Progress Report on Alzheimer's Disease, 1999      
    Contents:
    * Introduction
          o The Impact of Alzheimer's Disease 
          o Alzheimer's Disease: An Urgent National Health and Research
            Priority
    * The AD Research Effort
    * Alzheimer's Disease: A Puzzle Being Solved 
    * What Are the Main Characteristics of AD? 
          o Amyloid Plaques 
          o Neurofibrillary Tangles 
          o Genetic Factors in AD Development 
          o Non-Genetic Factors in AD Development 
    * What Do We Know About Diagnosing AD? 
    * How Can Alzheimer's Disease be Treated? 
    * 1999 AD Research Advances: Building on the Foundation 
    * Understanding the Etiology of AD 
          o Amyloid 
          o Presenilins 
          o Tauopathies and Tangles 
          o Genetic Links to Late-Onset AD 
          o Inflammation 
          o Oxidative Stress 
          o Brain Infarction 
          o Diet 
    * Improving Early Diagnosis 
          o Mild Cognitive Impairment 
          o Neuroimaging 
    * Developing Drug Treatments 
          o Treating Cognitive Decline 
          o Slowing the Progress, Delaying the Onset, or Preventing the
            Disease 
          o Treating Behavioral Symptoms
    * Future Considerations for AD Clinical Research 
          o Improving Support for Caregivers 
          o REACH
          o Special Care Units 
          o Building a Research Infrastructure 
          o Innovative Mechanisms for Funding AD Research 
    * Support for AD Research by Other NIH Institutes 
          o National Institute of Neurological Disorders and Stroke
          o National Institute of Mental Health 
          o National Institute of Nursing Research 
          o National Institute on Alcohol Abuse and Alcoholism
          o National Center for Research Resources 
          o National Institute of Child Health and Human Development
          o National Institute of Environmental Health Sciences
          o National Institute on Deafness and Other Communication
            Disorders 
    * Outlook for the Future 
    * References (Abstracts From Medline)
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*_INTRODUCTION_*
Alzheimer's disease (AD) is an irreversible, progressive brain disorder
that occurs gradually and results in memory loss, behavior and
personality changes, and a decline in thinking abilities. These losses
are related to the death of brain cells and the breakdown of the
connections between them. The course of this disease varies from person
to person, as does the rate of decline. On average, AD patients live for
8 to 10 years after they are diagnosed, though the disease can last for
up to 20 years.
AD advances by stages, from early, mild forgetfulness to a severe loss
of mental function. This loss is called dementia. In most people with
AD, symptoms first appear after age 60. The earliest symptoms often
include loss of recent memory, faulty judgment, and changes in
personality. Often, people in the initial stages of AD think less
clearly and forget the names of familiar people and common objects.
Later in the disease, they may forget how to do simple tasks, such as
washing their hands. Eventually, people with AD lose all reasoning
ability and become dependent on other people for their everyday care.
Finally, the disease becomes so debilitating that patients are bedridden
and likely to develop other illnesses and infections. Most commonly,
people with AD die from pneumonia.
Although the risk of developing AD increases with age, AD and dementia
symptoms are not a part of normal aging. AD and other dementing
disorders are caused by diseases that affect the brain. In the absence
of disease, the human brain often can function well into the tenth
decade of life.
 
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*The Impact of Alzheimer's Disease*
AD is the most common cause of dementia among people age 65 and older.
It presents a major health problem for the United States because of its
enormous impact on individuals, families, the health care system, and
society as a whole. Scientists estimate that up to 4 million people
currently suffer with the disease, and the prevalence (the number of
people with the disease at any one time) doubles every 5 years beyond
age 65. It is also estimated that approximately 360,000 new cases
(incidence) will occur each year, though this number will increase as
the population ages (Brookmeyer et al., 1998). A number of research
groups have examined differences in AD prevalence among racial and
ethnic groups, and it appears from some studies that the risk is higher
for African Americans and Hispanic Americans than it is for Caucasians,
though not all studies provide similar results. These differences are
important to study, not only because of the growing percentage of
non-Caucasians in the older U.S. population (by the year 2050, the
percentage of the population over the age of 85 that is non-Caucasian
will have increased from 16 percent to 34 percent), but because the
variations in prevalence may reflect different roles of particular
genetic and environmental factors in the development of AD.
AD puts a heavy economic burden on society. A recent study estimated
that the annual cost of caring for one AD patient is $18,408 for a
patient with mild AD, $30,096 for a patient with moderate AD, and
$36,132 for a patient with severe AD. The annual national cost of caring
for AD patients is estimated to be slightly over $50 billion (Leon et
al., 1998).
These numbers gain significance when they are placed against the
backdrop of increasing life expectancy and changing demographics in the
United States. Since the turn of the century, life expectancies have
increased dramatically. More than 34 million people--13 percent of the
total population of the United States--are now aged 65 and older.
According to the U.S. Bureau of the Census, this percentage will
accelerate rapidly beginning in 2011, when the first baby boomers reach
age 65, and will reach 18 percent of the total population by the year 2025.
Approximately 4 million Americans are 85 or older, and in most
industrialized countries, this age group is one of the fastest growing
segments of the population. The Bureau of the Census estimates that this
group will number nearly 8.5 million by the year 2030; some experts who
study population trends suggest that the number could be even greater.
As more and more people live longer, the number of people affected by
diseases of aging, including AD, will continue to grow. For example,
some studies show that nearly half of all people age 85 and older have
some form of dementia.
Slightly more than half of AD patients receive care at home, while the
remainder are in many different types of health care institutions. Many
spouses, relatives, and friends take care of people with AD. During
their years of caregiving, these families and friends experience
emotional, physical, and financial stresses. They watch their loved ones
become more and more forgetful, frustrated, and confused. Eventually,
the person with AD may not even recognize his or her nearest and dearest
relatives and friends. Caregivers--most of whom are women--must juggle
child care, jobs, and other responsibilities with caring for relatives
with AD who cannot function on their own. As the disease runs its course
and the abilities of people with AD steadily decline, family members
face difficult decisions about the long-term care of their loved ones.
Frequently, they have no choice but to place their relative in a nursing
home. The numbers of caregivers--and their needs--can be expected to
grow significantly as the population ages and as the number of people
with AD increases.
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*Alzheimer's Disease: An Urgent National Health and Research Priority*
Given our aging population, the magnitude of AD as a national health
problem is steadily increasing, making the disease an urgent research
priority. Interventions that could delay the onset of AD will have an
enormous positive public health impact because they will reduce the
number of people with the disease at any one time. This in turn will
reduce the costs associated with caring for them. A recent epidemiologic
study provides a vivid illustration of the impact of delaying AD by even
a short period of time:
"If onset could be delayed, on average, 1 year, there would be nearly
210,000 and 770,000 fewer persons afflicted with Alzheimer's disease
than projected 10 and 50 years after initiation of the intervention,
respectively. If onset could be delayed, on average, only 6 months,
there would be nearly 100,000 and 380,000 fewer persons afflicted with
Alzheimer's disease than projected after 10 and 50 years,
respectively....An average 1-year delay in disease onset would result in
an annual savings of nearly $10 billion at 10 years after initiation of
the intervention....Even a modest 6-month delay would correspond to an
annual savings of perhaps $4.7 billion at 10 years after initiation of
the intervention and nearly $18 billion annually after 50 years"
(Brookmeyer et al., 1998).
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*The AD Research Effort*
AD research supported by the Federal Government is divided into three
broad, overlapping areas: causes/risk factors, diagnosis, and
treatment/caregiving. Research into the basic biology of the aging
nervous system is critical to understanding what goes wrong in the brain
of a person with AD. Understanding how nerve cells lose their ability to
communicate with each other and the reasons why some nerve cells die is
at the heart of scientific efforts to discover what causes AD.
Many researchers also are looking for better ways to diagnose AD in the
early stages and to identify the earliest brain changes that eventually
result in AD. Investigators are striving to identify markers
(indicators) of dementias, develop and improve ways to test patients,
determine causes and assess risk factors, and improve case-finding and
sampling methods for population studies. Finally, scientists and many
health care professionals are seeking better ways to help patients and
caregivers cope with the decline in mental and physical abilities and
the problem behaviors that accompany the disease and to support
caregivers of people with AD.
The National Institute on Aging (NIA), part of the Federal Government's
National Institutes of Health (NIH), has primary responsibility for
research aimed at finding ways to prevent, treat, and cure AD. The
Institute's AD research program is integral to one of its main goals,
which is to enhance the quality of life of older people by expanding
knowledge about the aging brain and nervous system. The 1999 Progress
Report on Alzheimer's Disease summarizes AD research conducted or
supported by NIA and other components of NIH, including:
    * National Institute of Neurological Disorders and Stroke
    * National Institute of Mental Health
    * National Institute of Nursing Research
    * National Institute on Alcohol Abuse and Alcoholism
    * National Center for Research Resources
    * National Institute of Child Health and Human Development
    * National Institute of Environmental Health Sciences
    * National Institute on Deafness and Other Communication Disorders
Other more modest AD research efforts not summarized in this report are
supported by the National Cancer Institute, National Institute of
Arthritis and Musculoskeletal and Skin Diseases, National Institute of
Diabetes and Digestive and Kidney Diseases, and the Fogarty
International Center.
Twenty-five years ago, we knew relatively little about the processes in
the brain that lead to Alzheimer's disease. Physicians assumed that AD
dementia was merely an inevitable consequence of aging. Scientists have
made enormous progress since then. Today, we know much more about
Alzheimer's--what it is, who gets it, how it develops, and what course
it follows. We have also made significant progress in the critical area
of early diagnosis and have some promising leads on possible treatments.
All of this research has deepened our understanding of this devastating
disease. It also has expanded our knowledge about brain function in
healthy older people and ways in which to minimize normal age-related
cognitive decline.
The 1999 Progress Report on Alzheimer's Disease is a window on this
important research effort. It begins with a summary of our current
knowledge about AD. This summary provides the backdrop for the next two
sections, which present highlights of recent research conducted by NIA
and other NIH Institutes. The report closes with a section called
"Outlook for the Future," which describes the new NIH Alzheimer's
Disease Prevention Initiative. AD research has progressed to a point
where scientists, while still thinking about the basic biology of the
disease, are increasingly able to consider strategies for slowing AD's
progress, delaying its onset, or even preventing it altogether. The
Prevention Initiative is designed to accelerate laboratory and clinical
research and collaboration across the Federal Government and the private
sector to make these strategies not a future possibility but a current
reality.
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*_ALZHEIMER'S DISEASE: A PUZZLE BEING SOLVED_*
In normal aging, nerve cells in the brain are not lost in large numbers.
In contrast, AD disrupts three key processes--nerve cell communication,
metabolism, and repair. This disruption ultimately causes many nerve
cells to stop functioning, lose connections with other nerve cells, and
die.
At first, AD destroys neurons in parts of the brain that control memory,
especially the hippocampus (a structure deep in the brain that helps
encode memories) and related structures. As nerve cells in the
hippocampus stop functioning properly, short-term memory fails, and
often, a person's ability to do easy and familiar tasks begins to
decline. AD also attacks the cerebral cortex, particularly the areas
responsible for language and reasoning. Here, AD begins to take away
language skills and change a person's ability to make judgments.
Personality changes also may occur. Emotional outbursts and disturbing
behavior, such as wandering and agitation, begin to happen and become
more and more frequent as the disease runs its course. Eventually, many
other areas of the brain are involved, all these brain regions atrophy
(shrink), and the AD patient becomes bedridden, incontinent, totally
helpless, and unresponsive to the outside world.
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*What Are the Main Characteristics of AD?*
Two abnormal structures in the brain are the hallmarks of AD: amyloid
plaques and neurofibrillary tangles. Plaques are dense, largely
insoluble (cannot be dissolved) deposits of protein and cellular
material outside and around the brain's neurons (nerve cells). Tangles
are insoluble twisted fibers that build up inside neurons. Though
scientists have known about plaques and tangles for many years, more
recent research has revealed much about their composition, how they
form, and their possible roles in the development of AD.
*Amyloid Plaques*
In AD, plaques develop first in areas of the brain used for memory and
other cognitive functions. They consist of largely insoluble deposits of
beta-amyloid--a protein fragment snipped from a larger protein called
amyloid precursor protein (APP)--intermingled with portions of neurons
and with non-nerve cells such as microglia (cells that surround and
digest damaged cells or foreign substances that cause inflammation) and
astrocytes (cells that serve to support neurons). Researchers still do
not know whether amyloid plaques themselves cause AD or whether they are
a by-product of the AD process. Certainly, changes in the APP protein
can cause AD, as shown in the inherited form of AD caused by mutations
in the APP gene (see p. 13 for more on inherited AD).
APP is one of many proteins that are associated with cell membranes. The
cell membrane encloses the cell and acts as a barrier that selects which
substances can go in and out of the cell. After it is made, APP becomes
embedded in the nerve cell's membrane, partly inside and partly outside
the cell, like a needle poking through a piece of fabric. Recent studies
using transgenic (genetically engineered) mice show that APP appears to
play an important role in the growth and survival of neurons. For
example, certain forms and amounts of APP may protect neurons against
both short- and long-term damage. In test tube studies, scientists have
found that APP may play a role in making damaged neurons better able to
repair themselves and help parts of neurons grow after brain injury.
While APP is embedded in the cell membrane, proteases (a particular kind
of enzyme, or substance, that speeds up or causes chemical reactions in
the body--in this case, cutting proteins into fragments) act on
particular sites in APP, cleaving it into protein fragments. One
protease helps cleave APP to form beta-amyloid, and another protease
cleaves APP in the middle of the amyloid fragment so that beta-amyloid
cannot be formed. The beta-amyloid formed is of two different lengths, a
shorter beta-amyloid that is more soluble and aggregates slowly, and a
slightly longer, "sticky" beta-amyloid that rapidly forms insoluble
clumps. While beta-amyloid is being formed, scientists do not yet know
exactly how it moves through or around nerve cells. In the final stages
of this process, the "sticky" beta-amyloid aggregates into long
filaments outside the cell and, along with fragments of dead and dying
neurons and the microglia and astrocytes, forms the plaques that are
characteristic of AD in brain tissue.
Many studies have centered on identifying the enzymes that cause
beta-amyloid to be formed and on determining exactly how they work. By
seeking clues in the beta-amyloid environment, scientists hope to
understand just how beta-amyloid aggregates to form the plaques that
build up in huge numbers in particular regions of the brain. Results
from very recent research suggest that beta-amyloid is formed inside a
part of the cell called the trans-Golgi network. Other work has found
that certain organelles in the neuron, called early endosomes, are much
larger in brains affected by some forms of AD than are endosomes in
healthy brains, giving scientists clues about some intracellular
processes affected by AD.
It is logical to expect that as the disease progresses, more and more
plaques will be formed, filling more and more of the brain. However,
this is not necessarily the case. In fact, the amount of beta-amyloid
often seems to be relatively constant over time. Studies with a confocal
scanning laser microscope, which allows investigators to view the
three-dimensional structure of plaques, have revealed that plaques are
not solid, but have minute holes through them. It may be that the
beta-amyloid is aggregating and disaggregating at the same time, in a
sort of dynamic equilibrium. This raises the hope that it may be
possible to break down the plaques after they have formed.
Many scientists believe that beta-amyloid is toxic to neurons, perhaps
by causing inflammation in the brain or by generating free radicals (a
particular type of molecule that easily reacts with other molecules and
that can be harmful if too many are produced). Another harmful effect of
beta-amyloid may be that it makes neurons more susceptible to different
kinds of damage, for example that caused by ischemia (poor blood flow).
The neurons become more susceptible because beta-amyloid disrupts
connections between cells in the immediate area around the plaque and
reduces the ability of some blood vessels in the brain to dilate and
compensate for the diminished blood flow. Beta-amyloid could also cause
damage by increasing intracellular calcium. Calcium is an element that
helps cells do many things, including carry nerve signals. However, too
much calcium inside cells leads to cell death.
------------------------------------------------------------------------
*Neurofibrillary Tangles*
This second hallmark of AD consists of abnormal collections of twisted
threads found inside nerve cells. The chief component of tangles is one
form of a protein called tau. In the central nervous system, tau
proteins are best known for their ability to bind and help stabilize
microtubules, which are one constituent of the cell's internal support
structure, or skeleton.
In healthy neurons, microtubules form structures like train tracks,
which guide nutrients and molecules from the bodies of the cells down to
the ends of the axon, a long thin structure that extends far out from
the cell body and forms a communicating bridge with other neurons. In
cells affected by AD, the train track structures collapse. Tau normally
forms the "railroad ties" or connector pieces of the microtubule tracks.
However, in AD tau is changed chemically, and this altered tau can no
longer hold the railroad tracks together, causing the microtubules to
fall apart. This collapse of the transport system first may result in
malfunctions in communication between nerve cells and later may lead to
neuronal death.
In AD, chemically altered tau twists into paired helical filaments--two
threads of tau that are wound around each other. These filaments are the
major substance found in neurofibrillary tangles. In one recent study,
researchers found neurofibrillary changes in fewer than 6 percent of the
neurons in a particular part of the hippocampus in healthy brains, in
more than 43 percent of these neurons in people who died with mild AD,
and in 71 percent of these neurons in people who died with severe AD.
When they studied the loss of neurons, they found a similar progression.
Evidence of this type supports the idea that the formation of tangles
and the loss of neurons progress together over the course of AD.
 
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*What Causes AD?*
Knowing the clinical and behavioral characteristics of AD is one
important part of solving the AD puzzle. Another is knowing the cause of
the disease: What makes the disease process begin in the first place and
what contributes to its development? Why does its prevalence increase
with age? Some diseases, like tuberculosis, have clear-cut causes.
Others, such as diabetes or arthritis, result from many interrelated
factors, including genetic, environmental, and other factors. AD fits
into this latter group of diseases. Scientists do not yet fully
understand what causes AD, but it is clear that AD develops as a result
of a complex cascade of events that takes place over time inside the
brain. The disease can be triggered by any number of small changes in
this cascade, and these events interact differently in different people.
Researchers have come a long way toward elucidating the genetic and
non-genetic factors that contribute to the development of AD.
*Genetic Factors in AD Development*
Two types of Alzheimer's disease exist: familial AD (FAD), which follows
a certain inheritance pattern, and sporadic AD, where no obvious
inheritance pattern is seen. Because of differences in the age at onset,
AD is further described as early-onset (occurring in people younger than
65) or late-onset (occurring in those 65 and older). Early-onset AD is
rare (about 10 percent of cases) and generally affects people aged 30 to
60. Some forms of early-onset AD are inherited and run in families.
Early-onset AD also often progresses faster than the more common,
late-onset form.
All FAD known so far has an early onset, and as many as 50 percent of
FAD cases are now known to be caused by defects in three genes located
on three different chromosomes. These are mutations in the APP gene on
chromosome 21; mutations in a gene on chromosome 14, called presenilin
1; and mutations in a gene on chromosome 1, called presenilin 2. Even if
one of these three mutations is present in only one of the two genes
inherited from the parent, the person will inevitably develop that form
of early-onset AD. There is as yet no evidence, however, that any of
these mutations play a major role in the more common, sporadic or
non-familial form of late-onset AD. Scientists are now working to reveal
the normal function of APP and presenilins and to determine how
mutations of these genes cause the onset of FAD. Some evidence exists
that the mutations in APP make it more likely that beta-amyloid will be
snipped out of the APP precursor, thus causing either more total
beta-amyloid or relatively more of the "sticky" form to be made. It
appears that the presenilin mutations may contribute to the degeneration
of neurons in at least two ways: by modifying beta-amyloid production or
by triggering the death of cells more directly. Most people with
early-onset AD and presenilin 1 and 2 mutations have more of the longer
and "stickier" form of beta-amyloid in their brains than do those with
the sporadic form. This suggests that mutations in the presenilins can
in some way drive the production of this form of amyloid. Another theory
about the possible roles for mutated presenilins in altering the
production of beta-amyloid is that they interact directly with APP on
the surface of neighboring cells, an interaction that eventually
triggers beta-amyloid production. Other researchers suggest that mutated
presenilins 1 and 2 may be involved in accelerating the pace of
apoptosis, a name for one way in which cells are programmed to die.
Genetics play a role in the development of late-onset AD as well as FAD.
In the early 1990s, researchers at the NIA-supported Alzheimer's Disease
Center at Duke University in Durham, North Carolina, found an increased
risk for late-onset AD with inheritance of one or two copies of the
apolipoprotein E epsilon4 (APOE e4) allele on chromosome 19
(Strittmatter et al., 1993). An allele is one of two or more possible
versions of the same gene, each of which has a slightly different base
sequence from the others (polymorphism). Different alleles produce
variations in inherited characteristics, such as eye color or blood
type. In this case, the variations are in the gene that directs the
manufacture of the ApoE protein, which helps carry blood cholesterol
throughout the body, among other functions. It is found in glial cells
and neurons of healthy brains, but it is also associated in excess
amounts with the plaques found in the brains of people with AD. AD
researchers are particularly interested in three common alleles of the
APOE gene: e2, e3, and e4. The finding that increased risk is linked
with inheritance of the APOE e4 allele has helped explain some of the
variations in age of onset of AD based on whether people have inherited
zero, one, or two copies of the APOE e4 allele from their parents. The
relatively rare APOE e2 allele may protect some people against the
disease; it seems to be associated with a lower risk for AD and later
age of onset if AD does develop. APOE e2 also appears to protect people
with Down syndrome from developing AD-like damage. APOE e3 is the most
common version found in the general population and may play a neutral
role in AD.
The mere inheritance of one or two APOE e4 alleles does not predict AD
with certainty; that is, unlike early-onset FAD, a person can have one
or two APOE e4 alleles and not get the disease and a person who develops
AD may not have any APOE e4 alleles. The ways in which the ApoE e4
protein increases the likelihood of developing AD are not known with
certainty, but one possible theory is that it facilitates beta-amyloid
buildup and this contributes to lowering the age of onset of AD.
Several new candidates for additional AD risk factor genes for
late-onset disease have recently been identified, and this is an
exciting avenue for new research. Building on the improving
understanding of AD genetics, scientists can continue to look for clues
as to which protein structures hasten the initiation of the disease
process, what mechanisms cause AD, and what the sequence of events is.
Once they understand these, they can then look for new ways to diagnose,
treat, or even prevent AD.
One of the most intriguing issues in this area is possible differences
in risk among various racial and ethnic groups. Some recent studies have
shown that carrying an APOE e4 allele is a greater determinant of risk
of AD in Caucasians than it is in Hispanic Americans or in African
Americans. However, African Americans and Hispanic Americans may have a
higher overall risk of AD than do Caucasians (Tang et al., 1998). Other
studies have found conflicting results (Fillenbaum et al., 1998).
Clearly, further investigation is needed to examine the role that ethnic
and racial differences play in determining the risk of AD and the
contribution of APOE and other genes to this risk. Current NIA-funded
studies should provide some answers.
 
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*Non-Genetic Factors in AD Development*
Researchers have also investigated a number of avenues related to
non-genetic factors involved in AD. Exploration of these factors may
suggest new theories about the mechanisms involved in triggering or
continuing the disease process.
One promising area relates to a longstanding theory of aging. This
theory suggests that the buildup of damage from oxidative processes in
neurons causes a loss of function. Scientists believe that particular
types of molecules, called free radicals, which are themselves
short-lived and produced through normal metabolic mechanisms, play a
role in several diseases, including cancer and AD. The body produces
free radicals as a by-product of metabolism, and free radicals may help
cells in certain ways, such as in fighting infection. However, too many
free radicals can injure cells because free radicals are highly reactive
and can readily modify other nearby molecules, such as those in the cell
membrane or in DNA. The resulting, newly combined molecule can then set
off a chain reaction, releasing additional free radicals that can
further damage neurons. Oxidative damage due to free radicals may
contribute to the development of AD by several means, including
upsetting the delicate membrane machinery that regulates the flow of
substances in and out of the cell, and altering the structure of certain
proteins. Unique characteristics of the brain, including its high rate
of metabolism and the long life span of its non-dividing cells, may make
it particularly vulnerable to oxidative stress.
Another promising possibility is that inflammation in the brain may play
an important role in AD. Brain inflammation increases with age, but it
is much more pronounced in AD patients. Investigators have both direct
and indirect evidence that inflammation contributes to AD damage.
Indirect evidence comes from the fact that in epidemiologic studies and
in the NIA's intramural Baltimore Longitudinal Study of Aging, frequent
use of anti-inflammatory agents is correlated with a decreased
prevalence of AD (Stewart et al., 1997). More direct evidence comes from
the fact that various compounds known to be involved in inflammatory
processes can be found in AD plaques, and a number of studies suggest
ways in which inflammatory pathways could destroy neurons in an
ever-repeating vicious cycle (Griffin et al., 1998). Many scientists are
currently conducting studies to understand this process more fully and
to explore possible therapeutic approaches that involve
anti-inflammatory medications.
In a third area, investigators at the Sanders-Brown Center on Aging and
the NIA-supported Alzheimer's Disease Research Center at the University
of Kentucky in Lexington have demonstrated a possible link between brain
infarction (stroke) and AD. A brain infarction is an area of injury in
brain tissue that usually occurs when the blood supply to that area is
interrupted, depriving neurons of essential oxygen and glucose. The
researchers have been working with a group of 678 elderly nuns from the
School Sisters of Notre Dame who live in convents throughout the United
States. In this long-term study of aging and AD, each participating
sister agrees to have a yearly physical and cognitive examination and to
donate her brain to the study at her death. Results from this ongoing
work show that study participants who had had infarctions in certain
brain regions had more clinical symptoms of dementia than could be
explained by the number of plaques and tangles in their cerebral cortex
(Snowdon et al., 1997). These findings suggest that some brain infarcts,
which may not themselves be sufficient to cause dementia, may play an
important role in increasing the severity of AD's clinical signs. Other
diseases related to the brains' blood vessels or blood supply, such as
atherosclerosis, also may be involved in the development of AD.
Finally, it is becoming clear that there are important parallels between
AD and other neurological diseases, including prion diseases,
Parkinson's disease, Huntington's disease, and fronto-temporal dementia.
All involve deposits of abnormal proteins in the brain.
Dr. Stanley Prusiner won the 1997 Nobel Prize in Physiology or Medicine
for his discovery of prions, a novel and controversial infectious type
of protein. AD and prion diseases, such as Creutzfeldt-Jakob disease in
humans and bovine spongiform encephalopathy ("mad cow disease"), cause
dementia and death, and both are associated with the formation of
insoluble amyloid fibrils, but from membrane proteins that are different
from each other. Findings from studying amyloid formation in prion
diseases may be useful in studying the similar process in AD.
In 1997, scientists studying Parkinson's disease, the second most common
neurodegenerative disorder after AD, discovered the first gene linked to
the disease. This gene codes for a protein called synuclein, which,
intriguingly, is also found in the amyloid plaques of AD patients'
brains. Investigators have also discovered that genetic defects in
Huntington's disease, another progressive neurodegenerative disorder
that causes dementia, cause the Huntington protein to form into
insoluble fibrils very reminiscent of the beta-amyloid fibrils of AD and
the protein fibrils of prion disease. Thus, research into each of these
neurologic disorders is yielding unexpected insights into the other
diseases.
 
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*What Do We Know About Diagnosing AD?*
Currently, clinicians use several tools to diagnose "possible AD" or
"probable AD" in a patient who is having difficulties with memory or
other mental functions. These tools include a patient history, physical
exam, laboratory tests, brain scans, and a series of tests that measure
memory, language skills, and other abilities related to brain
functioning. However, in these patients, AD can be diagnosed
conclusively only by examining the brain after death in an autopsy to
determine the presence of characteristic plaques and tangles in certain
brain regions.
The earlier an accurate diagnosis of AD is made, the greater the gain in
managing symptoms and determining the natural history of AD. An early,
accurate diagnosis of AD is especially important to patients and their
families because it helps them plan for the future and pursue care
options while the patient can still take part in making decisions.
Researchers have made significant progress in developing accurate
diagnostic tests and techniques that can be used in living patients. In
specialized research facilities, clinicians can now diagnose AD with up
to 90 percent accuracy. For example, work is underway to develop new
tests of mental status that might be used to distinguish between people
who might have very early AD symptoms and those experiencing age-related
normal memory loss. Other investigators have explored the utility of
analyzing cerebrospinal fluid for levels of "sticky" beta-amyloid and
tau for diagnosing AD. Researchers also have used positron emission
tomography (PET) scans, an imaging method in living patients, to see
whether they can detect changes in the way glucose is metabolized in
parts of the brain that are most affected by AD. Another imaging method,
known as single photon emission computed tomography (SPECT), also has
been combined with genetic and psychological testing to predict which
people with memory problems eventually will develop clinically diagnosed
AD.
A particularly exciting area of work involves yet another imaging
technique in the diagnosis of AD. This technique uses magnetic resonance
imaging (MRI) to measure the size of various structures in the brain.
Many studies have shown that AD causes some brain structures,
particularly the hippocampus, to shrink early on in the disease, and
scientists are exploring exactly how early this shrinkage, or atrophy,
can be detected. Several teams of NIA-funded scientists have established
the usefulness of MRI as a tool to help determine which people with
memory problems are in the earliest stages of AD; to identify people who
will later be diagnosed with AD; and to measure hippocampal volume to
distinguish between people with mild cognitive impairment (MCI) and
those with no memory or learning problems, and between people without AD
and those with very mild AD.
 
------------------------------------------------------------------------
*How Can Alzheimer's Disease be Treated?*
For those who are already suffering from the effects of AD, the most
immediate need is for drugs to control their symptoms, including problem
behaviors such as verbal and physical aggression, agitation, wandering,
depression, sleep disturbances, and delusions. Treatments are needed
that work on many patients, stay effective for a long time, ease a broad
range of symptoms, improve patients' cognitive function and ability to
carry out activities of daily living, and have no serious side effects.
Eventually, scientists hope to develop drugs that attack fundamental AD
processes, preventing them from damaging function and quality of life.
The Food and Drug Administration has approved two medications for AD.
Both act by inhibiting acetylcholinesterase, an enzyme that normally
breaks down acetylcholine, a key neurotransmitter in cognitive
functioning. This neurotransmitter is produced by one set of neurons
that are lost in AD. The first of these medications, approved in 1993,
was tacrine (Cognex). The second, approved in 1996, was donepezil
hydrochloride (Aricept). This drug has less severe side effects than
does Cognex and is now commonly used to treat mild to moderate symptoms
of AD. However, the drug does not stop or reverse the progression of AD,
and it appears to help only some AD patients for a period of time
ranging from months to about 2 years, so its usefulness is limited.
The growing understanding of the variety of factors involved in AD's
development, including oxidative damage and inflammation, have suggested
new potentially fruitful avenues for drug treatment research to modify
disease progression or to halt it early on. The NIA's intramural
Baltimore Longitudinal Study of Aging and NIA-supported epidemiologic
studies are showing that use of estrogen replacement therapy (ERT) and
regular use of some non-steroidal anti-inflammatory drugs (NSAIDs) are
associated with lower risks of developing AD. Scientists caution,
however, that individuals should not take these medications just in
hopes of preserving cognitive function or reducing the chances of
developing AD. Results from epidemiologic studies do not mean a
cause-and-effect relationship, and much research still needs to be done
in studies involving human AD patients (clinical trials) to determine
whether the treatments are safe and effective and to see whether they
have a beneficial effect on AD development or progression.
 
< >
------------------------------------------------------------------------
*1999 AD RESEARCH ADVANCES:BUILDING ON THE FOUNDATION*
As can be seen from the previous section, one of the primary
characteristics of the NIH AD research effort over the last 25 years has
been support for a wide range of studies on many topics by many
researchers. Some of these investigations have developed to the point of
suggesting new ways of treating AD. All have contributed to building the
solid base of knowledge that exists today. This base is pointing
scientists in several potentially productive research directions. It is
also helping investigators ask better questions about the issues that
still remain unclear. During the last year, researchers supported by NIA
and other NIH Institutes made advances in a number of areas important to
Alzheimer's disease, including:
    * understanding the etiology of AD--the biological events that cause
      the changes in brain cells and tissues that lead to AD;
    * improving early diagnosis;
    * developing drug treatments;
    * improving support for caregivers; 
    * and building the research infrastructure.
  
------------------------------------------------------------------------
*Understanding the Etiology of AD*
In the last year, scientists continued to improve their understanding of
the complex ways in which aging and genetic and non-genetic factors
affect and damage brain cells over time and eventually lead to AD. For
example, investigators made progress in unraveling such questions as how
and why amyloid plaques form and cause neuronal death; the relationship
between various forms of tau and, possibly, impaired function leading to
neuronal death; the roles of inflammation and oxidative stress; and the
contribution of brain infarctions to the disease. Answers to these
questions about the fundamental nature of the disease and the way in
which it evolves will help investigators create improved methods for
diagnosing AD before a patient has any behavioral symptoms, develop
effective treatments, or perhaps someday, even prevent this devastating
disease.
 
------------------------------------------------------------------------
*Amyloid*
Scientists know that amyloid in the brain, formed by the aggregation of
individual fragments derived from a larger protein, APP, is a prominent
feature of AD. Understanding the function of the APP protein itself,
apart from its role as the precursor of amyloid, should provide clues to
whether APP is involved in the development of the disease. This is a
central question that still confronts researchers: Just how does APP
biology affect the onset and development of AD? Are APP and beta-amyloid
central factors in most forms of the disease or is the disruption of APP
metabolism and beta-amyloid deposition only a secondary consequence of
some other, more immediate factor? A number of NIH-supported research
advances this past year helped reveal some answers.
For example, researchers at the University of California at San
Francisco (Xu et al., 1999) may have pointed to a possible role of APP
in the brain through its involvement in preventing apoptosis. Apoptosis
is a series of carefully regulated cellular events that lead eventually
to cell death. This biological process is an important part of the
normal functioning of developing and adult organisms. However, when this
process goes awry, it can have devastating consequences, especially when
it occurs in generally irreplaceable cells such as neurons. Activation
of the apoptosis process may play a role in AD and other neurological
diseases that are characterized by abnormal rates of cell death, so it
is an important topic to investigate. In this study, the research team
compared the ability of mutant and normal, or "wild-type," forms of APP
to protect neurons in tissue culture against apoptosis. The researchers
induced apoptosis in the neurons using two well-established methods
(stauro-sporine and ultraviolet radiation) and found that wild-type APP
inhibited cell death, whereas mutant APP did not. The investigators
established that APP worked by interfering with p53 activation. P53 is a
tumor suppressor protein that is involved in cell cycle control and
apoptosis. In additional experiments, neurons were infected with p53 to
directly induce apoptosis. Neurons with wild-type APP survived, whereas
those with mutant APP had increased levels of cell death. The
researchers conclude that APP can protect neurons by preventing p53
activation and they proposed several different ways in which this could
happen.
Other NIA-supported investigators have attempted to shed light on the
ways in which beta-amyloid deposits in plaques might actually disrupt
brain cell function and cause neuronal death. For example, one team of
Harvard Medical School researchers used triple immunofluorescent
confocal microscopy and three-dimensional reconstructions of specially
treated brain tissue samples to study two groups of deceased patients
who had been treated at the Massachusetts General Hospital Alzheimer's
Disease Research Center. One group had clear clinical histories of AD
dementia; the other group had no history of neurological disease. The
researchers found that neurites that pass through amyloid deposits in AD
lose their normal straight shape and become twisted and longer (Knowles
et al., 1999). This lengthening causes tiny delays in the normal
communications between nerve cells. The researchers postulate that these
delays, occurring over widespread areas of the brain affected by amyloid
plaques, could significantly disrupt the cell-cell signaling essential
for the particular cognitive functions related to memory, resulting in
cognitive impairment and the clinical manifestations of AD.
Given that increased beta-amyloid generation, its aggregation into
plaques, and the resulting neurotoxicity may lead to AD, scientists are
interested in investigating conditions under which beta-amyloid
aggregation into plaques might be slowed or blocked. Scientists at the
New York University School of Medicine showed that, in test tube
studies, a small peptide similar in structure to part of the
beta-amyloid itself inhibited beta-amyloid aggregation. Other studies in
rats showed that this peptide dissolved preformed fibrils (the
thread-like structures at the core of the amyloid plaques) and prevented
fibril-induced death of special types of neurons in tissue culture (Soto
et al., 1998). Importantly, injection of high levels of the peptide into
the brains of rats that had beta-amyloid deposition resulted in smaller
beta-amyloid deposits than in control rats that were not injected with
peptide. The use of such peptides, which mimic the region of the protein
involved in aggregation and prevent it, may be a useful strategy to
treat not only AD but also a number of other neurodegenerative diseases
involving abnormal protein aggregation.
In another study, which also focused on the formation of amyloid,
scientists at Evanston Northwestern Healthcare Research Institute used
an atomic force microscope to study beta-amyloid in the process of
forming fibrils. They found precursors to insoluble amyloid, which were
freely diffusible small amyloid aggregates. The experiments suggested
that these precursors might actually be more toxic than plaque amyloid
(Lambert, M.P. et al., 1998). These results were obtained in tissue
culture and it is not yet certain whether those small aggregates
actually exist in the human brain and, if they do, whether they are
actually more toxic than the insoluble plaque amyloid.
In another study examining APP's and amyloid's role in the development
of AD, the University of California at San Francisco research team used
a transgenic mouse model to show that overproduction of a human mutant
APP in hippocampal neurons causes damaging neurophysiologic changes in
the synapse and synapse loss well before any amyloid plaques build up
(Hsia et al., 1999). These results underscore the fact that deposits of
amyloid plaques outside the cells may not be necessary for the function
of neurons to become severely impaired. The investigators note that
caution has to be exercised when extrapolating these animal findings to
human AD. However, both this study and that of Lambert and colleagues
suggest that therapeutic drugs that only target plaque deposition might
not be as effective as drugs that prevent build-up of newly formed
beta-amyloid.
Other recent studies have attempted to gain further insights into the
APOE gene itself and how it affects a person's risk of developing AD.
For example, one large non-Federal study conducted in France examined
the impact of several APOE polymorphisms in the regulatory region of the
APOE gene and found that these differences also can have an impact on
the development of AD quite apart from the APOE e4 risk (Lambert, J.C.
et al., 1998). Two of the three polymorphisms examined by this research
team may have a deleterious effect, while the other may be protective.
The investigators conclude that these and other differences, together
with whatever risks are associated with the different APOE alleles (e2,
e3, or e4) themselves may contribute to the overall risk of developing
late-onset AD.
Another study, conducted by researchers at the Washington University
Medical Center, St. Louis, Missouri, used a well-developed transgenic
mouse model to show that certain factors, such as the ApoE protein, can
indeed influence AD-like plaque formation (Holtzman et al., 1999). This
study lays the foundation for further studies to elucidate the
mechanisms that underlie the clearance or aggregation of beta-amyloid
plaques under pathological conditions.
This year, scientists published evidence showing that the different
degrees of risk associated with inheritance of the APOE alleles might be
related to more than just their effect on amyloid deposition. A study
conducted by investigators at the University of California at San
Francisco, presents compelling evidence to suggest that the presence or
absence of particular APOE alleles affects the way neurons respond to
injury (Buttini et al., 1999). In these studies, mice whose own APOE
gene had been removed from their DNA ("knockout" mice) were made
transgenic for one or the other human APOE alleles. The knockout
transgenics made only human ApoE e3 or ApoE e4 proteins at high levels.
The researchers showed that the human ApoE e3 protein protected the
brains of these mice against injury due to overexcitation or aging but
that the ApoE e4 protein did not. The significance of this finding is
that it may help to explain why the APOE e4 gene is a risk factor for
the development of AD, and, if confirmed, might suggest useful
therapeutic strategies that could be started before any cognitive
impairment occurs in at-risk individuals.
Finally, a recent study conducted by NIA intramural AD investigators may
shed light on future therapeutic strategies for AD. In this tissue
culture study, the researchers observed an increase in death of
hippocampal neurons in cells that they had engineered to over-express
mutated forms of human APP compared to neurons over-expressing the
normal human APP (Luo et al., 1999). The death caused by mutant APP
over-expression appeared to be apoptotic and led to the generation of
more intracellular terminal fragments of APP. These results suggest that
abnormal metabolism of APP leading to more beta-amyloid or terminal
fragments of APP may be toxic to cells.
 
------------------------------------------------------------------------
**
*Presenilins*
In the past year, researchers also took several big steps toward a
better understanding of the role of presenilins in AD development.
Naturally occurring mutations in presenilin 1 are found in about 40
percent of people with early-onset familial Alzheimer's disease (FAD).
Previous studies have suggested that these inherited gene mutations
increase the total amount of beta-amyloid clipped out from the larger
APP or of the longer and "stickier" form of beta-amyloid, but no one had
determined how that clipping occurred, though they knew that an enzyme
was involved. Researchers named this elusive enzyme gamma-secretase.
Working with nerve cells grown in tissue culture, an NIA- and
NINDS-supported research team at Harvard Medical School and the Brigham
and Women's Hospital, Boston, gained an important insight into this
process (Wolfe et al., 1999). When the investigators altered the normal
sequence of presenilin amino acids (the building blocks of the
presenilin protein) in two critical locations buried within the cell
membrane, they found that beta-amyloid formation was reduced. This
evidence strongly suggests that presenilin 1 is either gamma-secretase
itself, or a unique cofactor required for gamma-secretase activity. This
study is important because if its findings prove to be true, it could
lead to significant advances in therapeutics research by showing
investigators one exact place to intervene before plaques form.
A second, supporting study from a research team at the University of
Pennsylvania, used a particular Drosophila fruit fly model to
demonstrate a similar link between the presenilin protein and another
protein called Notch (Ye et al., 1999). The Notch protein is a large
transmembrane receptor protein involved in cell-cell interactions,
especially during development. These two proteins appear to share a
mechanism of regulated proteolysis (the process by which proteins are
clipped to create small chains of amino acids). The researchers showed
that in this fruit fly model, a proteolytic cleavage, required for Notch
activity, did not occur in the absence of presenilin. Proteolysis of the
human APP has similarities to Notch receptor processing and so a better
understanding of presenilin function in Notch proteolysis may yield
enormous dividends with respect to understanding APP processing and may
lead to new insights into the development of AD.
In a collaborative study with scientists at The Johns Hopkins University
and the University of Chicago, NIA intramural AD researchers also
examined the effects of a deficiency of presenilin 1 on tissue culture
neuronal cells isolated from genetically engineered mice (Naruse et al.,
1998). They found that a lack of presenilin 1 in cortical neurons
eliminated the secretion of beta-amyloid. Furthermore, this deficit in
presenilin 1 caused an increase both in the accumulation of a secreted
form of APP and in the buildup of certain fragments of APP within the
cells. The processing of several other proteins also was affected. These
results suggest that presenilin 1 plays an important role in the
movement and metabolism of selected membrane and secretory proteins
within cells, and this has implications for the function of presenilin 1
beyond its role in the modulation of APP processing.
NIA-supported investigators at the University of Kentucky have been
exploring the role that presenilin mutations play in the death of
neurons and the development of AD. In this study, the investigators used
transgenic mice to demonstrate a link between a mutation in presenilin 1
and an increased susceptibility of cultured hippocampal neurons to
excitotoxic injury stemming from a dose-dependent challenge with a
particular kind of neurotransmitter called glutamate (Guo et al., 1999).
The researchers suggest that the mechanism involved may be to increase
intracellular levels of free calcium resulting in oxidative stress and
the dysfunction of mitochondria. Thus, by changing the normal balance of
calcium in the cells, presenilin 1 mutations may predispose neurons to
multiple forms of cell death.
  
------------------------------------------------------------------------
*Tauopathies and Tangles*
Several neurodegenerative diseases, including AD, are characterized by
the aggregation of tau into insoluble filaments in neurons and glia,
leading to dysfunction and death. Until now, there was no evidence that
changes in the tau protein itself could actually initiate neuronal
degeneration in humans with any forms of dementia. Rather, the tangles
of Alzheimer's disease were seen as secondary to some other insult or
genetic change, for example, the buildup of beta-amyloid. Determining
exactly what relationship exists between plaques and tangles is a major
goal of AD research.
Very recently, several groups of NIA-supported researchers at the
University of Pennsylvania, Mayo Clinic, University of Washington, and
Cambridge University, who were studying families with a variety of
hereditary dementias other than AD, found the first mutations in the tau
gene on chromosome 17 (Clark et al., 1998; Hutton et al., 1998; Poorkaj
et al., 1998; Spillantini et al., 1998). In these families, mutations in
the tau gene cause neuronal cell death and dementia. These disorders,
collectively called "frontotemporal dementia and parkinsonism linked to
chromosome 17" (FTDP-17), share some characteristics with AD but differ
in several important respects. Patients with FTDP-17 differ from AD
patients in the cognitive and behavioral problems they exhibit, for
example. They also differ in the area of the brain most affected
(frontotemporal dementia disorders primarily affect the frontal cortex).
In addition, only neurofibrillary tangles made up of abnormal tau
proteins form--there are usually no amyloid plaques in these diseases.
However, a recent scientific article describes a 55-year-old individual
with FTDP-17 who did have plaques in his brain, suggesting the
possibility that tau mutations could sometimes result in beta-amyloid
deposition (D'Souza et al., 1999).
These studies describing tau mutations are important because they
support the idea that tau in and of itself can be an important
contributor to neurodegeneration. Researchers speculate that these
families have slightly different mutations, but that they all work in
one of two ways to kill neurons--either by preventing tau from binding
to the microtubules, which provide support for cellular structures such
as axons (Dayanandan et al., 1999; Hong et al., 1998) or by causing tau
to aggregate to form neurofibrillary tangles (Nacharaju et al., 1999).
These disruptions to the cell's basic function and structure could lead
to its death.
The benefits of this research lead far beyond FTDP-17, for a better
understanding of the impact of tau mutations in this disease may well
provide clues to other age-dependent neurologic diseases that also are
characterized by abnormal aggregation of tau protein, such as AD,
Parkinson's disease, some forms of amyotrophic lateral sclerosis,
corticobasal degeneration, progressive supranuclear palsy, and Pick's
disease.
  
------------------------------------------------------------------------
*Genetic Links to Late-Onset AD*
Scientists are continuing to pursue research into the relationship
between genetics and late-onset AD. In the early 1990s, researchers
discovered that the APOE gene on chromosome 19 was associated with
late-onset AD, and the APOE e4 allele remains the single most
significant risk factor gene in this form of the disease, accounting for
about 50 percent of the genetic effect in the development of late-onset
AD (Strittmatter et al., 1993). Recently, one team of investigators at
The Johns Hopkins University suggested that the APOE e4 allele
influences when susceptible individuals might develop Alzheimer's
disease, but in those who survive to very old age (older than 84), it
has no bearing on whether a person might develop AD (Meyer et al.,
1998). These results suggest that late-onset AD is a genetically complex
disorder involving some, perhaps many, genes apart from APOE e4. A
number of different methods are being employed to find these other risk
factor genes.
All these genetic studies involve looking at the occurrence of specific
polymorphisms in individuals or groups and comparing them with the
occurrence of particular diseases in those groups. For example,
scientists supported in part by NIA recently used a methodology called
genome scanning, in which all the chromosomes are scanned for genes that
are inherited in families along with a particular disease, to search for
candidates for risk factor genes in AD other than APOE e4. Researchers
at five sites (Jacksonville, Florida; St. Louis, Missouri; Cardiff,
Wales; London, U.K.; and Lille, France) conducted a genome scan on 292
sibling pairs, each of whom had AD, and results do suggest that there
are other risk factor genes in addition to APOE e4 (Kehoe et al., 1999).
Other types of studies, called family- and population-based association
studies, look at polymorphisms in specific genes that frequently occur
along with the disease but not in unaffected individuals. In particular,
scientists are using these research methods to focus on a small region
of chromosome 12, which studies have suggested is a potential area of
susceptibility to AD. Using a family-based association method,
investigators at Massachusetts General Hospital and Harvard University
found that a common polymorphism in a protease inhibitor gene that makes
a protein called alpha 2-macroglobulin (a2M) may be a major risk factor
determining whether Alzheimer's disease will develop in later life
(Blacker et al., 1998). There is some biological evidence to support a
role of a2M in AD. a2M can act to prevent beta-amyloid from accumulating
by binding to it and degrading it, and ApoE e4 may interfere with this
process, thus allowing amyloid plaques to accumulate (Blacker
<http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9697696&dopt=Abstract>
et al., 1998; Rebeck et al., 1998). However, there is no evidence that
the a2M polymorphisms have different biological activities. Moreover,
results from other laboratories in this country, the United Kingdom, and
Canada (Rogaeva et al., 1999) have not confirmed this association and
suggest that another, entirely different, risk factor gene may reside on
chromosome 12.
Other associations, suggesting new risk factor genes, have been found in
population-based studies. Many of these may be spurious, caused by
differences in genetic backgrounds and in environment between the
control and AD groups other than the polymorphism being tested. Because
families share the same genetic and often the same environmental
backgrounds, family-based analyses reduce the possibility that
associations with the disease may be related to the genetic or
environmental differences that exist between unrelated persons.
The statistical and other family-based methods for detecting risk factor
genes in genetically complex diseases such as AD are still evolving.
Only as additional families are tested and as the various research
groups share their raw data will it become clear exactly which gene on
chromosome 12 is a risk factor gene for AD. The NIA will hold a workshop
on the genetics of AD and related dementias at the end of 1999 to
address these issues. The workshop will provide an opportunity for many
genetic researchers to come together to discuss their different findings
and assess the various techniques being used to hunt for risk factor
genes in diseases such as AD.
  
------------------------------------------------------------------------
*Inflammation*
Work on the links between inflammation and AD continue to bear fruit.
For example, a recent study by University of Arizona scientists compared
the effects on a specific area of rat brain that contains cholinergic
neurons, lost in AD, of short-term, high-dose injections of an
inflammatory agent with the effects of longer-term, lower-doses of the
agent (Willard et al., 1999). They found that both treatments were
deleterious but that the chronic inflammation caused more damage to the
cholinergic neurons that are vulnerable in AD than did the short-term,
intense inflammation. These results suggest that neuro-inflammation over
a longer period of time has the potential to underlie the genesis of
some of the cellular damage seen in healthy aging as well as in AD.
 
------------------------------------------------------------------------
*Oxidative Stress*
Investigators continue to tease out the ways in which oxidative stress,
which occurs as a result of over-production of free radicals, may play a
role in neuronal damage and death. For example, one research team from
Case Western Reserve University in Cleveland, Ohio, has attempted to
distinguish the particular cell types in the brain that are most
vulnerable to oxidative stress (Nunomura et al., 1999). They found that
most of the oxidative damage to DNA and RNA in vulnerable neurons of AD
involves RNA, not DNA. The several classes of RNA molecules, which are
chemically similar to DNA, play essential roles in carrying genetic
information from DNA in the nucleus to the outer portion of the cell,
where the information serves as a blueprint for the manufacture of
specific proteins. RNA also plays a critical role in the actual
synthesis of the proteins. Oxidatively damaged RNA may interfere with
these processes, and this may cause a malfunctioning protein to be made
(one that has either gained a toxic function or lost a normal function).
In turn, this could be one cause of the neuronal death that
characterizes AD.
Other recent studies, conducted by scientists at the Sanders-Brown
Center on Aging and the NIA-supported Alzheimer's Disease Research
Center, have built on previous work detailing the direct evidence for
free radical damage to neurons in AD. In one of these studies,
scientists confirmed that certain types of free radicals, called
4-hydroxynonenal (HNE), which are toxic to neurons, are increased in
several regions of the brain that have the most AD damage (Markesbery
and Lovell, 1998). This study, in conjunction with cell culture studies
and previous studies showing HNE elevation in cerebrospinal fluid of AD
patients, suggests that HNE may also be important in the development of
neuron damage in AD.
In a review of many studies on oxidative stress, the same team of
investigators present evidence that the oxidative process damages brain
fats, carbohydrates, proteins, and DNA, and also summarize the evidence
for inflammatory processes in the brains of AD patients (Markesbery and
Carney, 1999). They suggest that it is these two processes, working in
concert, that contribute to the death of brain neurons and the
consequent decline in mental function seen in AD patients.
 
------------------------------------------------------------------------
*Brain Infarction*
The interest in studying a possible association of brain vascular
disease and AD pathology has grown with the publication of results from
a study of patients with autopsy-proven AD who were enrolled in the
NIA-supported Consortium to Establish a Registry for Alzheimer's Disease
(CERAD) (see p. 45 for a more detailed description of CERAD). Confirming
results from the earlier Nun Study (Snowdon et al., 1997, see p. 14),
these researchers found that AD patients who also had evidence of a
brain infarction at autopsy had more severe clinical dementia and poorer
performance on specific tests of language and cognitive function and
higher frequency of dementia than did those with AD alone (Heyman et
al., 1998). These results are spurring collaborative efforts by the NIA
and other NIH institutes, such as the National Institute of Neurological
Disorders and Stroke, the National Institute of Mental Health, and the
National Heart, Lung, and Blood Institute, to explore the
interrelationships among age-related cognitive decline, dementia,
cerebrovascular disease, and cardiovascular disease in order to develop
better methods to identify early those people at risk of dementia and to
provide new approaches to treatment and prevention. The NIA is funding
epidemiologic studies to uncover possible interactions among these
various entities. It is also funding an add-on component to two clinical
trials to measure cognitive decline in elderly women both with and
without cardiovascular risk factors. These cognitive components are
being added to the ongoing NIH Women's Health Initiative and the Women's
Anti-oxidant Cardiovascular Study (see page 44 for more on these studies).
 
 
------------------------------------------------------------------------
*Diet*
A 1998 study provides another intriguing clue to the origins of AD. This
study, conducted by scientists from Oxford University and Norway's
University of Bergen showed that blood levels of homocysteine (an amino
acid) were significantly higher and blood levels of folate were lower in
patients with diagnosed AD than in controls (Clarke et al., 1998). The
study's authors suggest that high levels of homocysteine might be a risk
factor for AD.
Recent findings from the Nun Study also suggest a link between folate
and brain dysfunction. In this research, investigators determined blood
levels of folate and other nutrients from selected nuns living in a
convent in Mankato, Minnesota (Snowdon et al., in press). They then
compared these folate levels with the degree of AD pathology present in
the brains of any nuns who died. All of the participating nuns ate from
the same kitchen and lived similar lives. Examinations of the brains of
30 nuns who have died since the beginning of the study showed that the
neocortex--one of the primary regions of the brain affected in AD--of
those who had low blood folate levels showed significant shrinkage, and
that the correlation was particularly evident among 15 nuns who had many
AD plaques and tangles. None of the other nutrients examined showed the
same correlations. Folate, also called folic acid, plays an important
role in the development of the central nervous system (CNS) and may play
a role in maintaining its integrity throughout life. One of folate's
functions, along with vitamins B6 and B12, is to convert homocysteine to
the more useful amino acid methionine. High levels of homocysteine have
been linked in epidemiologic studies to risk of heart disease, and, in
the study by Clarke and colleagues, to risk of AD.
 
------------------------------------------------------------------------
*Improving Early Diagnosis*
The clinical diagnosis of AD has improved significantly in recent years.
However, important gaps in knowledge remain, and work continues on the
search for reliable, valid, and easily attained ways to identify cases
very early in the course of the disease, when treatment may be most
effective. Tests are also needed that can reliably separate people with
incipient Alzheimer's from those with cognitive problems that stem from
other causes.
In the last year, researchers made significant progress in several areas
related to early diagnosis, including increasing their focus on mild
cognitive impairment with memory loss, which may be an early stage of
AD, and improving neuroimaging techniques for diagnostic purposes.
 
------------------------------------------------------------------------
*Mild Cognitive Impairment*
Individuals who have a memory problem but who do not meet the generally
accepted clinical criteria for AD are considered to have mild cognitive
impairment (MCI). They are becoming an increasingly important group for
AD researchers because it is now known that about 40 percent of them
will develop AD within 3 years. A recent study, conducted by researchers
at the Mayo Clinic Alzheimer's Disease Center/Alzheimer's Disease
Patient Registry in Rochester, Minnesota, broke new ground in this area
by confirming that MCI is a distinct clinical entity different from mild
AD and from normal age-related changes in memory (Petersen et al.,
1999). This study involved three groups: healthy older people, people
with MCI, and patients with mild AD. The groups were followed over time
and compared on demographic factors and on several different measures of
cognitive function. Results showed that the main difference between the
healthy study participants and those with MCI was in memory abilities.
The MCI participants and the AD patients had similar memory impairments,
very much worse than the healthy participants, but the AD patients had
other cognitive impairments as well. Over time, the cognitive
performance of individuals with MCI declined more rapidly than that of
the healthy participants and more slowly than that of the AD patients.
However, some patients diagnosed with MCI did not progress to AD,
suggesting that the MCI group is composed of two subgroups, only one of
which is sure to progress to AD. The findings from this study will
enhance clinicians' ability to diagnose this particular impairment as
well as AD and has provided a firm foundation for NIA's new Memory
Impairment Study (see page 36 for a full description of this study).
 
------------------------------------------------------------------------
*Neuroimaging*
One of the most exciting developments in neuroscience research during
the past 10 years has been the refinement of techniques that allow
scientists to visualize the activity and interactions of particular
brain regions as they are used during cognitive operations such as
memorizing, recalling, speaking, reading, learning, and other sorts of
information processing. This window on the living brain can help
scientists measure early changes in brain function or structure to
identify those individuals who are at risk of Alzheimer's disease even
before they develop the symptoms of the disease. These imaging
techniques include positron emission tomography (PET) scans and single
photon emission computed tomography (SPECT), which produce "maps" of the
brain that give information about activity in particular regions as a
person responds to a task or stimuli, and magnetic resonance imaging
(MRI), which provides a way to look at the size and characteristics of
brain structures. Three different recent studies using MRI show how it
may be useful in the early diagnosis of AD and in evaluating its
progression. Eventually, clinicians may be able to use imaging
techniques to assess a patient's response to treatment over time.
Researchers at the Mayo Clinic have conducted several important studies
in the use of MRI to measure shrinkage in the volume of the hippocampus.
The initial studies were cross-sectional studies, which compared groups
of individuals with various levels of mental function, from healthy to
diagnosed AD. In their newest study, the team actually followed a group
of men and women with MCI over time (a longitudinal study) to test the
hypothesis that MRI-based measurements of hippocampal volume could
predict the risk of future development of AD (Jack et al., 1999). The
team followed the patients for nearly 3 years, providing annual clinical
exams and tests of mental function. Twenty-seven of the 80 MCI patients
developed dementia over the course of the study, and the investigators
found that there was indeed a clear association between hippocampal
shrinkage at the beginning of the study in these patients and later
conversion to AD.
In a second study, investigators at the New York University School of
Medicine hypothesized that changes in the size of the entorhinal cortex
(EC), a part of the brain important in recent memory and the site where
tangles first begin to appear as AD develops, could be potentially
useful in the early diagnosis of the disease (Bobinski et al., 1999).
Using brain tissue from deceased individuals with and without AD, the
researchers first developed and validated a way to measure EC size using
MRI. Then they applied the method in living study participants to
compare those with mild AD with age-matched healthy individuals. Using
three different types of measurements, the researchers showed that the
size of the EC was smaller in mild AD patients than in the healthy
individuals, suggesting that this use of MRI could also be useful in the
early diagnosis of the disease.
A third study using MRI was a follow-up to an earlier study of
individuals at risk of AD. All of the individuals had a family history
of AD; some also carried the APOE e4 allele. In the earlier study, which
used PET, a group of investigators at the University of Arizona showed
that compared to those without the APOE e4 allele, those with the allele
had significantly reduced glucose metabolism in particular brain regions
(Reiman et al., 1996). In the new study, the team used MRI to compare
hippocampal volume in the same two groups of patients (Reiman et al.,
1998). They found that although the individuals with the APOE e4 allele
tended to have smaller hippocampal volumes, this was not statistically
significant. However, the smaller volumes were associated with lower
scores on a test of long-term memory. The researchers suggest that
perhaps the results seen in the PET scans indicate changes occurring
before the onset of memory decline, whereas the changes in hippocampal
volume seen with MRI occur at the same time as memory declines.
 
------------------------------------------------------------------------
*Developing Drug Treatments*
Improvements in our understanding of AD are making it possible to design
new therapeutic strategies to intervene at multiple stages of the
disease process. Insights into the neurochemistry and neurobiology of
the disease and epidemiologic studies pinpointing risk factors have
resulted in a marked expansion of the types and numbers of drugs that
are now being tested or may be tested in the future. Today, it is
estimated that NIA, other NIH Institutes, and a number of pharmaceutical
companies are or will be testing 50 to 60 compounds in human trials.
They focus on three major aspects of AD--treatments for the cognitive
decline associated with AD; treatments to slow the progress of the
disease, delay its onset, or prevent it; and treatments for
AD-associated behavioral problems.
 
------------------------------------------------------------------------
*Treating Cognitive Decline*
A number of drugs that maintain the cholinergic system have been
developed or are now being tested to treat the cognitive decline
experienced by Alzheimer's patients. For example, the current drug of
choice for AD, donepezil, acts by slowing down the metabolic breakdown
of acetylcholine. These agents do not, however, alter the underlying
course of the disease. Another clinical trial to investigate potential
cholinergic treatments for AD cognitive decline is being supported by
the Belgian pharmaceutical company, Janssen Pharmaceutica. In this
study, to be conducted in the United States, researchers will
investigate the effect on cognitive performance of galantamine, an
experimental medication that is thought to increase the amount of
acetylcholine available in the brain. Galantamine does this both by
inhibiting the enzyme that breaks down acetylcholine and by stimulating
certain receptors in the brain to release more acetylcholine.
 
------------------------------------------------------------------------
*Slowing, Delaying, or Preventing the Disease*
Scientists are working at a stepped-up pace to examine a number of
compounds that might delay the onset of AD, slow its progress, or
prevent it altogether. These compounds include:
/Anti-Inflammatory Agents/--One of the hallmarks of AD is inflammation
in the brain, but whether it is a cause or an effect of the disease is
not yet known. Epidemiologic evidence strongly suggests that
anti-inflammatory agents, such as prednisone (a steroid) and
nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen and
indomethacin, are associated with a decreased risk of AD. NIA has
supported a study to compare the effects of prednisone versus a placebo
(inactive pill) on patients with diagnosed AD to see whether progression
of the disease can be slowed. This study, the results of which are
presently being analyzed, was conducted through the Alzheimer's Disease
Cooperative Study (see p. 46 for a description of the ADCS). Another
ADCS study with AD patients, which will begin at the end of 1999, will
compare treatment with a traditional NSAID to treatment with a COX2
inhibitor, a more specific type of NSAID with pain relieving qualities
but without some of NSAIDs' side effects on the gastrointestinal system.
/Estrogen and Estrogenic Compounds/--Estrogen use also has been
associated in epidemiologic studies with a decreased risk of AD and with
enhanced cognitive function. It has both antioxidant and
anti-inflammatory effects and enhances the growth of select neurons that
release acetylcholine. Researchers hope that three current estrogen and
AD studies may be able to determine whether estrogen actually affects
development or progression of AD. The first is a small ADCS study of
estrogen replacement therapy (ERT) in post-menopausal women who have had
a hysterectomy. Results of this study, which evaluated the effects of
ERT on cognitive decline in AD, are now being analyzed. The second
study, called the Women's Health Initiative Memory Study, is a component
added to the NIH's Women's Health Initiative. This component, which is
being supported by Wyeth-Ayerst Laboratories, will determine whether
hormone replacement therapy decreases the incidence of cognitive decline
and dementia. The third study, which is in the patient recruitment
phase, is a multi-site, NIA-supported clinical trial to determine
whether the use of estrogen in women without AD but with a family
history of the disease may prevent the development of AD. Scientists at
Columbia University are coordinating this study.
Estrogen replacement therapy is limited to women because of its
potential feminizing effects in men. In women, compliance is limited by
side effects, including increased risk of cancer. Researchers are
developing synthetic compounds, such as those called selective estrogen
receptor modulators (SERMS), that mimic the positive effects of estrogen
on various organ systems, including the brain, without having the
negative side effects of estrogen itself. The first SERM to be approved
by the Food and Drug Administration (FDA) for replacement therapy is
raloxifene. A recently awarded NIA grant has added analysis of
age-related cognitive decline and onset of dementia onto an ongoing Eli
Lilly and Company-supported study that is testing the effects of
raloxifene on osteoporosis.
/Antioxidants/--Over-production of free radicals, produced in normal
levels during metabolism, can result in oxidative damage to cells.
Researchers hypothesize that free radicals may play a role in the
Alzheimer's disease process, and they are studying agents that inhibit
and protect against oxidative damage. One of the most important
antioxidants is vitamin E (alpha-tocopherol), which was shown in a
recent study to delay by about 7 months several important dementia
milestones, such as patients' institutionalization or progression to
severe dementia (Sano et al., 1997). Many Alzheimer's patients are
currently taking vitamin E, and a new NIA-supported study--the Memory
Impairment Study--will examine this agent further to see if it can
prevent patients with mild cognitive impairment from developing AD (see
the accompanying box for a description of this trial). Another
potentially promising compound is ginkgo biloba, an extract derived from
the leaves of the ginkgo tree. It appears to have antioxidant properties
as well as anti-inflammatory and anticoagulant properties, and a recent
meta-analysis of previously published clinical trials suggested a slight
positive effect on AD symptoms (Oken et al., 1998). The NIH's National
Center for Complementary and Alternative Medicine is supporting a new
clinical trial of this compound to determine whether it can delay or
prevent dementia in older individuals.
/Nerve Growth Factor (NGF) and Other Neurotrophic Factors/--NGF is the
best known of a class of compounds known as neurotrophic factors and has
been well studied in animal models for its regenerative properties. NIA
is currently supporting a clinical trial of AIT-082, a promising
neurotrophic factor (see sidebar on p. 43 for more on AIT-082)
/Cholinergic Agents/--Novartis Pharmaceuticals, a company based in
Switzerland with U.S. headquarters in New Jersey, is sponsoring a
clinical trial to compare the length of time of progression from MCI to
a clinical diagnosis of AD in participants taking a placebo or an
experimental cholinesterase inhibitor called rivastigmine. This drug is
under review with the FDA as a treatment for AD. Participants in the
3-year study will be assessed every 3 months for any adverse reactions
to the drug as well as for vital signs, ability to carry out activities
of daily living, and signs that they may have converted from MCI to
dementia.
 
------------------------------------------------------------------------
*Treating Behavioral Symptoms*
Behavioral symptoms--agitation, aggression, wandering, and sleep
disorders--are common in AD patients and can be serious. Physicians now
have several treatments for these symptoms, such as antidepressants,
antipsychotic drugs, and sedatives, but researchers continue to search
for better treatments, including non-drug approaches.
One new ADCS clinical trial is focusing on alleviating sleep
disturbances, a common problem for AD patients. Nighttime wandering and
agitation can result in injury for patients and disrupted sleep for
caregivers. In this study, groups of patients will be given either a
slow-release preparation of melatonin (a naturally occurring hormone
that induces sleepiness), an immediate-release preparation of melatonin,
or a placebo. This trial is now in progress.
Another ADCS study focuses on agitation, a problem affecting 70 to 90
percent of AD patients and one that can make caring for a patient at
home very difficult. Drugs are commonly used to control signs of
agitation, but they can have distressing side effects. This study
compared, over a 4-month period, non-drug behavior management techniques
with traditional medication approaches and no intervention to see which
were more effective. The trial has been completed and results are now
being analyzed.
 
------------------------------------------------------------------------
*Future Considerations for AD Clinical Research*
Scientists engaged in the design and development of clinical trials to
test potential treatments for AD face a number of challenges. One is the
need to recruit large numbers of participants--those with diagnosed AD,
those earlier in the course of the disease (before clinical diagnosis),
and healthy elderly--so that the effects of the drug being tested and
its safety and effectiveness can be measured with confidence. Close
collaboration with existing research and treatment facilities, such as
the Alzheimer's Disease Centers and Alzheimer's Disease Cooperative
Study sites, help to ensure a sufficient pool of potential study
participants. Recruitment strategies being developed for trials such as
the Memory Impairment Study will also help to ensure strong participation.
A second challenge is the need to incorporate into study designs the
special characteristics of people with AD. In many
respects--cognitively, behaviorally, psychologically, and
medically--this patient population is different from patients who
participate in clinical trials for other diseases. Because of their
dementia, many may not even be fully aware that they are participating
in clinical research. Extra care must be taken to accommodate AD
patients and protect their interests and rights. Their condition also
means that family members and other caregivers need to be included as
full partners in the research effort if participation of the patient is
to be successful.
Finally, the fact that several therapeutic drugs, such as donepezil and
vitamin E, are now available to treat AD has raised an important ethical
issue about study designs in which one group of participants is given
the investigational drug and the other group is given a placebo (Farlow,
1998; Karlawish and Whitehouse, 1998; Knopman et al., 1998). Researchers
are discussing whether this type of design should be abandoned in AD
research in favor of designs that compare new drugs against these
existing therapies, or whether placebo-controlled trials should be
continued because these therapies are not yet considered definitive
standards of care for AD.
 
------------------------------------------------------------------------
*Improving Support for Caregivers*
Perhaps one of the greatest costs of Alzheimer's disease is the physical
and emotional toll on family, caregivers, and friends. As Alzheimer's
disease makes inroads into a person's memory and mental skills, it also
begins to alter his or her emotions and behaviors. Patients can
experience extreme agitation and feelings of anger, frustration, and
depression. They can begin to exhibit bizarre behaviors such as pacing,
wandering, screaming, and physical or verbal aggression. These changes
in a loved one's personality and the need to provide constant, loving
attention for years on end are major reasons for caregiver exhaustion
and depression, and for why AD patients are placed in nursing homes. A
recent study analyzing data from more than 1,500 caregivers who
participated in the 1996 National Caregiver Survey provides details on
the physical and other costs of caregiving (Ory et al., 1999). These
data show that dementia caregivers spend significantly more time on
caregiving tasks than do people caring for those with other types of
illnesses. In addition, they report that this type of caregiving has a
greater impact in terms of employment complications, caregiver strain,
mental and physical health problems, time for leisure and other family
members, and family conflict than do other types of caregiving. The
authors suggest that these findings point to a need for programs and
support services tailored to the unique challenges faced by AD
caregivers. This suggestion is supported by research conducted at
Cornell University, which demonstrated the effectiveness of peer support
programs that link caregivers with trained volunteers who have also been
dementia caregivers (Pillemer et al., 1999). Not surprisingly, the
researchers found that these programs were especially effective for
those caregivers whose social support networks were weak before the
program began. They also found that the intervention had the strongest
positive effects on the psychological well-being of caregivers who were
in the most stressful situations.
Other research conducted at the University of Washington, Seattle, and
at the University of California at San Diego has attempted to fill gaps
in our understanding of the psychological and physiological responses of
caregivers to the chronic stress of taking care of an AD patient. These
studies suggest that there is not a generic response to caregiving
burdens, but that certain caregiver characteristics (being male), a lack
of respite from caregiving responsibilities, and the presence of
preexisting illnesses (such as heart disease), make some caregivers
especially vulnerable to the stresses associated with dementia care.
These vulnerabilities include increases in heart disease risk factors,
such as cholesterol levels and blood pressure, and decreases in immune
function indicators (CD4 counts) (Mills et al., 1999; Vitaliano et al.,
1998).
 
------------------------------------------------------------------------
*REACH*
In 1995, the NIH established a major 5-year initiative to carry out
social and behavioral research on interventions designed to help
caregivers of patients with AD and related disorders. Resources for
Enhancing Alzheimer's Caregiver Health (REACH) is co-sponsored by NIA
and the National Institute of Nursing Research (NINR).
Participating researchers are from universities and medical centers
around the country:
    * University of Alabama and University of Alabama at Birmingham;
    * Veterans Affairs Medical Center and University of Tennessee at
      Memphis;
    * Center on Adult Development and Aging at University of Miami, Florida;
    * Veterans Affairs Palo Alto Health Care System and Stanford
      University, California;
    * Center for Collaborative Research at Thomas Jefferson University
      in Philadelphia, Pennsylvania;
    * Hebrew Rehabilitation Center for the Aged and Boston University; and
    * University Center for Social and Urban Research at the University
      of Pittsburgh.
REACH projects focus on characterizing and testing the most promising
home- and community-based interventions for helping caregivers,
particularly in minority families. The interventions include
psychoeducational support groups, behavioral skills training programs,
family-based interventions, environmental modifications, and
computer-based information and communication services. An important
outcome of this initiative will be a shared database that will enable
investigators to answer key questions about the best intervention
strategies for maintaining and improving the health and quality of life
of caregivers of dementia patients. Investigators are particularly
interested in exploring issues related to depression among caregivers,
but they are also assessing the effects of caregiving on health status,
health practices, and use of health care services. To date, over 1,000
families with diverse ethnic backgrounds have entered the study (57
percent are White; 22 percent are African American, and 20 percent are
Hispanic American); preliminary outcome findings are expected in the
next year. Information about the project is available on the REACH
website (http://www.edc.gsph.pitt.edu/reach/). Results are being
published in the scientific literature and in a book entitled Handbook
of Dementia Caregiving Intervention Research.
 
------------------------------------------------------------------------
*Special Care Units*
As the population ages and the number of people with AD grows, the
issues surrounding caring for dementia patients in nursing homes become
ever more important. Special care units (SCUs) are separate sections in
nursing homes for residents with dementia. It is estimated that in the
U.S. today there are 16,840 nursing homes, with 1.65 million residents
(Rhoades et al., 1998). The past decade has witnessed a tremendous
growth in the number of SCUs in licensed nursing facilities; as of 1996,
nearly one in four nursing homes had at least one organized dementia
care unit, wing, or program. The idea behind SCUs is that people with
dementia might benefit from specially designed programs or environments
that are different from those provided in a traditional nursing home
setting. Dementia-oriented programs include small group activities,
short programs, and activities arranged by functional or cognitive
ability levels. Dementia-oriented environmental design features include
secured exits, small dining rooms, single-occupancy rooms, and special
indoor or outdoor areas for wandering.
The rapid proliferation of SCUs has underscored the need for research
into their organization, services, and effectiveness. In 1991, NIA began
an SCU Initiative, a set of collaborative research projects located at
ten sites around the country. These projects were designed to examine
the nature and effectiveness of SCU care in institutional settings using
state-of-the-art research methods. Results from these studies have made
a significant contribution to current knowledge about the organization
and impact of these settings. For example, the lack of a standard
definition of what constitutes an SCU has meant an enormous variability
in the care provided by units that identify themselves as SCUs. A recent
study supported through the SCU Initiative has addressed this problem by
developing and testing a method for classifying unit types that serve
dementia residents in nursing homes (Grant, 1998). This classification
system will help to standardize the attributes that define SCUs and will
serve as a useful tool for researchers to use in comparing different
models of Alzheimer's care in nursing homes. It contains seven
attributes of care that distinguish SCUs from other types of care: 1) a
greater degree of separation between dementia residents and cognitively
intact residents in physical space and social activities; 2) a greater
effort to eliminate noxious auditory stimulation, such as radios and
door alarms; 3) a greater number of simple activities planned for
residents; 4) a greater tolerance of problematic behaviors; 5) a greater
degree of dementia patient participation in organized recreational
programs; 6) less participation by residents in therapeutic programs
aimed at promoting activities of daily living, such as eating and
dressing; and 7) more methods used to train staff about dementia care.
 
------------------------------------------------------------------------
*Building a Research Infrastructure*
An important component of the success of NIH's AD research effort is its
vibrant network of research institutions and investigators who work
together, as well as independently, to further the process of discovery
in AD. Building this research infrastructure is an ongoing effort and it
ranges from developing a variety of innovative mechanisms for funding
research to sponsoring research conferences on cutting-edge issues (such
as the September 1999 workshop on imaging and biological markers and the
December 1999 conference on the genetics of AD and other dementias).
 
------------------------------------------------------------------------
*Innovative Mechanisms for Funding AD Research*
Because of the cost, time, and effort involved, relatively few
medications or treatment strategies are tested in full-scale clinical
trials. However, it is important to provide as many opportunities as
possible to explore the potential of multiple compounds and strategies.
NIA has therefore developed a number of mechanisms for funding research
aimed at each stage of drug development, from efforts to identify useful
drugs, through testing in animals and pilot clinical trials, to
full-scale clinical trials. At each step, the NIA is fostering and
developing industry participation. The accompanying sidebar gives one
example of how these mechanisms work together to further the process of
AD drug development.
/Small Business Innovation Research Grants (SBIRs )--/SBIRs are grant
mechanisms designed to establish the merit and feasibility of ideas that
may eventually lead to commercial products or services, and to support
in-depth development of those whose feasibility have been established. A
number of these grants have been funded in the area of AD research and
they provide an important way for small businesses to participate in the
research process. They also serve as a bridge between laboratory work
and commercial development. Recent examples include projects to explore
the feasibility of using a training program to improve the sleep of
older adults with insomnia and co-existing diseases, including AD;
develop individualized interventions to enhance patient-family
interactions in the later stages of the disease; isolate the active
ingredient from cat's claw (a plant whose extract seems to inhibit
amyloid formation); and test compounds from marine microbes for
plaque-inhibiting activity.
/Drug Development Contract--/NIA maintains a contract mechanism for
funding investigators or small companies who have a potentially
interesting candidate AD treatment drug but who lack the means to begin
the formal drug testing process. This contract, Investigational New Drug
Toxicology for Drugs to Treat Alzheimer's Disease, funds contractors to
conduct animal studies to evaluate drugs for toxicity. If the toxicology
screening is successful, the data generated are used to file a request
to the Food and Drug Administration for approval to carry out initial
tests for safety and efficacy in humans. This contract mechanism has
already yielded several potentially promising compounds, and
applications to test several more drugs are in process.
/Pilot Trial and Trial Planning Grants/--These grant mechanisms give
investigators funding to plan future clinical trials and conduct
smaller-scale clinical trials aimed at treating AD's cognitive and
behavioral symptoms. The trials allow investigators to develop
recruitment strategies and diagnostic procedures, test drug responses,
and generate data necessary to apply for funding of a full-scale
clinical trial."Add-on" Research Components to Ongoing Clinical
Trials--One efficient way to conduct AD clinical trials is to add a
cognitive or dementia component onto an ongoing trial. For example, NIA
recently added two cognitive components to existing NIH trials. In one
trial (The Women's Health Initiative), healthy older women are taking
aspirin or the antioxidant vitamin E; in the other (The Women's
Antioxidant Cardiovascular Study), older women at high risk for
cardiovascular disease are taking either antioxidants or a combination
of folate and vitamins B6 and B12. In both of these trials,
investigators are testing the effects of these compounds on age-related
cognitive decline.
/Alzheimer's Disease Centers (ADC)/--The NIA supports a number of
Centers that conduct research; provide investigator training and patient
care; and support the research process through the development of
centralized databases, research tools and instruments, and clinical
trials. In 1984, Congress authorized and NIA funded the first five ADCs
to promote research, training and education, technology transfer, and
multi-center and cooperative studies of AD diagnosis, etiology,
pathology, and treatment. At present, there are 28 NIA-supported centers
across the United States. ADCs also receive funding to perform specific
research studies on AD or have a particular focus on techniques such as
neuroimaging or data analysis. In addition, a number of the ADCs
participate in the Satellite Diagnostic and Treatment Clinics program.
This program, established in 1990, is designed to extend the ability of
ADCs to offer diagnostic and treatment services to minority, rural, and
other underserved communities. As well, it provides an opportunity for
these Americans to participate in clinical drug studies and other
clinical research efforts. This benefits the participants because of the
care they receive, and it benefits the ADCs because a broad diversity of
research volunteers helps to ensure that answers to research questions
apply to a wide group of people.
Much of the success in AD research in the last 15 years can be
attributed to the work of the ADCs. These advances include identifying
the links between genes of chromosomes 1, 14, and 21 to FAD and
identifying the inherited gene risk factors related to APOE. ADC
researchers also have helped to lay the groundwork for studying how the
proteins that make up amyloid plaques and neurofibrillary tangles are
processed. They have also contributed significantly to the understanding
of normal aging processes and how they differ from the changes seen in AD.
Besides providing well-characterized populations of healthy individuals
and AD patients who can be studied over time to determine healthy aging
as well as the clinical course of the disease, the ADCs have developed
banks of brain tissue for analysis. These tissue banks have been
instrumental in helping researchers understand the pathological course
of the disease and how it relates to the clinical symptoms. The Centers
provide a valuable patient and tissue resource for a vast array of
separately funded projects throughout the United States. The Centers
also have played an important role in educating and training physicians,
nursing home staff, and family members, and have worked closely with
local Alzheimer's Association chapters in education and training
initiatives. The result of these various projects is state-of-the-art
care provided to many thousands of AD patients--more than 37,000
patients have been seen at Centers since the inception of the program.
/Consortium to Establish a Registry for Alzheimer's Disease
(CERAD)/--CERAD was a 24-site research consortium of NIA-sponsored
Alzheimer's Disease Centers and other university medical centers in the
United States engaged in dementia research. It was first funded in 1986
by the NIA for the purpose of standardizing procedures for the
evaluation and diagnosis of patients with AD. Since then, participating
researchers have worked with more than 1,500 carefully screened AD
patients and healthy elderly control volunteers to develop such
standardized diagnostic rating tests as a Behavior Rating Scale for
Dementia, family history interviews, and assessments of services needs,
and tests to assist in neuropsychology, neuroimaging, and
neuropathology. CERAD tests have been translated into several languages
to meet increasing demands for their use in a variety of clinical and
research settings. Versions of selected assessments and supporting
materials exist in French, Spanish, Italian, Portuguese, Dutch, Korean,
Chinese, Japanese, Bulgarian, Hebrew, German, and Finnish.
The data obtained with these tests have been pooled and compiled on a
CD-ROM that is available to investigators. This CERAD database contains
up to 7 years of longitudinal data on the natural progression of the
disease and it has become a major resource for research in AD.
/Alzheimer's Disease Data Coordinating Center (ADDCC)/--
As research on AD has progressed, it has become increasingly clear that
many factors contribute to its development and that the dementias of
aging (including AD) are a family of diseases with a variety of
overlapping characteristics. The ability to pool data on patients from
many ADCs will help investigators understand these complexities in AD
and other dementias as well as help in diagnosis, monitoring, and
treatment. For 2 years, NIA has funded an interim ADDCC to
systematically collect data from all of the ADCs. In July 1999, NIA
awarded a grant to the University of Washington in Seattle to establish
a permanent ADDCC. This will make it possible to address important and
novel research issues that are not feasible with the resources and
patient populations available in any one Center. Many of these issues
relate to distinguishing among the subtypes of AD and the interface
between normal age-related cognitive decline, AD, and other dementias.
The existence of the ADDCC will also encourage standardized methods of
data collection and management and of tissue collection and
dissemination. These standardized methods will help in building a
coordinated and smoothly functioning research infrastructure.
Alzheimer's Disease Cooperative Study (ADCS)--NIA established the ADCS
in 1991 to build an organizational structure so that many Centers could
cooperate in investigating promising drugs for AD and develop and
improve tests for evaluating AD patients in clinical trials. The studies
funded by the ADCS are carried out largely through the clinical cores of
ADCs. During the first 5-year grant period, the ADCS began four drug
studies and two studies of cognitive impairment assessment tests for
Alzheimer's disease clinical trials (one each in English and Spanish).
In 1996, NIA funded the ADCS for another 5 years. The new studies
include work to develop a written test to measure MCI; the Memory
Impairment Study; a study of two different kinds of anti-inflammatory
compounds; the study of melatonin and sleep disorders in AD; and
research on divalproex sodium (Depakote), an antiseizure drug, as a
possible therapy for agitation and dementia in nursing home residents.
Tests developed by the ADCS have become the benchmarks for clinical
trials on AD carried out by both the private and public sectors.
/Exploratory Centers on the Demography of Aging: Alzheimer's
Disease/--NIA also supports research at nine collaborating Exploratory
Centers on the Demography of Aging. The goal of these centers is to
provide innovative and public policy-relevant research on issues related
to the health, long-term care, and economic aspects of aging. Each
center brings experts from different backgrounds together to conduct the
research. By collecting and analyzing data about health and economic
trends in the older population, exploratory centers foster a better
understanding of aging and its effects on individuals and society.
This program supports a variety of projects that examine aspects of AD
in relation to demographic factors. For example, researchers at Duke
University are trying to forecast the life expectancy of older people
and their health service needs, studying how life expectancy can be
extended, and measuring the rate of disease and disability in the U.S.
population. They are also looking at the costs and benefits of different
medical treatments for older people.
In another exploratory center study, scientists at the University of
Chicago are investigating the well-being of spouses of institutionalized
AD patients. They are also studying the economics of aging from a
historical perspective, retirement prospects and minority issues for
Hispanic Americans, and differences in family care and social supports
between African Americans and Caucasians. Researchers at the University
of Pennsylvania in Philadelphia are studying AD and life in nursing
homes. These investigators are working to develop new measures of AD
progression so that they can more accurately project future population
and disability rates. They also are examining relationships between
members of different generations, measuring death rates of African
Americans from 1930 to the present, comparing English and Spanish
versions of a test that measures the severity of dementia, and looking
for ways to encourage minority researchers to address research issues in
aging.
 
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*SUPPORT FOR AD RESEARCH* *BY OTHER NIH INSTITUTES*
*National Institute of Neurological Disorders and Stroke (NINDS)*
Scientists supported by the NINDS are conducting a variety of studies
aimed at increasing knowledge about the causes of AD and at finding new
and better interventions for AD. In studying the causes of AD,
investigators are looking at the organization of memory in the cerebral
cortex of mammals; the structure and function of neurons in this system;
the pathology of these neurons, including plaques and tangles; and
genetic factors.
For example, an NINDS- and NIA-supported research team at The Johns
Hopkins University School of Medicine in Baltimore, Maryland, tested the
relation between the severity of dementia and loss of brain volume,
comparing autopsy findings from individuals without AD to those from
patients diagnosed with AD (Mouton et al., 1998). Cortical atrophy in
patients with AD was 20 to 25 percent greater than in controls. In
addition, AD patients who died at older ages showed less severe cortical
atrophy than did those who died at younger ages. For all patients with
AD, cognitive performance was strongly correlated with cortical volume
loss. These findings confirm earlier studies that have identified
cortical degeneration as the major basis for cognitive decline in
patients with AD, and the investigators believe that the currently
unknown mechanisms that lead to cortical atrophy may play a key role in
the progression of AD. This research is an excellent example of patients
followed by an NIA-funded Alzheimer's Disease Research Center
participating in research funded by another Institute.
Another team of NINDS-supported scientists used new biophysical and
molecular techniques to examine the steps that take place between the
cleaving of APP to form beta-amyloid and the deposition of the
beta-amyloid protein in plaques (Dewji and Singer, 1998). Confirming an
earlier hypothesis that the formation of beta-amyloid in AD might
involve an unspecified pair of cells in the brain first adhering
(joining) to one another through the binding of APP to one of the
presenilin proteins, the investigators suggest that a process may be
stimulated in which vesicles (small sacs) containing intact APP and
presenilin molecules bound to one another are pinched off the adherent
cell surface of the APP-expressing cell and taken into the cell's
interior. These vesicles fuse with other bodies inside the cells, where
proteases break down the APP, forming beta-amyloid. The beta-amyloid
then travels to the outside of the cell, where it accumulates into
plaques. Further studies in this area will help to determine whether
this process results in the production of the forms of beta-amyloid that
are important in AD.
NINDS-supported investigators are also conducting studies on potential
new treatments for AD. For example, one new study is investigating the
safety and effectiveness of an agent called CX516 to improve mental
function in patients with mild to moderate AD. In earlier studies with
healthy animals and human volunteers, CX516 was shown to improve memory.
 
------------------------------------------------------------------------
*National Institute of Mental Health (NIMH)*
NIMH supports research on the causes of AD, its clinical course, and
treatment and services for AD patients. In the last year, researchers
supported by NIMH have made advances in a number of areas, including the
use of advanced imaging techniques, improvements in understanding
depression in both caregivers and AD patients, and the basic molecular
underpinnings of the disease.
NIMH-supported researchers have conducted several different studies
using techniques that permit scientists to visualize brain regions as
they are being used during certain cognitive operations. In one study,
researchers at the University of Pittsburgh used positron emission
tomography (PET) to study the semantic memory system of people with AD.
Semantic memory is the knowledge of words, word meaning, and the
relationships among these concepts. Many of the processes required for
semantic memory may be found in the temporal lobe--predominantly in the
left (language-dominant) hemisphere when words are used, and on both
sides (bilaterally) when pictures or drawings of objects are the
stimuli. Specific regions of the temporal lobes are responsible for
specific aspects of semantic memory processing.
Available evidence suggests that as a person ages, the normal activation
in the temporal lobe is reduced--in AD, this activity is reduced even
more. In addition, activity in other brain regions is also decreased as
an AD patient performs semantic memory tasks. By contrast, when people
age, or have AD, and are to perform certain types of memory tasks (for
example, recalling lists of words), brain activity can actually
increase, suggesting that these regions may be trying to overcome
functional limitations. These data suggest that in AD the way that the
brain responds to the developing abnormality differs depending at least
on what cognitive operation is being performed, and perhaps as a
function of the specific brain region involved. This is important
because it may have implications for how to treat the disease: Are there
specific brain regions (or brain neurochemical systems) that seem better
able than others to respond to cognitive challenge? Further research
will better delineate how AD affects these brain systems and whether
they respond to specific therapeutic interventions.
In other imaging studies, a second group of scientists at the University
of Pittsburgh used PET to test the hypothesis that cognitive and
behavioral symptoms of AD represent a failure of acetylcholine to
modulate other functionally linked neurotransmitters, specifically
dopamine and serotonin. These investigators found that the ability of
acetylcholine to affect dopamine function is not impaired in healthy
older people, but is impaired in AD. This suggests that healthy older
people are able to compensate for age-related changes in brain function,
whereas AD patients have difficulty doing so. Measuring cholinergic
modulation of other neurotransmitter systems provides a more
comprehensive way to think about the complex neurochemical systems and
multiple symptoms of AD and may have implications for the future
treatment of symptoms such as agitation, apathy, and psychosis, which
are affected by multiple neurotransmitters.
Another team of University of Pittsburgh scientists have used a
technique called magnetic resonance spectroscopy (MRS) to examine the
naturally occurring chemicals present in the brains of patients who have
died with AD. This technique can also be used to measure many of the
same chemicals in the brains of living patients. Much more detailed
information can be obtained from studying tissue extracts than from
studying living brains, however, so these data are extremely helpful in
interpreting the information obtained from living patients. The sum of
the two techniques--one more detailed and one more representative of the
disease in living patients--is more powerful than either in isolation.
Ultimately, knowledge of metabolic abnormalities will be critical in
determining the pathology of AD. To date, these studies have shown that
the AD brain shows evidence for breakdown of cell membranes, loss of a
marker of healthy neurons, and loss of inhibitory and excitatory
neurotransmitters. The data have also shown that genetic risk factors
(APOE genotype) are related to increased metabolic abnormalities and
that subtypes of AD show different metabolic patterns.
Related studies ongoing in this same laboratory are aimed at developing
small molecule probes that can enter the brain and specifically label
the amyloid plaques located there. Some of these probes are fluorescent
and can be visualized. Others are radiolabeled so that investigators can
carry out quantitative studies of amyloid deposition. The probes
developed so far have been able to bind specifically to all of the
common pathological structures in AD brain. Future plans involve
combining these two areas of research by comparing previously determined
metabolic abnormalities to quantitative measurements of pathological AP
deposits. Ultimately, both of these techniques could be applied in
living individuals to study the causes of AD, provide very early
diagnosis, and follow response to treatment.
NIMH is also providing extensive support to scientists to investigate
aspects of depression, an important problem that affects both AD
patients and caregivers. It is estimated that as many as 20 to 25
percent of patients with Alzheimer's disease suffer from major
depression, and an additional 25 to 30 percent suffer minor depression.
The Depression in Alzheimer's Disease Study (DIADS), currently ending
its second year, was developed to investigate further the treatment of
depression in patients with Alzheimer's disease. The purpose of the
trial is to determine whether sertraline, a selective serotonin reuptake
inhibitor, may help to ameliorate depression in these patients. The
trial, which was conducted at The Johns Hopkins Medical Institutions and
the Copper Ridge Institute, also is investigating the specific benefits
of depression reduction for patients and caregivers. It is anticipated
that depression reduction will lead to improved memory, better
functioning with activities of daily living, and less caregiver burden.
The study already has produced several findings regarding depression in
AD. For example, researchers have documented a strong link between
depression and physical aggression in patients with dementia. This
finding offers the theoretical possibility that depression treatment may
reduce aggression in patients with dementia. DIADS investigators also
have found notable differences in the relationship between cognitive and
functional impairment and depressive features among patients with AD,
vascular dementia, and undifferentiated dementia. These results suggest
that the mechanisms underlying AD depression may be different from those
of other types of dementia.
The DIADS study also has supported the development of a new bedside
global measure that can assess the presence of other specific diseases
in patients with dementia. This scale is now being used by DIADS and
will be available for use in many clinical and research settings, where
it is important to quantify the seriousness of other medical conditions
in patients with dementia.
In other work on depression associated with AD, scientists at Ohio State
University, Columbus, have been evaluating the longer-term effects of
dementia caregiving by examining depressive symptoms among caregivers
whose spouse died several years previously with AD (Glaser et al.,
1998). These "former" caregivers continue to have elevated levels of
depressive symptoms even 5 to 6 years after the loss of the spouse. In
fact, the former caregivers are, on average, indistinguishable from
current caregivers, with both groups reporting significantly greater
depression than controls.
These data are not typical of bereaved spouses in general. Research on
bereavement shows that the average person recovers within 1 to 2 years
and thus, this long-term change is not simply a reflection of the loss
of the spouse. These scientists are trying to find out why AD caregivers
do not recover as quickly as other bereaved spouses. One possible reason
is that these former caregivers also continue to report higher levels of
loneliness and lower social support than do controls. The multiple
sacrifices made during caregiving, such as those related to jobs,
finances, social activities, and hobbies, may be difficult to redress
when caregiving ends, and this may effectively accelerate diminution of
some facets of their social networks. The continued elevations in
depressive symptoms also appear to have immunologic consequences. Data
on influenza vaccine responses showed that both former and current
caregivers showed significantly poorer immune system response to
influenza vaccine than did controls. This suggests that both groups of
caregivers were at greater risk for influenza and perhaps other
infectious diseases.
Another important area of AD work supported by NIMH is identifying the
reasons why particular sets of neurons are vulnerable and die while
other neuron types are spared. In other types of dementia, different
populations of neurons from those in AD are vulnerable and again, the
cause is unknown. In the case of AD, neuronal death is likely to be
caused by a number of stresses, including oxidative stress and neuronal
over-excitation. Researchers working on studies at the University of
Southern California School of Medicine suggest that these stresses may
have additive effects that converge through a common cell signaling
pathway, ultimately exceeding a threshold and killing the cell. At the
same time, neuroprotective factors also may operate through these
pathways. Stress-activated protein kinases (SAPKs), especially c-Jun
N-terminal kinases (JNKs), are prime candidates to mediate these
effects. The team has found JNK3, a neuron-specific kinase, is activated
either by the oxidant stress caused by beta-amyloid or by
hypoxia/ischemia followed by reperfusion. This activation results in
cell death. Using neural cell and tissue culture systems and mouse
models, the investigators are examining very early steps in this
cell-death process, including JNK interactions with other proteins,
especially in the cell nucleus. They are characterizing and testing
molecules such as human JNK interacting protein (hJIPI/IBI), which acts
at an early stage in the process before cell death becomes inevitable.
These studies may ultimately lead to intervention strategies early in
the disease course.
Another NIMH-supported area of research deals with the chronic
inflammatory state that appears to exist in the AD brain. This state is
thought to injure nerve cells and contribute to decline in memory and
other brain functions. One NIMH-supported research team at Stanford
University is working to identify factors that initiate and perpetuate
this inflammatory state. Microglia, specialized inflammatory cells found
in the brain, are thought to be key in this process. Normally, microglia
are beneficial because they can rapidly initiate an inflammatory
response that protects the brain against invading microorganisms or
tumor cells by secreting toxic compounds. In AD, however, microglia are
chronically activated and over time, the secretion of toxic compounds
injures nerve cells. One stimulus that activates microglia in AD is
beta-amyloid, although the effects of beta-amyloid alone on microglia
are insufficient to account for the degree of nerve cell injury that
occurs in AD. Augmenting factors must also be present. The researchers
have identified macro-phage colony stimulating factor (M-CSF), a protein
found at increased levels in the brain in AD, as an important
co-activator of microglia along with beta-amyloid. When microglia grown
in the laboratory were treated with beta-amyloid and M-CSF, the
production of toxic compounds was dramatically increased. Other
activating compounds were tested, but none was as effective as M-CSF in
conjunction with beta-amyloid in activating microglia. Further, the
investigators have shown that activated microglia themselves can produce
beta-amyloid. Thus, in AD, microglia activated by beta-amyloid and M-CSF
may produce more beta-amyloid, which further activates nearby microglia,
thus initiating a vicious cycle of microglial production of toxic compounds.
Currently, these scientists are studying animal brain tissue to learn
more about the role of M-CSF, beta-amyloid, and microglia in AD. To
visualize the densely packed cells in the brain tissue, the researchers
use a laser scanning confocal microscope, a special type of microscope
that allows them to differentiate among the many cell types present.
They are also developing ways of introducing mutated genes known to be
important in causing AD in humans into the animal brain tissues. By
genetically engineering the brain tissue to produce abnormal proteins
found in the brain in AD, including beta-amyloid, they can simulate the
inflammatory process that occurs in AD under the controlled conditions
of the laboratory.
The team is also conducting studies using cerebrospinal fluid donated by
patient volunteers with AD. Preliminary results show that M-CSF levels
in cerebrospinal fluid from AD patients are correlated with levels of
tau. Thus, patients with high levels of M-CSF also show high levels of
an important marker for nerve cell injury in AD. These clinical studies
will allow these scientists to test the relevance of laboratory models
to the actual AD process in patients.
A group of investigators at the Massachusetts Institute of Technology
(MIT) have been studying what controls the rate at which brain cells
make APP and what controls whether the APP is broken down to
beta-amyloid or to soluble APP, a molecule derived from APP that may
help neurons grow and function normally. They have discovered that
certain neurotransmitters promote, or inhibit, APP formation, and other
neurotransmitters promote, or block, its breakdown to beta-amyloid. With
this information, the team has "cured" APP generation of beta-amyloid in
tissue culture cells. Now they are developing animal models to see
whether the same neurotransmitters, or drugs that mimic them, also work
in the brains of intact animals. If these studies are successful, they
may lead to tests of these compounds in patients.
Patients with AD vary considerably in the clinical characteristics of
their disease, including the age at which symptoms appear; the rate at
which the disease progresses; the emergence of disturbances of mood,
thought, perception, and behavior; the development of parkinsonian
features; and the presence of a family history of AD-like dementia. This
clinical variability suggests that AD, as currently defined, may more
closely resemble disorders such as mental retardation or anemia, which
have multiple contributing causes, rather than a disease with only one
cause. In research supported by NIMH and NIA, a group of investigators
at Carnegie Mellon University's Western Psychiatric Institute and Clinic
are teasing out the reasons behind this clinical variability by
searching for genetic
and other biological factors, demographic characteristics, and
environmental exposures that may influence the susceptibility of
individuals to developing AD. Identifying these AD risk factors will
provide clues about the causes of the disease and lead to the
development of effective treatments. Furthermore, because the
degeneration of brain cells that leads to AD appears to begin decades
before the first symptoms emerge, risk factor profiles will be important
in identifying asymptomatic individuals who are in the earliest stages
of developing AD. Such individuals are the most likely to benefit from
preventive treatments.
In this research, the investigators recruited over 300 healthy
first-degree relatives (brothers, sisters, or children) of patients who
suffer from AD. These relatives, who are at risk of developing AD, were
carefully evaluated for numerous characteristics that might contribute
to their increased susceptibility. The study team also established a
library of cell lines from most of this group so that the search for
genetic and biological risk factors for AD could continue indefinitely
even after the study was concluded.
This at-risk group has now been followed for approximately 10 years and,
so far, 18 have developed AD-like dementia. As this number grows, the
team will continue to search for traits that contribute to the risk of
developing AD.
The research team also has conducted studies on the brains of patients
who have died with AD to learn more about the development of depression
and related behavioral disturbances in patients with dementia. These
studies have shown that the death of neurons in the brain that release
particular neurotransmitters is associated with the development of
serious depression (more subtle dysfunctions of these neurons may
contribute to the development of clinical depression in nondemented
patients). This finding may partially explain why depression in AD is
more difficult to treat with antidepressant medications. Moreover, the
recurrent nature of major depression in AD may reflect the progressive
loss of these brain cells over time. Current studies are focusing on the
molecular and cellular processes that lead to the death of aminergic
neurons in the brains of patients with AD as well as other aspects of
the clinical biology of depression and related behavioral disturbances
in AD. Advances in this area may suggest interventions that spare these
and other brain cells in AD and other neurodegenerative disorders. These
efforts are an example of including ADC patients in a study funded by
another Institute, for the research is being pursued by a consortium of
four NIA-funded Alzheimer's Disease Centers (University of California at
Los Angeles, Indiana University, Baylor School of Medicine, and Mount
Sinai School of Medicine) as well as the Geriatric Psychiatry Branch of
the NIMH.
*National Institute of Nursing Research (NINR)*
NINR supports research on biobehavioral aspects of AD and related
dementias. The primary focus of current studies is on behavioral,
physical, and functional problems such as wandering, agitation and
aggression, and maintaining activities of daily living.
Disruptive behaviors by nursing home residents occur frequently, and
nursing home staff need to manage these behaviors more effectively with
nonpharmacologic methods. Unfortunately, conventional behavioral
management training for nursing assistants does not ensure that they
translate their training into practice, especially over time.
NINR-funded researchers from the University of Alabama at Birmingham
have developed a formal staff management system that helps to maintain
taught skills (Stevens et al., 1998). This system includes monitoring of
skills by supervisors, a weekly lottery for those who maintain the
skills, and a monthly feedback letter to the nursing assistant
summarizing his or her performance. Although nursing assistants who
participated in conventional and the new training system improved their
behavior management skills with AD patients immediately after the
training, more of those in the formal management system were still using
the skills 22 weeks after training.
In two other NINR-supported studies, researchers examined some of the
approaches used by caregivers of patients with Alzheimer's disease. The
first study, conducted at Florida Atlantic University in Boca Raton, was
designed to try to find evidence that patients in the middle and late
stages of AD are able to maintain a sense of self or of personal
identity (Tappen et al., 1999). A diminishing sense of self is a
commonly-held belief about AD in both the popular and professional
literature. Investigators conducted 30-minute conversations with nursing
home residents who had been diagnosed with probable AD. Analyses of
these taped interviews indicate that the patients did continue to
maintain a sense of self into the middle and late stages of the disease.
They were aware of their cognitive decline, but did not have an
explanation for the changes. The study authors suggest that patients
should be told of their AD diagnosis and be offered an explanation of
what the diagnosis means for them.
The second study was designed to investigate whether AD patients in the
late stages of the disease can still develop a therapeutic relationship
with their caregivers (Williams and Tappen, 1999). This issue is of
practical importance because a common caregiver approach is to avoid
most communication with AD patients except for task-oriented
conversations. These University of Miami School of Nursing investigators
found that most moderate- to late-stage AD patients were able to develop
new relationships with the study's nurse practitioners. The study
authors conclude that strategies are needed to encourage communication
and the development and maintenance of relationships between caregivers
and AD patients. These strategies may help to prevent the dehumanization
that may occur as individuals progress through the later stages of
Alzheimer's disease.
*National Institute on Alcohol Abuse and Alcoholism (NIAAA)*
Researchers supported by the Division of Clinical and Biological
Research in the NIAAA are conducting a large, 5-year study to
investigate the cognitive changes and dementia that are induced by
alcohol consumption in order to differentiate clearly alcohol-related
dementia from Alzheimer's or other conditions. Dementia in older adults
with a history of alcohol abuse can be caused by a number of factors,
including Alzheimer's disease, vascular disease, or alcohol.
Alcohol-related neurotoxicity may be causally related to 20 to 25
percent of dementia cases in the elderly population (Smith and Atkinson,
1995). Because alcohol dementia is thought to be at least partly
reversible with abstinence, its prognosis is very different from that
for Alzheimer's disease. Establishing criteria for differential
diagnoses of these two dementias thus has major practical and
public-health implications.
In a separate study, NIAAA-supported researchers are using proton
magnetic resonance spectroscopy to characterize the longitudinal course
of metabolic changes in regions of the brain that are sensitive to
alcohol-induced damage, including the cerebellar vermis, frontal cortex,
and frontal white matter. Cognitive functions, such as memory, are being
evaluated simultaneously.
NIAAA-supported scientists also recently developed a novel strategy for
identifying cognition-enhancing drugs. This strategy has potential
implications for treating a variety of diseases, including AD. Working
with awake, freely moving rats and using a technique called
microdialysis-coupled place-cell detection, the research team
simultaneously linked a cognitive behavior --visually triggered memories
of spaces--with directly measured neurotransmitter and
electrophysiological responses of nerve cells exposed to pharmacologic
agents in an area of the brain involved in memory. Other studies using
techniques such as the one developed by these researchers may allow
scientists to evaluate the potential of various cognition-enhancing
drugs in treating AD.
*National Center for Research Resources*
NCRR develops and supports critical research technologies and shared
resources that underpin research across the NIH. NCRR supports the
development and use of sophisticated instrumentation and technology, new
animal models for studies of human disease, and enhanced clinical
research environments. NCRR also supports efforts to enhance the
research capacity of minority institutions and of scientists who belong
to minority groups.
In a major study of the incidence of AD in ethnic groups, Columbia
University scientists supported by NIA and an NCRR-funded General
Clinical Research Center, found that African Americans and Hispanic
Americans are at greater risk of developing AD than Caucasians (Tang et
al., 1998). The new finding of the study was that African Americans and
Hispanic Americans had an increased frequency of AD regardless of their
APOE genotype. African Americans and Hispanic Americans with an APOE e4
allele were as likely as Caucasians with an APOE e4 allele to develop
AD. However, in the absence of an APOE e4 allele, African Americans and
Hispanic Americans were 2 to 4 times more likely than Caucasians to
develop AD. These observations provide evidence that, in addition to the
APOE e4 allele, previously unidentified genes and/or other risk factors
apparently contribute to the etiology of AD among African Americans and
Hispanic Americans.
In another study, NCRR-supported investigators at Boston's Brigham and
Women's Hospital used single photon emission computed tomography (SPECT)
to determine whether regional cerebral perfusion was a preclinical
predictor of AD (Johnson et al., 1998). Regional decreases in perfusion
in several key brain areas (the hippocampalamygdaloid complex, the
posterior cingulate, the anterior thalamus, and the anterior cingulate)
were most prominent among study participants who may have had AD at the
beginning of the study and who definitely converted to AD over time
(these participants were called "converters"). Three of the four brain
regions important for discriminating converters from healthy
participants involve a distributed brain network pertaining to memory,
suggesting that this network may be selectively affected in the earliest
stages of AD.
NCRR-supported investigators at the University of Pennsylvania School of
Medicine also examined the role oxidative stress plays in the
pathogenesis of AD by measuring isoprostane levels in AD and control
brains (Pratico et al., 1998). The levels of both isoprostanes (iPF2-III
and iPF2-VI) were markedly elevated in both the frontal and temporal
cortex, but not in the cerebellar cortex (a relatively unaffected
region), of the brains of people who had died with AD. Levels were also
elevated compared to corresponding areas of brains from patients who had
died with schizophrenia, Parkinson's disease, or from
non-neuropsychiatric disorders. These data suggest that specific
isoprostane levels may reflect increased oxidative stress in AD.
Researchers at the University of Connecticut General Clinical Research
Center evaluated the allele frequency for polymorphisms in six different
genes of neuropsychiatric interest in six different populations
(Gelernter et al., 1998). One of these six genes is the APOE gene, which
has been shown to be a genetic risk factor for AD. The results revealed
significant allele frequency variation among populations at all six
loci. These results will provide a global framework of normal variation
at these loci that might have functional significance or otherwise be
related to susceptibility to various disorders or behavioral phenomena.
Knowledge of this variation can be important for study design and data
interpretation when individuals from various population groups are
participating in research, and may eventually help lead to a better
understanding of behavioral changes resulting from these variations in
gene structure.
The delivery of human nerve growth factor (NGF) by gene transfer to the
brain has shown promise as a means of preventing cholinergic neuronal
degeneration in human disorders such as Alzheimer's disease. In 1996,
NCRR-supported investigators affiliated with the California Regional
Primate Research Center (CRPRC) showed that NGF could rescue 80 to 100
percent of basal forebrain cholinergic neurons in nonhuman primates
(NHPs) and reverse spontaneous age-related cholinergic neuronal atrophy.
However, preliminary studies indicated that NGF also upregulates
expression of APP, which could lead to an increase in the deposition of
mature beta-amyloid in brain plaques. To examine this prospect in NHPs,
the CRPRC scientists more recently studied aged rhesus monkeys treated
with NGF (Tuszynski et al., 1998). After 3 months of treatment, the
investigators found no significant increases in amyloid plaque formation
in the treated monkeys over that found in healthy aged controls. This
finding therefore supports NGF as a potential ameliorating agent in the
treatment of AD and other dementias.
NCRR-supported investigators at the University of Alabama at Birmingham
have found that overexpression in transgenic mice of a specially
engineered portion of APP resulted in vacuolation and increasing
accumulation of beta-amyloid and APP fragments in skeletal muscle fibers
during aging (Fukuchi et al., 1998). This pathology has similarities to
the disease called inclusion body myopathy, and the results suggest that
these transgenic mice may be a useful model for studying this disease.
*National Institute of Child Health and Human Development (NICHD)*
NICHD supports research related to AD primarily through its research
programs involving neurobiology and mental retardation and developmental
disabilities. NICHD-supported advances in basic neurobiology stem from
the Institute's efforts to understand the processes underlying both
normal and abnormal human development. These advances are helping
researchers understand how brain functions, such as memory and thought
processing, are established in early embryonic development, and may
ultimately lead to therapeutic drugs that can address the gradual loss
of memory function in patients with AD. For example, NICHD researchers
recently confirmed the role of a substance known as brain-derived
neurotrophic factor (BDNF) in sustaining memory. Using genetically
engineered mice, NICHD-supported researchers demonstrated that BDNF,
acting in concert with electrical impulses within the brain, enhances
the ability of brain cells to store information. While there is no solid
evidence that BDNF and other neurotrophic factors are involved in the
development of AD, BDNF and its derivatives may one day serve as
potential therapeutic agents for a variety of learning and memory deficits.
Through research on Down syndrome (DS), NICHD-supported investigators
are making other new inroads into understanding AD. While adults with DS
are believed to be at increased risk for the type of dementia that is
associated with AD, the natural history of dementia in these individuals
is not well understood. Thus, researchers are comparing adults with DS
to those with other forms of mental retardation to understand the
differences and similarities in their neuropsychological and behavioral
functioning. These efforts should contribute to improved diagnosis,
treatment, and prediction of risk for all types of dementia, including AD.
The NICHD also supports several studies that are directed at
characterizing the cellular and molecular biology of presenilin genes
and developing molecular and animal models to profile patterns of
degeneration in AD. Many of these studies are designed to complement
larger AD initiatives at various NIH Institutes.
Finally, a recent breakthrough supported by NICHD may one day offer
better prevention and treatment options for women with AD. Researchers
at Yale University have used functional magnetic resonance imaging
(fMRI), to show that estrogen alters brain activation patterns in
postmenopausal women as they perform memory tasks. The fMRI produces
computer-generated images of blood flow in the brain during such tasks
as thinking, reading, or remembering. Researchers in the Yale study
compared brain activation patterns in postmenopausal women when they
were taking estrogen and when they were taking a placebo. The women were
then asked to perform simple tasks, such as remembering a telephone
number, which were designed to test their ability to store verbal
information and hold it in memory for brief periods of time. The
researchers found that estrogen changed the brain activation patterns of
the postmenopausal women and that the changes resembled brain activation
patterns typically seen in younger people. These findings show that it
is possible to alter brain organization in older women, indicating that
the memory systems of mature women are responsive to external stimuli
rather than being fixed or immutable. In addition, these results suggest
that the use of functional imaging, coupled with protocols examining
proper dosing regimens for estrogen, may yield important new information
concerning the effects of estrogen on cognitive function in
postmenopausal women.
*National Institute of Environmental Health Sciences (NIEHS)*
Scientists supported by NIEHS are examining the ways in which metals and
other compounds found in the environment may affect brain tissues and
possibly contribute to the development of AD. For example, in studies in
rat cerebrocortex, investigators working at the University of California
at Irvine have shown that the neurotoxic peptide fragment from
beta-amyloid is able to enhance the ability of metal ions such as iron,
copper, and aluminum to produce free radicals (Bondy et al., 1998a).
This may explain one mechanism underlying beta-amyloid-induced
degeneration of nerve cells.
This same research team also has studied the mechanism by which aluminum
interacts with iron and other transition metals in protein-free systems
(liposomes) (Bondy et al., 1998b). They were able to show that
aluminum-induced potentiation of iron-effected oxidation was not
dependent on the presence of protein and thus could not be attributed to
membrane protein configurational changes. Although aluminum salts in
biological tissue do not have any direct oxidation capacity, it has been
shown that aluminum is able to increase the ability of iron salts to
promote reactive oxygen species formation, which may be an important
mechanism of nerve cell damage. Both iron and aluminum are present at
high concentrations in the neurofibrillary tangles associated with
Alzheimer's disease, but it is still unclear whether their accumulation
is a cause of neurodegeneration or a result of it.
In other work, NIEHS intramural scientists have found evidence for a new
role for a specialized neurotransmitter receptor, the nicotinic
receptor, in a subset of nerve cells in the hippocampus, a region of the
brain important in learning and memory processes (Jones and Yakel,
1997). The receptor's function may be a key to understanding AD, and it
may also be important in other diseases such as Parkinson's or
depression. Alterations of nicotinic binding sites in the hippocampus
have been reported in neurodegenerative disorders such as AD, and
nicotine enhances cognitive function in some Alzheimer's patients. This
discovery provides a molecular mechanism that may help explain some of
the pathology of these disorders as well as of nicotine addiction.
Activation of glial cells in the brain stimulates the expression of
several cytokines and is believed to contribute to the pathogenesis of a
variety of neurodegenerative diseases, including Alzheimer's. In other
research, NIEHS intramural scientists have investigated the effects of
several cytokines (interleukin-1, interferon-gamma, and tumor necrosis
factor-alpha) in mouse cell cultures of neuronal and glial cells (Jeohn
et al., 1998). These cytokines were shown to act as triggering signals
for glia-mediated nerve cell injury.
*National Institute on Deafness and Other Communication Disorders (NIDCD)*
This NIH institute has focused its AD research on changes in the ways
patients communicate with each other and understand and process
information as their disease progresses. For example, several teams of
researchers supported by NIDCD have investigated the semantic memory
impairment in patients with probable AD. One team at the University of
Pennsylvania School of Medicine has used a threshold oral word reading
task to assess priming of different word relationships (Glosser et al.,
1998a). Another team at the University of Pennsylvania Medical Center
has worked with AD patients who have semantic memory difficulties and AD
patients with relatively preserved semantic memory to determine whether
the two groups differ in the way they name pictures and judge the
category membership of words and pictures of natural kinds and
manufactured artifacts that varied in their representativeness (Grossman
et al., 1998a). Only semantically impaired patients were insensitive to
representativeness in their category judgments.
In other NIDCD-supported research, the University of Pennsylvania
Medical Center scientists have used high-resolution single photon
emission computed tomography in patients with neurodegenerative
conditions to see how profiles of language comprehension difficulty are
related to patterns of reduced cerebral functioning (Grossman et al.,
1998b). This team found different patterns of reduced relative cerebral
perfusion (blood flow) in patients with frontotemporal degenerative (FD)
diseases and patients with AD. Cognitive assessments also showed
different patterns of impaired comprehension in patients with FD and
those with AD. Grammatical comprehension difficulty in FD correlated
with relative cerebral perfusion in left frontal and anterior temporal
brain regions; impaired semantic processing in AD correlated with
relative cerebral perfusion in the inferior parietal and superior
temporal regions of the left hemisphere. These findings are consistent
with the hypothesis that a neural network distributed throughout the
left hemisphere, rather than a single brain region, is responsible for
understanding language.
NIDCD-supported investigators also have evaluated the spontaneous
communicative hand-arm gestures in older patients with probable AD
(Glosser et al., 1998b). Patients with AD produced proportionately more
referentially ambiguous gestures, fewer gestures referring to metaphoric
as opposed to concrete contents, and fewer conceptually complex bimanual
gestures.
Other NIDCD investigators have focused on basic science issues,
including studies to demonstrate the feasibility of using olfactory
receptor neurons (ORNs) from biopsies to study changes in aging and
neurodegenerative diseases (Rawson et al., 1998) studies to show that
increased numbers of APOE-immunoreactive ORNs in AD patients compared to
nondemented subjects demonstrates another manifestation of AD-related
neuropathology that parallels changes in neurons in the AD brain
(Yamagishi et al., 1998) and studies that have used MRI to gather and
compare data on age-related changes within specific areas of the brain
such as the insular cortex and the lateral ventricles of the brain
(Foundas et al., 1998).
 
------------------------------------------------------------------------
*OUTLOOK FOR THE FUTURE*
Alzheimer's is an old disease. Ancient Greek and Roman writers described
symptoms similar to those that we know as AD. In the 16th century,
Shakespeare wrote about very old age as a time of "second childishness
and mere oblivion," suggesting that the symptoms of AD, or something
quite like it, were known and recognized then. For many years, the
clinical signs and symptoms of Alzheimer's disease were seen as an
inevitable part of growing older.
In the last 25 years, scientists have produced an extraordinary body of
research findings on AD. Many of these findings have defined the genetic
and biologic changes that underlie AD and offer possible targets for
treatment. Researchers have identified drugs and other agents that could
potentially counteract or compensate for the pathologic changes that
occur in AD. They have made gains in identifying the means of detecting
persons at high risk of developing AD. As methodologies are refined,
scientists and clinicians will be able to investigate and understand the
very earliest pathological and clinical signs of AD--perhaps 10 to 20
years before an actual clinical diagnosis is made. A variety of
approaches also have been applied to improve methods of providing
quality care for AD patients, reduce caregiver burden, and decrease the
need for institutionalization. In seeking to understand AD,
investigators are also describing normal aging. The research is
beginning to shed light on healthy cognition and how to minimize normal
age-related cognitive decline.
Federal support of AD research has been the foundation of many of these
breakthroughs in our understanding of the disease. This funding has also
helped establish an infrastructure that will continue to facilitate
research advances. Novel grant award mechanisms, such as the Alzheimer's
Disease Centers Program and the Leadership and Excellence in Alzheimer's
Disease award, have attracted distinguished scientists to AD research
promoted interdisciplinary research collaborations enhanced coordination
of research data from multiple studies developed patient examination
facilities and biologic resources that are necessary for research on the
disease and enabled patient outreach efforts.
These scientific advances, and the research infrastructure that supports
them, have made it possible for the NIH to launch a new initiative that
builds on current activities and gives a new focus to future work. This
initiative, the NIH Alzheimer's Disease Prevention Initiative, is
designed to expedite the progress toward finding effective medications
and other approaches to delaying or preventing the onset of Alzheimer's
disease. In collaboration with other Federal agencies and the private
sector, this initiative is moving forward on several fronts simultaneously:
    * fostering new approaches to basic biologic and epidemiologic research;
    * increasing the focus on drug discovery and development;
    * improving methods to identify early those people who are at
      increased risk of developing AD;
    * facilitating movement of possible new treatments into the clinic
      for testing in clinical trials; and
    * actively pursuing research into drug and non-drug strategies for
      treating behavioral disturbances in AD patients.
Potential targets for AD prevention have been identified. These include
estrogen-like compounds, anti-inflammatory agents, and antioxidants, as
well as drugs that target cell death, the accumulation of abnormal
insoluble molecules, and other harmful processes involved in AD. These
targets were completely unknown only a few years ago, and the pace of
discovery is accelerating. The AD Prevention Initiative will stimulate
laboratory and clinical research in these areas.
Some of the clinical trials that are part of the AD Prevention
Initiative are already underway, and many more are planned. For example,
the first NIH clinical trial aimed at preventing or delaying the onset
of clinically diagnosed AD in persons at risk--the Memory Impairment
Study--was launched in March 1999. Other trials will be added onto
already ongoing trials that are investigating treatments or prevention
strategies for other conditions. This "piggy-backing" approach will
produce results much more swiftly and cost-effectively than will newly
initiated, freestanding studies.
Importantly for those who now have the disease, NIH also is intensifying
its AD research and information efforts on issues related to supporting
patients and the family members, friends, and providers who care for
them. These efforts will include a special emphasis on the needs of a
diverse patient population.
A defining aspect of the AD Prevention Initiative is collaboration among
NIH institutes and with other Federal agencies, private pharmaceutical
companies, and the private sector. The major NIH funders of AD
research-- the National Institute on Aging, the National Institute of
Neurological Disorders and Stroke, the National Institute of Mental
Health, and the National Institute of Nursing Research--make up the NIH
AD Working Group that will coordinate and direct the Prevention
Initiative. Other NIH institutes that fund AD research also will be
closely involved in the initiative.
For several years, NIA staff have worked with other Federal agencies,
including the Health Care Financing Administration, the Department of
Veterans Affairs, the Food and Drug Administration, and the Centers for
Disease Control and Prevention on various areas related to AD. These
areas include developing data sets for research purposes, collaborating
in research, developing appropriate standards for testing drug efficacy,
and pursuing outreach and education efforts. NIH will continue this
collaboration, as well as efforts to develop relationships with State
and local agencies so that effective AD prevention and treatment
strategies can be successfully carried out in the community.
The NIH also will continue to cooperate with pharmaceutical companies in
basic research, drug development, and testing and, in particular, will
continue to encourage small companies to apply for drug development
grants. As part of this aspect of the Prevention Initiative as well as
for other future research initiatives, NIH will continue to identify
partners for collaboration and to encourage its grantees to build
collaborative research relationships with the private sector.
Last, but by no means least, the NIH will continue to work closely with
voluntary organizations such as the Alzheimer's Association. One example
of this partnership is NIH/Alzheimer's Association co-sponsorship of
conferences on different aspects of AD research. The Alzheimer's
Association also collaborates in research, education, and outreach at
the local and national levels with Alzheimer's Disease Centers,
NIH-supported AD investigators, and the NIA's ADEAR Center. Executives
of the Institute for the Study of Aging, Inc., a non-profit organization
recently established primarily to facilitate development and testing of
effective drugs for AD, also will be discussing possible joint
initiatives with the NIH. The AD Prevention Initiative will work to
expand and strengthen these interactions.
This multifaceted collaborative AD Prevention Initiative, which combines
an accelerated search for causes, an assault on the effects of the
disease, and vigorous efforts to prevent onset, will energize the fight
against AD and bring us closer to the day when we will be able to
prevent or even cure this terrible disease, which robs our older
relatives and friends of their most precious faculty--their minds.
 
------------------------------------------------------------------------
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*For further information about
Alzheimer's* *disease, please contact:*
Alzheimer's Disease Education and Referral (ADEAR) Center
PO Box 8250
Silver Spring, Maryland 20907-8250
Phone: 800-438-4380
Fax: 301-495-3334
E-mail: adear@alzheimers.org <mailto:adear@alzheimers.org>
Web address: http://www.alzheimers.org <http://www.alzheimers.org>
National Institute on Aging
National Institutes of Health
U.S. Department of Health and Human Services
Public Health Service
National Institutes of Health
National Institute on Aging
NIH Publication No. 99-4664