought to be influenced by many common genetic variants. In the case of 

Alzheimer’s, these genetic variants play a role in degenerative changes in brain structure that occur in the disease. 

By identifying such variants, it may be possible to 

uncover additional risk-factor genes. New technologies 

are making this discovery possible, as recent advances in 

neuroimaging enable scientists to compare millimeter by 

millimeter the brains of people with and without 

Alzheimer’s disease. Scientists can then harness GWAS 

data to look for genetic variations and link them to 

structural changes in Alzheimer’s brains.

The computational power required for such analyses 

is enormous (one recent GWAS involved about 100 trillion bytes of data). The Alzheimer’s Disease Neuroimaging 

Initiative (ADNI) helped make this work possible. A 

public-private partnership led by the NIA, ADNI was 

launched in 2004 with the goal of identifying Alzheimer’srelated structural and functional changes in the brain, as 

well as standard biomarkers that could predict disease 

risk and progression. In 2009, ADNI research expanded 

to embrace the wealth of genetics data coming from 

GWAS (Saykin et al., 2010). Three papers in 2010 

analyzed ADNI data side by side with GWAS data in 

search of possible candidate Alzheimer’s risk-factor 

genes. (See ADNI details in Advancing the Future of 

Alzheimer’s Research, page 62.) 

At the University of California, Los Angeles, one 

group analyzed brain scans using magnetic resonance 

imaging (MRI) and GWAS data from 742 people with 

Alzheimer’s, MCI, or normal cognition. The study 

focused on the temporal lobe, the brain region first and 

most strongly affected in Alzheimer’s (Stein, Hua, 

Morra, et al., 2010). By checking through more than a 

half million SNPs for each participant, the researchers 

found one that significantly correlated with temporal 

lobe shrinkage. The significant SNP was located in the 

gene GRIN2B. This gene has not previously been implicated in Alzheimer’s, so it is not known yet whether it 

plays a role in disease development. It does, however, 

play a role in the functioning of receptors for the 

neurotransmitter glutamate, which affects learning, memory, and the death of neurons. Indeed, this receptor protein is already a target for Alzheimer’s treatments. This 

study shows that coupling brain imaging with genetics 

might be useful in finding new genetic risk factors. 

Scientists at the University of Indiana and University 

of California, Los Angeles (Shen et al., 2010), undertook 

even more extensive analyses, examining MRI data from 

ADNI. The Indiana group identified SNPs in two genes, 

APOE and TOMM40, which were strongly associated 

with structural changes in multiple brain regions in people 

with Alzheimer’s. Both of these genes had been previously 

identified as risk-factor genes for Alzheimer’s, but three 

novel candidate SNPs also emerged from this study. One 

was especially interesting because it is located near NXPH1, 

a gene involved in promoting synaptic integrity, or the 

strength of communications between brain cells. This 

SNP is also strongly associated with the loss of gray matter 

in the hippocampus of people with Alzheimer’s. A second 

SNP, EPHA4, is associated with a gene that also influences brain structure. These results suggest links to the 

mechanisms that may underlie the development and 

WHAT IS A SNP? 

A SNP, or single-nucleotide polymorphism, is 

a single change in nucleotides (the building 

blocks of DNA) that varies from person to 

person. Researchers use GWAS to identify 

the variations in SNPs among individuals to 

find genetic predispositions to health or disease.

 22 2010 Progress Report on Alzheimer’s Disease
progression of Alzheimer’s and suggests possible therapeutic targets. 

Additional references:

Kramer PL et al. (2010) Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study. Oregon Health & 

Science University. Supported by NIA.

Stein JL et al. (2010) Voxelwise genome-wide association study 

(vGWAS). University of California, Los Angeles, School of 

Medicine. Supported by NCRR, NIBIB, NICHD, and NIA.

Cognitive Decline and the APOE Gene

Of the late-onset disease genes discovered to date, the 

one that confers the most risk is apolipoprotein E, or 

APOE. This gene, found on chromosome 19, comes in 

several different forms, or alleles: ε2, ε3, and ε4. The 

APOEε2 allele is rare, found in 5 to 10 percent of people. APOEε3 is the most common allele, found in about 

70 percent to 80 percent of people. Significantly, the 

APOEε4 allele, found in 10 percent to 15 percent of the 

gene pool, increases risk for Alzheimer’s disease by threeto eight-fold, depending on whether a person has one or 

two copies of the allele, and is associated with an earlier 

age of disease onset. 

An ongoing question is whether changes in the 

brain that may lead to cognitive decline differ in people 

who carry APOEε4 and those who do not. Researchers 

at the University of California, San Diego, and Brown 

University in Providence, RI, found that APOEε4 carriers with MCI have more rapid rates of cognitive decline 

than do noncarriers, as shown by their performance on 

cognitive tests and/or their ability to carry out normal 

activities of daily living (Whitehair et al., 2010; 

Okonkwo et al., 2010). In MRI studies done by the 

Brown team, decreased brain volumes indicating shrinkage of brain tissue correlated with increased cognitive 

decline in both APOEε4 carriers and noncarriers. 

Decreased brain volume was also more evident in 

APOEε4 carriers than in noncarriers. 

Even when deemed cognitively normal, APOEε4 

carriers display more signs of age-related brain declines 

than do noncarriers. In the NIA’s Baltimore Longitudinal 

Study of Aging, 94 participants with a mean age of 69 

underwent annual neuropsychological testing and received 

positron emission tomography (PET) scans to track blood 

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flow in the brain (Thambisetty, Beason-Held et al., 2010). 

The group included both APOEε4 carriers and noncarriers. Over the course of the 8-year study, the two 

groups performed equally well on most of the neuropsychological tests. However, the APOEε4 carriers showed 

more precipitous declines in blood flow in the cortex, an 

area of the brain that typically declines early in 

Alzheimer’s disease. 

These findings may inform the design and interpretation of clinical trials. For example, if treatment and control 

groups in a trial include people who carry the APOEε4 

allele, results may be affected by differences in disease 

progress between carriers and noncarriers, as well as potential differences in their response to specific treatments.

APOEε2 might be considered the “lucky card” of 

the three APOE alleles, as it is associated with both 

reduced risk for Alzheimer’s disease and a slower rate of 

cognitive decline. How APOEε2 benefits the brain is 

unclear. The relatively small percent of the population 

who carry at least one copy of the allele may benefit, for 

example, from slower rates of shrinkage of the hippocampus, a brain region critical for learning and memory. 

There is also evidence that people with the allele have 

less buildup of abnormal deposits of beta-amyloid and 

tau proteins. A University of California, San Francisco, 

team analyzed rates of hippocampal shrinkage in 134 

cognitively normal ADNI participants (Chiang et al., 

2010). Over the 2-year study, the hippocampus brain 

regions of APOEε2 carriers shrank at a much slower rate 

than in noncarriers. Also, tests of CSF indicated fewer 

Alzheimer’s-like changes in these participants. 

Animal Studies Describe Roles of 

ApoE4 Protein

How the ApoE4 protein increases the brain’s susceptibility to Alzheimer’s disease remains unknown. We do 

know that as the protein circulates in the blood, it helps 

to regulate cholesterol levels and protect against vascular 

disease. ApoE is also produced in the brain, where it is 

involved in clearing away beta-amyloid as well as regulating the transport of cholesterol. Animal studies are 

also uncovering roles for ApoE and other proteins in the 

development and function of synapses, the tiny structures 

that connect neurons and enable them to communicate 

with each other. 

Scientists at Georgetown University in Washington, 

DC, and Duke University in Durham, NC, discovered 

abnormalities in the synaptic development in mouse 

models carrying the APOEε4 allele even before the mice 

 23 2010 Progress Report on Alzheimer’s Disease
reached puberty. Their neurons had fewer dendrites, the 

branch-like structures that receive messages from other 

neurons, than those of APOEε3 or APOEε2 model mice 

(Dumanis et al., 2009). This was associated with less synaptic activity in the amygdala, a brain region important 

for emotional memory (Klein et al., 2010). In both cases, 

the deficits were already evident at 1 month of age and 

progressed as the mice grew older. These studies suggest 

that while the impact of APOEε4 on cognition is not 

apparent until later in life, its presence may be harmful 

to the structure and function of neurons much earlier.

Conversely, the APOEε2 allele associated with 

decreased risk for Alzheimer’s in humans appears to promote synaptic development and, presumably, synaptic 

function in mice. The neurons of young APOEε2 mice 

had longer and more elaborate dendrites and as a result, 

more synaptic contacts than those of APOEε3 or 

APOEε4 model mice. 

The protein ApoE4 may impair synaptic plasticity, 

or the ability of synapses to weaken or strengthen connections to other synapses—a function critical to learning 

and memory. When investigators from the University of 

Texas Southwestern Medical Center added the protein 

to mice brain segments in the lab, it interfered with the 

usual chain of cellular responses critical to plasticity, 

including activity of the protein Reelin, which is involved 

in plasticity and neuronal function (Chen Y et al., 2010). 

It particularly affected LTP. This finding could explain 

the decline in synaptic function seen in both MCI and 

Alzheimer’s disease and suggests a possible target for 

therapeutic intervention. 

Genetic Counseling and 

Coping with Alzheimer’s 

People who have parents or siblings with Alzheimer’s 

disease often worry about their risk for developing the 

disorder. Some seek genetic testing for the APOEε4 riskfactor gene for late-onset disease. It is important to 

know how people understand and cope with their test 

results. In particular, scientists are interested in exploring 

a much-observed phenomenon: while people seem to 

understand and accurately remember what the clinician 

tells them about their test results, they still perceive their 

personal risk differently than it was reported to them. 

To identify potential sources of this disconnect, 

University of Michigan researchers studied 246 people 

who had undergone APOE testing and genetic counseling due a family history of the Alzheimer’s (Linnenbringer 

et al., 2010). They found that 6 weeks after learning 

their test results, 158 participants accurately recalled the 

risk estimates provided by the counselor, but nearly half 

of the group perceived their risk to be different than 

actually reported: 7 in 10 believed that their chances of 

developing Alzheimer’s disease were significantly higher, 

while 3 in 10 perceived their risk as lower than the value 

they’d been given. Notably, some 20 percent of ε4 allele 

carriers, those with the allele most linked to increased 

risk of Alzheimer’s, perceived a lower lifetime risk of 

developing the disease. 

WHAT IS LTP? 

LTP, or long-term potentiation, is a process used in research settings to 

stimulate by mechanical means the connections between neurons in slices of 

animal brains. LTP studies have shown that the stronger the connection, the better 

the neurons are able to relay messages across synapses. Researchers theorize 

that LTP may play a role in learning and memory, but this experimental 

model has yet to be proved in animals or humans. 

 24 2010 Progress Report on Alzheimer’s Disease
3Understanding the 

Biology of Alzheimer’s 

Disease

Understanding what biological processes go awry in 

Alzheimer’s disease is a key step toward developing treatments. Plaques and tangles are the most obvious postmortem hallmark of the disorder; brain imaging and 

biomarkers suggest that beta-amyloid is deposited early 

on in the disease, while tau accumulation occurs later. 

Research in 2010 offered new insights about how betaamyloid and tau act and interact to derail synaptic function and kill neurons. However, it has become increasingly 

clear that the abnormal deposits of these two proteins 

are not the only molecular culprits in Alzheimer’s. 

Scientists are chasing down other leads and finding out 

how each may aid and abet beta-amyloid and tau—

together or separately—in causing disease.

Investigating Changes in Brain Tissue

A brain damaged by Alzheimer’s is characterized by 

plaques, tangles, neuronal cell death, and degenerative 

changes in blood vessels. Other abnormal features 

associated with the disorder continue to be 

discovered and may provide new diagnostic 

markers and fresh insights into underlying mechanisms.

For example, studies of how 

Alzheimer’s changes brain structure have 

generally focused on gray matter, brain 

regions where neurons and dendrites are 

found. Deeper in the brain lies white 

matter, regions that contain large bundles 

of axons that connect neurons in one region of the brain 

with neurons in other regions. Because white matter 

degenerates in people with Alzheimer’s, researchers want 

to know how these changes might relate to changes in 

gray matter. 

 Researchers at the University of California, Berkeley, 

used diffusion tensor imaging to measure the integrity of 

axons in the white matter of 16 people who ranged from 

cognitively normal to those with dementia (Kuczynski et 

al., 2010). The images were then compared to FDG-PET 

scans showing changes in the participants’ brain glucose 

metabolism. Scientists found that white matter degeneration was linked to reduced metabolism in nearby regions 

of gray matter, an indicator of decline in neuronal health 

and function. This finding prompts the question: Do 

cells in gray matter degenerate first and then damage 

axons in white matter, or vice versa? Studies investigating 

white-matter metabolism are underway and may provide 

new insights into Alzheimer’s disease mechanisms.

 The accumulation of abnormal amounts of betaamyloid that occurs in Alzheimer’s could result from 

excessive production of the protein, impaired clearance 

from the brain, or both. Early-onset Alzheimer’s disease 

involves excess beta-amyloid production, but it is unclear 

whether the same is true for late-onset Alzheimer’s. 

Researchers at Washington University, St. Louis, developed 

a method to label beta-amyloid and monitor its turnover 

in real time in 12 people with Alzheimer’s and 12 cognitively normal people of the same age (Mawuenyega et al., 

2010). Similar rates of beta-amyloid production were 

seen in both groups. However, those with Alzheimer’s 

cleared beta-amyloid about 30 percent more slowly than 

those free of the disease. These data suggest that sluggish 

clearance of beta-amyloid for a decade or more may 

WHAT IS PIB IMAGING?

Researchers can detect abnormal deposits of amyloid protein in the brain by using 

positron emission tomography (PET) imaging and a tracer, Pittsburgh Compound B (PiB), 

a radioactive agent specially developed to detect levels of beta-amyloid in the living brain.

 25 2010 Progress Report on Alzheimer’s Disease
contribute to its accumulation in late-onset Alzheimer’s. 

This finding is of particular interest, as most amyloidrelated therapies in development so far have targeted production rather than clearance.

Brain Amyloid: Is It Ever Benign?

The advent of PiB imaging brought with it the surprising finding that many cognitively normal older people 

carry substantial loads of brain amyloid. Is it possible 

that some people are relatively resistant to the accumulation of brain amyloid and, despite accumulating it, 

never develop problems with cognitive function?

The answer to that question seems to be a qualified 

“no.” Researchers at Washington University, St. Louis, 

used PiB imaging to look at 159 cognitively normal people with a mean age of 72 and then tested their cognition 

for up to 5 years (Morris et al., 2010). Those with higher 

amounts of beta-amyloid on their initial PiB scans were 

significantly more likely to develop Alzheimer’s symptoms 

than those who showed little or none. 

An NIA-led study found similar results, using PiB 

imaging to examine 57 people (average age 79) who had 

undergone annual cognitive testing for the previous 8 to 

12 years (Resnick et al., 2010). All had been cognitively 

normal when they first entered the study but had shown 

varying degrees of cognitive decline during the subsequent years. PiB scanning showed that the participants 

with higher brain beta-amyloid levels had also experienced greater losses in cognition and memory during the 

years prior to their scans.

Finally, a Washington University study of 68 cognitively normal older people and 35 people with Alzheimer’s 

used PiB imaging as well as functional MRI (fMRI), 

which looks at brain function while doing tasks (Sheline, 

Morris et al., 2010). Even the cognitively normal people 

with elevated beta-amyloid levels showed reduced connectivity among brain cells in the default-mode network 

(brain areas used when the mind “wanders,” such as when 

daydreaming or retrieving memories), compared to individuals with low beta-amyloid. In fact, the disruptions of 

default-mode network connectivity seen in the cognitively 

normal participants were similar to those of the people 

with Alzheimer’s disease. Together, these studies suggest 

that beta-amyloid accumulation signals the presence of 

preclinical Alzheimer’s, even in people free of symptoms.

At the same time, however, evidence shows that some 

people seem better able to bear the burden of beta-amyloid 

accumulation than others, despite the likelihood of 

advancing disease. For some time, scientists have thought 

this might be due to “cognitive reserve,” or an ability of 

the brain to function effectively despite loss of brain cells 

or other damage. A number of studies have suggested that 

higher levels of education and intelligence (as measured 

on standardized tests) contribute to cognitive reserve and 

confer some protection against Alzheimer’s disease. 

Those factors also appear to moderate the effect of 

beta-amyloid on cognitive function. Researchers at 

Harvard University, Cambridge, MA, found higher betaamyloid levels were associated with worse performance 

on tests of memory, language, vision, and navigation in 

a study of 66 cognitively normal older people and 17 

with Alzheimer’s (Rentz et al., 2010). However, elevated 

beta-amyloid levels had a weaker effect on cognitive 

function in people who were more highly educated and 

scored higher on an intelligence test. 

Additional reference:

Lachman ME et al. (2010) Frequent cognitive activity compensates for education differences in episodic memory. Brandeis 

University. Supported by NIA.

Imaging “Normal” Brain Aging

Distinctions between age-related cognitive change and 

change caused by Alzheimer’s and other dementias 

remain an area of debate and intensive research. 

Dementias are marked by notable declines in cognitive 

function that reflect underlying brain disease, such as the 

accumulation of abnormal amounts of plaque and tangles seen in Alzheimer’s. Age-related cognitive decline, 

however, can be more subtle, gradual, and not associated 

with significant impairments in everyday function. 

It is unclear to what extent Alzheimer’s-related brain 

changes may also contribute to “normal” brain aging, 

especially since PiB imaging has revealed beta-amyloid 

deposits in a substantial percentage of cognitively normal older people. Indeed, prior to the availability of 

amyloid imaging, it was impossible to know how many 

of the older people who participated in previous studies 

of “normal” aging had some cognitive decline due to the 

early stages of Alzheimer’s or other dementias. 

To address this question, researchers at Rush 

Alzheimer’s Disease Center, Chicago, did a postmortem 

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 26 2010 Progress Report on Alzheimer’s Disease
study of 354 older Catholic nuns, priests, and brothers. 

The participants had annual clinical and cognitive evaluations starting in 1994 as part of the Religious Orders 

Study (Wilson, Leurgans, et al., 2010). The scientists 

found a pattern of gradual age-related cognitive decline, 

followed by more precipitous decline in the last few 

years before death (mean age 87). Postmortem findings 

associated brain tangles and Lewy bodies (pathologies 

seen in Alzheimer’s and Lewy body dementia) with the 

final stage of decline. Even during the gradual phase of 

decline, however, some people had significant brain 

pathology, including tangles, evidence of small or large 

strokes, and Lewy bodies. 

Importantly, those participants who remained cognitively normal to the end had no signs in their brains of 

Alzheimer’s or Lewy body pathology. These observations 

suggest that neurodegeneration may play a role in the 

cognitive decline that is often seen in later life. Research 

is helping us to understand not only the specific effects 

of various brain changes on cognition, but also the factors that may aid in maintaining normal cognition 

despite the presence of pathology. 

Cellular Changes in 

Alzheimer’s Disease

Calcium Imbalance in Neurons

Scientists have known since 1995 that two gene mutations—presenilin-1 and presenilin-2—cause early-onset 

Alzheimer’s disease, but exactly how is unclear. Because 

abnormal presenilin proteins are involved in a cascade of 

events that eventually results in amyloid plaques, previous 

research has focused on that aspect of presenilin function. 

However, presenilin mutations also disturb the calcium 

balance in neurons. Researchers at the University of Texas 

Southwestern Medical Center, Dallas, have now linked 

this phenomenon to the development of Alzheimer’s-like 

pathology in mice (Zhang, Sun, et al., 2010). 

The researchers studied cultured hippocampal and 

other brain cells from mouse models with a mutant form 

of the human presenilin gene. Disabling the presenilin 

function caused calcium to build up inside the hippocampal cells and prevented the slow release of calcium that is 

necessary for the health of the cell. In further testing, the 

researchers blocked other channels the cells might use to 

release calcium so that the cells could not find other ways 

to compensate for presenilin dysfunction. This made the 

Alzheimer’s-like pathology even worse. These results 

unveil a new mechanism explaining how presenilin 

mutations might lead to the disease. They also suggest 

that calcium imbalance in neurons may fuel beta-amyloid accumulation and the onset of Alzheimer’s. 

Additional references:

Gleichmann M et al. (2012). Molecular changes in brain aging 

and Alzheimer’s disease are mirrored in experimentally silenced 

cortical neuron networks. Supported by NIA.

Yang L et al. (2009). Amyloid precursor protein regulates 

Cav1.2 L-type calcium channel levels and function to influence 

GABAergic short-term plasticity. Baylor College of Medicine. 

Supported by NIA.

How Tau Tangles with Neurons 

Tangles and other abnormal forms of tau protein accumulate inside the brain cells of people with Alzheimer’s. 

Together with beta-amyloid, they contribute to neurodegeneration. Tangles were long considered the toxic 

form of tau protein, but increasing evidence points to 

abnormal forms of soluble tau as more likely suspects. In 

healthy neurons, soluble tau is concentrated in axons and 

less abundantly in cell bodies and dendrites. In studying 

mouse neurons expressing either normal or mutant 

forms of tau, University of Minnesota, MinneapolisSt. Paul, researchers found that mutant tau ignores its 

usual cellular boundaries and strays into dendrites, 

where it accumulates inside spines and interferes with 

the ability of synapses to communicate via chemical 

messengers and receptors (Hoover et al., 2010). 

The scientists further discovered that mutant tau’s 

movement into dendrites results from excessive (hyper) 

phosphorylation of the protein. Phosphorylation is a 

process cells often use to regulate a protein’s function or 

level of activity. Less heavily phosphorylated forms of 

tau stayed out of dendrites; heavily phosphorylated 

forms penetrated them more extensively. These findings 

support other studies pointing to hyperphosphorylated 

forms of tau as culprits in Alzheimer’s disease, and suggest that their toxic effects result in part from disruption 

of the brain cell’s ability to signal other neurons. 

Normal as well as mutant forms of tau may contribute to neurodegeneration. For example, in Alzheimer’s 

model mice that accumulate high levels of beta-amyloid, 

lowering tau levels can reduce damage to brain cells. 

What role does tau plays in disease progression? 

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 27 2010 Progress Report on Alzheimer’s Disease
A University of California, San Francisco-led study suggests that tau offers beta-amyloid a foothold in the disruption of axonal transport, a process by which neurons 

move no longer needed fats, proteins, and other cell 

parts down their axons and away from the cell body. 

They looked at how the process differed between cultures of brain cells of normal mice and mice whose tau 

levels had been reduced or removed. They found the 

transport of certain cell parts were similar in both normal and tau-deficient neurons—at least until betaamyloid was added to the mix. With beta-amyloid, the 

percentage of cell parts being transported dropped by 

almost half in the normal neurons, but was unchanged 

in the neurons with reduced tau levels. These results 

indicate tau interacts with beta-amyloid during axonal 

transport and may play a role in the toxic effects of 

Alzheimer’s disease (Vossel, 2010).

Additional reference:

Luebke JI et al. (2010) Dendritic vulnerability in neurodegenerative disease: insights from analyses of cortical pyramidal 

neurons in transgenic mouse models. Boston University School 

of Medicine. Supported by NIA, NIDCD, and NIMH.

Mitochondria and Energy Disruption 

Mitochondria are the parts of the cell that use oxygen to 

produce energy for the cell via a chemical process. The 

mitochondria are highly mobile; pushed and pulled by 

proteins, they travel along a network of protein rods that 

connect various parts of the cell. Disruption of energy 

production can be disastrous for cells, as activities grind 

to a halt without the energy supplied by mitochondria. 

Abnormal accumulation of beta-amyloid around 

neurons may impair mitochondria involved in cell-tocell communications between synapses. Researchers at 

Columbia University, New York City, studying 

Alzheimer’s model mice found that beta-amyloid is also 

deposited inside synaptic mitochondria, and that the 

deposits increased with age (Du, Guo, et al., 2010). 

Synaptic mitochondria showed impaired energy production, increased vulnerability to damage by calcium, and 

earlier signs of distress. The scientists also found that 

low concentrations of beta-amyloid added to mouse 

neurons in culture slowed the movement of mitochondria up and down axons and decreased their size. 

n

Mitochondrial size was also decreased in neurons treated 

with beta-amyloid. The findings suggest that synaptic 

mitochondria appear especially sensitive to injury by 

beta-amyloid, and their dysfunction may be an early 

step in the Alzheimer’s disease process.

Injury to synaptic mitochondria caused by betaamyloid may also negatively impact their ability to respond 

to neurotransmitters, or chemical messengers, in the 

brain. An Emory University, Atlanta, study showed that 

beta-amyloid added to neurons in culture could disrupt 

the movement of energy-vital mitochondria into dendritic spines, a process necessary to stimulate synapses 

and communication (Rui et al., 2010). At the same time, 

a type of neurotransmitter receptor—AMPA, which is 

important to memory formation—failed to function 

normally. The scientists examined several hundred individual spines and found that spines lacking mitochondria 

were the same ones that had lost their supply of AMPA 

receptors. Treating neurons with a compound known to 

block beta-amyloid suppression of mitochondrial transport reversed this loss. These findings suggest that synaptic mitochondria may be essential for supporting the 

ongoing supply of AMPA receptors to synaptic membranes, and that function is disrupted by beta-amyloid.

Sometimes cells release free radicals, a molecule 

(typically oxygen or nitrogen) that can cause damage. 

While cells maintain complex systems of antioxidants 

(molecules that block free radicals), a buildup of free radicals may result in a condition known as “oxidative stress.” 

A Baylor College of Medicine, Houston, study suggests 

that mitochondria may be a major source of the free radicals that cause the oxidative stress typically found in 

Alzheimer’s disease (Massaad et al., 2010). The scientists 

developed an Alzheimer’s disease mouse model that 

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 28 2010 Progress Report on Alzheimer’s Disease
produces extra high levels of superoxide dismutase-2 

(SOD-2), an enzyme that specifically scavenges free radicals produced by mitochondria. Ramping up the levels of 

this enzyme reversed two Alzheimer’s disease-like factors—

impaired blood flow in the brain and impaired communication between axons. This study points to free radicals 

from mitochondria as a major influence in Alzheimer’s disease, and suggests that antioxidants specifically targeting 

them might be explored as possible therapeutics.

Nerve cells use glucose as their main energy source; 

mitochondria are responsible for converting glucose to 

energy. When mitochondrial function declines, the 

function of nerve cells declines, and they are forced to 

shift to less efficient fuel sources. One factor that may 

aggravate this decline in mitochondrial function and 

brain metabolism could be the loss of estrogen experienced during menopause, according to a University of 

Southern California, Los Angeles, study of female mice 

(Yao et al., 2010). 

The researchers found that the brains of postmenopausal but cognitively normal mice indicated a shift 

from glucose to alternative energy sources, resembling 

those of premenopausal Alzheimer’s model mice. 

Meanwhile, the early metabolic changes occurring in 

Alzheimer’s model mice accelerated even further after 

menopause. These results expand upon previous evidence 

that estrogen supports mitochondrial use of glucose as a 

primary energy source and suggest that loss of this support may underlie the increased risk for Alzheimer’s disease in menopausal women. They are also consistent 

with new evidence from human studies that there may 

be a critical “window of opportunity” around the time 

of menopause when estrogen therapy may be of cognitive benefit. See Hormones and Cognitive Health in 

Postmenopausal Women, page 47.

Additional references:

Crews L et al. (2010) Increased BMP6 levels in the brains of 

Alzheimer’s disease patients and APP transgenic mice are accompanied by impaired neurogenesis. University of California, San 

Diego. Supported by NIA.

Du H, Yan SS. (2010) Mitochondrial permeability transition 

pore in Alzheimer’s disease: cyclophilin D and amyloid beta. 

Columbia University College of Physicians and Surgeons. 

Supported by NIA.

Gleichmann M et al. (2012) Molecular changes in brain aging 

and Alzheimer’s disease are mirrored in experimentally silenced 

cortical neuron networks. National Institute on Aging. 

Supported by NIA.

n

n

n

Iijima-Ando K et al. (2009) Mitochondrial mislocalization 

underlies Abeta42-induced neuronal dysfunction in a Drosophila 

model of Alzheimer’s disease. Thomas Jefferson University, 

Philadelphia. Supported by NIA.

Sametsky EA et al. (2010) Synaptic strength and postsynaptically silent synapses through advanced aging in rat hippocampal 

CA1 pyramidal neurons. Northwestern University Feinberg 

School of Medicine. Supported by NIA.

4Determining Risk 

Factors for Alzheimer’s 

and Cognitive Decline

Unlike age and genetics, we potentially can control certain biological and lifestyle factors associated with higher 

risk of dementia. Scientists are exploring prevention 

strategies to determine whether or not mental stimulation, exercise, and dietary supplements can delay or 

reduce the severity of age-related decline or the onset and 

progression of disease. Additionally, scientists are investigating how certain medical conditions, such as high cholesterol, high blood pressure, and diabetes, influence risk 

for cognitive decline and Alzheimer’s disease. 

In April 2010, the NIH convened a State-of-theScience Conference on Preventing Alzheimer’s Disease 

and Cognitive Decline to review the available scientific 

evidence and to hear public comment on prevention 

research. The independent panel of experts charged with 

this review found that currently no conclusive scientific 

evidence supports the use of drugs, dietary supplements, 

or interventions like exercise to reduce risk for the disorder. In its suggestions for areas for scientific exploration, 

the panel cited promising areas of study, such as ongoing 

clinical trials testing the usefulness of blood pressure medications, omega-3 fatty acids, physical activity, and cognitive engagement. Many of these interventions are being 

actively pursued by NIH-funded investigators. To read 

the panel’s final statement and view archived video of the 

conference, go to http://consensus.nih.gov/2010/alz.htm.

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 29 2010 Progress Report on Alzheimer’s Disease
Links Between Cardiovascular Disease 

and Cognitive Decline

Research shows that cerebrovascular disease is a major 

player in age-related cognitive decline, and that many 

older people suffer from cerebrovascular disease in addition to Alzheimer’s. Some evidence suggests that atherosclerosis, or the buildup of cholesterol and other fatty 

materials within blood vessel walls, may contribute to 

the Alzheimer’s disease process. If so, perhaps improved 

control of atherosclerosis could be one way to reduce 

Alzheimer’s risk. 

Johns Hopkins University, Baltimore, researchers 

examined the relationship between atherosclerosis, 

Alzheimer’s pathology (abnormal deposits of plaques 

and tangles), and dementia in a postmortem study of 

200 participants from the NIA’s Baltimore Longitudinal 

Study of Aging (Dolan et al., 2010). Cognitively normal 

at the beginning of the study, each participant received 

medical evaluations and cognitive testing for an average 

of 8.7 years prior to their deaths. While the researchers 

found no correlation between the presence of atherosclerosis, cerebral mini-strokes, and levels of Alzheimer’s 

pathology—plaques and tangles—in the brains of these 

individuals, they observed a significant relationship 

between atherosclerosis and dementia found by cognitive testing. Atherosclerosis of brain blood vessels was 

calculated to be responsible for 34 percent of the 

dementia seen in this group. This study suggests that 

reducing one’s exposure to atherosclerosis risk factors, 

such as high cholesterol, diabetes, and smoking, could 

be one strategy for reducing risk of dementia. 

Heart disease is common in people over age 65. To 

determine whether there is a relationship between heart 

function and cognitive aging, researchers at the 

Framingham Heart Study in Framingham, MA, examined the connection between heart health and brain volume in 1,504 participants, average age 61 (Jefferson et 

al., 2010). They assessed heart health using the cardiac 

index, which looks at how much blood the heart pumps 

per unit of body surface area. Comparing cardiac indexes 

with brain volumes measured by MRI, the researchers 

found that people with lower cardiac indexes, those 

pumping less blood, were more likely to have reduced 

brain volumes, suggesting they had accelerated brain 

aging. This correlation was seen even among individuals 

who did not have clinically evident heart failure. The 

results suggest that inadequate pumping of blood to the 

brain could lead to neurodegenerative changes and eventual cognitive decline. Longer-term studies are needed to 

learn whether people with reduced cardiac function do, 

in fact, have faster rates of cognitive decline. 

Additional reference:

Iadecola C. (2010) The overlap between neurodegenerative and 

vascular factors in the pathogenesis of dementia. Weill Cornell 

Medical College. Supported by NHLBI and NINDS.

Physical Frailty and Cognitive Decline

The physical weakness that often accompanies old age is 

considered a risk factor for Alzheimer’s disease. Physical 

frailty may also increase risk of developing MCI, according to a Rush Alzheimer’s Disease Center, Chicago, 

study (Boyle et al., 2010). Researchers followed 750 

older people from 40 retirement communities in the 

Chicago metropolitan area, all of whom were cognitively 

normal at the start of the study. Individuals who were 

more physically frail, as indicated by lower grip strength 

and slower walking speed, were significantly more likely 

to develop MCI over the next 12 years. Together with 

prior studies showing an association between frailty and 

Alzheimer’s, these data suggest examining whether there 

may be common disease mechanisms underlying physical frailty and cognitive impairment. In addition, measures of physical frailty may help identify people likely 

to develop MCI and who might benefit from interventions to maintain cognitive function.

Exercise and Maintaining 

Cognitive Health

Many observational studies associate physical exercise 

with successful cognitive aging. Now, a University of 

California, San Francisco-led epidemiological study suggests that regular exercise during teenage years might be 

even more effective in boosting cognitive health in old 

age than exercise in later years (Middleton et al., 2010). 

Researchers had 9,344 women aged 65 and older (average age 71.6) report their levels of physical activity as 

n

 30 2010 Progress Report on Alzheimer’s Disease
teenagers, at ages 30 and 50, and in late life. Overall, 

women who were physically active at any age were 

found to have better cognitive performance and less risk 

of cognitive impairment in late life than those who were 

inactive. Those who said they had exercised as teenagers 

had the best outcomes of all.

Importantly, exercise at any age proved beneficial: 

Even women who were sedentary teenagers but became 

more active later had better cognitive function in late 

life. These findings may suggest that physical activity in 

early life and ideally throughout life may help reduce 

risk of age-related cognitive decline.

Brain-derived nerve growth factor (BDNF), a protein 

produced by brain cells, is essential for both early brain 

development and healthy brain function in adulthood. 

BDNF is highly concentrated in the hippocampus, 

where it supports synaptic plasticity and promotes the 

generation of new neurons. But serum levels of BDNF 

decline with age. A University of Illinois at UrbanaChampaign study suggests that loss of circulating BDNF 

may contribute to age-related cognitive decline 

(Erickson, Prakash, et al., 2010). In a group of 142 older 

adults without dementia, increasing age was associated 

with reduced levels of serum BDNF, smaller hippocampal volumes, and poorer memory performance. Exercise 

can increase BNDF levels in humans and also has been 

linked to larger hippocampal volumes and better cognitive function in old age (Middleton et al., 2010). This 

result suggests that the beneficial effects of exercise on 

brain function may be gained through its effect on BDNF.

The Role of Diet in Maintaining 

Cognitive Health 

Cholesterol Levels and Risk for Alzheimer’s

High cholesterol levels during midlife have been linked to 

increased risk of developing Alzheimer’s disease. University 

of Arizona, Phoenix, researchers used PET imaging to 

look at potential links between cholesterol levels and brain 

metabolism, or the ability of the brain to use oxygen and 

glucose (Reiman et al., 2010). Brain scans of 117 cognitively normal people aged 53 to 65 showed the brains of 

people with high cholesterol levels were less efficient in 

using oxygen and glucose, especially in areas affected by 

normal aging and Alzheimer’s disease. This deficit was 

more pronounced in carriers of APOEε4. This research 

suggests that cholesterol may interact with certain 

Alzheimer’s risk factors (including ApoE4, a cholesterol 

transporter) to increase disease risk, and may also accelerate brain changes that accompany normal aging. This 

study also points to the potential use of brain scans that 

measure metabolism as both a way to both predict risk for 

Alzheimer’s in people free of symptoms and to track the 

effectiveness of treatments in clinical trials. 

What Animal Studies Say About 

“Good” Cholesterol

Apolipoprotein A-1 (ApoA-1) is the main component 

of high-density lipoprotein (HDL, known as “good” 

cholesterol). Higher levels of HDL and ApoA-1 are associated with reduced risk for Alzheimer’s. Studies from 

the University of Pittsburgh and University of Illinois, 

Chicago, suggest that ApoA-1 may prevent the disease 

by protecting the health of the brain’s blood vessels. 

In Alzheimer’s, abnormal amounts of beta-amyloid 

accumulate not only around brain cells but in the walls 

of cerebral blood vessels, leading to impaired cerebral 

blood flow neuronal function. University of Pittsburgh 

researchers created an Alzheimer’s disease mouse model 

that lacks the gene for ApoA-1. Compared to Alzheimer’s 

mouse models with an intact ApoA-1 gene, these “knockout” mice developed more significant memory deficits 

(Lefterov et al., 2010). Examination revealed both models had similar amounts of beta-amyloid deposited in 

their brains, but the knockout mice had more in the 

walls of blood vessels. The beta-amyloid accumulation 

in the vessel walls destroyed the smooth muscle cells that 

line blood vessels and inhibited their ability to contract 

and expand and propel blood. 

In a complementary study, University of Illinois, 

Chicago, researchers created Alzheimer’s model mice 

that overproduced human ApoA-1 and, as a result, twice 

as much “good” cholesterol HDL (Lewis et al., 2010). 

These mice continued to perform well on tests of learning and memory during aging and showed significantly 

less beta-amyloid accumulation around their blood 

vessels compared to normal mice. Together, these two 

studies suggest that ApoA-1 may benefit cognitive 

health, in part by preventing and inhibiting the toxic 

effects of beta-amyloid on brain blood vessels. 

 31 2010 Progress Report on Alzheimer’s Disease
What Animal Studies Say About 

High Fat/Carbohydrate Diets

Saturated fats and refined carbohydrates (such as white 

sugar) are the main ingredients contributing to weight 

gain in the modern Western diet. These dietary factors 

also have been associated with cognitive dysfunction 

and/or increased risk of Alzheimer’s. To learn more 

about how dietary factors affect brain function, scientists 

at Purdue University, West Lafayette, IN, fed rats a 

high-energy diet similar to the one found in Western 

cultures—high in fats and simple carbohydrates 

(Kanoski et al., 2010). The results showed that rats fed 

this high-energy diet for 90 days performed significantly 

worse on certain memory tests compared to rats fed a 

diet containing one-third the fat. 

Notably, the rats scored poorly on learning and 

memory tests that require the hippocampus. When the 

scientists examined the brains of these rats, they found 

evidence of a breakdown of the blood-brain barrier 

(BBB) that protects the hippocampus. (The BBB is 

composed of specialized, protective cells that prevent 

most molecules and bacteria circulating in the blood 

from entering and injuring the brain.) Because damage 

to the BBB was not seen in other regions of the rats’ 

brains, it appeared that the cells of the BBB surrounding 

the hippocampus were particularly vulnerable to injury 

as a result of the high-energy diet. 

Insulin is a hormone that helps glucose (blood 

sugar) get into the cells, where it is used as fuel to produce energy. There is growing evidence from human 

studies that type 2 diabetes, in which a person is deficient in or resistant to insulin, is associated with 

increased risk for Alzheimer’s. This is not surprising 

given that insulin plays a role in several molecular processes involved in cognitive function. 

Researchers at Yale University in New Haven, CT, 

showed that delivery of insulin to the hippocampus in 

rodents enhanced memory performance; conversely, 

blocking insulin function in the hippocampus impaired 

memory performance (McNay et al., 2010). Insulin 

delivery into the hippocampus also stimulated local glucose uptake, suggesting that insulin supports memory by 

generating extra fuel for hippocampal nerve cells. Rats 

with diabetes symptoms fed a high-fat diet exhibited 

impaired memory performance compared to rats fed a 

standard diet. The “diabetic” rats were also resistant to 

the memory-enhancing and metabolism-boosting benefits of insulin delivered into the hippocampus. These 

results suggest that impaired delivery and uptake of 

insulin in the brain may contribute to age-related cognitive decline and increased risk for Alzheimer’s.

Additional reference:

Dieckmann M et al. (2010) Lipoprotein receptors—an evolutionarily ancient multifunctional receptor family. University of 

Texas Southwestern Medical Center. Supported by NHBLI.

Obesity and Risk for Cognitive Decline

Several human studies have found that being overweight 

or obese during midlife is associated with reduced cognitive function, markers of brain degeneration, and 

increased risk of Alzheimer’s disease later in life. A 

University of California, San Francisco, team discovered 

that older individuals with an elevated body mass index 

(BMI, a measure of body fat based on height and weight) 

show metabolic changes in the brain (Gazdzinski et al., 

2010). The researchers used a specialized brain scanning 

technique, proton resonance spectroscopy, to measure levels of N-acetyl-aspartate (NAA), a molecule that reflects 

metabolic activity of neurons. They found that cognitively 

normal older people with higher BMIs have lower levels 

of NAA compared to older people with a normal BMI. 

While NAA functions are still poorly understood, reduced 

levels are thought to signal problems in neuronal metabolism and loss of dendrites and axons. 

Additional reference:

de la Monte SM et al. (2010) Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. Rhode 

Island Hospital. Supported by NIAAA.

Vitamin D and Brain Health As We Age

A significant number of older people in the United 

States and Europe living in the community may have 

vitamin D deficiencies, studies show. To determine if 

vitamin D plays a role in cognitive health, NIA investigators and an international team of researchers followed 

a group of 858 people age 65 or older living in Tuscany, 

Italy (Llewellyn et al., 2010). During the 6-year study, 

subjects who were severely deficient in vitamin D 

experienced significantly faster rates of cognitive decline 

than those with adequate levels. This finding adds to 

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 32 2010 Progress Report on Alzheimer’s Disease
emerging evidence that vitamin D may be important for 

brain health and function and may protect neurons 

from damage. Future clinical trials could tell us more 

directly about the importance of vitamin D, which can 

be obtained through the diet or sensible sun exposure, 

in preventing age-related cognitive decline.

Caregiver Stress and Cognitive Health 

Spouses often take on much of the burden and stress of 

caring for loved ones with dementia in a system of 

“informal,” or unpaid, care. Now, a University of Utah, 

Salt Lake City, study suggests that this type of caregiving 

also may contribute to the caregiver’s own risk of 

dementia (Norton et al., 2010). The researchers studied 

a group of 1,221 married couples aged 65 or older, in 

which both partners were free of dementia at the start of 

the study and lived together at home. Compared with 

individuals whose spouses remained dementia-free, 

people whose spouses were diagnosed with dementia 

were at six times greater risk of developing dementia 

within an average of 4 years following the diagnosis. 

This correlation was not influenced by how long the 

couple had been married, and husbands had a nearly 

three-fold greater risk of dementia than their wives. 

Further research should help determine whether the 

chronic and often severe stress associated with dementia 

caregiving is a major risk factor for the development of 

dementia in spouse caregivers. 

Aging Animals, Stress, and Cognition

Older brains seem less resilient to stress than younger 

ones, and exposure to stress may accelerate cognitive 

aging. Rockefeller University, New York City, researchers 

found that the brains of older rats self-repair less readily 

after stress (Bloss et al., 2010). In both young and old 

confined rats, stress caused degenerative changes in an 

area of the brain vulnerable to aging—the prefrontal 

cortex, which is vital to planning and decision making. 

Immediately after a period of stress, the rat brains revealed 

withered dendrites, with a loss of 20 percent of their 

branches. By the end of a post-stress recovery period, the 

dendrites of young rats had returned to their normal 

lengths and branch numbers, but the dendrites of old rats 

had not. These observations suggest that neuronal resilience to stress may be lost with age. Certain interventions, 

including exercise and exposure to more interesting environments, have been found to improve neuronal resilience 

in aged rodents and might be further explored in humans.

5Developing 

New Treatments

The prevalence of Alzheimer’s disease is expected 

to rise with the aging of the population, increasing the 

urgency to develop new therapies to treat, delay, and, ultimately, prevent the disease. Drugs currently used in treatment include cholinesterase inhibitors and memantine, 

both of which help support neurotransmitters important 

to memory function. These drugs provide symptomatic 

relief and may slow symptoms of cognitive decline for 

some people for a limited amount of time. But because 

they do not target underlying molecular pathways 

believed to be involved in Alzheimer’s, they neither halt 

nor reverse progression of the disease. 

Translational research is a multidisciplinary, multistep process that uses basic science discoveries to develop 

medicines or other interventions that improve human 

health. The process of discovering and developing new 

View a brief video of the NIA’s 

Dr. Suzana Petanceska on the goals and 

challenges of translational research.

 33 2010 Progress Report on Alzheimer’s Disease
drugs for neurological disorders like Alzheimer’s is 

extremely challenging and expensive. It takes 10 to 15 years 

from the discovery of a new therapeutic target until a new 

drug reaches the market, with an average cost of about 

$1.8 billion (Paul et al., 2010). 

Intensive efforts are underway in translational research 

to identify and test therapies that interfere with a variety of 

disease processes involved in the development of Alzheimer’s. 

A range of disease pathways are being explored, from 

Alzheimer’s-related abnormal deposits of amyloid and tau 

proteins to the potentially protective roles played by growth 

factor molecules. The NIA supports several innovative programs that foster the preclinical drug development and 

testing of novel compounds described in this section (see 

Advancing the Future of Alzheimer’s Research, page 60). At 

the same time, the NIA is putting new interventions to 

the test by supporting and conducting human clinical trials (see Testing Therapies to Treat, Delay, or Prevent 

Alzheimer’s Disease, page 43). 

Beta-Amyloid Directed Therapies

Efforts to design drugs targeting beta-amyloid have been 

hindered by uncertainty as to exactly which form or 

forms of the protein are toxic to neurons—single fragments called monomers, combinations of two or more of 

the monomers, or still larger groups of fragments, known 

as aggregates, that eventually form plaques. Researchers 

at the Broad Institute, Cambridge, MA, sought to move 

beyond this issue by developing a new method for 

screening molecules based simply on their ability to bind 

beta-amyloid monomers (Chen J et al., 2010). They reasoned that regardless of which form of beta-amyloid is 

toxic, any compound that could block its toxicity would 

first have to bind to the protein. The researchers prepared 

small-molecule microarrays—glass slides onto which 

they bound spots of thousands of different chemical 

compounds—and then applied fluorescently labeled 

beta-amyloid to the slides to track where the betaamyloid latched onto specific spots. In a screen of close 

to 20,000 compounds, researchers found 79 that bound 

beta-amyloid; one of these, compound 2002-H20, significantly reduced beta-amyloid toxicity.

Beta-amyloid plaque production involves the cleavage, or cutting, of the larger amyloid precursor protein 

by two enzymes, beta-secretase and gamma-secretase. 

While scientists have developed a number of compounds 

that can block gamma-secretase, completely blocking the 

enzyme could have negative side effects since it is 

involved in the processing of many cellular proteins. 

Researchers at Torrey Pines Therapeutics, La Jolla, CA, 

and Memorial Sloan Kettering Cancer Center, New 

York City, looked for “hits” that would block betaamyloid production without affecting gamma-secretase’s 

cleavage of Notch, a protein important to gastrointestinal health (Kounnas et al., 2010).

The researchers screened more than 80,000 compounds to develop a drug candidate to test. Named 

“Compound 4,” the drug was 1,000 to 10,000 times 

more potent than tarenflurbil (a leading beta-amyloid 

buster) in blocking beta-amyloid production by cells in 

culture. The researchers fed Compound 4 to Alzheimer’s 

model mice for 29 weeks starting at 8 months of age, 

when beta-amyloid plaques were just starting to accumulate. Compared to the brains of control mice, which 

were loaded with beta-amyloid plaque, the drug reduced 

the load two- to three-fold in the treated group. The 

treated mice were also free of gastrointestinal lesions, 

showing that Compound 4 did not inhibit the positive 

role played by gamma-secretase.

The prevalence of Alzheimer’s disease is expected to 

rise with the aging of the population, increasing the urgency to 

develop new therapies to treat, delay, and, ultimately,

prevent the disease.

 34 2010 Progress Report on Alzheimer’s Disease
Identifying New Therapeutic Targets

The search for new drugs begins with the identification of 

new therapeutic targets. Each year, NIA-funded researchers 

discover new molecular players in the Alzheimer’s disease 

process that are potential therapeutic targets. As research 

on anti-beta-amyloid therapies progresses, there is increasing interest in identifying other possible targets for drug 

development. After beta-amyloid, the next “most wanted” 

protein is tau, the focus of a number of drug development 

efforts. Other new molecular suspects in the Alzheimer’s 

disease process continue to be identified, and some show 

particular promise as drug targets. 

Tau and Tau-Related Targets

Like many proteins, tau may undergo extensive chemical 

processes during its lifetime inside the cell, the most 

prominent of which is phosphorylation—the addition of 

a phosphate group that may switch on or off certain 

enzymes or receptors. This process can run amok. Tau 

that is too heavily phosphorylated is toxic to neurons, 

tends to clump together and form tangles, and may 

contribute to neurodegeneration in Alzheimer’s disease. 

Researchers have focused on blocking this tau hyperphosphorylation. Now, other cellular mechanisms of tau 

processing are being uncovered and could provide alternative targets for drug development. 

A team at the Gladstone Institute of Neurological 

Disease/University of California, San Francisco, has discovered that in addition to tau phosphorylation, a process 

called acetylation (the adding of an acetyl group, usually 

an acid, into a compound) may contribute to tau damage 

to neurons (Min et al., 2010). Specifically, acetylation 

appears to block the cell’s ability to destroy worn-out tau 

molecules, so that toxic forms of tau pile up in the cell. 

Moreover, increased tau acetylation was seen in neurons 

treated with beta-amyloid and in postmortem human 

brains with tau pathology (for example, hyperphosphorylated tau accumulation and tangles). Finally, the researchers identified a brain enzyme, SIRT-1, that can remove 

acetyl groups from tau. Interestingly, studies this year 

revealed additional mechanisms whereby SIRT-1 appeared 

to protect cognitive health, making this enzyme a particularly enticing target for drug development.

Sometimes, the process of folding and packaging 

proteins fails, resulting in a misfolded or misshapen protein that can damage the cell. However, cells have a 

quality control mechanism called the unfolded protein 

response (UPR) that can detect and remove misfolded 

proteins. The cell then resets its protein making machinery. The UPR mechanism is overly active in the brains of 

people with Alzheimer’s, perhaps as the brain’s response 

to the abnormal accumulation of misfolded proteins. 

Harvard University, Cambridge, MA, researchers 

studying a fruit fly model found that increasing tau 

expression activated the UPR mechanism and that 

highly mutant forms of tau further increased UPR activity (Loewen and Feany, 2010). This finding suggests 

that the UPR mechanism can protect cells from tau 

neurotoxicity, and that its activation could be explored 

as a new therapeutic avenue in Alzheimer’s disease.

Additional reference:

Ballatore C et al. (2010). Discovery of brain-penetrant, orally 

bioavailable aminothienopyridazine inhibitors of tau aggregation. 

University of Pennsylvania. Supported by NIA.

STEP61 Enzyme

Increasing evidence suggests that disruption of the protein recycling and degradation pathways, which are critical 

to the health of neurons, may contribute to Alzheimer’s 

disease. A Rockefeller University, New York City, study 

suggests that beta-amyloid disrupts synaptic function in 

the hippocampus by blocking the degradation of the 

enzyme STEP61 (Kurup et al., 2010). STEP61 appears 

to impair synaptic plasticity in the hippocampus by 

removing the glutamate receptors necessary for maintaining proper communication between neurons. The scientists found that STEP61 levels are abnormally elevated in 

the brains of people with Alzheimer’s and in Alzheimer’s 

model mice with high levels of beta-amyloid. Laboratory 

experiments revealed that accumulation of beta-amyloid 

led to increased levels of STEP61, resulting in the loss of 

glutamate receptors at the synapse. 

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 35 2010 Progress Report on Alzheimer’s Disease
In a subsequent study in mouse models with reduced 

levels of STEP61, the Rockefeller team showed that these 

mice had restored levels of glutamate receptors and measures of synaptic plasticity (Zhang, Kurup, et al., 2010). 

This was associated with improved performance on a 

memory test. These findings suggest that STEP61 could 

be a therapeutic target for Alzheimer’s disease.

SIRT-1 

SIRT-1 is an enzyme mostly known as a regulator of lifespan in yeast and worms. In 2010, SIRT-1 emerged as a 

new candidate drug target for Alzheimer’s, based on two 

new-found possible roles in brain function. In one study, 

researchers found SIRT-1 was capable of removing damaging acetyl groups from tau and alleviating tau neurotoxicity (Min et al., 2010). Studies led by a team of scientists 

from the University of Southern California, NIA, Florida, 

Mexico, and Ontario (Michán et al., 2010) and a team 

from the Massachusetts Institute of Technology, 

Cambridge, (Gao et al., 2010) suggested that SIRT-1 is 

linked to learning and memory in mice. Both teams used 

mouse models lacking SIRT-1 and observed impaired performance on learning and memory tests, reduced synaptic 

plasticity, and abnormal branching of hippocampal 

neurons. The two teams also identified several new 

molecular pathways through which SIRT-1 may support 

synaptic plasticity in the hippocampus. Further research 

will pinpoint which molecules from the pathways could 

be useful as therapeutic targets for Alzheimer’s disease. 

Toll-like Receptors

Proteins involved in immune system responses keep popping up with unexpected roles in how brain cells communicate with other neurons. The latest of these proteins are 

toll-like receptors (TLRs), previously thought to function 

in the brain only during infection and injury. NIA 

researchers found that one of these receptors, TLR-3, 

plays a role in memory retention, apparently unrelated to 

any immune function (Okun et al., 2010). Significantly, 

TLR-3 appears to inhibit rather than promote forms of 

memory that depend on the hippocampus. Mouse models 

lacking TLR-3 show improved working memory performance, together with increased hippocampal size, 

increased generation of new hippocampal neurons, and 

higher levels of signaling molecules required for synaptic 

plasticity. Control mice with TLR-3 did not display these 

attributes. At the same time, anxiety-like behavior was 

diminished in the experimental mice, which performed 

better than the control mice. More research is needed into 

how TLR-3 affects memory and learning. 

Additional references:

Douglas PM, Dillin A. (2010) Protein homeostasis and aging 

in neurodegeneration. Salk Institute for Biological Studies. 

Supported by NIA.

Miller TW et al. (2010) Amyloid beta inhibits NO-cGMP 

signaling in a CD36- and CD47-dependent manner. National 

Cancer Institute. Supported by NCI.

Stewart CR et al. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Harvard Medical School. Supported by NIA, NIAID, 

and NINDS.

Testing of Therapeutic Candidates 

As we learn more about the biology and genetics of 

Alzheimer’s disease, currently available compounds or 

newly developed agents targeting specific Alzheimer’s disease mechanisms are typically tested in animal models 

before they are tested in human clinical trials. The animal 

models are usually transgenic mouse models that have 

been genetically developed to have proteins that function 

like those thought to be involved in human disease. 

In studies conducted in 2010, the following agents 

were among those that had beneficial effects on 

Alzheimer’s pathology in these animal models:

● Resveratrol. Several observational studies have 

associated moderate consumption of red wine with a 

lower incidence of dementia. Antioxidant compounds 

found in red wine, including resveratrol, have been shown 

in animal studies to have neuroprotective effects, and 

researchers are exploring the mechanisms by which these 

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 36 2010 Progress Report on Alzheimer’s Disease
compounds may work. In one study, Albert Einstein 

College of Medicine, Bronx, NY, researchers found that 

resveratrol lowered beta-amyloid accumulation in cultures 

of neurons and other cells from Alzheimer’s model mice 

(Vingtdeux et al., 2010). Resveratrol lowered beta-amyloid 

by increasing calcium levels in cells (depleted calcium levels 

are linked to the disorder) and by activating an enzyme 

known as AMPK that triggers the destruction of betaamyloid. When the scientists fed resveratrol to Alzheimer’s 

model mice, the compound crossed the blood-brain barrier, activated brain AMPK, and reduced beta-amyloid 

accumulation. These results suggest that resveratrol’s ability to reduce brain beta-amyloid levels might explain the 

beneficial link between wine consumption and cognitive 

health. They also provide impetus for further study of the 

therapeutic potential of resveratrol and other compounds 

that activate AMPK.

● Grape seed extracts. In related research, Mt. 

Sinai School of Medicine, New York City, researchers 

have been studying a grape seed polyphenolic extract 

(GSPE) rich in certain antioxidant molecules. The scientists found previously that GSPE inhibits the buildup of 

beta-amyloid. Now, they have discovered that GSPE also 

strongly interferes with the assembly of tau proteins into 

neurotoxic clumps in an animal model (Wang, SantaMaria, et al., 2010). Oral administration of GSPE also 

reduced tau tangle formation in a tau mouse model, 

where the beneficial effect of GPSE appeared to affect 

activation of ERK1/2, an enzyme that promotes the 

accumulation of toxic forms of tau. This finding 

suggests that GPSE may be explored as a potential therapeutic target to prevent damage caused by toxic forms 

of both beta-amyloid and tau.

● Glucagon-like peptide-1 (GLP-1). This hormone 

produced in the stomach helps stimulate pancreatic insulin 

secretion when blood glucose levels rise. Drugs that mimic 

the hormone are used to treat type 2 diabetes. It appears 

that activating the GLP-1 receptor may play a role in protecting brain cells, as shown in a study led by the NIA. 

Researchers discovered that the diabetes drug Exendin-4 

activates the GLP-1 receptor and can protect cultured 

neurons from beta-amyloid toxicity and oxidative stress 

in Alzheimer’s mice models (Li Y et al., 2010). It could 

also reverse some of the increase in beta-amyloid found 

in Alzheimer’s mice with diabetes. The compound is 

being tested in humans in a clinical trial.

● Rapamycin. The mTOR pathway is involved in 

regulating cell growth, death, and metabolism. Rapamycin, 

a drug that inhibits mTOR, has been shown to extend 

lifespan in mice. Two independent teams at the University 

of Texas Health Science Center, San Antonio, found that 

rapamycin treatment reduced Alzheimer’s-like pathology 

and prevented cognitive deficits in two different mouse 

models (Caccamo et al., 2010; Spilman et al., 2010). 

They showed that rapamycin stimulated the process cells 

use to digest and clear away waste proteins and other 

debris. The studies also found that the accumulation of 

beta-amyloid in cultured cells increased mTOR signaling, 

while inhibiting mTOR signaling reduced cellular betaamyloid levels. This result suggests a molecular link 

between beta-amyloid and mTOR, and that stimulating 

the cell clearance process could be one therapeutic avenue 

in Alzheimer’s. 

● Fibrinogen depletion. Fibrinogen is a fibrous 

protein that helps blood clots form. While not normally 

found in the brain, it accumulates in the brains of people 

with Alzheimer’s and is linked to increased risk for the 

disorder. Rockefeller University, New York City, scientists 

found that beta-amyloid can be trapped in the sticky 

matrix fibrinogen forms during clot formation, producing 

clots that are more resistant to degradation (CortesCanteli et al., 2010). They also found that clots developed 

more rapidly and persisted longer in the brains of 

Alzheimer’s model mice than in control mice. To further 

test the impact of such clots, they treated two different 

Alzheimer’s mouse models with ancrod, a protein from 

Malaysian pit viper venom that reduces blood fibrinogen 

levels. They found that ancrod treatment reduced the 

blood clot pathology and improved cognition in the mice. 

More research must be done to understand amyloid-

 37 2010 Progress Report on Alzheimer’s Disease
related cerebrovascular pathology, but this study suggests 

the possibility of developing drugs that block the effects 

of beta-amyloid on clot stability. Because beta-amyloid is 

found primarily in the brain, such drugs should not influence clot formation elsewhere in the body.

● Allopregnanolone. This derivative of the female 

sex hormone progesterone stimulates proliferation of 

neuron precursors, or developing brain cells. Scientists 

know that many regions of the brain produce new neurons 

throughout life, and they speculate that declining neurogenesis contributes to Alzheimer’s disease. Consistent with 

that idea, scientists at the University of California, Los 

Angeles, found an almost 50 percent reduction in the 

number of neural cell precursors in the hippocampus of 

3-month-old Alzheimer’s model mice compared to control mice (Wang, Singh, et al., 2010). This defect in 

neurogenesis was evident a full 3 months before the 

Alzheimer’s model mice first showed beta-amyloid deposits and impaired performance on a learning task involving 

the hippocampus. Because the Alzheimer’s model mice 

also had reduced brain levels of allopregnanolone, the scientists treated them with the hormone. A single injection 

restored neurogenesis in the model mice back to the levels 

seen in normal mice and also corrected their learning deficit. These results may stimulate interest in allopregnanolone and other treatments that boost neurogenesis as 

potential Alzheimer’s therapeutics.

Additional references:

Cook JJ et al. (2010) Acute gamma-secretase inhibition of 

nonhuman primate CNS shifts amyloid precursor protein (APP) 

metabolism from amyloid-beta production to alternative APP 

fragments without amyloid-beta rebound. Washington University 

School of Medicine. Supported by NIA, NCRR, and NINDS.

O’Leary JC III et al. (2010) Phenothiazine-mediated rescue of 

cognition in tau transgenic mice requires neuroprotection and 

reduced soluble tau burden. Byrd Alzheimer’s Research Institute, 

University of South Florida. Supported by NIA and NINDS.

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6Advances in Detecting 

Alzheimer’s Disease

Many researchers believe that treatments for 

Alzheimer’s are more likely to be effective if initiated 

early in the disease. Because scientists believe that 

changes in the brain leading to Alzheimer’s disease can 

occur one to two decades before cognitive impairment 

becomes evident, they are trying to develop methods to 

detect these changes at their earliest stages. In addition, 

a growing body of research suggests that other early 

symptoms, including changes in sensory and motor 

function, may precede memory changes in Alzheimer’s. 

These efforts are designed to determine who is at the 

highest risk for Alzheimer’s so that possible treatments 

can be tested more rapidly, as well as to improve diagnosis in clinical practice. Through NIA-led ADNI and 

other studies, these efforts are already showing some 

success. (See Advancing the Future of Alzheimer’s Research 

for more on ADNI, page 62.)

Scientists are currently exploring three main approaches 

to early diagnosis: measurements of CSF biomarkers, brain 

imaging, and standardized clinical tests of memory and 

thinking abilities to determine cognitive health. 

View a brief video of the NIA’s 

Dr. Laurie Ryan on the Alzheimer’s Disease 

Neuroimaging Initiative (ADNI), a novel 

effort to identify biomarkers.

 38 2010 Progress Report on Alzheimer’s Disease
CSF Biomarkers and 

Risk Assessment, Diagnosis

Using CSF biomarkers to diagnose and track the progress of Alzheimer’s disease is an increasingly productive 

area of research. Previous studies showed that changes in 

CSF levels of three proteins (beta-amyloid 1-42, tau, 

and phosphorylated tau) can, in a controlled experimental setting, reliably identify individuals with Alzheimer’s 

(Jack, Knopman, et al., 2010). 

Brain imaging has built upon and complemented 

that advance by detecting both amyloid accumulation 

and neurodegeneration, suggesting that it may be possible to identify individuals at risk for Alzheimer’s well 

before the disease is clinically apparent. Recent studies 

have focused on a number of questions: How do 

changes in levels of CSF biomarkers relate to structural 

changes occurring in the brain? Can CSF biomarkers be 

used not only to diagnose Alzheimer’s but also to identify individuals at risk? Are CSF biomarker changes 

more or less accurate predictors of cognitive decline than 

brain structural changes detectable by brain imaging?

Independent teams at the University of California, 

Los Angeles; the Department of Veterans Affairs, San 

Francisco; and the University of Oslo used data from 

ADNI to find that changes in specific CSF biomarkers 

could be linked to shrinkage of specific brain regions that 

degenerate in Alzheimer’s (Apostolova et al., 2010; Tosun 

et al., 2010; Fjell et al., 2010). However, they found that 

the relationships between CSF biomarker and brain 

structural changes were not entirely straightforward. 

In the Oslo study, for example, MCI patients 

showed more degeneration in some brain regions than 

would have been predicted by their CSF marker levels 

compared to control subjects. In addition, both the San 

Francisco and UCLA groups found that patterns of CSF 

marker changes relative to brain structural changes differed, depending on the individual’s stage of disease. The 

relationship between genetic risk factors and CSF biomarkers and imaging was difficult to discern since it varied by brain region and clinical group (cognitively 

normal, MCI, or Alzheimer’s). While an individual’s 

CSF marker profile alone does not provide a perfect 

snapshot of degenerative changes taking place in the 

brain, these results suggest the emergence of patterns in 

certain biomarkers that, with measures of brain atrophy, 

may be useful in early detection of Alzheimer’s.

Several groups of researchers have compared CSF 

biomarkers and brain structure changes to see which 

most accurately predicts future cognitive decline in 

patients with MCI. Studies led by investigators at the 

Mayo Clinic, Rochester, MN, (Vemuri et al., 2010) and 

the University of Oslo (Fjell et al., 2010) found that 

structural changes predicted cognitive change more accurately than did CSF biomarker levels. Indeed, the Mayo 

study followed ADNI participants with either normal 

cognition, MCI, or Alzheimer’s for 1 year and saw little 

change in CSF biomarker levels. However, MRI brain 

This diagram illustrates how Alzheimer’s-related changes 

in the brain may contribute to disease progression, from 

normal cognitive aging to early mild cognitive impairment 

(eMCI) to late MCI (LMCI) and to Alzheimer’s dementia. 

The curves represent the sequence in which specific markers may play a role in disease progression. This model 

suggests that different imaging tools, measurements, and 

biochemical biomarkers may serve as predictors (measures 

that predict future change) and outcomes (measures that 

detect change) at different stages in the transition from 

normal aging to MCI to dementia. The NIA-led ADNI study 

(see page 62) is gathering data to test this model.

Alzheimer’s Disease Progression

 39 2010 Progress Report on Alzheimer’s Disease
scans indicated brain degeneration and cognitive decline 

in all participants. Many of the same Mayo Clinic investigators in a later study (Jack, Wiste, et al., 2010) found 

that measurements of brain amyloid (using CSF and 

brain imaging) and structural MRI were equally accurate 

in predicting cognitive decline in 218 ADNI participants 

diagnosed with MCI. However, when they looked at just 

the participants with significant levels of brain amyloid, 

structural changes more accurately predicted cognitive 

decline as opposed to amyloid levels. 

At this stage, in a research setting, brain structural 

changes seem more reliable than CSF biomarkers in predicting cognitive decline. These observations also support the ideas that cognitive dysfunction is more closely 

associated with loss of brain tissue, especially with 

shrinkage of the hippocampus, than with amyloid or tau 

deposition, and that individuals vary in the rates at 

which they develop CSF abnormalities, changes in brain 

structure, and cognitive decline.

Additional references:

Jack CR Jr. et al. (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Mayo Clinic, 

Rochester, MN. Supported by NIA.

Montine TJ et al. (2011) Tau protein and beta-amyloid(1-42) 

CSF levels in different phenotypes of Parkinson’s disease. Palacky 

University, Olomouc, Czech Republic. Supported by NIEHS, 

NINDS, and NIA.

Imaging the Living Brain

Imaging enables researchers to study the structure and 

functioning of the brain. Tools include PET imaging 

using radioactive PiB, an agent that detects levels of betaamyloid in the living brain, and MRI to measure brain 

volume. There is already evidence that structural and PiB 

imaging can identify early disease stages of Alzheimer’s 

before symptoms of cognitive decline appear. 

Scientists are also looking for ways to detect even 

earlier stages of the disease—before significant betaamyloid deposition, cell loss, and brain atrophy, when 

treatment might be more effective in preventing disease 

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progression. New research suggests that fMRI scanning, 

which measures changes in blood flow related to brain 

activity, may be able to capture such signs of Alzheimer’s 

disease.

Two fMRI studies have identified early changes in 

the activity of the default-mode network (DMN), or 

brain regions engaged when a person is focused inward, 

such as when daydreaming, envisioning, or recalling the 

past. The first study, at Harvard University, Cambridge, 

MA, involved 75 older participants, ranging from people 

with normal cognition to those with mild Alzheimer’s 

dementia, who performed a memory task while their 

brains were being scanned (O’Brien et al., 2010). The 

researchers then compared the fMRI patterns of APOEε4 

carriers (those with a known genetic risk for late-onset 

Alzheimer’s) and noncarriers. Even among cognitively 

normal subjects, carriers showed greater activity in a 

DMN-related part of the brain that is normally less active 

during memory tasks and is one of the earliest sites of 

beta-amyloid deposition. Loss of the ability to properly 

“quiet” this region may impair the formation of memories. The abnormal fMRI response pattern in this region 

may be an early indicator of Alzheimer’s-related changes 

taking place in the brain and may help identify those at 

risk of developing the disease.

The second study, at Washington University School 

of Medicine, St. Louis, suggests that disruption of DMN 

function may occur independently of other markers, such 

as abnormal amounts of amyloid in the brain (Sheline, 

Raichle, et al., 2010). The researchers performed fMRI 

scans on 100 cognitively normal people (mean age 62) 

whose brains showed little or no evidence of betaamyloid deposition on PiB scans. They found APOEε4 

carriers showed significant disruption of the DMN 

compared to noncarriers. This disruption was also seen 

in 70 of the 100 participants who, besides being free of 

amyloid buildup in the brain, also had normal levels of 

the protein in their CSF. These findings suggest that 

 40 2010 Progress Report on Alzheimer’s Disease
changes in the DMN may be a precursor rather than a 

consequence of beta-amyloid deposition and may help 

to identify those at risk. 

Additional references:

Chao LL et al. (2010) Evidence of neurodegeneration in brains 

of older adults who do not yet fulfill MCI criteria. San Francisco 

VA Medical Center. Supported by NIA.

Chen K et al. (2010) Twelve-month metabolic declines in 

probable Alzheimer’s disease and amnestic mild cognitive impairment assessed using an empirically pre-defined statistical regionof-interest: findings from the Alzheimer’s Disease Neuroimaging 

Initiative. Banner Alzheimer’s Institute and Banner Good 

Samaritan PET Center. Supported by NIA and NIMH.

Pihlajamäki M et al. (2010) Evidence of altered posteromedial 

cortical FMRI activity in subjects at risk for Alzheimer disease. 

University of Kuopio, Kuopio, Finland. Supported by Academy 

of Finland, NINDS, and NIA.

Yassa MA et al. (2010) Pattern separation deficits associated 

with increased hippocampal CA3 and dentate gyrus activity in 

nondemented older adults. University of California, Irvine. 

Supported by NIA.

Developing New Cognitive Tests

Dementia screening is not routine in medical practice 

and, as a result, the early stages of MCI and Alzheimer’s 

dementia often are not detected. A primary reason for 

the lack of routine screening is that no single screening 

tool has been shown to detect cognitive impairment 

quickly and accurately in older adults. Among the benefits of screening is the opportunity to learn about therapeutic options, including clinical trials, as well as to 

understand and prepare for expected changes in the 

future, if dementia is diagnosed.

In one study, researchers examined a relatively new 

diagnostic tool, the AD8, to compare it to existing tools. 

They also wanted to see if the AD8 relates to the presence 

of biomarkers for Alzheimer’s disease determined from 

analysis of cerebrospinal fluid or through brain imaging. 

The value of a highly accurate instrument is that it would 

spare patients from unnecessary diagnostic testing that 

may be invasive and/or expensive. 

The AD8 consists of eight yes-or-no questions about 

everyday function. It can be given to the person being 

screened or to family members or others familiar with 

that person. In a Washington University, St. Louis, study, 

n

n

n

n

AD8 test scores of 257 older people correlated well with 

results of more extensive neuropsychological tests and 

Alzheimer’s biomarkers from the same participants 

(Galvin et al., 2010). Researchers also found the AD8 

test to be more sensitive than the Mini Mental State 

Exam, one of the most commonly used tests for 

Alzheimer’s dementia. Researchers and clinicians continue to examine the AD8 and other ways to easily and 

quickly screen for Alzheimer’s disease in a clinical setting.

As the new Alzheimer’s disease diagnostic guidelines 

point out, early cognitive changes in Alzheimer’s dementia may be evident in cognitive domains other than 

memory. One such domain is “executive function,” 

which includes control of attention. The Stroop test 

measures a person’s ability to stay focused on a task 

while being presented with distracting information (for 

example, to name the color of ink in which words are 

printed while ignoring the words themselves—a task 

that becomes harder if the word “red” is printed in blue 

ink). Washington University, St. Louis, researchers created a new version of the Stroop test that engages more 

of the brain’s thinking capacity by asking a person to 

switch back and forth between two different tasks with 

two different sets of instructions (Hutchison et al., 

2010). In a small study of 64 cognitively normal older 

adults and 32 adults with very mild Alzheimer’s dementia, the new test version was particularly good at discriminating between people with Alzheimer’s and those 

with normal cognition for their age.

Fluctuating Symptoms in 

Alzheimer’s Disease

As caregivers often notice, people with Alzheimer’s can 

have “good days” and “bad days.” Fluctuations in cognition, attention, and alertness have long been recognized as 

a central feature of Lewy body dementia, but their occurrence in Alzheimer’s has been less well studied. These fluctuations can also occur in people with normal cognition.

Researchers from Washington University School of 

Medicine, St. Louis, assessed the prevalence of cognitive 

fluctuations in 511 people, more than half of whom 

were cognitively normal and the remainder with varying 

severity of dementia (Escandon et al., 2010). Fluctuations 

were assessed via questionnaires filled out by their spouses 

or adult children.

 41 2010 Progress Report on Alzheimer’s Disease
 The researchers found that 12 percent of the participants with Alzheimer’s had spontaneous changes in cognition, including episodes of daytime drowsiness or lethargy 

(sleeping for more than 2 hours during the daytime), and 

episodes of illogical, disorganized thinking, or staring into 

space for long periods. People with three or four symptoms of cognitive fluctuation were eight times more likely 

to be diagnosed with dementia, and those with fluctuations were more likely to have a greater severity of dementia. Not surprisingly, they also performed more poorly on 

neuropsychological tests, particularly if their symptoms 

included disorganized or illogical thinking. This finding 

suggests that assessing patients for cognitive fluctuations 

could be an important factor for clinicians when evaluating and treating people with Alzheimer’s. 

Sensory Changes

People with Alzheimer’s disease often experience problems with their sense of smell, even in the earliest stages 

of the disease. To root out why Alzheimer’s might cause 

such problems, researchers at Northwestern University 

in Evanston, IL, performed fMRI scans of 10 participants with Alzheimer’s and 10 who were cognitively 

normal (Li W et al., 2010). The people with normal 

cognition could correctly judge whether pairs of odors 

were more similar or different, but those with 

Alzheimer’s could not. At the same time, fMRI scans 

showed the people with Alzheimer’s had impaired functioning of the piriform cortex, a pear-shaped region of 

the brain that plays an important role in distinguishing 

odors. This study suggests that impaired function of the 

piriform cortex might help in diagnosing Alzheimer’s.

In another study, New York University, New York 

City, researchers used a mouse model to probe how 

Alzheimer’s affects the sense of smell (Wesson et al., 2010). 

They first measured how long the mice sniffed at scented 

cotton swabs after repeated presentations of the same odor. 

Normally, mice lose interest in odors they have already 

smelled, and the speed at which they do so is a measure of 

olfactory function. Alzheimer’s disease model mice spent 

more time sniffing smells they had already encountered, 

while the normal mice spent more time investigating new 

smells. This difference continued as the mice aged, with 

the model mice much slower at detecting familiar smells. 

Similar to people with Alzheimer’s, the model mice 

also had difficulty discriminating between different 

odors. These deficits appeared as early as 3 months of 

age, as did very early signs of Alzheimer’s pathology—

deposits of beta-amyloid in various parts of brain important to the sense of smell. Because the earliest stages of 

beta-amyloid deposition appear to impact odor learning 

tasks in mice, researchers are continuing to study such 

odor learning tasks for their use in diagnosis and, ultimately, in testing of new therapies. 

Motor Changes

Slowing of motor function—such as walking—is associated with greater risk of cognitive decline in older people 

and may precede the onset of cognitive impairment. 

Researchers at Oregon Health Sciences University in 

Portland analyzed the rate of motor decline over the course 

of 20 years in 204 older adults who were cognitively normal at the start of the study (Buracchio et al., 2010). 

Although a decline in gait speed is common in older 

adults, participants who eventually developed MCI 

showed faster rates of decline in both walking speed and 

finger-tapping speed than those who remained cognitively 

normal. In addition, motor function declined dramatically 

at distinct points among those who eventually developed 

MCI. For men, the sudden acceleration in gait-speed 

decline occurred about 14 years before the onset of MCI; 

for women, at 6 years. What causes this acceleration in 

gait-speed decline among those destined to develop MCI 

is unclear. Walking requires a complex interplay of sensory, 

cognitive, and motor functions, and these systems may be 

impacted early in the Alzheimer’s disease process.

Additional reference:

Wilkins CH et al. (2010). A brief clinical tool to assess physical 

function: the mini-physical performance test. Washington 

University School of Medicine. Supported by NIA.

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 42 2010 Progress Report on Alzheimer’s Disease
7Testing Therapies to 

Treat, Delay, or Prevent 

Alzheimer’s Disease

Clinical trials are the only way to test whether a potential 

intervention for Alzheimer’s disease is safe and effective in 

humans. During a clinical trial, the experimental treatment is compared to the standard treatment or a placebo 

(an inactive ingredient). During a Phase I trial, a research 

team gives the treatment to a small number of participants 

and examines its safety and action in the body. The main 

goals are to establish the highest dose of a new drug that 

people can tolerate and to define the dose at which harmful side effects may begin. If the treatment appears to be 

safe, it will go on to Phase II and Phase III clinical trials. 

Phase II trials involve larger numbers of people. In 

these trials, the study team wants to know whether the 

treatment is safe and effective at changing the course of the 

disease. Phase II trials occasionally also involve the use of a 

placebo. Results from Phase II trials give researchers an 

indication of the effective dose to use in Phase III trials.

Phase III trials are large studies that compare an 

experimental treatment with a placebo or standard treatment to determine safety and efficacy (whether the 

treatment has the power to produce an effect). Phase III 

trials are complex, expensive studies involving hundreds 

or even thousands of volunteers and are often conducted 

over a long period of time. 

The most compelling scientific evidence comes from 

clinical trials that are randomized (participants are randomly 

assigned to receive either the treatment or placebo), doubleblinded (neither participant nor researchers know which 

treatment the participant receives), and placebo-controlled 

(an inactive substance is given to one group of participants, 

while the drug being tested is given to another group). 

Randomized, double-blind, placebo-controlled studies 

are considered the “gold standard” of clinical trials.

Within NIH, the NIA is the primary institute supporting and conducting clinical trials on Alzheimer’s disease, MCI, and age-related cognitive decline. NIA funds 

a wide array of investigator-initiated clinical trials for 

Alzheimer’s, MCI, and age-related cognitive decline. 

Some trials focus on treatments for Alzheimer’s that may 

preserve cognitive function for as long as possible and 

alleviate behavioral or psychiatric problems. Others 

involve efforts to slow disease progression, such as delaying MCI’s progression to Alzheimer’s dementia, a type of 

research called secondary prevention. Still others focus on 

primary prevention, or helping cognitively healthy people 

reduce their risk of developing Alzheimer’s disease in the 

future. (See Table 1, page 48).

NIA Programs Support Clinical Trials 

The NIA supports an infrastructure and funding opportunities to develop and test new Alzheimer’s treatments 

via two major clinical trial programs: the Alzheimer’s 

Disease Cooperative Study (ADCS) and the Alzheimer’s 

Disease Pilot Clinical Trials Initiative. The latter initiative 

supports a number of preliminary clinical evaluations of 

interventions for MCI, Alzheimer’s, and age-related cognitive decline that might not otherwise be pursued by 

industry. 

The ADCS, a large clinical trials consortium with 

sites throughout the United States and Canada, is a 

major research initiative investigating both the cognitive 

and behavioral symptoms of Alzheimer’s disease. ADCS 

investigators are developing innovative clinical trial 

designs, tools, and interventions, including therapies 

that might not otherwise be developed by industry. (See 

page 61 for more about the ADCS.) The most recent 

round of ADCS studies, funded since 2006, explore a 

variety of promising areas:

● Docosahexaenoic Acid (DHA). This completed 

trial examined whether treatment with DHA, an omega-3 

fatty acid found in fish, would slow cognitive decline in 

View a brief video of the NIA’s 

Dr. Laurie Ryan describing the NIA’s clinical 

trials program. 

 43 2010 Progress Report on Alzheimer’s Disease
people with Alzheimer’s. Observational studies associate 

high fish consumption with reduced risk of the disorder, 

and studies in Alzheimer’s mouse models show that 

dietary DHA reduces brain levels of beta-amyloid, oxidative damage associated with beta-amyloid, and neurotoxicity. The primary results of this trial are described below.

● Intravenous Immunoglobulin (IVIg). A blood 

product administered intravenously, IVIg contains naturally occurring antibodies against beta-amyloid. Preliminary 

studies have shown it may improve cognition. In addition, 

IVIg increased levels of anti-beta-amyloid antibodies in 

plasma and promoted clearance of beta-amyloid from CSF 

in a Phase III clinical trial. This ongoing, double-blind, 

randomized controlled trial will demonstrate whether IVIg 

is effective in treating Alzhiemer’s. 

● Home-based Assessment. This ongoing study, 

conducted in people age 75 and older, is examining the 

development and use of home-based assessments in clinical trials, using interviews over the telephone and/or via 

computer. Cognition, daily functioning, mood, and other 

factors will be evaluated in each of these innovative assessment and data collection methods, and then compared 

against traditional in-person methods. The findings from 

this study will provide information on how home-based 

assessments might be used in prevention trials. Such 

methods could significantly reduce the cost and increase 

the feasibility of participation in long-term clinical trials. 

● Resveratrol. This Phase II, double-blind, randomized controlled trial, scheduled to begin in early 2012, will 

evaluate the impact of resveratrol treatment on Alzheimer’s 

biomarkers and clinical outcomes in people with mild to 

moderate Alzheimer’s disease. Resveratrol is an antioxidant 

compound found in grapes and red wine. Observational 

studies have shown that moderate consumption of red 

wine is associated with a lower incidence of Alzheimer’s 

disease, and animal studies have demonstrated resveratrol’s 

neuroprotective properties. 

NIA-Funded Clinical Trials

The NIA currently supports more than 30 active clinical 

trials, including pilot and large-scale trials, of a wide range 

of interventions to prevent, slow, or treat Alzheimer’s disease and/or MCI (see Tables 1 and 2). Of the primary 

prevention trials, two are NIA-funded add-ons to large 

NIH trials that address other primary outcomes. 

One of these add-ons is part of the National Heart, 

Lung, and Blood Institute’s Systolic Blood Pressure 

Intervention Trial (SPRINT), which will evaluate the 

health effects of lowering systolic blood pressure from 

140 to 120. The add-on study, funded by NIA and 

NINDS, called SPRINT-MIND, will assess the effect of 

lowering systolic blood pressure on cognitive decline and 

the development of MCI and Alzheimer’s disease. The 

study will also use brain imaging to measure treatment 

effects on brain structure, including white matter lesions 

typical of vascular disease. 

The second add-on study is Action to Control 

Cardiovascular Risk in Diabetes, a national study supported 

by the National Heart, Lung, and Blood Institute to 

examine the effect of different glucose-lowering strategies 

on the risk for cardiovascular disease. Based on previous 

studies linking diabetes with increased risk of cognitive 

decline and Alzheimer’s disease, the trial’s Memory in 

Diabetes substudy looked at cognitive function and brain 

volume in this population. 

NIA-funded clinical trials are exploring the connection between Alzheimer’s and various diseases, such as 

diabetes and cardiovascular disorders, as well as lifestyle 

factors that may influence disease onset and progress, 

such as exercise, stress, and hormones.

The NIA currently supports more than 30 active clinical trials 

testing a wide range of interventions to prevent, slow, or 

treat mild cognitive impairment and/or Alzheimer’s disease.

 44 2010 Progress Report on Alzheimer’s Disease
Reports from Recently 

Completed Clinical Trials

While no new Alzheimer’s disease interventions were 

found effective and safe in 2010, the results of clinical 

trials reported during this period still provide important 

insights into the disease and will benefit future studies. 

For example, researchers found what may be important 

differences in treatment effects in people who do and do 

not carry the APOEε4 risk-factor gene for late-onset 

Alzheimer’s. One private study involved bapineuzumab, 

an antibody that binds to beta amyloid. A 2009 report 

found different responses to treatment among APOEε4 

carriers and noncarriers. A second finding, involving 

DHA, is described below. Results such as these are propelling further trials targeting select subgroups of 

Alzheimer’s patients. 

DHA

Epidemiological studies have suggested that consumption of DHA supplements or fish containing DHA may 

reduce risk of Alzheimer’s disease. Additionally, 

Alzheimer mouse model studies have shown that DHA 

consumption reduces beta-amyloid pathology. In a clinical trial conducted by the NIA-supported Alzheimer’s 

Disease Cooperative Study (ADCS), 402 participants 

with mild to moderate Alzheimer’s were given daily supplements of either 2 grams of DHA or a placebo (Quinn 

et al., 2010). After 18 months of treatment, there were 

no significant differences in the rate of cognitive decline 

between the DHA-treated and control groups. However, 

DHA did appear to slow cognitive decline in those who 

did not carry the APOEε4 gene.

These results raise the possibility that DHA supplementation could be effective if started before the appearance of cognitive symptoms. Alternatively, because the 

disease may progress differently in APOEε4 carriers and 

non-carriers, treatments may need to be tailored according to genetic type.

Insulin Nasal Spray 

In a pilot clinical trial conducted by the Veterans Affairs 

Puget Sound Health Care System in Seattle and Tacoma, 

WA, researchers tested whether restoring normal insulin 

function in the brain might provide cognitive benefit 

and slow the progression of Alzheimer’s disease (Craft et 

al., 2011). More than 100 volunteers with MCI or mild 

to moderate Alzheimer’s disease received insulin nasal 

spray or a placebo and had their memory, cognition, 

and functional ability measured before and after the 

4-month treatment. Cerebrospinal fluid was analyzed 

and brain scans conducted before and after treatment.

The results showed that a nasal-spray form of insulin 

delayed memory loss and preserved general cognition 

and did not raise the insulin levels outside of the brain. 

These results point to the need for larger trials of insulin 

nasal-spray therapy to further test its effectiveness in 

treating Alzheimer’s disease. 

Cholesterol-Lowering Statins

Researchers have hypothesized that statins (cholesterollowering drugs), may be useful for treating Alzheimer’s. 

Animal studies have shown that high-fat diets increased 

accumulation of amyloid in the brain and that statins 

reduced those levels. Some but not all epidemiological 

studies in humans have suggested that statins may 

decrease risk for Alzheimer’s, and some small clinical 

trials supported the use of statins to benefit cognition.

However, an ADCS-supported, randomized, doubleblind study of simvastatin did not show delayed progression of the disease (Sano, Bell, et al., 2011). Some 

400 people with mild to moderate Alzheimer’s disease 

participated in the 18-month trial. One half received the 

drug and the other half received a placebo. Cognitive 

testing of the participants did not show any benefits 

among those taking the statin. 

 45 2010 Progress Report on Alzheimer’s Disease
Cholinesterase Inhibitors

Many people continue to drive after receiving a diagnosis of Alzheimer’s. Because people diagnosed with mild 

to moderate Alzheimer’s are usually treated with a 

cholinesterase inhibitor drug, researchers wondered how 

these drugs affect tasks related to driving performance. 

Researchers at Brown University in Providence, RI, 

studied attention and executive function in 24 participants newly diagnosed with Alzheimer’s, testing their 

performance before and after 3 months of treatment 

with a cholinesterase inhibitor (Daiello et al., 2010). 

They found that participants performed significantly 

better after treatment on both a computer-simulated 

driving test and on visual attention tasks.

Additional references:

Farlow MR et al. (2010) Effectiveness and tolerability of highdose (23 mg/d) versus standard-dose (10 mg/d) donepezil in 

moderate to severe Alzheimer’s disease: A 24-week, randomized, 

double-blind study. Indiana University School of Medicine. 

Supported by NIA.

n

Wang L et al. (2010) Donepezil treatment and changes in hippocampal structure in very mild Alzheimer disease. Washington 

University School of Medicine. Supported by NIA and NIMH.

Weintraub D et al. (2010) Sertraline for the treatment of 

depression in Alzheimer disease. University of Pennsylvania 

School of Medicine. Supported by NIMH.

Exercise

Epidemiological studies as well as some intervention 

studies have suggested that physical exercise may play a 

role in reducing risk for Alzheimer’s disease (see Exercise 

and Maintaining Cognitive Health, page 30). Researchers 

at the University of Illinois, Urbana-Champaign have 

shown that exercise can stimulate the brain’s ability to 

maintain and make new network connections that are 

vital to healthy cognition (Voss et al., 2010). In the yearlong study, 65 older people exercised daily, doing either 

an aerobic exercise program of walking for 40 minutes or 

a nonaerobic program of stretching and toning exercises.

 At the end of the trial, the walking group showed 

improved connectivity in the brain’s default-mode network, or DMN. In fact, their DMN activity—which is 

the part of the brain engaged in daydreaming, envisioning the future, and recalling the past—closely resembled 

those of young adults. The walking group also improved 

on executive function tasks necessary to planning and 

carrying out specific behaviors, like figuring out what to 

have for dinner, and then going to the kitchen and 

selecting the appropriate ingredients. This study suggests 

that exercise could be explored to see whether it can 

even help reverse cognitive decline and if aerobic exercise 

allows the brain to function at a more youthful level.

Additional references:

Rubright J et al (2010) A memory and organizational aid 

improves Alzheimer disease research consent capacity: results of a 

randomized, controlled trial. University of Delaware School of 

Education. Supported by NIA. 

Sano M et al. (2010) Pilot study to show the feasibility of a 

multicenter trial of home-based assessment of people over 75 

years old. Mount Sinai School of Medicine. Supported by NIA. 

n

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 46 2010 Progress Report on Alzheimer’s Disease
Hormones such as estrogen and progesterone have important 

effects on the brain, many of which are potentially relevant to 

cognitive aging and Alzheimer’s disease. Over the years, 

research findings have led to a variety of seemingly conflicting 

reports—both positive and negative—as to whether menopausal hormone therapy can prevent cognitive decline in 

postmenopausal women. 

Some animal and observational studies comparing women 

who chose to take estrogen with those who did not have 

shown that estrogen may benefit cognition. However, controlled clinical trials of menopausal hormone therapy in older 

women have generally failed to show similar beneficial effects. 

The Women’s Health Initiative Memory Study (WHIMS) reported in 2003 that prolonged treatment with estrogen and progestin (substances with a progesterone-like effect) actually 

increased the risk of cognitive decline and dementia in postmenopausal women age 65 and older. 

How to reconcile these conflicting data? One central issue 

may be timing. The women in the WHIMS trial started treatment a decade or more after menopause. In contrast, the 

majority of women in the observational studies that showed 

estrogen benefited cognition began treatment soon after 

menopause. This difference has led researchers to wonder if it 

may be advantageous to begin treatment closer to menopause. 

Support for that idea comes from a University of 

Pittsburgh study, in which women who began estrogen in the 

first year after menopause had the largest hippocampal volume (Erickson, Voss, et al., 2010). Two NIA-funded clinical trials are currently studying the timing of menopausal hormone 

therapy on cognition and other health factors: the Kronos 

Early Estrogen Prevention Study-Cognition and Affective 

Study (KEEPS-CA) and the Early Versus Late Intervention Trial 

with Estrogen (ELITE). 

Response to estrogen may also depend on whether the 

transition to menopause occurs naturally over a number of 

years or is the result of surgery, such as a hysterectomy to 

remove the uterus. Researchers at Arizona State University 

found that estrogen had different effects on cognition in 

animal models that allow such a comparison. Estrogen 

Hormones and Cognitive Health in Postmenopausal Women 

impaired memory-test performance in rats transitioning naturally into menopause, but it improved performance in surgically menopausal rats. The reason for this difference is 

unknown (Acosta et al., 2010). 

Today, most women who receive menopausal hormone 

therapy use estrogen in a variety of forms and doses and 

often in combination with progesterone or a progestin such as 

medroxyprogesterone acetate (MPA). Animal studies point to 

progestins, particularly MPA, as possibly having a negative 

impact on cognition. A University of Illinois study of aged, 

surgically menopausal rats treated with estrogen and MPA 

showed the animals performed less well on memory tests 

than rats treated with estrogen alone or with estrogen and 

progesterone (Lowry et al., 2010). In a study of aged, surgically menopausal rats at Arizona State University, animals treated 

with high-dose MPA showed impaired memory performance 

compared to untreated rats (Braden et al. 2010). 

Additionally, it appears that progesterone and progestins 

differ in their impact on brain health. University of Southern 

California researchers compared the effects of four clinically 

prescribed progestins on hippocampal cell growth and survival in adult female rats (Liu et al., 2010). When administered in 

combination with estrogen, two of the progestins appeared to 

have largely beneficial effects on hippocampal cell health. In 

contrast, a different set of progestins had mixed effects; they 

supported cell proliferation but simultaneously increased cell 

death. Because progestins are used in fertility therapy and for 

contraception as well as menopausal hormone therapy, their 

potentially varying effects on cognitive health warrants further 

investigation.

Additional references:

Janicki SC, Schupf N. (2010) Hormonal influences on cognition and risk for Alzheimer’s disease. Columbia University 

Medical Center. Supported by NIMH, NIA, NICHD, and NCI.

Zhao Z et al. (2010) Epigenetic alterations regulate estradiolinduced enhancement of memory consolidation. Yale University. 

Supported by NIA.

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 47 2010 Progress Report on Alzheimer’s Disease
TABLE 1. Ongoing Alzheimer’s Disease/Mild Cognitive 

Impairment Prevention Trials Funded by NIA

TRIAL NAME

PRINCIPAL 

INVESTIGATOR/ 

INSTITUTION INTERVENTION POPULATION TYPE OF TRIAL

ANTICIPATED 

COMPLETION 

DATE

Nutritional

AREDS2 

(Age-Related Eye 

Disease Study 2)*

John Paul San 

Giovanni (Study 

Director), NEI

Macular xanthophylls (lutein and 

zeaxanthin) and/or 

omega-3 fatty 

acids (DHA and 

EPA)

People age 50-85 

with age-related 

macular degeneration (AMD) in 

both eyes or 

advanced AMD 

in one eye

Primary Prevention 2015

PREADVISE 

(Prevention of 

Alzheimer’s 

Disease by 

Vitamin E and 

Selenium)†

Frederick Schmitt, 

University of 

Kentucky

Vitamin E, 

selenium, vitamin 

E + selenium

Men age 60-90 Primary Prevention 2014

Vitamin E in Aging 

Persons with 

Down Syndrome

Arthur Dalton, 

Institute for Basic 

Research in 

Developmental 

Disability 

Vitamin E People age 

50+ with Down 

syndrome, at high 

risk of developing 

Alzheimer’s 

disease

Primary Prevention 2012

Hormones

ELITE (Early 

Versus Late 

Intervention with 

Estradiol)

Howard Hodis, 

University of 

Southern 

California

17β-estradiol Healthy early (less 

than 6 years) or 

late (10 years +) 

menopausal 

women

Primary Prevention 2014

SMART 

(Somatotrophics, 

Memory, and 

Aging Research 

Trial) 

Michael Vitiello,

University of 

Washington 

Growth hormone 

releasing hormone 

(GHRH)

People with 

mild cognitive 

impairment and 

healthy older 

adults age 55-80

Secondary

Prevention

2011

Testosterone 

Supplementation 

in Men with MCI

Monique Cherrier,

University of 

Washington

Testosterone Older men with 

MCI and low 

testosterone

Secondary Prevention 2011

Cardiovascular

ASPREE (Aspirin 

in Reducing 

Events in the 

Elderly)

Richard Grimm, 

Berman Center for 

Outcomes and 

Clinical Research; 

John McNeil, 

Monash University

Aspirin Healthy adults age 

70+

Primary Prevention 2017

 48 2010 Progress Report on Alzheimer’s Disease
TRIAL NAME

PRINCIPAL 

INVESTIGATOR/ 

INSTITUTION INTERVENTION POPULATION TYPE OF TRIAL

ANTICIPATED 

COMPLETION 

DATE

Cardiovascular (Continued)

SPRINT-MIND 

(Systolic Blood 

Pressure 

Intervention 

Trial-MIND)†

David Reboussin, 

Wake Forest 

University 

Blood pressure 

lowering to <140 

mmHg versus 

<120 mmHg

Adults age 55+ 

with systolic blood 

pressure of 130 

mmHg or higher, 

history of cardiovascular disease, 

high risk for heart 

disease

Primary Prevention 2017

Metabolic

Metformin in 

Amnestic Mild 

Cognitive 

Impairment

Jose Luchsinger, 

Columbia 

University 

Metformin Overweight/obese 

older adults with 

mild cognitive 

impairment

Secondary Prevention 2012

Pioglitazone and 

Exercise Effects 

on Older Adults 

with Mild Cognitive 

Impairment and 

Metabolic 

Syndrome

Robert Schwartz, 

University of 

Colorado, Denver 

Pioglitazone Overweight/obese 

older adults with 

mild cognitive 

impairment 

Secondary Prevention 2012

Nonpharmacological 

Exercise Versus 

Cognitive 

Interventions for 

Elders at Risk for 

Dementia

David 

Loewenstein, 

University of 

Miami 

Cognitive training, 

aerobic exercise 

training, cognitive 

training + aerobic 

exercise training

People with 

mild cognitive 

impairment

Secondary Prevention 2012

Memory Training 

Intervention in 

Mild Cognitive 

Impairment

Miriam Mintzer, 

Johns Hopkins 

University

Repetition lag 

training procedure 

(RLTP)

People with 

mild cognitive 

impairment

Secondary Prevention 2014

Preventing 

Cognitive Decline 

in African 

Americans with 

Mild Cognitive 

Impairment

Barry Rovner, 

Thomas Jefferson 

University

Home-based 

behavioral 

treatment

African Americans 

with mild cognitive 

impairment

Secondary Prevention 2016

Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/alzheimers or ClinicalTrials.gov.

* Co-funded primary prevention trial: AREDS2 (led by National Eye Institute).

† NIA-funded primary prevention add-on trials: PREADVISE (add-on to National Cancer Institute’s SELECT trial); SPRINTMIND (add-on to National Heart, Lung, and Blood Institute’s and National Institute of Diabetes and Digestive and Kidney 

Diseases’ SPRINT trial; co-funded with the National Institute of Neurological Disorders and Stroke).

TABLE 1 continued

 49 2010 Progress Report on Alzheimer’s Disease
TABLE 2. Ongoing Alzheimer’s Disease/

Mild Cognitive Impairment Treatment and 

Feasibility Clinical Trials Funded by NIA

TRIAL NAME

PRINCIPAL 

INVESTIGATOR/ 

INSTITUTION INTERVENTION POPULATION

ANTICIPATED 

COMPLETION 

DATE

Treatment Trials—Cognition

Nutritional

Lipoic Acid and 

Omega-3 Fatty Acids in 

Alzheimer’s Disease

Lynne Shinto, 

Oregon Health & 

Science University 

Lipoic acid and/or 

omega-3 fatty acids 

(DHA and EPA)

People with Alzheimer’s 

disease

2014

Hormones

Raloxifene for Women 

with Alzheimer’s Disease

Victor Henderson, 

Stanford University

Raloxifene (selective 

estrogen receptor 

modulator or SERM)

Older women with 

Alzheimer’s disease

2012

Nonpharmacological

ADMIT (Alzheimer’s 

Disease Multiple 

Intervention Trial )

Chris Callahan, 

Indiana University

Home-based 

occupational therapy

People with Alzheimer’s 

disease

2016

Aerobic Fitness in 

Slowing the Progression 

of Alzheimer’s Disease

Jeffrey Burns, 

University of Kansas

Aerobic exercise training People with Alzheimer’s 

disease

2014

Therapeutic Effects of 

Cataract Removal in 

Alzheimer’s Disease

Grover Gilmore, 

Case Western 

Reserve University

Cataract removal Adults 65 and older 

with both Alzheimer’s 

disease and cataracts

2014

Other Interventions

AAV-NGF Gene Delivery 

in Alzheimer’s Disease

Paul Aisen, University 

of California, San Diego

Nerve growth factor 

(NGF) gene delivery

People with Alzheimer’s 

disease

2014

Intravenous 

Immunoglobulin (IVIg) 

for Treatment of 

Alzheimer’s Disease 

(passive immunization)*

Norman Relkin, Weill 

Medical College of 

Cornell University 

IVIg People with Alzheimer’s 

disease

2013

Treatment Trials—Neuropsychiatric Comorbidities

ADMET (Apathy in 

Alzheimer’s Disease 

Methylphenidate Trial)

Jacobo Mintzer, 

Medical University of 

South Carolina;

Krista Lanctot; 

University of Toronto;

Paul Rosenberg, Johns 

Hopkins University

Methylphenidate People with Alzheimer’s 

disease 

2012

Antipsychotic 

Discontinuation in 

Alzheimer’s Disease

Davangere Devanand,

NYSPI/Columbia 

University

Risperidone People with 

Alzheimer’s disease

2011

 50 2010 Progress Report on Alzheimer’s Disease
TRIAL NAME

PRINCIPAL 

INVESTIGATOR/ 

INSTITUTION INTERVENTION POPULATION

ANTICIPATED 

COMPLETION 

DATE

Treatment Trials—Neuropsychiatric Comorbidities (Continued)

CITAD (Citalopram 

Treatment for Agitation 

in Alzheimer Dementia)

Constantine Lyketsos, 

Johns Hopkins 

University

Citalopram People with Alzheimer’s 

disease

2014

Pilot Combination 

Treatment Trial of Mild 

Cognitive Impairment 

with Depression

Davangere Devanand, 

New York State 

Psychiatric Institute/ 

Columbia University 

Citalopram and 

donepezil

People with mild 

cognitive impairment

2015

Prazosin Treatment for 

Disruptive Agitation in 

Alzheimer’s Disease

Elaine Peskind, 

University of 

Washington

Prazosin People with Alzheimer’s 

disease 

2013

TREA (Treatment Routes 

for Exploring Agitation)

Jiska Cohen-Mansfield, 

Hebrew Home of 

Greater Washington

TREA–systematic 

approach to individualizing nonpharmacological 

interventions for persons 

with dementia

Nursing home residents 

with Alzheimer’s disease 

2012

Proof of Concept Trials

Cardiovascular

Effects of Simvastatin 

on CSF Alzheimer’s 

Disease Biomarkers in 

Cognitively Normal 

Subjects

Gail Li, University of 

Washington

Simvastatin Cognitively normal 

adults age 45-64 

2013

Pilot Trial of Carvedilol in 

Alzheimer’s Disease

Giulio Maria Pasinetti, 

Mt. Sinai School of 

Medicine; Paul 

Rosenberg, Johns 

Hopkins University

Carvedilol People with Alzheimer’s 

disease

2015

Statin Effects on BetaAmyloid and Cerebral 

Perfusion in Adults at 

Risk for Alzheimer’s 

Disease

Cynthia Carlsson, 

University of Wisconsin, 

Madison

Simvastatin Adults age 45-65 at 

high risk of Alzheimer’s 

disease (family history, 

APOE4)

2013

Hormones

Estrogen Receptor-beta 

phytoSERMs for 

Management 

Lon Schneider, 

University of Southern 

California 

ER2-selective phytoestrogens (phytoSERMs—

selective estrogen 

receptor modulators)

Postmenopausal women 

age 50-59

2014

Metabolic

Glucose Regulation and 

Memory in Alzheimer’s 

Disease

Suzanne Craft, 

University of 

Washington

Improved insulin resistance, 3 studies: diet, 

triglyceride emulsion, 

rosiglitazone

People with 

Alzheimer’s disease 

and age-matched 

healthy older adults

2016

TABLE 2 continued

 51 2010 Progress Report on Alzheimer’s Disease
TRIAL NAME

PRINCIPAL 

INVESTIGATOR/ 

INSTITUTION INTERVENTION POPULATION

ANTICIPATED 

COMPLETION 

DATE

Nonpharmacological

Conversational 

Engagement As a 

Means to Delay 

Alzheimer’s Disease 

Onset

Hiroko Dodge, Oregon 

Health & Science 

University

Internet-based 

conversational 

engagement 

 Adults age 75+ 2014

Effects of Standardized 

Aerobic Exercise 

Training on 

Neurocognition and 

Neurodegeneration

Thomas Obisesan, 

Howard University 

Aerobic exercise 

training

African Americans 

with Alzheimer’s 

disease

2012

Exercise and Health 

Promotion for Mild 

Cognitive Impairment

Linda Teri, University of 

Washington 

Two exercise programs 

(one for individuals 

with mild cognitive 

impairment and the 

other for cognitively 

intact older adults)

People with mild 

cognitive impairment

2012

Lifestyle Interventions 

and Independence for 

Elders (LIFE)

Marco Pahor, University 

of Florida

Aerobic exercise, 

resistance, and 

flexibility exercises

Sedentary adults 

age 70-89

2015

Mild Cognitive 

Impairment: 

Cerebrovascular 

Dysfunction and 

Exercise Training

Rong Zhang and

Hanzhang Lu, University 

of Texas Southwestern

Endurance exercise 

training

People with mild 

cognitive impairment

2014

Neural Effects of 

Exercise, Cognitive, or 

Combined Training in 

Alzheimer’s Disease 

At-Risk Elders

Stephen Rao, 

Cleveland Clinic

Cognitive training, 

aerobic exercise 

training, cognitive 

training + aerobic 

exercise training

Healthy adults 

age 65-85

2012

Other Interventions

fMRI Activation in Mild 

Cognitive Impairment

Michela Gallagher, 

Johns Hopkins 

University

Levetiracetam People with mild 

cognitive impairment

2012

Thalidomide As BACE1 

Inhibitor in Alzheimer’s 

Disease

Yong Shen, Roskamp 

Insititute; Marwan 

Sabbagh, Banner Sun 

Health Research 

Institute 

Thalidomide People with 

Alzheimer’s disease

2012

Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/alzheimers or ClinicalTrials.gov.

*Alzheimer’s Disease Cooperative Study trial.

TABLE 2 continued

 52 2010 Progress Report on Alzheimer’s Disease
TABLE 3. Ongoing Age-Related Cognitive Decline 

Clinical Trials Funded by NIA

TRIAL NAME

PRINCIPAL 

INVESTIGATOR/

INSTITUTION INTERVENTION POPULATION

ANTICIPATED 

COMPLETION 

DATE

Cognitive Training

Active Interventions for 

the Aging Mind 

Denise Park, University 

of Texas, Dallas 

Cognitive enrichment 

through training in digital 

photography or quilting 

Healthy adults age 60+ 2012 

Brain-Based Approach 

to Enhancing Executive 

Control Functions in 

Healthy Aging 

Mark D’Esposito, 

University of California, 

Berkeley 

Cognitive training Healthy adults age 50+ 2012 

Expanding the 

Implementation of an 

Effective Cognitive 

Aging Intervention 

Helga Noice, Elmhurst 

College

Cognitive enrichment Healthy adults age 65+ 2010

Experience Corps Trial: 

Improving Health in 

Older Populations 

through Generativity 

George Rebok, Johns 

Hopkins University 

Health promotion 

for older adults 

embedded within a 

social engagement 

program (volunteering 

in schools) 

Healthy adults age 60+ 2011 

Senior Odyssey: A Test 

of the Engagement 

Hypothesis of Cognitive 

Aging 

Elizabeth Stine-Morrow, 

University of Illinois, 

Urbana-Champaign 

Cognitive enhancement 

through participation in 

the Odyssey of the Mind 

program 

Healthy adults age 60+ 2012 

Speed of Processing 

Modes to Prevent 

Cognitive Decline in 

Older Adults 

Fredric Wolinsky, 

University of Iowa 

Comparison of standard 

versus enhanced visual 

processing training 

Healthy adults age 50+ 2011 

Omega-3 Fatty Acids and Antioxidants

Omega-3 and Blueberry 

Supplementation in 

Age-Related Cognitive 

Decline 

Robert Krikorian, 

University of Cincinnati 

Omega-3 and blueberry 

supplements 

Healthy adults age 

62-80 

2012 

Cardiovascular

Aging and the ReninAngiotensin System in 

Elderly Hypertensive 

Individuals

Ihab Hajjar, University of 

Southern California

Angiotensin receptor 

blocker, angiotensinconverting enzyme 

inhibitor, diuretic

Adults age 60+ 

with uncontrolled 

hypertension and 

cognitive impairment 

2012 

Hormones

Estrogen Effects on 

Cholinergic Function in 

Older Women 

Paul Newhouse, 

Vanderbilt University

Acute or chronic 17βestradiol + muscarinic 

and nicotinic cholinergic 

antagonist 

Healthy women age 50+ 2014 

 53 2010 Progress Report on Alzheimer’s Disease
TRIAL NAME

PRINCIPAL 

INVESTIGATOR/

INSTITUTION INTERVENTION POPULATION

ANTICIPATED 

COMPLETION 

DATE

Hormones (Continued)

Estrogen Use in 

Protection from 

Cognitive Decline 

Natalie Rasgon, 

Stanford University 

Continuation of or 

removal from postmenopausal estrogen 

treatment 

Healthy women age 

50-65 

2011 

Hormones and 

Cognitive Processing in 

Early Postmenopausal 

Women 

Yolanda Smith, 

University of Michigan 

Estradiol and 

prometrium 

(progesterone) 

Healthy early postmenopausal women 

age 45-55 

2011 

KEEPS-CA (Kronos 

Early Estrogen 

Prevention Study– 

Cognitive and Affective 

Study) 

Sanjay Asthana, 

University of Wisconsin, 

Madison 

Oral conjugated equine 

estrogen and transdermal 

17β-estradiol 

Healthy postmenopausal 

women age 42-58 

2012 

Sex Steroids and 

Cognition in 

Postmenopausal 

Women 

Elliot Hirshman, 

University of Maryland, 

Baltimore County

Dehydroepiandrosterone 

(DHEA) 

Healthy postmenopausal 

women age 55-65 and 

70-80 

2011 

Testosterone Trial Peter Snyder, University 

of Pennsylvania 

Testosterone gel Older men 2015 

Exercise

Cognitive Benefits of 

Aerobic Exercise Across 

the Lifespan 

Yaakov Stern and 

Richard Sloan, 

Columbia University 

Stretching/toning or 

aerobic conditioning 

Healthy adults age 

25-65 

2015 

Dose-Response Study 

of Exercise in Older 

Adults 

Jeffrey Burns, 

University of Kansas 

Aerobic exercise Healthy older adults 2012 

Exercise, Age-Related 

Memory Decline, and 

Hippocampal Function 

Scott Small and 

Richard Sloan, 

Columbia University 

Exercise training or 

maintenance of 

sedentary lifestyle 

Healthy adults age 

20-65 

2015 

Exercise and Cognitive Training

Brain and Cognitive 

Changes after 

Reasoning or Physical 

Training in Cognitively 

Normal Seniors 

Sandra Chapman, 

University of Texas, 

Dallas 

Cognitive training, 

aerobic exercise 

Adults age 60-75 2011 

Combined Exercise and 

Cognitive Training 

Intervention in Normal 

Aging 

Yaakov Stern, 

Columbia University 

Aerobic exercise and 

cognitive training 

Healthy adults age 

65-75 

2012 

Combining Exercise and 

Cognitive Training to 

Improve Everyday 

Function 

Ellen Binder and Mark 

McDaniel, Washington 

University 

Aerobic exercise and 

cognitive training 

Healthy adults age 

55-75 

2012 

TABLE 3 continued

 54 2010 Progress Report on Alzheimer’s Disease
TRIAL NAME

PRINCIPAL 

INVESTIGATOR/

INSTITUTION INTERVENTION POPULATION

ANTICIPATED 

COMPLETION 

DATE

Exercise and Cognitive Training (Continued)

Impact of Exercise and 

Engagement on 

Cognition in Older 

Adults 

Denise Park, University 

of Texas, Dallas 

Walking, exercise regimen (aerobic tasks); 

quilting, photography 

(cognitive tasks) 

Healthy adults age 60-

85 

2011 

Improvement of Visual 

Processing in Older 

Adults 

Karlene Ball, University 

of Alabama, Birmingham 

Combination of visual 

processing training and 

exercise 

Healthy adults age 65+ 2011 

Influence of Fitness and 

Cognitive Training on 

Brain and Cognition 

Arthur Kramer, 

University of Illinois, 

Urbana-Champaign 

Aerobic training (walking), combined aerobic 

training/cognitive training (dancing) 

Adults age 60-75 2015 

Tai Chi and Guided 

Autobiography for 

Remediation of AgeRelated Cognitive 

Decline 

Victor Henderson, 

Stanford University 

Low-impact Tai Chi 

exercise and autobiographical writing 

Healthy adults age 70+ 2012 

Other

Guanfacine Treatment 

for Prefrontal Cognitive 

Dysfunction in Elderly 

Subjects 

Christopher Van Dyck, 

Yale University 

Guanfacine Healthy adults age 75+ 2011 

Mechanisms of 

Cognitive Impairment in 

Chronic Kidney Disease 

Manjula Kurella Tamura, 

Stanford University 

Frequent hemodialysis Adults age 55+ 2012 

Note: For information on new and currently recruiting trials, visit: www.nia.nih.gov/alzheimers or ClinicalTrials.gov.

TABLE 3 continued

 55 2010 Progress Report on Alzheimer’s Disease
8Advancing Support for 

Caregivers

As the search for more effective interventions 

continues, people with Alzheimer’s and their caregivers 

can turn to strategies that may improve their quality of 

life. These strategies include seemingly simple but 

important approaches, such as providing clear and informative information, learning about changes to expect as 

the disease progresses, and having resources to help prepare for these changes. 

More intensive, formalized treatment programs 

aimed at improving patient care and reducing stress for 

caregivers are also being developed and tested. Some of 

these programs use occupational therapy-based strategies 

to improve the lives of people with Alzheimer’s and to 

teach their caregivers skills to protect their own health 

and cope with the intense demands of caregiving. 

Several of these nonpharmacological interventions have 

been tested in controlled clinical trials and found to significantly improve the well-being of people of people 

with Alzheimer’s and their caregivers.

Factors in Caregiving and Mortality

Caring for people with dementia is challenging, but support for caregivers can help ease the burden and may 

result in better outcomes for Alzheimer’s patients. A 

University of Pittsburgh team looked at which factors 

predicted how care was provided—at home or elsewhere, 

by family or others—to 950 people with Alzheimer’s 

who were residing at home when the study began 

(Schulz et al., 2010). Over the course of 18 months, 

people whose caregivers reported increasing difficulty in 

coping with the person’s memory problems were more 

likely to be placed in care facilities, as were people who 

were Caucasian as opposed to African American or 

Hispanic. Importantly, people whose caregivers received 

the Resources for Enhancing Alzheimer’s Caregiver 

Health (REACH) intervention were also found to be at 

reduced risk of death. Understanding factors that influence care transitions and mortality in dementia is 

important both to those with the disorder and their 

caregivers and physicians, so that everyone involved can 

plan for the future.

Reducing Caregiver Stress

Surveys suggest that more than 70 percent of people 

diagnosed with Alzheimer’s disease live at home, where 

family and friends provide nearly most of their care. The 

amount of time caregivers spend taking care of their 

loved ones ranges from 69 to 117 hours per week 

(Elliott et al., 2010). Not surprisingly, the burden and 

stress of these demands can wear on the physical and 

emotional health of caregivers. Finding effective strategies to alleviate their burden would benefit not only 

caregivers but also those with Alzheimer’s. 

Researchers at Yale University, New Haven, CT, 

investigated which patient symptoms caused the most 

burden and emotional distress for caregivers (Mohamed 

et al., 2010). They studied 421 people diagnosed with 

or suspected of having Alzheimer’s who lived at home 

and required a significant amount of care that might 

otherwise place them in a care facility. Some of the clinical trial participants received medications intended to 

reduce Alzheimer’s-related psychosis, agitation, and 

aggressive behaviors, while others received placebos. 

 Consistent with other studies, the researchers found 

it was not declines in their loved one’s cognition or 

memory that affected caregivers most. Rather, caregivers’ 

feelings of depression and stress depended on the severity of the patients’ psychiatric and behavioral symptoms 

and declines in the patients’ quality of life. Notably, 

those caring for their spouses reported more feelings of 

distress than did other caregivers. This result suggests 

that two effective steps toward alleviating caregiver burden might be targeting problem behaviors with both 

drug and other interventions and enhancing the quality 

of life of the person with Alzheimer’s.

Receiving a dementia diagnosis is a life-altering 

event, and people often need education and psychosocial 

support to better cope with the news. Chapters of the 

Alzheimer’s Association and the Alzheimer’s Foundation 

of America and other community-based organizations 

offer group education and support programs for those 

with the disease and their caregivers. These programs 

enable people to share their experiences and concerns, 

learn more about their disease, reduce feelings of isolation, and get help coping with lifestyle changes and 

long-term care planning. 

University of Washington researchers looked at the 

effectiveness of support in a controlled clinical trial of 

142 pairs of participants, comprised of a person diagnosed 

 56 2010 Progress Report on Alzheimer’s Disease
with early-stage dementia and his or her caregiver. The 

pairs were split into two groups: 96 received program 

support while 46 controls were put on a program waiting list (Logsdon et al., 2010). Compared to the control 

group, the Alzheimer’s patients who received program 

support had reduced depression and behavioral problems, improved family communication, and a greater 

sense of self-efficacy. The improvements were modest, 

but were more pronounced for those who were more 

distressed after their diagnosis. Caregivers who attended 

the support groups did not report significant changes in 

their own quality of life, perhaps because the support 

program focused primarily on the needs of the person 

diagnosed with early-stage disease.

REACH-ing Out to Caregivers

Since 1995, the NIA and the National Institute of 

Nursing Research have funded two phases of a clinical 

trial to develop and test strategies for helping dementia 

caregivers manage their stress and emotional burden. 

The results of phases I and II of REACH (Resources for 

Enhancing Alzheimer’s Caregiver Health) clinical trials 

are now being put into practice through two Federal 

agencies, the Veterans Administration and the 

Administration on Aging. The interventions include 

education on dementia, training in specific caregiving 

skills, and encouragement and techniques for emotional 

and physical self-care. 

Nearly 500 caregivers participating in REACH II 

received either the intervention (nine in-home visits and 

three telephone contacts from REACH staff providing 

instruction and support in caregiving skills, stress management, and self-care) or no intervention. In 2010, 

researchers at the University of Alabama examined the 

self-reported health status of participants at the start of 

the study compared to its end (Elliott et al., 2010). The 

intervention also provided caregivers tools and resources 

to track and maintain their own health, and researchers 

were interested in the effectiveness of these tools. 

Caregivers who received the intervention reported better 

physical and emotional health and quality of sleep than 

those who did not. 

Behavioral problems common in people with 

Alzheimer’s—repeating statements over and over, waking 

others at night, refusing care or being combative—can 

cause considerable distress and depression for caregivers. 

However, caregivers are reluctant to discuss these 

problems with physicians, a University of Pittsburgh 

study found (Hunsaker et al., 2010). In a small study of 

25 caregivers, 80 percent cited dementia-related problem 

behaviors in a questionnaire, but only 23 percent of 

them discussed those behaviors during medical visits. 

Caregivers were much more forthcoming with reports of 

patient memory problems, bringing them up almost 

70 percent of the time they met with doctors. 

Reporting problem behaviors requires the caregiver 

to raise a potentially sensitive topic, often while the person being discussed is in the room. The researchers 

noted that caregivers may be reluctant to discuss the 

behaviors, even when the doctor is the first to broach 

the topic. Caregivers who experienced more serious or 

frequent problem behaviors were more likely to discuss 

them, however. The study suggests exploring ways to 

encourage caregivers to be more assertive in discussing 

behavioral problems with clinicians, since these symptoms are some of the most stressful aspects of caregiving 

and, in many cases, can be treated. 

Support for Patient/Caregiver Pairs

Thomas Jefferson University in Philadelphia developed 

the Care of Persons with Dementia in their Environments 

(COPE) program to support the physical function and 

quality of life for people with dementia and their caregivers. In the program, occupational therapists worked 

with caregivers during as many as 10 sessions over 4 months 

to identify patient routines, habits and interests, and 

caregiver concerns. The therapists also tested the cognition and functioning of the care recipient to identify 

strengths and deficits. The therapists then trained caregivers in home safety, to simplify tasks, and to reduce 

stress.

In a clinical trial, Jefferson researchers tested the 

COPE intervention in a group of 102 pairs of caregivers and their loved ones (Gitlin et al., 2010a). 

Compared to those who did not receive the intervention, 

the COPE participants with dementia were significantly 

less dependent on caregivers in carrying out activities of 

daily living and showed greater engagement in and 

enjoyment in activities. Caregivers with COPE had significantly improved well-being and confidence in their 

caregiving skills.

 57 2010 Progress Report on Alzheimer’s Disease
The same team from Thomas Jefferson University, 

Philadelphia, also looked at how a nondrug intervention 

aimed at helping family caregivers manage distressing 

behaviors in loved ones with dementia might improve 

patient and caregiver outcomes (Gitlin et al., 2010b). 

The program, called Advancing Caregiver Training or 

ACT, focused on problems arising from three sources: 

the patient (unmet needs, discomfort or pain, undiagnosed medical conditions); the caregiver (stress, communication style); and the environment (clutter, other 

Additional references:

McCurry SM et al. (2010) Predictors of short- and long-term 

adherence to a daily walking program in persons with 

Alzheimer’s disease. University of Washington, Seattle. Supported 

by NIMH.

Williams VP et al. (2010) Video-based coping skills to reduce 

health risk and improve psychological and physical well-being in 

Alzheimer’s disease family caregivers. Duke University Medical 

Center. Supported by NIA.

n

n

Caring for people with dementia is 

challenging, but support for caregivers can help 

ease the burden and may result in better 

outcomes for Alzheimer’s patients.

hazards). The 24-week program included up to 11 home 

visits and telephone calls by health professionals, who 

identified potential triggers of patient behaviors. 

Caregivers received training and support in strategies to 

modify those triggers and reduce their own stress levels. 

Blood and urine samples found undiagnosed medical 

conditions in 34 percent of the patients.

Compared to control caregivers, those who received 

the ACT intervention reported significant improvements in difficult patient behaviors, reduced upset and 

enhanced confidence in managing the behaviors, less 

negative communication, less burden, and improved 

well-being. In this study, the overwhelming majority of 

caregivers identified behaviors typically not responsive 

to medications as being the most troublesome, highlighting the importance of nondrug interventions for 

these problems.

 58 2010 Progress Report on Alzheimer’s Disease
9Examining Social and 

Economic Risk Factors 

Research suggests that certain racial, ethnic, 

and socioeconomic groups may be at greater risk for 

cognitive decline and dementia. Scientists are exploring 

ways to better define and overcome these differences, in 

part by broadening the diversity of people participating 

in research aimed at finding interventions. 

For example, lower levels of education are tied to 

lower levels of cognitive function throughout adulthood 

and a higher risk for dementia. Researchers at Brandeis 

University, Waltham, MA, were interested in examining 

whether this association might be counteracted by 

activities that engage the mind and intellect. They surveyed 3,343 people between ages 32 and 84 and asked 

how often they engaged in four categories of cognitive 

activities: reading books, magazines, or newspapers; 

doing crosswords, puzzles, ScrabbleTM, or other word 

games; attending educational lectures or courses; and 

writing, such as letters, journal entries, or stories 

(Lachman et al., 2010). 

The researchers administered memory tests to the 

participants and compared their answers about activities 

with performance on the tests. Participants with fewer 

than 4 years of college generally performed more poorly 

on memory tests than those with more education. However, 

those with less education who frequently engaged in 

cognitive activity had relatively better memory performance. 

In fact, less educated people who engaged in frequent 

cognitive activity had memory performance comparable 

to that of people with 4-year college degrees or higher. 

More research would be needed to test whether encouraging more frequent engagement in cognitive activities 

can reduce risk of cognitive decline in less advantaged 

populations.

The prevalence of Alzheimer’s and other age-related 

cognitive disorders in America among African Americans 

and Hispanics equals or exceeds that among Caucasians. 

However, participation of these ethnic groups in biomedical research studies falls far below their representation in the general population. The most commonly 

reported barrier to recruiting ethnic minorities for 

research studies is a historical mistrust of researchers and 

the medical system. 

Two NIA-funded Alzheimer’s Disease Centers 

focused on that issue and reported an increase in their 

minority recruitment efforts. The University of 

California, Davis, Alzheimer’s Disease Center developed 

an outreach program that included educational presentations at community churches, senior centers, and support groups. The program also encouraged word-of-mouth 

referrals from study participants (Hinton et al., 2010). 

The Bryan Alzheimer’s Disease Research Center at Duke 

University, Durham, NC, emphasized partnerships 

between community members and researchers to identify 

problem issues, recruit participants, and share research 

findings with the community, with transparency and 

accountability of the research investigators being a key 

goal (Ballard et al., 2010). Researchers hope that efforts 

such as these will lead to greater representation in 

research by these groups, so that interventions can be 

more effectively developed and tested to benefit everyone 

with cognitive decline and dementia. 

Additional reference:

Wilson RS et al. (2010) Cognitive decline in incident 

Alzheimer disease in a community population. Rush University 

Medical Center. Supported by NIEHS and NIA.

n

 59 2010 Progress Report on Alzheimer’s Disease
As the lead institute at NIH on Alzheimer’s disease, the 

NIA is looking to the future in several ways:

● convening and collaborating in workshops in new 

scientific areas

● working across the NIH to vigorously discuss new 

science and opportunities for new investment

● partnering with other Federal agencies, not-for-profit 

groups, and industry in the shared goal of improved 

treatments, new prevention strategies, and better programs for caregivers and patients.

Infrastructure support includes:

NIA Intramural Research Program (IRP). In addition to funding a broad portfolio of aging-related and 

Alzheimer’s research at institutions across the country, 

the NIA supports its own laboratory and clinical research 

program, based in Baltimore and Bethesda, MD. The 

NIA IRP focuses on understanding age-related changes 

in physiology and behavior, the ability to adapt to biological and environmental stresses, and the pathophysiology of age-related diseases such as Alzheimer’s. 

Laboratory research ranges from studies in basic biology, 

such as neurogenetics and cellular and molecular neurosciences, to examinations of personality and cognition. 

The IRP also conducts clinical trials to test possible new 

imaging

memory

clinical risk beta

biomarkers

alpha

Advancing Future the of

Alzheimer’s Research:

NIA Research Infrastructure and Initiatives

It is critical that the Federal research program for Alzheimer’s disease create 

and sustain an infrastructure that supports and enhances the scientific enterprise. 

The NIA's coordinating mechanisms and key initiatives are critical to this effort. 

By pooling and sharing data widely and efficiently using a well-established 

Alzheimer’s disease research infrastructure, science is advancing even within the 

limits of constrained resources.

 60 2010 Progress Report on Alzheimer’s Disease
interventions for cognitive decline and Alzheimer’s disease. The IRP leads the Baltimore Longitudinal Study of 

Aging, America’s longest-running scientific study of 

human aging, begun in 1958, which has provided valuable insights into cognitive change with age.

Alzheimer’s Disease Centers (ADCs). The NIA’s 

ADCs form the backbone of the national Alzheimer’s 

disease research effort. These multidisciplinary centers, 

located at 29 institutions nationwide, promote research, 

training and education, and technology transfer. With 

participation by the community, the Centers conduct 

longitudinal multicenter and collaborative studies of 

Alzheimer’s disease diagnosis and treatment, age-related 

neurodegenerative diseases, and predictors of future 

change in people without dementia that may indicate the 

initial stages of development of the disease. The ADCs 

also conduct complementary studies, such as imaging 

studies and autopsy evaluations. All participants enrolled 

in the Centers receive a standard annual evaluation. Data 

from these evaluations are collected and stored by the 

National Alzheimer’s Coordinating Center (NACC, see 

below) as the Uniform Data Set. The ADCs serve as sites 

for a number of major studies, such as national initiatives 

in clinical trials and imaging and biomarker research (see 

descriptions of ADCS and ADNI below). 

National Alzheimer’s Coordinating Center (NACC). 

The NIA established NACC in 1999 with the goal of 

pooling and sharing data on participants in Alzheimer 

Disease Centers studies. By 2005, NACC had collected 

data from some 77,000 ADC study participants, including neuropathic data from 10,000 brain autopsies. The 

NACC then added clinical evaluations and annual followups to its protocol, enriching the database with detailed 

longitudinal data from 24,000 participants and 1,600 

brain autopsies. The data are available to Alzheimer’s 

researchers worldwide. 

The NACC data are helping to reveal different 

symptom patterns in different subsets of Alzheimer’s 

patients, patterns that would not have become apparent 

without analyzing a dataset of this size. The NACC also 

helps coordinate other NIA efforts, such as the identification and selection of appropriate postmortem material 

collected at ADCs to send to the National Cell Repository 

for Alzheimer’s Disease for use in GWAS conducted by 

the ADGC. 

In 2010, NACC data proved vital to research conducted 

on hippocampal sclerosis, an age-related condition often 

confused with Alzheimer’s. Researchers used data from 

participants enrolled at ADCs and other major studies to 

take the first step—clinical differentiation comparing the 

features of hippocampal sclerosis with pure Alzheimer’s 

disease (Nelson et al., 2010 ). The study involved the 

largest series of autopsy-verified patients with hippocampal 

sclerosis ever assembled and could only be done with 

coordination and funding by the NACC.

Alzheimer’s Disease Cooperative Study (ADCS). 

The NIA launched the ADCS in 1991 to develop and 

test new interventions and treatments for Alzheimer’s 

disease that might not otherwise be developed by industry. Operated under a cooperative agreement with the 

University of California, San Diego, this large clinical 

trials consortium comprises more than 75 sites throughout the United States and Canada. The ADCS focuses 

on testing agents that lack patent protection, patented 

drugs that are marketed for other indications, and novel 

compounds developed by individuals, academic institutions, and small biotech companies. It also develops new 

evaluation instruments for clinical trials and innovative 

approaches to clinical trial design. The group provides 

infrastructure support to other Federally funded clinical 

efforts, including ADNI and the Dominantly Inherited 

Alzheimer Network (DIAN, a study of familial 

 61 2010 Progress Report on Alzheimer’s Disease
Alzheimer’s). See www.adcs.org for a summary of current 

trials and studies conducted by the ADCS.

National Cell Repository for Alzheimer’s Disease 

(NCRAD). This NIA-funded repository, located at 

Indiana University Medical Center in Indianapolis, provides resources that help researchers identify the genes 

that contribute to Alzheimer’s and other types of 

dementia. NCRAD collects and maintains biological 

specimens and associated data on study volunteers from 

a variety of sources, primarily from the people enrolled 

at the ADCs as well as those in ADNI, the ADGC, and 

other studies. NCRAD also houses DNA samples and 

data from more than 900 families with multiple members affected by Alzheimer’s. Qualified research scientists 

may apply to NCRAD for samples and data to conduct 

genetic research. Since it was funded 20 years ago, more 

than 50,000 biological samples have been requested and 

sent to investigators across the United States, resulting 

in more than 200 scientific publications, 33 of which 

were issued in 2010. For more information on NCRAD, 

go to http://ncrad.iu.edu. 

NIA Genetics of Alzheimer’s Disease Data Storage 

Site (NIAGADS). Located at the University of 

Pennsylvania, NIAGADS is a Web-based data warehouse 

for Alzheimer’s disease genetic data. All genetic data 

derived from NIA-funded studies on the genetics of lateonset Alzheimer’s are deposited at NIAGADS, another 

NIA-approved site, or both. Data from GWAS that are 

stored at NIAGADS are also made available through the 

database of Genotype and Phenotype (dbGaP) at the 

National Library of Medicine’s National Center for 

Biotechnology Information, which was developed to 

archive and distribute the results of large-scale GWAS 

analyses. Through dbGaP, data sets from multiple GWAS 

done on different platforms can be merged, and data 

from thousands of study participants can be analyzed 

together, increasing the probability of gene discovery.

Major NIA program initiatives include: 

Alzheimer’s Disease Neuroimaging Initiative 

(ADNI). The NIA in 2004 launched this groundbreaking initiative, the largest public-private partnership to 

date in Alzheimer’s disease research. The goal was to find 

neuroimaging and other biological markers that could 

be used to detect disease progression and measure the 

effectiveness of potential therapies. The study recruited 

800 participants, a mix of cognitively healthy people 

and those with Alzheimer’s disease or MCI. To speed the 

pace of analysis and findings, ADNI investigators agreed 

to make their collected data widely available. MRI and 

PET scan brain images as well as clinical, genetic, and 

fluid biomarker data are available to qualified researchers 

worldwide through a Web-based database.

The first phase of ADNI was remarkably fruitful: 

more than 170 papers using ADNI data have been published from investigators around the world, and many 

more will come as more data are collected and analyzed. 

Early findings have generated excitement about using brain 

and fluid markers to identify people at risk for developing 

Alzheimer’s or to characterize the pace of deterioration. 

Accomplishments include new findings about how changes 

in the structure of the hippocampus may help detect disease progression and effectiveness of potential treatments, 

and the establishment of biomarker and imaging measures 

that predict risk for cognitive decline and conversion to 

dementia. The success of ADNI has inspired similar 

efforts in Europe, Japan, and Australia. 

 62 2010 Progress Report on Alzheimer’s Disease
A follow-on effort, ADNI-GO, was launched with 

American Recovery and Reinvestment Act funds in 

2009, followed by ADNI 2 in fall 2010. ADNI 2 set a 

5-year goal of recruiting approximately 1,000 people, 

age 55 to 90, at 55 sites in the United States and 

Canada. They will be followed to define changes in 

brain structure and function as people transition from 

normal cognitive aging to MCI, and from MCI to 

Alzheimer’s dementia. The study will use imaging techniques and biomarker measures in blood and cerebrospinal fluid specially developed to track changes in the 

living brain. Researchers hope to identify who is at risk 

for Alzheimer’s, track progression of the disease, and 

devise tests to measure the effectiveness of potential 

interventions. ADNI 2 will continue to follow participants in the other ADNI cohorts. 

Dominantly Inherited Alzheimer’s Disease 

Network (DIAN). In 2008, the NIA launched the 

6-year DIAN study to better understand the biology of 

early-onset Alzheimer’s, a rare, inherited form of the disorder that can occur in people as early as their 30s and 

40s. Scientists involved in this collaborative, international effort hope to recruit 300 adult children of people 

with Alzheimer’s disease to help identify the sequence of 

brain changes that take place even before symptoms of 

the disorder appear. By understanding this process, 

researchers hope to gain additional insights into the 

more common late-onset form of the disease. 

Until DIAN, the rarity of the condition and geographic distances between patients and research centers 

hindered research. Today, volunteers age 18 and older 

with at least one biological parent with the disorder are 

participating in DIAN at a network of research sites in 

the United States, England, and Australia. Each participant receives a range of assessments, including genetic 

analysis, cognitive testing, and brain scans, and donates 

blood and CSF so scientists can test for biomarkers. 

DIAN researchers are building a shared database of the 

assessment results, samples, and images to advance 

knowledge of the brain mechanisms involved in 

Alzheimer’s, eventually leading to targets for therapies 

that can delay or even prevent progress of the disease. 

The study is being led by the ADC at Washington 

University School of Medicine in St. Louis. Research 

collaborators include Massachusetts General Hospital; 

Brigham and Women’s Hospital; Brown University; 

Columbia University; Indiana University; the University 

of California, Los Angeles; the University College, London 

Institute of Neurology at Queen’s Square; and a consortium of the Universities of Melbourne and New South 

Wales and Edith Cowan University in Australia. For 

more information about DIAN, go to www.dian-info.org.

Alzheimer’s Disease Genetics Initiative (ADGI) and 

Alzheimer’s Disease Genetics Consortium (ADGC). 

The study of Alzheimer’s disease genetics is complicated 

by the likelihood that the risk of late-onset Alzheimer’s is 

influenced by many genes, each of which probably confers a relatively small risk. Identifying these genes requires 

analyzing the genomes of large numbers of people. 

ADGI was launched in 2003 to identify at least 1,000 

families containing multiple members who have lateonset Alzheimer’s as well as family members who do not. 

In 2009, the NIA funded the ADGC to support the use 

of large-scale, high-throughput genetics technologies 

needed by researchers studying late-onset Alzheimer’s.

These initiatives are achieving important results. In 

April 2011, an ADGC-led study confirmed one gene 

variant and identified several others that may be risk factors for late-onset Alzheimer’s disease, the most common 

form of the disorder. In the largest GWAS ever conducted 

in Alzheimer’s research, investigators studied DNA samples 

from more than 56,000 study participants and analyzed 

shared datasets to detect gene variations that may have 

subtle effects on Alzheimer’s risk. In addition to providing 

 63 2010 Progress Report on Alzheimer’s Disease
additional insight into the pathology of Alzheimer’s and 

suggesting therapeutic targets, these new gene discoveries may also one day help predict who is at risk for the 

disease. 

Alzheimer’s Disease Translational Research 

Program. Launched in 2004, this program supports 

early drug discovery and preclinical drug development 

research by academic scientists and small biotechnology 

companies, with the goal of finding ways to treat and 

prevent Alzheimer’s, MCI, and age-related cognitive 

decline. This effort is broadening the range of potential 

treatments and therapeutic targets by supporting critical 

steps of the drug discovery process that are traditionally 

not supported by the pharmaceutical industry. In 2009, 

the NIA committed 5 million dollars to continue two 

funding initiatives for early drug discovery and preclinical drug development through 2012. 

Alzheimer’s Disease Pilot Clinical Trials Initiative. 

This initiative, begun in 1999, is aimed at increasing the 

number and quality of preliminary clinical evaluation of 

interventions for Alzheimer’s, MCI, and age-associated 

cognitive decline. The goal is not to duplicate or compete with the efforts of pharmaceutical companies but to 

encourage, complement, and accelerate the process of 

testing new, innovative, and effective treatments. 

Initially focused on drug interventions, the program has 

been broadened to nonpharmacologic as well as pharmacologic interventions. NIH sister institutes—the 

National Center for Complementary and Alternative 

Medicine and the National Institute of Neurological 

Disorders and Stroke—also participate in this initiative. 

Research Partnership on Cognitive Aging. Through 

the Foundation for NIH, NIA and the McKnight Brain 

Research Foundation convened a Cognitive Aging 

Summit in 2007 focused on healthy brain aging and 

function. This summit helped galvanize the field and 

served as a catalyst for two subsequent research initiatives. The first initiative is testing pilot interventions to 

reverse age-related decline or maintain successful function. The second initiative is determining the neural and 

behavioral profiles of age-related cognitive change and 

identifying components of these profiles that distinguish 

normal age-related change from pathological decline. 

Investigators heading these pilot studies have met annually 

to share their initial findings and to receive feedback 

from their colleagues on this exciting area of research. A 

second Summit, held in October 2010, shared progress 

from studies and identified future research directions. 

Investigators supported by the partnership have had 

30 papers published in scientific journals. 

NIH Toolbox for Assessment of Neurological and 

Behavioral Function. Supported by the NIH Blueprint 

for Neuroscience Research and the NIH Office of 

Behavioral and Social Sciences Research, researchers are 

developing a set of brief tests to assess cognitive, sensory, 

motor, and emotional function, particularly in studies 

that enroll many people (such as epidemiological studies 

and clinical trials). Developed under a contract with 

NIH, these royalty-free tests will be available in English 

and Spanish and applicable for use in people age 3 to 85 

years, enabling direct comparison of cognitive and other 

abilities at different ages across the lifespan. Now in the 

final stages of development, this NIH Toolbox resource 

will be available to researchers and clinicians in fall 2012.

Human Connectome Project. Supported through 

the NIH Blueprint for Neuroscience Research, the 

Human Connectome Project was started in 2010 to 

develop and share knowledge about the structural and 

functional connectivity of the healthy human brain. 

This collaborative effort will use cutting-edge neuroimaging instruments, analysis tools, and informatics 

technologies to map the neural pathways underlying 

human brain function. The project will map the connectomes in 1,200 healthy adults—twin pairs and their 

siblings—and will study anatomical and functional connections between regions of the brain. This information 

will be related to behavioral test data collected using 

another NIH Blueprint research tool, the NIH Toolbox 

for Assessment of Neurological and Behavioral Function, 

and to data on the genetic makeup of the participants. 

The goal is to reveal the contributions of genes and 

environment in shaping brain circuitry and the variability in such connectivity. The human connectome map of 

the healthy adult brain will serve as a foundation to further understand how brain networks change with age 

and neurological diseases like Alzheimer’s.

 64 2010 Progress Report on Alzheimer’s Disease
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Bimonte-Nelson HA. The cognitive effects of conjugated equine 

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www.ncbi.nlm.nih.gov/pubmed/20555031

Anderson DW, Brayne C (eds.). Alzheimer’s & Dementia 2011;7(1):3-123. 

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Apostolova LG, Hwang KS, Andrawis JP, Green AE, Babakchanian S, 

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CR Jr, Petersen RC, Aisen PS, Jagust WJ, Koeppe RA, Mathis CA, 

Weiner MW, Thompson PM. Alzheimer’s Disease Neuroimaging 

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Ballard EL, Gwyther LP, Edmonds HL. Challenges and opportunities: 

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Bendlin BB, Ries ML, Canu E, Sodhi A, Lazar M, Alexander AL, 

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Bloss EB, Janssen WG, McEwen BS, Morrison JH. Interactive effects of 

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Borson S, Scanlan JM, Lessig M, DeMers S. Comorbidity in aging and 

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Boyle PA, Buchman AS, Wilson RS, Leurgans SE, Bennett DA. 

Physical frailty is associated with incident mild cognitive impairment in 

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biomarkers image

genetics

risk

memory

clinica

trials alpha

geneticsbeta

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National Institute on Aging

National Institutes of Health

U.S. Department of Health and Human Services

December 2011 

NIH Publication No. 11-7829 

biomarkers

beta riskalpha

brain

dementia care trials

prevent

plaques

tau

inflammation

care