|2001-2002 Progress Report on Alzheimer's Disease|
and AD Research
2: 2001-2002 Research Advances: Opening Doors to New Discoveries
Happens in the Brain to Cause the Transformation from Healthy Aging to Alzheimer's
Mild Cognitive Impairment
Markers and Oxidative Stress
Certain Factors Increase the Risk of or Protect Against AD?
Can Be Done to Halt AD, Slow Its Progress, or Lessen its Effects on People
with the Disease and their Caregivers?
to Help Families and Caregivers
3: Outlook for the Future
The National Institute
on Aging (NIA), part of the Federal Governmentâ€™s National Institutes of Health
(NIH), has primary responsibility for research aimed at finding ways to prevent,
treat, and cure Alzheimerâ€™s disease (AD). The Instituteâ€™s AD research
program is integral to one of its main goals, which is to enhance the quality
of life of older people by expanding knowledge about the aging brain and nervous
system. This 2001- 2002 Progress Report on Alzheimerâ€™s Disease summarizes
recent AD research conducted or supported by NIA and other components of NIH,
Modest AD research
efforts also are supported by the National Cancer Institute, National Institute
of Nursing Research, National Institute of Arthritis and Musculoskeletal and Skin
Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institute
on Deafness and Other Communication Disorders, National Center for Complementary
and Alternative Medicine, National Center on Minority Health and Health Disparities,
and the John E. Fogarty International Center.
- National Institute
of Neurological Disorders and Stroke (pages 21, 27)
- National Institute
of Mental Health (pages 10, 12, 15, 21, 30, 31, 39, 40)
- National Center
for Research Resources (pages 11, 29, 38)
- National Human
Genome Research Institute (pages 30, 31)
- National Institute
of Environmental Health Sciences (pages 16, 19)
- National Institute
of Child Health and Human Development (pages 21, 26)
Alzheimer's disease (AD) is an age-related and irreversible brain disorder that
develops gradually and results in memory loss, behavior and personality changes,
and a decline in thinking abilities. These losses are related to the breakdown
of the connections between nerve cells in the brain and the eventual death of
many of these cells.
The course of this disease varies from person to person, as does the rate of
decline. On average, patients with AD live for 8 to 10 years after they are
diagnosed, though the disease can last for up to 20 years. AD advances progressively,
from mild forgetfulness to a severe loss of mental function. In most people
with AD, symptoms first appear after age 60. Although the risk of developing
AD increases with age, AD and dementia symptoms are not part of normal aging.
AD and other dementing disorders are caused by diseases that affect the brain.
The Impact of 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 have the disease,
and the prevalence (the number of people with the disease at any one time)
doubles every 5 years beyond age 65.
These numbers are significant now and will become even more so in the future
because of dramatic increases in life expectancies since the turn of the century.
Furthermore, the group over 85 - the group with the highest risk of AD - is
the fastest growing group in the population. Researchers estimate that by 2050,
14 million Americans will have Alzheimer's disease if current population trends
continue and no preventive treatments become available (Hebert et al., 2001).
The increasing number of people with AD and the costs associated with the disease
mean that AD puts a heavy economic burden on society. The annual national direct
and indirect costs of caring for AD patients are estimated to be as much as
$100 billion (Ernst and Hay, 1994; Ernst et al., 1997; Huang et al., 1988).
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. This makes the disease an urgent research priority.
Interventions that could delay the onset of AD would have an enormous positive
public health impact because they would reduce the number of people with
the disease. This in turn would ease the personal and financial costs associated
with caring for them.
AD research supported by the Federal Government is divided into three broad,
overlapping areas: causes/risk factors, diagnosis, and treatment/caregiving.
Research into the basic biology of the aging nervous system is critical to
understanding what goes wrong in the brain of a person with AD. Understanding
how nerve cells lose their ability to communicate with each other and the reasons
why some nerve cells die and others do not is a central element 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 of dementia, improve ways
to test patient function, determine causes and assess risk factors, and improve
case-finding and sampling methods for population studies.
Other researchers are working hard to discover and develop drugs that may help
treat symptoms or slow the progress of the disease, and eventually delay the
onset of and prevent AD. Many of these drugs are now being tested in clinical
trials. 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 those who care for people with AD.
An important complement to the National Institutes of Health's (NIH) research
initiatives in AD are its efforts to educate and inform people with AD, their
families, the public, providers, and others interested in the disease. The
National Institute on Aging (NIA) has recently revised and updated its booklet
Alzheimer's Disease: Unraveling the Mystery, which uses illustrations and text
to explain Alzheimer's disease. Designed for a lay audience, Unraveling also
describes ongoing research in the cause, diagnosis, and treatment of AD and
in ways to support caregivers of people with AD. This booklet is available
from NIA's Alzheimer's Disease Education and Referral (ADEAR) Center (www.alzheimers.org
or 1-800-438-4380). The ADEAR Center provides a variety of information materials
on AD, including booklets on caregiving, fact sheets, and reports on research
findings (many of which were developed by NIA-funded investigators). ADEAR
also maintains a database of AD clinical trials and studies, develops recommended
reading lists, and provides referrals to local AD resources.
2001-2002 Research Advances: Opening Doors to New Discoveries
During the last year, scientists supported by NIA and other NIH Institutes
made advances in a number of areas important to Alzheimer's disease. This report
focuses on new research that is attempting to answer three key questions:
happens in the brain to cause the transformation from healthy aging
to Alzheimer's disease?
certain factors increase the risk of or protect against AD?
can be done to slow the progression of AD or lessen its effects?
These questions are important because they get to the heart of this complex
disease - what happens during the very first steps of the disease process,
what might we be able to do to prevent AD, and what can be done once the disease
takes hold. They can be asked only because of the knowledge that has accumulated
through research over the last 25 years. The answers are slowly emerging, and
they hold the key to future prevention, treatment, and caregiving strategies.
What Causes the Transformation from Healthy Aging to Alzheimer's Disease?
As a person gets older, changes occur in all parts of the body, including
Some neurons shrink, especially large ones in areas
important to learning, memory, planning, and other complex mental activities.
In certain brain regions,
chemical and electrical changes occur in neurons and their connections to
lower their efficiency and ability to communicate with other cells. These changes
may make neurons more vulnerable to damage.
Neurofibrillary tangles develop in neurons and beta-amyloid
plaques develop in surrounding areas, though in much smaller numbers than
Damage by free radicals increases (a free radical
is a kind of molecule that reacts easily with other molecules; too many of
these molecules can
Inflammation (the complex process that occurs when
the body responds to an injury or abnormal situation) also increases.
Many investigators are now focused on understanding more fully these changes
in normal aging and their effects on memory and thinking. For example, scientists
have examined whether older adults differ from younger adults in the types
of information they use to make decisions and their actual decision-making
processes. NIA intramural scientists found that older adults' memory and decision
accuracy improved when they perceived the task to be personally relevant or
when they were held accountable for their performance (Hess et al., 2001).
Other studies comparing the performance of older and younger adults on memory
tasks also showed that when older adults were given materials that engaged
their emotional interest, their performance on memory tests equaled that of
young adults (Rahhal et al., 2001). Other work shows that older adults perform
better on most memory tasks at their optimal time of day. This time is determined
by a biological clock that appears to shift toward the morning as a person
ages (West et al., 2002). These results further reinforce the growing understanding
that many factors besides age influence memory and cognitive ability.
By identifying the changes that occur in normal aging, investigators hope to
be able to understand the transformation from healthy aging to Alzheimer's
disease. In addition, learning more about the very earliest stages of the disease
process may open doors to treatments that may delay the onset of the disease
or prevent its progression. In the past year, scientists have examined this
early stage from several perspectives: mild cognitive impairment, biological
markers and oxidative stress, and beta-amyloid.
Mild Cognitive Impairment
As they get older, some people develop memory problems greater than those expected
for their age. However, these problems do not necessarily meet all the accepted
criteria for AD. For example, a person with memory problems might not experience
the personality changes or difficulties in making decisions experienced by
those with AD. These people are thought to have mild cognitive impairment
(MCI) with memory loss. In certain studies, about 40 percent of these individuals
develop AD within 3 years. Other people with MCI, however, have not progressed
to AD, even after 8 years.
Some scientists think MCI with memory loss is often a very early stage of
AD. One recent study provided some support for this notion (Morris et al.,
In this study, researchers at the Washington University School of Medicine
in St. Louis, Missouri, examined 404 people who had either mild memory loss
(classified as MCI) or no memory problems. These participants agreed to have
annual memory assessments, and 42 agreed to donate their brains to the study
after death. The 227 people with MCI were placed into one of three categories
that reflected the researchers' degree of confidence that the subtle signs
of memory loss might indicate the onset of AD. The categories were: "fairly
confident" of dementia, "suspicious" of dementia, and "uncertain" of
dementia. The volunteers were reassessed annually for up to 91/2 years. After
5 years, AD symptoms had developed in 7 percent of the healthy volunteers,
20 percent of the individuals in the "uncertain" group, 36 percent
of those in the "suspicious" group, and 60 percent of those in the "fairly
confident" group. By 91/2 years, all the volunteers with the most severe
form of MCI had developed the clinical symptoms of AD. In studying the donated
brain tissue of those who died, investigators also found that 21 of the 25
volunteers who originally were diagnosed with MCI had damage to brain tissue
that was characteristic of AD. The investigators interpreted these findings
to mean that MCI is an early stage of AD.
It must be noted that most of the participants in the MCI studies done thus
far have been recruited from clinics that specialize in memory problems. The
diagnosis of MCI in general populations may be less predictive of the development
of AD. However, because it appears that many more of those with MCI develop
AD than do cognitively healthy individuals, many scientists are intensely interested
in this clinical state, and they are studying it using a number of approaches.
Several research teams have hypothesized that performance on specific cognitive
tests might predict whether an individual will develop AD. For example,
in one recent study, Boston University investigators gave 1,076 participants
in the ongoing Framingham Heart Study a series of cognitive tests every
2 years for up to 22 years (Elias et al., 2000). At the time of the first
tests, participants were at least 65 years old. None had had a stroke or
dementia. The investigators found that lower scores in a number of areas
- learning new things, recall, retention, and abstract reasoning - obtained
during any time period that a participant did not have dementia were associated
with the later development of AD. The study team also found that a detectable
lowering of cognitive functioning preceded the appearance of AD by many
years. Changes in abstract reasoning ability and capacity to retain verbal
information were the strongest predictors of AD when there was a long interval
between the initial assessment and development of AD.
A smaller study of cognitively normal elders and people with mild memory
difficulty, conducted by investigators at Massachusetts General Hospital
and Harvard Medical School, also showed that neuropsychological tests can
predict the development of AD to some extent (Albert et al., 2001). Of the
20 neuropsychological measures used in the initial tests given in this study,
four were useful in discriminating those who converted to a diagnosis of
probable AD from those who did not. Tests of memory and executive functions
(such as the ability to reason and make decisions) had the most power to
discriminate between those who were likely to develop AD and those who were
Although scientists know that a majority of people with dementia experience
neuropsychiatric symptoms, such as depression, apathy, and irritability,
it has not been clear whether those with MCI also suffer the same symptoms.
Depression and other neuropsychiatric symptoms are a major source of added
disability for patients and caregivers and contribute to the costs of care.
Johns Hopkins University researchers supported by the National Institute
of Mental Health (NIMH) and the NIA analyzed more than 10 years' worth of
data from the Cardiovascular Health Study (CHS) Cognition Study, which was
designed to evaluate the prevalence of neuropsychiatric symptoms in dementia
and MCI (Lyketsos et al., 2002).
A total of 824 study participants completed the Neuropsychiatric Inventory
(NPI), a state-of-the-art rating of neuropsychiatric symptoms in dementia.
Of these, 362 were classified with dementia and 320 with MCI. Forty-three
percent of MCI participants exhibited neuropsychiatric symptoms in the previous
month, with depression, apathy, and irritability being most common. These
are the first population-based estimates for neuropsychiatric symptoms in
MCI, indicating a high prevalence associated with this condition. The research
team concluded that these types of symptoms should be asked about and treated
as necessary, and called for further studies of possible treatments. Study
of the causes of neuropsychiatric symptoms will not only help those with
dementia and MCI, but will also improve our understanding of brain-behavior
relationships and the development of neurodegenerative diseases like AD.
Based on the results of these and similar neuropsychological studies, the
Quality Standards Subcommittee of the American Academy of Neurology has developed
clinical practice guidelines for clinicians who work with patients with memory
complaints (Petersen et al., 2001). The guidelines recommend that clinicians
use general cognitive screening instruments, such as the Mini-Mental State
Examination, and neuropsychological tests to evaluate and monitor patients
with MCI. These tests may help clinicians assess the degree of cognitive
impairment and help them detect signs that might indicate the development
of dementia. In addition, the Subcommittee suggested that clinicians consider
using structured interviews of caregivers or relatives when screening patients
for cognitive impairment. The investigators also recommended a number of
avenues for future research, including better definition of the course of
cognitive function in normal aging, and studies to identify which screening
instruments might be most practical and useful in busy clinical practices.
Investigators are continuing to use neuroimaging techniques, such as magnetic
resonance imaging (MRI) and positron emission tomography (PET), to assess
whether it is possible to measure aspects of brain structure or function
that will identify those people who are at risk of AD before they develop
the symptoms of the disease. Over the past year, results from a number
of promising longitudinal neuroimaging studies have been published. These
studies have expanded our understanding of the potential usefulness of
imaging techniques for research and diagnostic purposes as well as increased
our knowledge about early AD changes in the brain.
For example, it is well known that the hippocampus, a region of the brain
important for learning and short-term memory, is affected early in the course
of AD. Using a series of MRI scans, researchers at the Mayo Clinic documented
for the first time the rate of hippocampal atrophy (shrinkage resulting in
loss of function) in patients with MCI (Jack et al., 2000). In this study,
the investigators grouped participants into those who were cognitively healthy,
those who had MCI, and those who had probable AD. Each participant had an
MRI at the beginning of the study and another one later during the course
of the study. The percent change in hippocampal volume was measured for each
participant. Within the cognitively healthy and MCI groups, those who declined
clinically over time had a significantly greater volume loss than those who
remained clinically stable. These results correlated the rate of change in
hippocampal volume and change in cognitive status. The data also suggest
that it should be possible to distinguish stable from declining members of
a group, both in persons showing early symptoms and in those who have not
yet shown symptoms. The research team concluded from this study that serial
hippocampal volume measurements may be a useful tool to monitor the efficacy
of therapeutic interventions in clinical trials for both progression and
prevention of AD, and that they may also be a way to identify people with
MCI who will not progress to AD.
Improvements in the Not-So-Simple Matter of Identifying Brain Structures
As particular areas of the brain are especially affected by AD atrophy
over time, neuroimaging studies of brain volume are becoming an increasingly
important research tool. In these brain volume studies, a trained anatomist
or technician manually outlines brain structures shown on an MRI scan.
This procedure is tedious and time-consuming. National Center for Research
Resources (NCRR)-supported scientists at the Massachusetts General
Hospital have now developed an automated procedure that is as accurate
as the manual procedure and takes about 30 minutes on computer workstations.
This improved technique enables scientists to process thousands of
images per day (Fischl et al., 2002).
Neuropathological studies have shown that neurons die in the entorhinal cortex
(EC), another brain region involved in memory function, even earlier than
in the hippocampus (Kordower et al., 2001; Price et al., 2001). Several
studies using MRI have shown that patients with AD and MCI also have reduced
as compared with cognitively normal older adults. Some researchers have
found that changes in EC volume are better than hippocampal volume for
individuals with AD from those with MCI (Du et al., 2001). Others have
found that conversion to dementia from MCI is better predicted by volume
EC, as opposed to the hippocampus (Dickerson et al., 2001). Further study
of the time course of change in the hippocampus, EC, and other structures
will help delineate which brain regions are best for diagnosing AD early
and following its progression.
A research team from the New York University School of Medicine has recently
published the first longitudinal PET imaging study of cognitively healthy
elderly declining to MCI (deLeon et al., 2001). Unlike MRI, which uses
powerful electromagnets to create the signals that are converted by computers
detailed images, PET scanning uses short-lived radio-labeled water or glucose
to measure blood flow and glucose metabolism throughout the brain. The
investigators in this study found that decreased glucose metabolism in the
EC at baseline
was the most accurate
predictor of conversion from normal cognition to MCI. That is, changes in
the EC were seen before cognitive decline and before changes in metabolism
in other parts of the brain. Reduced glucose metabolism in the EC accurately
predicted declining cognitive function in 83 percent of study participants
who got worse, and accurately predicted non-decline in 85 percent of participants
who remained cognitively healthy after 3 years. At the follow-up PET evaluation
in those who had progressed to MCI, reduced glucose metabolism was also
seen in the hippocampus and temporal neocortex, a development also seen in
In addition, those who experienced cognitive decline and were carriers
of the APOE-e4 allele (a genetic risk factor for AD) showed especially marked
reductions over time in glucose metabolism in the temporal neocortex (see
genetics section for more on genetics and AD). This finding is consistent
with earlier reports by other investigators that showed reductions in temporal
metabolism of APOE-e4 carriers compared to persons without APOE-e4.
Using Neuroimaging Techniques to See Deep Inside the Brain
Magnetic resonance imaging (MRI) is a technique used to image internal
structures of the body. Images are very clear and are particularly good
for soft tissue, brain and spinal cord, joints, and the abdomen.
Functional magnetic resonance imaging (fMRI) is a variant of MRI that measures
changes in the oxygenation level of the blood. This level depends on blood
flow and is correlated with changes in the activity of nerve cells. Since
its development in the early 1990s, nearly all studies using fMRI have
focused on the changes in blood flow that occur while a person is performing
an "activation" task, such as taking a memory test or looking
at pictures. This presents a difficulty, however. Because individuals must
perform an activation task, patients with moderate to severe dementia,
who cannot understand the experimental instructions, cannot be scanned.
Activation tasks also cannot be performed in small animals because they
must be anesthetized to prevent them from moving while the scan is being
fMRI also has another important limitation: The images generated have a
spatial resolution of a few millimeters, which is insufficient for evaluating
many small brain structures such as the subregions of the hippocampus.
The cells of the hippocampal subregions have unique patterns of gene expression
that are reflected in their electrical properties and chemical profiles.
These differences may account for the fact that cells of the different
subregions are selectively vulnerable to different pathological processes.
Thus, evaluating the hippocampus globally does not do full justice to its
To overcome these limitations and enhance the resolution of the images,
investigators needed a highly sensitive approach that was applicable to
both mice and humans and that was based on fMRIs taken while the person
or animal was not being asked to do anything. Because most causes of brain
dysfunction produce changes not only in the active but also in the resting
function of neurons, investigators reasoned that signals that could be
obtained at rest might also indicate brain damage.
Investigators from Columbia University are in the process of developing
such a method (Small et al., 2000). Using this technique, the investigators
found that signals from the hippocampus were significantly lower in elderly
people with memory decline than in cognitively healthy elderly individuals.
They also found that different people showed dysfunction in different subregions
of the hippocampus. Among healthy elders, signal intensity from one subregion
called the subiculum was correlated selectively with memory performance.
In tests with mice, the investigators found that the fMRI signal was sensitive
enough to detect functional changes in hippocampal neurons even in the
absence of underlying anatomical changes in animals with memory deficits.
The new techniques introduced in this study are beginning to make it possible
for researchers to conduct subregional analyses of the hippocampus, which
eventually might allow precise mapping of existing dysfunction and a greatly
enriched understanding of the earliest changes in the Alzheimer's disease
In another study, supported by the NIMH, NIA, and other funders, Arizona
State University researchers also investigated the potential of using
PET in longitudinal studies. In this study, the research team used PET
changes in brain activity that precede the onset of memory and thinking
problems in a group of individuals of late middle-age (Reiman et al.,
2001). The group
was divided into those who were APOE-e4 carriers and those who were not.
The scientists found that the cognitively normal APOE-e4 carriers had
significant declines in regional brain activity over a 2-year period,
and that these
declines were significantly greater than those found in non-APOE-e4 carriers.
Findings from this study suggest that PET could be a useful future tool
to test, in a relatively small number of people (APOE-e4 carriers), the
of AD prevention and treatment strategies that might benefit many thousands.
It is important to note that using PET to identify persons at risk of
developing MCI and AD is still at the experimental stage, and a number
studies will need to be completed and analyzed before its potential can
be usefully evaluated.
Biological Markers and Oxidative Stress
Scientists are also trying to discover whether biological markers exist that
could indicate early changes in the brain associated with AD. Understanding
more about these markers - what they are, how they function, and how and
when their levels change - will help investigators answer questions about
the cause and development of AD and may lead one day to treatments to delay
or prevent the onset of the disease.
One long-standing theory of aging and neurodegeneration is that damage from
highly reactive molecules called oxygen free radicals can build up in neurons
over time. If unchecked, this oxidative stress can modify or damage cellular
molecules such as proteins, lipids, and nucleic acids. Oxidative stress may
play a role in the pathogenesis of neurodegenerative disorders such as Alzheimer's,
Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis.
In the AD brain, in particular, such damage has been observed, especially
in the late stages, when both beta-amyloid plaques and neurofibrillary tangles
(the two main neuropathological features of AD) are present. However, scientists
do not know whether the oxidative stress causes or results from the process
of beta-amyloid plaque formation.
A number of markers of oxidative stress have been measured in the cerebrospinal
fluid (CSF) of people with AD, but for most of these markers, the amounts
found in those with AD and in cognitively healthy individuals overlap substantially.
Scientists have suggested that the extent to which lipids in the central
nervous system have been affected by free radical oxidative stress can be
assessed by measuring body levels of a newly described class of lipids -
the isoprostanes (iP). Isoprostanes are formed by the addition of oxygen
to particular lipids. In a new study, researchers at the University of Pennsylvania
School of Medicine worked with transgenic mice (mice that have been specially
bred to develop beta-amyloid plaques in the brain) to see whether iP accumulation
might be a useful biomarker of plaque pathology (Praticò et al., 2001).
Over 14 months, these investigators compared the amount of a particular iP
in urine, blood, CSF, and brain from transgenic mice and a control group
of mice at different ages. Results showed that after the age of 6 months,
the amounts of iP in the two groups began to diverge, and differences in
all the fluids and tissues increased in parallel with age. The levels of
iP began to increase just before a surge in beta-amyloid levels in the transgenic
mice and well before the appearance of amyloid plaques at 8-12 months. High
iP levels in the transgenic mice were observed only in the cortex and hippocampus,
brain regions that are heavily affected by plaque accumulation. Results from
this study suggest that oxidative stress in the brains of these transgenic
mice is a very early event, occurring just before the rise in amyloid peptide
levels and before amyloid plaque deposition. Because iP is chemically stable
and can be measured in plasma, urine, or CSF, it may have utility as a diagnostic
tool and to monitor development of pathology in AD or other neuro- degenerative
diseases in which oxidative stress has been implicated.
Cornell University investigators supported by NIMH also used CSF to hunt
for biological markers of AD. These researchers used state-of-the-art protein
analysis tools to identify changes in the composition of CSF that correlate
with Alzheimer's disease (Choe et al., 2002). Using this approach, the investigators
identified a panel of nine proteins that demonstrate altered expression in
patients with Alzheimer's disease. When taken together, these proteins suggest
the clinical state of Alzheimer's disease. This study is one of the first
to use a multiple-marker assay for the presence of Alzheimer's disease based
on changes in CSF composition. In the future, a biomarker assay like this
may help to improve the accuracy of AD diagnosis.
A study from a research team at the University of Kentucky Sanders-Brown
Center on Aging examined the possibility that a marker of oxidative stress
in DNA may identify persons with neurodegenerative disorders such as Alzheimer's
disease (Lovell and Markesbery, 2001). This marker of DNA oxidative stress
is called 8-hydroxy-2'-deoxyguanosine (8-OHG). It is formed by oxidation
of one of the four building blocks (bases) that make up DNA strands. In normal
cells, not very much oxidation of this base takes place, and the cell is
able to repair the DNA by removing the 8-OHG. The 8-OHG is then found free
in the cell. In AD, two changes to this process seem to take place. First,
a high level of oxidative stress causes more of the 8-OHG to be formed in
the DNA. Second, the repair process is much less efficient, so less of the
oxidized base is removed from the DNA and found free in the cell. After comparing
people with AD and cognitively healthy individuals, the University of Kentucky
investigators found that the ratio of DNA-bound 8-OHG to free 8-OHG increased
100-fold in the patients with AD. The investigators suggest that this marker
of DNA oxidation mirrors brain degeneration and might be a useful indicator
of disease progression.
A University of Wisconsin research team funded by the National Institute
of Environmental Health Sciences (NIEHS) studied the relationship between
free radicals, oxidative stress, and programmed cell death. Programmed cell
death, a process that occurs naturally in all cells, appears to be accelerated
in Alzheimer's disease, perhaps because of increased oxidative stress caused
by the accumulation of beta-amyloid. These researchers focused on ways to
increase defense mechanisms in the brain by activating multiple antioxidant
defense genes simultaneously, a process they refer to as programmed cell
life (Li et al., 2002a). A small molecule, tert-butylhydroquinone (tBHQ)
is known to activate the antioxidant response element and protect against
cell death induced by oxidative stress. The researchers used tBHQ and cell
culture models as a simple system to help them understand the genetic regulation
of antioxidant defenses (Lee et al., 2001). Their work led recently to the
identification of a factor that binds to the antioxidant response element
and helps activate a number of antioxidant-related genes. Scientists hope
that these and other similar studies may help elucidate the complex regulation
of the many programmed cell life genes and may lead to improved drug targets
and strategies in the future.
The study of beta-amyloid, the primary component of AD plaques, continues
to be a vitally important part of the quest to discover what happens in
the brain to cause the transformation from healthy aging to AD. Investigators
continue to work intensely to understand the process by which amyloid precursor
protein (APP) is cleaved by enzymes to release beta-amyloid fragments,
how the fragments accumulate in the brain to form plaques, and whether
the plaques themselves cause AD or whether they are a by-product of the
production of beta-amyloid fragments. In studies during the past year,
investigators examined several different issues related to beta-amyloid.
Beta-Amyloid and Neurofibrillary Tangles: the Hallmarks of AD
The brains of people with AD have an abundance of two abnormal structures
beta-amyloid plaques and neurofibrillary tangles. This is especially true
in certain regions of the brain that are important in memory.
are dense, mostly insoluble deposits of protein and cellular material
outside and around the neurons. They are made partly
of a protein called beta-amyloid, which is a fragment snipped from
a larger protein called amyloid precursor protein (APP). We don't yet
whether plaques themselves cause AD or are a by-product of the disease
are insoluble clumps of twisted fibers that build up inside neurons.
These fibers are made of a protein called tau, which
helps to stabilize the neuron's internal support structure. In AD,
is changed chemically, causing it to pair with other threads of tau
and become tangled up. This may result in malfunctions in communications
between neurons and later in the death of the cells.
Scientists know that cleavage of APP by two kinds of enzymes - beta-secretases
and gamma-secretases - generates the toxic beta-amyloid fragments. Two
very similar beta-secretases, BACE1 and BACE2, can generate beta-amyloid.
studies demonstrated that the BACE1 enzyme is likely responsible for cleaving
one end of the beta-amyloid fragment from APP. However, investigators thought
that BACE2 might also be involved. A new study was designed to determine
which of the beta-secretases is more important for the production of the
toxic beta-amyloid (Cai et al., 2001). In this study, investigators at
the Johns Hopkins University School of Medicine developed a transgenic "knockout" mouse
in which the gene for the BACE1 enzyme was eliminated. This allowed the team
to see whether removing the enzyme would interfere with the production of
beta-amyloid. With the enzyme eliminated, beta-amyloid protein fragments
no longer were produced in neuronal cultures from the knockout mice. These
results suggested that BACE1 was involved in the amyloid-producing activity,
and that BACE2 appeared to play a much smaller role in the cleavage of APP
in neurons. To further support this conclusion, the investigators also compared
the roles of BACE1 and alpha secretase, an enzyme involved in normal, nonpathological
processing of APP into soluble products. They found that the two enzymes
appear to compete with each other in the processing of APP, further demonstrating
that BACE1 is the primary enzyme in the production of beta-amyloid. Many
scientists believe that interfering with the deposition of beta-amyloid may
prevent AD or slow its progression. Because they play key roles in the processing
of APP and the resulting deposition of beta-amyloid, both beta- and gamma-secretase
activities represent potential targets for drug therapies. The finding that
BACE1 is the principal beta-secretase in neurons suggests that scientists
might want to focus on the design of therapeutics to inhibit BACE1 activity.
Progress on the Immunization Front
Immunization is a common practice that protects people against a wide
variety of diseases. Scientists questioned whether this might be a useful
strategy for AD as well, and the results of their intense work over the
last several years illustrate both the promise and the difficulties of
this type of research.
In early studies conducted at Elan Pharmaceuticals, scientists worked
with transgenic mice that gradually develop beta-amyloid plaques in the
brain, injecting them with a vaccine composed of very small amounts of
the beta-amyloid peptide, or protein fragment, mixed with another substance
known to stimulate the immune system (Schenk et al., 1999). They found
that the injections resulted in much less beta-amyloid being deposited
in the brains of the mice and better performance on memory tests.
The success of these studies in mice led to preliminary trials in humans,
conducted by Elan investigators and teams supported by NIH and other
funders. These trials tested the vaccine's safety and assessed its effectiveness.
In both trials, investigators also measured the immune response in those
who received the vaccine. These human trials were halted prematurely
in early 2002 because inflammation developed in the brains of some of
the participants. The researchers' disappointment was tempered by the
fact that the study still provided a wealth of important clinical and
pathology data on hundreds of participants and by the recognition that
cutting-edge research like this can suffer setbacks.
Simultaneously, other teams of investigators made additional progress
in this area by continuing work with several strains of transgenic mice.
One research team, from Washington University School of Medicine in St.
Louis, used a strain of transgenic mice that carries a mutation for the
APP gene. These mice develop beta-amyloid plaques as they get older.
The scientists found that passively immunizing these mice (administering
an antibody itself rather than stimulating the host's immune system to
make an antibody) decreased the deposition of beta-amyloid in the brain
and reduced the overall number of plaques (DeMattos, et al., 2001). In
other studies, they also found that prolonged administration of anti-beta-amyloid
antibody decreased the accumulation of beta-amyloid in plaques and rapidly
increased the amount of beta-amyloid in the blood, effectively removing
it from the brain (DeMattos et al., 2002a; DeMattos et al., 2002b). This
is an important finding because it suggests that there may be ways to
remove beta-amyloid from the brain without producing adverse side effects.
In conjunction with the researchers at Washington University, scientists
with Lilly Research Laboratories in Indianapolis, showed that the antibody
therapy rapidly reversed the impairment shown by the transgenic mice
in certain learning and memory tasks (Dodart et al., 2002).
A group of Johns Hopkins University School of Medicine investigators
replicated these results in another strain of transgenic mice that carries
a human presenilin gene mutation as well as the APP mutation (Vehmas
et al., 2001). This replication is significant because the AD-related
damage in the brain of the double mutant occurs sooner and the amount
of beta-amyloid deposited is greater than in mice with either mutation
alone. As with the Washington University studies, this research suggests
that binding antibodies to beta-amyloid clears it from the brain and
deposits it into the blood where it can be degraded further.
Although scientists still have much to learn, this exciting research
is helping them understand more fully the steps involved in the metabolism
of APP and beta-amyloid, and how beta-amyloid is distributed among body
compartments - including blood, cerebrospinal fluid, and brain. This
improved understanding may prove central to more effective AD diagnosis
and treatment in the future.
In other studies, intramural NIEHS researchers found that beta-amyloid
blocks the function of the nicotinic acetylcholine receptor, a key nerve
receptor in the hippocampus (Pettit et al., 2001). These results suggest
that beta-amyloid may exert its effects independently of plaque formation,
and they may provide an explanation for early cognitive problems experienced
by those with AD long before plaques begin to form. Potentially, better
drug therapies could result from finding compounds that can prevent beta-amyloid
from interacting with this receptor, thus maintaining communication between
nerve cells in the brain.
In other work on beta-amyloid, scientists at NIA followed up on earlier
research showing that, contrary to previous belief, the adult brain can
form new neurons.
These investigators wanted to see whether beta-amyloid had any effect
on the formation of these new neurons (Haughey et al., 2002). They discovered
that the ability of new nerve cells to form from stem cells is impaired
in the brains of transgenic AD mice. They further showed that beta-amyloid
a direct adverse effect on neural stem cells, inhibiting their ability
to form nerve cells. These findings suggest that an impaired ability
cells to form nerve cells may occur in AD, and might contribute to the
progressive depletion of nerve cells and cognitive impairment in this
together with other studies that have shown that dietary factors and
nerve cell growth factors can stimulate the production of new neurons
cells, the present findings suggest that it might be possible to increase
formation of stem cells in persons with AD, perhaps preventing or slowing
down the depletion of neurons that causes the memory impairment.
Other research in this area has looked to vascular diseases, such as
stroke, to provide clues about the formation of beta-amyloid and the
of both early- and late-onset forms of AD. AD and vascular diseases share
common risk factors, and stroke may be a risk factor for AD; this has
increased the interest in the possible relationship of cerebrovascular
neurodegeneration, and dementia (see sidebar on the Honolulu aging study
for a description of epidemiological research examining
possible links between vascular diseases and AD). We know that production
of transforming growth factor-beta1 (TGF- beta1), a protein that is part
of the inflammatory response to injury, is increased immediately following
brain injury. Previous work has shown that high levels of this protein
increase the deposition of beta-amyloid in cerebral blood vessels. In
scientists at the Gladstone Institute of Neurological Disease at the
University of California,
San Francisco, developed a double transgenic mouse by mating mice carrying
the gene for a mutated form of APP responsible for one form of early-onset
AD with other mice carrying the gene for an active form of TGF-beta1
(Wyss-Coray et al., 2001). This transgenic mouse allowed the researchers
directly the effect of TGF-beta1 on deposition of human beta-amyloid
plaques in the
brain and its blood vessels. The study showed that TGF-beta1 significantly
influenced the extent and localization of the beta-amyloid plaque deposition
in the mice. Cerebral blood vessels showed a significant accumulation
of beta-amyloid plaques while, at the same time, the formation of neuritic
plaques in brain tissue was dramatically reduced. Overall levels of brain
also were markedly reduced in the double transgenics. This reduction
associated with activation of microglial cells and an increase in inflammatory
molecules. In contrast to results from epidemiologic and other studies
that suggest that an increase in brain inflammation might increase
the risk of developing AD, this study's findings suggest that particular
the inflammatory response in the brain might act to reduce, not elevate,
plaque levels in brain tissue.
Syndrome Research May Shed Light on Alzheimer's Disease
Many older adults with Down syndrome develop dementia similar to that
seen in Alzheimer's disease, and results from several recent studies
in Down syndrome may contribute to a better understanding of AD. For
example, University of Colorado School of Medicine scientists funded
by the National Institute of Child Health and Human Development (NICHD),
NIMH, and NIA have found that a particular strain of transgenic mice
have learning deficits that may be related to problems with nerve fibers
that send impulses to the hippocampus (Hyde et al., 2001). These mice
are helping scientists understand Down syndrome, but because the hippocampus
is a critical brain region that is damaged in AD, these mice provide
a potentially useful animal model for researchers interested in examining
changing patterns of cognitive function in AD.
In another study, a University of Connecticut Health Sciences Center
research team funded by NICHD, the National Institute of Neurological
Disorders and Stroke (NINDS), and the Alzheimer's Association, examined
whether mitochondrial dysfunction associated with Down syndrome affects
APP and beta-amyloid plaque formation (Busciglio et al., 2002). Mitochondria
are structures inside a cell that provide energy to the cell and play
a role in synthesizing some cellular proteins. The researchers found
that the mitochondrial problems not only disrupted the normal functions
of the APP, but also contributed to the rapid accumulation of plaques.
Other research has indicated that vitamin E may be protective against
AD because of its antioxidant properties. The NIA is currently funding
a study of vitamin E treatment in people with Down syndrome, to explore
whether treatment may slow progression to dementia. Results may offer
insights into how some of the damage to nerve cells occurs in both illnesses.
work in beta-amyloid has built on earlier studies indicating that the amount
of copper and zinc is increased in the cortex of brains
who have died of AD. These metals are concentrated in beta-amyloid
plaques. Although controversial, some scientists believe that beta-amyloid
binding sites for copper and zinc that enhance the resistance of beta-amyloid
to breakdown by enzymes and encourage its tendency to clump together
to form plaques. In a new study, investigators in Australia, Sweden,
the U.S., led by scientists at the Massachusetts General Hospital,
treated 12-month-old transgenic mice with orally administered clioquinol
weeks (Cherny et al., 2001). Clioquinol is a chemical that binds metals
as copper and zinc and removes them from body tissues. The team found
with clioquinol reversed the deposition of beta-amyloid in the brain
of the transgenic mice with AD. The amyloid plaque surface area was
significantly reduced and membrane-associated (sedimentable) beta-amyloid
decreased by 65 percent. In fact, two of the six animals treated with
clioquinol had no sedimentable beta-amyloid, and no beta-amyloid could
very specific and sensitive immunological techniques. Twenty older
transgenic mice (21 months of age) treated at a higher dose for just
9 weeks also
were examined. After this treatment, sedimentable brain beta-amyloid
decreased by 49 percent and the study team found an overall clearance
from the brain. Clioquinol did not cause decreased levels of APP nor
did it result in decreased levels of a protein involved in neuron-neuron
suggesting that it was not toxic to brain tissue. Despite these encouraging
findings, safety issues in this therapy still need to be addressed
in human studies, as small amounts of these metals are necessary for
reactions in the body.
Honolulu-Asia Aging Study: A Rich Source of Clues about Vascular and
Other Risk Factors for AD
In 1965, NIH's National Heart, Lung, and Blood Institute (NHLBI) began
the Honolulu Heart Program, a prospective epidemiological study of environmental
biological causes of cardiovascular disease among Japanese-Americans
living in Hawaii. This study gave researchers an opportunity to investigate
how heart disease prevalence rates, pathologic findings, and risk factors
might be related in this population and to compare this population with
other groups, especially Japanese men living in Japan and in other parts
of the U.S. Initially, the study team examined 8,006 Japanese-American
men living on the island of Oahu, Hawaii, who were born between 1900
and 1919. Over the next 25 years, investigators examined this group four
additional times, and their findings have contributed enormously to our
knowledge of heart disease and its risk factors.
From 1991 to 1996, NIA intramural investigators worked with approximately
3,700 survivors of this same group of Japanese-Americans to explore possible
relationships between vascular factors - such as blood pressure, blood
cholesterol, and inflammation - and the later development of dementias
such as AD. This study, called the Honolulu-Asia Aging Study, built on
newly emerging evidence suggesting that vascular factors might contribute
to neurodegeneration, lead to co-existing illnesses that increase the
severity of dementia, or somehow influence different stages of the dementia
As they did for heart disease, this group of Japanese-American men has
made a valuable contribution to our understanding of dementia and AD
through their participation in the Honolulu-Asia Aging Study. More recently,
extramural grants have been awarded so that data collection and analysis
can continue. Highlights of recent findings from these grants have shed
light on the complex interrelationships among genetics, lifestyle and
environmental factors, vascular diseases, and dementia:
- Investigators examined the association of total cholesterol,
high-density lipoprotein (HDL), and low-density lipoprotein (LDL) with
brain plaques and tangles in deceased study participants (Launer et
al., 2001). Cholesterol levels for all participants were measured during
late life; for some participants, levels were measured 20 years earlier,
when they were middle aged. The investigators found a strong correlation
between increases in late-life and mid-life HDL levels and increases
in the number of plaques and tangles.
examination of the joint effect of the APOE-e4 allele and midlife
pressure on the risk of poor cognitive function
in late life showed that midlife high blood pressure had a stronger
adverse effect on cognitive function in those who carried the APOE-e4
allele than in those without it (Peila et al., 2001). However, the
investigators speculate that this effect might be modified by antihypertension
also explored the relationship between Type 2 diabetes, alone or
in combination with the APOE-e4 allele, and various
types of dementia, including AD and vascular dementia (Peila et al.,
2002). They found that study participants with both Type 2 diabetes
and the APOE-e4 allele had a higher risk of AD than did individuals
with neither risk factor. They also found that participants with both
factors had more plaques and tangles in their brains and had a higher
risk of cerebral amyloid angiopathy (CAA), a condition in which amyloid
is deposited in the walls of the arteries that supply the brain, resulting
in an increased risk of dementia and cerebral hemorrhage.
a study of brain tissue after death among 211 participants in the
investigators evaluated the relationship among CAA, dementia,
and cognitive function (Pfeifer et al., 2002). The researchers found
that 44 percent of these participants had CAA in at least one brain
region. The presence of CAA was associated with higher numbers of plaques
and tangles and having the APOE-e4 allele. Scores on cognitive function
tests that the participants took before they died were lower for those
individuals who were later found to have AD and CAA than for those
with AD and no CAA and those with no AD or CAA. The investigators concluded
that by interacting with other neuronal pathologic processes, CAA may
lead to more severe cognitive impairment.
specimens collected in 1968 during the second examination of Honolulu
Program participants, Honolulu-Asia Aging Study investigators
measured blood levels of C-reactive protein, a nonspecific marker of
inflammation, in 1,050 men (Schmidt et al., 2002). This sample was
divided into four groups based on their levels of high-sensitivity
C-reactive protein. Compared with men in the group with the lowest
level of the protein, men in the other three groups had a 3-fold increased
risk of all dementias, AD, and vascular dementia. This relationship
was independent of cardiovascular risk factors or cardiovascular disease.
The investigators concluded that inflammatory markers may reflect disease
mechanisms related to dementia and that these markers can be measured
long before clinical symptoms appear.
Other researchers are working to deepen our understanding of the relationship
between beta-amyloid plaques and neurofibrillary tangles. Scientists
at the Mayo Clinic in Jacksonville, Florida, have made an important
contribution to this work by developing an animal model that exhibits
and neurofibrillary tangles (Lewis et al., 2001). Many of the previous
models of AD developed plaques only. This research team, supported
by NIA, NINDS, and others, crossed strains of transgenic mice that
a mutation in the amyloid precursor protein or the tau protein. The
offspring expressed abnormal forms of both molecules. By comparing
changes in these animals to those observed in the parental strains,
found that the combination of these two mutations led to increases
in tangles in several regions of the brain affected in AD. In addition,
also exhibited movement abnormalities. These results suggest that
the same type of interactions may occur in the human brain as AD develops.
these animals exhibit both plaques and tangles, they may serve as
model for AD. In addition, the movement abnormalities exhibited in
these animals will allow for the testing of potential therapeutic
the behavioral level.
Can Certain Factors Increase the Risk of or Protect Against AD?
Scientists have known for some time that both genetic and non-genetic factors
can increase the risk of developing AD. More recently, evidence from some
studies suggests that certain protective factors may reduce the chances
of developing AD. Developing a clearer understanding of possible risk and
protective factors is important because it may provide clues to therapy
and also suggest ways in which people might be able to change their lifestyles
or environments to reduce AD risk.
Investigators have examined these issues in several different ways and results
in the past year have shed light on differences in the rates of new AD cases
(incidence) across populations, genetic links to the development of AD, and
the implications of lifestyle issues for the development of AD.
Comparing AD incidence and prevalence in different populations may provide
some clues to genetic, environmental, and lifestyle factors that may predispose
or protect individuals. If populations can be identified that have a significantly
lower or higher incidence of AD, this will greatly facilitate the search
for both genetic and non-genetic risk factors for the disease. For example,
over a 5-year period, an Indiana University Medical School research team
followed 2,147 African-Americans in Indianapolis and 2,459 Yoruba in Ibadan,
Nigeria, to see whether they developed dementia and AD (Hendrie et al.,
2001). All the study participants were aged 65 and older. In both communities,
two-thirds were female. To screen participants for AD, the study team used
the Community Screening Interview for Dementia, a test developed by this
group specifically for use in comparative epidemiological studies of dementia
in culturally disparate, non-literate and literate populations. All clinically
assessed participants at both sites received the same examination, which
included a structured interview, neuropsychological testing, and examination
by a physician. Some also received laboratory and imaging studies. The
investigators took great care to ensure that diagnostic consistency was
maintained within and between sites. Results indicated that in the U.S.
group, 3.24 percent per year developed dementia, including 2.52 percent
per year who developed AD. In the Nigerian group, 1.35 percent per year
developed dementia, including 1.15 percent per year who developed AD.
This study provides one of the first reports of incidence rate differences
for dementia and AD in studies of two populations from non-industrialized
and industrialized countries using identical methods of evaluation and the
same group of investigators in both sites. Further studies of these two populations
will focus on identifying genetic factors and potentially modifiable non-genetic
factors, such as heart disease, diabetes, high cholesterol, and lifestyle
and environmental factors. For example, the Yoruba have a much lower prevalence
of vascular risk factors than do African-Americans. These factors include
high cholesterol levels and body mass index, hypertension, and diabetes.
The lower rates of these risk factors may partially account for the reported
difference in AD.
A second large epidemiologic study examined the incidence of dementia in
a rural population living in Ballabgarh, India, south of New Delhi, and had
analogous results to the Indianapolis-Ibadan study (Chandra et al., 2001).
This 2-year prospective study of people aged 55 and older, conducted by researchers
from the University of Pittsburgh, used repeated cognitive and functional
ability screening measures followed by standardized clinical evaluation of
dementia and AD. All the evaluation instruments had been developed and validated
in light of the cultural and linguistic characteristics of this population.
The investigators took the Indian incidence rates, standardized them against
the age distribution of the 1990 U.S. Census, and then compared the rates
against those of a population from the Monongahela Valley in Pennsylvania
studied by the same researchers. The researchers calculated an overall incidence
rate for those more than 65 years old of 4.7 per 1,000 person-years, much
lower than the rate of 17.5 per 1,000 person-years in the Monongahela Valley
population. The reason(s) for this difference is not known, but may include
genetic differences as well as a variety of medical and demographic variables,
such as those being analyzed in the Indianapolis-Ibadan study.
A third epidemiologic study took a slightly different tack by comparing AD
incidence rates of different racial and ethnic populations living in one
country. This study focused on cognitive abilities and dementia in a population
of Caucasians, African-Americans, and Caribbean Hispanics in northern Manhattan
(Tang et al., 2001). In this study, investigators from Columbia University
studied 1,799 residents of the Washington Heights and Inwood communities
of New York City for 7 years, with interviews every 2 years. Results indicated
that probable or possible AD occurred more frequently among African-Americans
(10.5 percent) and Hispanics (9.8 percent) than among Caucasians (5.4 percent).
This differential risk did not seem to depend on diabetes, hypertension,
heart disease, or stroke. It also appeared that the differences in incidence
could not be attributed to differences in years of education or to frequency
of illiteracy. It is important to note, though, that many factors may be
responsible for these estimates, because populations vary in many respects.
Differences in socioeconomic status, health care, education, events occurring
prenatally or right around birth, and life history all may influence a person's
eventual risk of AD. Even the ways in which diagnostic tests that measure
language, memory, and cognitive function are constructed and applied may
play a role in determining whether a person is diagnosed with AD. Clearly,
further careful investigation is needed to examine the role that ethnic and
racial differences may play in determining risk of AD.
Scientists have made enormous strides in the past two decades in unraveling
the genetic components of AD and related dementias. For example, we now
know that mutations of particular genes on three chromosomes (1, 14, and
21) virtually always lead to early-onset AD. In addition, mutations in
the tau gene on chromosome 17 cause frontotemporal dementia and related
diseases. These discoveries are helping to broaden our understanding of
how mutations in particular genes cause changes in cellular pathways that
eventually cause different kinds of dementia. For example, in a recent
study funded by NICHD, investigators at the University of Connecticut Health
Sciences Center examined the ways in which a mutation in the presenilin-1
gene found on chromosomes 14 might affect the cellular structure of neurons
during development. They found that mutated presenilin-1 interferes with
the ability of brain cells to regulate and stabilize growing neurons by
promoting the formation of neurofibrillary tangles, and interfering with
brain receptors that help determine the fate of cells during development
(Pigino et al., 2001). In other studies, NIA investigators have found that
the spectrum of the dementias caused by mutations in the presenilin-1 and
APP genes is much wider than had been suspected. These investigators have
found that some presenilin-1 mutations can cause a variant of Alzheimer's
disease characterized by a spinal disorder resulting in lower body weakness
or paralysis (Houlden et al., 2000; Verkkoniemi et al., 2001).
In other genetics and AD research, a team of Columbia University investigators
conducted a family-based study series to identify mutations in genes related
to familial, early-onset AD among Caribbean Hispanics, a rapidly growing
population in the United States (Athan et al., 2001). The study was carried
out in an Alzheimer's Disease Research Center in northern Manhattan and in
clinics in the Dominican Republic and Puerto Rico. Participants were drawn
from 206 Caribbean Hispanic families with two or more living members with
AD. Nineteen families and several individuals had developed AD before they
were 55 years old. To identify possible genetic mutations, the investigators
sequenced the entire coding region of the presenilin-1 gene from these 19
families and their living relatives. Based on these analyses, the study team
found a nucleotide change resulting in an amino acid substitution in presenilin-1
that had not been previously described. This same mutation was observed in
23 people from eight of the 19 families. A Caribbean Hispanic with the mutation
and early-onset familial AD was also found by sequencing 319 unrelated individuals
in northern Manhattan. This mutation was later found in five people from
four Hispanic families with AD who had been referred for genetic testing.
Members from another five Hispanic families have also been identified with
this mutation. None of the families was related to one another and they came
from different places, yet all 18 carriers of the new mutation shared a variant
allele indicating a common ancestor. This genetic change probably accounts
for a high percentage of early-onset familial AD in the Hispanic population.
The researchers also sequenced the parts of the APP gene where mutations
are known to cause AD, but found no mutations.
A recent study funded by NINDS, NIA, and other organizations provided further
evidence on the genetic basis of AD. This research team identified a new
mutation in a Swedish family with a history of the disorder (Nilsberth et
al., 2001). Affected individuals have a mutation in a unique location within
APP, which leads to early-onset AD. Information collected from the family
with this variation as well as from test tube studies suggests that a novel
beta-amyloid processing mechanism may be involved, specifically one in which
the formation of protofibrils (a very small beta-amyloid toxic precursor
to a plaque) is an initial event in the degeneration of neurons.
The location of the mutations appears to have a direct effect on the nature
of beta-amyloid plaque formation in affected individuals. In turn, this may
affect the clinical features of their particular disease. The suggestion
that a novel form of beta-amyloid processing may be occurring in individuals
with this mutation may help researchers better understand the cellular mechanisms
that contribute to the development of AD.
We also know that slightly different forms of the APOE gene on chromosome
19 can influence a person's risk of developing late-onset AD. However, the
APOE-e4 allele of this gene may explain only about 10 to 15 percent of the
genetic risk of late-onset AD, and it is likely that other major risk factor
genes also are involved. The roles that genetic changes play in increasing
or decreasing a person's chances of developing late-onset AD are under intense
scrutiny by many scientists.
NIA's AD Genetics Initiative: Accelerating the Pace of Research
In the 10 years since APOE-e4 was identified as a risk factor gene, scientists
have made great progress in narrowing the search for other risk factor
genes that may have links to late-onset AD. They have drawn significantly
closer to identifying at least four regions of chromosomes where other
risk factor genes might be. As this research has intensified, however,
it has become increasingly clear that scientists need many more samples
of genetic material if they are to continue making progress.
In the spring of 2002, NIA invited a group of leading scientists to plan
a new AD Genetics Initiative that would significantly expand the collection
of blood samples from individuals with AD and their family members. These
blood samples will allow investigators to create and maintain "immortalized" cell
lines - cells that are continuously regenerated in the laboratory. These
cell lines are crucial for the exhaustive DNA analysis studies needed
to identify risk factor genes.
NIA hopes to gather between 1,000 and 2,000 samples from people with
AD and their family members, and has provided supplemental funding to
10 Alzheimer's Disease Centers (ADCs) so that they can recruit new people
for genetics research and encourage these people to provide blood samples
for the Initiative. (The ADCs conduct research, provide investigator
training and patient care, and support the research process by developing
centralized databases and research tools.) NIA also is collaborating
with the Alzheimer's Association to develop community outreach programs
to foster participation in the Initiative, especially among families
that have two or more members with late-onset AD.
The National Cell Repository for AD (NCRAD), located at Indiana University,
will serve as the centralized repository for the Initiative. NCRAD was
established to provide genetic researchers with cell lines and/or DNA
samples from people with well-documented family histories of AD. Since
1989, the Repository has been banking DNA and cells and building a database
of rare and unique DNA information, family histories, and medical records.
Many researchers working to identify genetic defects associated with
AD have used genetic material stored in the Repository. To enhance the
diversity of analysis and promote innovative research, NIA will provide
access to the Repository to AD genetics researchers and encourage them
to share data.
Future plans of the Initiative include creating a national case-control
sample set, in which the genes of people with AD (cases) will be compared
to those who have no symptoms of the disease (controls). Creating such
a sample set will give investigators additional opportunities to evaluate
potential candidates for risk factor genes for late-onset AD.
of investigators studying late-onset AD published papers recently reporting
results of studies investigating one particularly
- chromosome 10. In the first study, investigators at the Mayo Clinic in
Jacksonville, Florida, confirmed a linkage between high levels of beta-amyloid
in blood and a region on the long arm of chromosome 10 (Ertekin-Taner et
al., 2001). Because beta-amyloid is intimately associated with the neuropathology
of AD, the investigators think that genes that elevate these beta-amyloid
levels could be risk factor genes for AD. A second team, located at the
Washington University School of Medicine, conducted a study on pairs
of siblings who
had definite or probable AD. They also found a suggestive linkage to AD
in the same region of the long arm of chromosome 10 (Myers et al., 2000).
a third analysis, a Harvard Medical School research team focused upon a
specific gene called the insulin degrading enzyme (IDE) gene (Bertram
et al., 2000).
IDE is found in neurons and another type of brain cell called glia, and
it acts to degrade beta-amyloid. These investigators found a linkage
one form of IDE, present in a region on the long arm of chromosome 10,
with AD. These studies indicate that there may be more than one late-onset
gene on the long arm of chromosome 10 that affects the risk of developing
Chromosome 10 is of interest for another reason as well. Little is currently
known about genes that might influence the age at which AD begins ("age
of onset"). Because AD and Parkinson's disease (PD) share some common
characteristics, including dementia, Duke University Medical Center investigators
supported by NCRR and NIA performed a genomic screen in the families of 449
AD and 174 PD families to see whether one or more genes controlled age at
onset for both diseases. Results showed that this characteristic is highly
heritable and that a specific region on chromosome 10 affects age of onset
for both diseases (Li et al., 2002b).
Chromosomes 9 and 12 are also stirring interest as possible sites of genes
that might affect AD risk. In collaboration with researchers at Washington
University School of Medicine and Cardiff University, scientists at NIA
have used genetic analysis strategies to find potentially promising regions
these two chromosomes. They are now conducting sequence analyses to pinpoint
the locations more exactly (Myers et al. 2002). These investigators also
are sequencing genes that might be involved in oxidative stress and lipid
metabolism, two other factors thought to be involved in the development
Scientists at NIA and investigators from Duke University also have recently
completed a study designed to examine whether cognitive decline associated
with the APOE-e4 allele is different in older African-Americans than in
Caucasians (Fillenbaum et al., 2001). The study involved more than 4,000
five adjacent counties in the Piedmont area of North Carolina. Participants
were given a brief cognitive function test at the beginning of the study
and again 3 years later. The investigators found that participants who
had the APOE-e4 allele scored lower on the first test than did those without
APOE-e4, and that having the allele increased by 59 percent the odds of
decline. However, age and race were not related to performance on the tests.
Other research is demonstrating that finding genes that are involved in
protecting cognitive health in the elderly is as important as finding risk
for cognitive decline and AD. University of Pittsburgh scientists supported
by NIMH recently began a systematic genome survey to identify the locations
of particular genes that might affect the likelihood of reaching age 90
with preserved cognitive abilities (Zubenko et al., 2002). Participants
100 young adults, aged 18-25 and 100 elders (94 nonagenarians and 6 centenarians).
All of the elderly participants were cognitively normal, as reflected by
clinical and psychometric assessments and "good" average capacity
to carry out their activities of daily living. The majority were living independently
despite multiple medical conditions. None had a history of mental disorders
in early or middle adulthood, only one was a current smoker, and 80 percent
consumed alcohol less than once each month. The genome survey method revealed
an elevated frequency of the APOE-e2 allele (the relatively rare APOE form
that is thought to provide some protection against AD), and a reduced frequency
in the APOE-e4 allele among the elders compared to the young adults. These
results suggest that several behavioral and genetic factors may contribute
to the likelihood of achieving exceptional longevity with preserved cognition.
Increasing knowledge about the genetics of Alzheimer's disease has led
to an urgent need for accurate information and materials to educate families,
health care providers, and the public about the challenges they may face
and to provide models for genetics education in other, equally complex
The National Human Genome Research Institute (NHGRI) has funded a group
of researchers at the Massachusetts General Hospital/Harvard Medical School
and the University of Alabama to address the ethical, legal, and social
of the genetics of AD from the critical perspective of a group at high
risk of the disease: currently unaffected relatives of people with AD (Tanzi
Blacker, 2001). The researchers have been working together since 1990 as
part of the NIMH Genetics Initiative to identify families with Alzheimer's
disease for genetic linkage studies. Nearly 350 such families, predominantly
affected sibling pairs and over 300 of their unaffected siblings, have
been identified. The researchers will use a variety of approaches to study
attitudes, and behavior related to genetic studies and genetic testing
in the unaffected people in these AD families and their primary care physicians,
and will develop and pilot educational materials designed to address their
needs for genetic information.
A second study, funded by NHGRI and conducted by Boston University School
of Medicine investigators, has estimated risk of AD among adult children
of persons with AD to determine who chooses to obtain genetic susceptibility
testing for AD and to assess the risks and benefits of providing such information
(Green et al., 2002). Study investigators hope that their results can inform
the development of guidelines for clinicians for genetic testing, risk
assessment, and appropriate counseling scenarios.
Another area that is capturing an increasing amount of attention and interest
is the possible influence of education, leisure, physical, and intellectually
stimulating activities on the risk of developing AD. The interaction of
genetic and lifestyle factors is also of interest. A number of studies
over the past few years have provided intriguing hints that these activities
may be linked to a reduced risk of AD, and they are consistent with what
we know about other health benefits of lifelong physical and intellectual
Several studies in the past year have revealed some clues about the effect
of these potentially protective activities. The first study, conducted by
a research team at Case Western Reserve University School of Medicine, explored
the longstanding notion that high levels of education and occupation are
correlated with protection against development of AD (Friedland et al., 2001).
Some researchers have speculated that such protective effects occur because
these activities may build up brain reserves that delay or buffer against
cognitive decline. Others have argued that the protective effect of education
is related to its complex associations with economic, medical, and occupational
factors. This study attempted to differentiate between these two explanations
by investigating the potential protective effects of three general categories
of recreational activities. These categories included passive (e.g., watching
television), intellectual (e.g., playing chess, solving crossword puzzles),
and physical (e.g., bowling, skating) activities. Patients with AD were found
to have been much less active than healthy control persons of similar background
in terms of both diversity and intensity of recreational activities engaged
in during early and middle adulthood. These differences were not explained
by differing educational or income levels, age, or gender. People who were
relatively inactive in midlife had a 250 percent increased risk of developing
AD. Differences were greatest for intellectual activities, but were significant
for passive and physical activities as well. This study suggests that engaging
in physical and intellectual activities may buffer against cognitive decline
and that underactivity is related to increased risk of AD. Although these
results are provocative, the study authors suggest that they be interpreted
with caution because it was not possible to evaluate whether AD could be
the cause rather than the consequence of underactivity. The disease may develop
several decades before the onset of symptoms and very early deficits might
adversely affect participation in recreational activities.
In a similar study, investigators with the Religious Orders Study, an ongoing
examination of aging among older Catholic nuns, priests, and brothers across
the U.S., tested the hypothesis that frequent participation in intellectually
stimulating activities is associated with a reduced risk of AD (Wilson et
al., 2002a). About 800 Religious Order Study participants were rated at the
beginning of the study for frequency of participation in such cognitive activities
as reading a newspaper.
A 5-point cognitive activity score was derived from these data, with the
highest score given to daily or almost daily participation and the lowest
score given to participation less than once a year. Investigators also gathered
information on time spent in physical activities. For up to 7 years, participants
underwent annual evaluations that included detailed cognitive function testing
to determine whether they had developed AD. During an average of 4.5 years
of follow-up, 111 people developed AD. In an analytic model that controlled
for age, sex, and education, each 1-point increase in the cognitive activity
score was associated with a 33 percent reduction in risk of AD. Results were
comparable when those with memory impairment were excluded at the beginning
of the study and when the presence of the APOE-e4 allele and medical conditions
were factored in. In other analytic models that controlled for age, sex,
education, and beginning level of cognitive function, a 1-point increase
in cognitive activity was associated with reduced decline in global cognition
(by 47 percent), working memory (by 60 percent), and perceptual speed (by
30 percent). Participation in physical activity was unrelated to risk of
disease or rate of cognitive decline. The results suggest that more frequent
participation in intellectually stimulating activities is associated with
reduced risk of AD.
Another research project with the Religious Orders Study participants examined
individual differences in the rates of change in cognitive abilities (Wilson
et al., 2002b). Participants, who were aged 65 years and older and free of
clinical evidence of AD at the beginning of the study, underwent annual clinical
evaluations for up to 6 years. Cognitive function was assessed at each evaluation
with a battery of tests, from which summary measures of performance in seven
cognitive areas, or domains, were derived. On average, decline occurred in
each domain and was more rapid in older persons than in younger persons.
However, wide individual differences were evident at all ages. The rate of
change in a given domain was not strongly related to the beginning level
of function in that domain, but was moderately associated with rates of change
in other cognitive domains. The results suggest that change in cognitive
function in old age primarily reflects person-specific factors rather than
an inevitable developmental process.
A recent study by scientists at the University of Washington in Seattle explored
how environmental risk may interact with the APOE genotype to clarify the
possible relationships between early life environment and the development
of AD (Moceri et al., 2001). The researchers used information from Census
data to index socioeconomic risk through measures of the father's occupation,
parental age, household size, number of siblings, and birth order. They found
that the risk of AD increased among individuals whose fathers were unskilled
manual workers or laborers compared to those whose fathers had nonmanual
occupations, but this increased risk was significant only among individuals
who carried the APOE-e4 allele. Therefore, compared to those with neither
risk factor, the risk for Alzheimer's disease was greatly elevated when both
the genetic and the environmental risk factors were present. These findings
highlight some intriguing clues about the possibility that the APOE-e4 allele
may modify any relationship between early-life environmental factors and
the development of Alzheimer's disease.
Cholesterol and Homocysteine
A third exciting area of research is providing data about factors that may
protect against or increase the risk of AD. In recent years, a number of
studies have suggested a connection between AD and cholesterol in the blood.
For example, the APOE-e4 allele is a variant of the APOE gene, which codes
apolipoprotein E, a protein that helps to carry cholesterol in the blood.
Test tube studies also have shown that blood cholesterol increases production
of beta-amyloid from its APP precursor, and animal studies show a relationship
between blood cholesterol and brain plaque levels in transgenic mice. Epidemiologic
studies linking vascular risk factors to dementia have lent further support
to this relationship (see the sidebar on the Honolulu-Asia Aging
Study for more on findings from these studies). Many questions remain about
the relationship between blood cholesterol and AD, but these intriguing
findings have spurred new research and led scientists to hypothesize that
drugs that lower blood cholesterol might also lower risk of developing
dementia and AD.
Two recent observational studies examined changes in AD risk with prescription
of statins, the most commonly prescribed cholesterol-lowering drugs. Both
studies have stirred considerable interest because they showed a significant
reduction in dementia risk correlated with individuals who take these drugs.
In the first study, a research team at the Boston University School of Medicine,
the University of Massachusetts Medical School, and Harvard School of Public
Health analyzed data on more than 1,300 people in the United Kingdom (Jick
et al., 2000). They found that people with high cholesterol who were prescribed
statins had a risk of dementia 70 percent lower than those who did not have
high cholesterol (or hyperlipidemia) or who were not on lipid-lowering treatment.
The effect was similar regardless of the specific statin prescribed. People
with high cholesterol who were prescribed a non-statin drug or those who
remained untreated did not have reduced risk for dementia, suggesting that
the effect was not due to lowering lipid levels per se.
Investigators at Loyola University Medical School in Maywood, IL, conducted
a second study, which involved cases listed in a three-hospital database
in the U.S. This study showed a relationship between either lovastatin or
pravastatin prescription and a 60 to 73 percent lowered risk of developing
AD (Wolozin et al., 2000). This relationship was not found with non-statin
medications for hypertension or cardiovascular disease.
Clinical Research and Care by Improving Outreach
To thoroughly understand the factors that might increase the risk of
AD or protect against it and to develop effective treatment strategies,
researchers need to study people who come from a variety of locations,
racial and ethnic groups, and demographic backgrounds. For some years,
NIH has made a concerted effort to improve the diversity of its research
participants and to reach out to groups who traditionally have not participated
in clinical studies. Increasing the numbers of non-Caucasians who are
over 65 and therefore at higher risk of AD, has been an important priority
for Alzheimer's disease researchers.
As part of this effort, in 1990, the NIA began a program of Satellite
Diagnostic and Treatment Clinics through its existing Alzheimer's Disease
Centers (ADCs) Program. The satellite clinic program was significantly
expanded in following years; currently 25 clinics are operating across
Many satellite clinics are located in areas where staff can reach out
to minority, rural, or underserved populations. The clinics are primarily
focused on providing diagnostic and treatment services to people with
AD and their families, but through their connection with the ADCs, they
can offer families opportunities to participate in research protocols
and clinical drug trials.
Before NIA established the satellite clinic program, minority enrollment
in the ADCs was approximately 4 percent. Since 1990, the overall ADC
rate of minority enrollment has increased significantly, ranging between
10 and 14 percent for African-Americans and 4 to 7 percent for Hispanics.
The satellite clinics have had similar success in enrolling Native Americans.
For example, the University of Texas Southwestern ADC in Dallas has developed
close ties with the Choctaw Nation, with a subsequent enrollment of 146
subjects, representing 6.6 percent of the Center enrollment. This effort
comes almost exclusively from their satellite clinic. American Indian/Alaskan
Natives represent 18.7 percent of the registry from the University of
Washington ADC. Almost all of these study participants come from their
ADCs are also using other strategies to promote diversity in clinical
trial enrollment, such as active community outreach and education activities.
Memory screening at health fairs, mass mailing of brochures, educational
presentations, and high visibility research projects have all helped
to promote enrollment. For example, the Indiana ADC was highly successful
in recruiting African-American participants because of its association
with the Indianapolis-Ibadan Dementia Project (see the epidemiology section
for more on this study). The Rush-Presbyterian-St. Luke's ADC in Chicago
a successful working relationship with the president of the National
Black Sisters Conference and the National Black Catholic Clergy Caucus
and this has led to increased enrollment of African-American nuns, priests,
and brothers in the Religious Orders Study. Efforts to cement the relationship
with the African-American Catholic Communities continue with the formation
of an Advisory Panel of African-American Catholic religious leaders to
gain a better appreciation of potential barriers to participation of
individual nuns, priests, and brothers.
studies do not prove causality, the implications of this research could
be considerable. The authors of these studies
that AD risk may be reduced because onset of dementia is delayed or because
age-related changes that result in cognitive impairment are delayed, and
they suggest that the use of statins could substantially reduce the risk
for dementia in older people. The only way to determine whether statins
delay onset of AD is to perform a clinical trial.
A recent epidemiologic study from investigators at Boston University, based
on data from the Framingham Heart Study, also found that elevated levels
of an amino acid called homocysteine, a risk factor for heart disease,
are associated with an increased risk of developing AD (Seshadri et al.,
Investigators at NIA have shown in transgenic mice that high homocysteine
levels make neurons vulnerable to dysfunction and death (Kruman et al.,
2002). The relationship between AD and homocysteine is particularly interesting
because blood levels of homocysteine can be reduced by increasing intake
of folic acid and vitamins B6 and B12. These findings have led the NIA
fund a multicenter, randomized, placebo-controlled clinical trial, currently
underway, to determine whether reducing homocysteine levels through high-dose
supplements of folate and vitamins B6 and B12 will slow the rate of decline
in people with AD.
Can Be Done to Halt AD, Slow Its Progress, or Lessen Its Effects?
As the earlier sections of this report have shown, recent advances in genetics
and molecular biology have vastly increased our understanding of the brain
- how it works normally and what happens when something goes wrong. Improvements
in this understanding have opened the doors to a number of potential therapeutic
targets for AD. NIA, other NIH Institutes, and private industry are conducting
studies on an estimated 30 compounds that may be active against AD. These
studies focus on four issues:
people with AD maintain cognitive function over the short-term;
the progress of the disease;
AD-associated behavioral problems; and
The remainder of this section provides highlights of several ongoing clinical
Memory Impairment Study - Launched in March 1999, this study has completed
enrollment with 769 participants in 68 sites
in the Alzheimer's
Disease Cooperative Study (ADCS) network. The ADCS is a study in which many
Alzheimer's Disease Centers and other clinical sites cooperate to investigate
promising drugs for AD and develop and improve tests for evaluating AD patients
in clinical trials. The purpose of the Memory Impairment Study is to determine
whether daily doses of vitamin E or donepezil (Aricept) given over a 3-year
period can delay or prevent the onset of AD in people who have MCI. A major
challenge for this trial was screening and recruiting enough people with
MCI and retaining them for the long study period. The design of the trial
and the success of the recruitment phase represent a major advance in AD
clinical trial methodology, and this protocol has been widely copied by the
pharmaceutical industry, which has now used this study design to set up several
independent trials of various agents using volunteers with MCI. Results of
this trial are expected in mid-2004.
and cognitive function - Over the past 25 years, animal studies have
suggested that estrogen has some positive
effects on the brain
and memory function. Some human epidemiological studies have supported this
notion. These findings have created scientific interest in the relationship
among estrogen, memory, and cognitive function. Although scientists still
don't know whether normally aging women who take estrogen alone will be protected
from developing AD, women aged 65 and older taking a combination of estrogen/progestin
(Prempro) in a recent clinical trial were found to have a significantly increased
risk of developing dementia (Shumaker et al., 2003). Another part of this
same study, the Women's Health Initiative, previously showed that combined
estrogen/progestin therapy also increases risk of heart disease, stroke,
blood clots, and breast cancer, while decreasing the risk for hip fracture
and colon cancer. The NIA continues to explore potential benefits of estrogen
alone in an ongoing clinical trial on cognitively normal older women with
a family history of dementia. Safety monitoring boards that include expert
physicians and scientists are carefully monitoring the side effects of treatment
for women participating in this study. Clearly, more research is needed on
this complex issue.
and AD progression - This study, which is actively recruiting, is testing
whether simvastatin (Zocor), a commonly
drug, can slow the rate of disease progression in people with AD. Results
of this trial are expected in late 2005.
and inflammation - 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 suggests that anti-inflammatory agents,
such as non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen,
naproxen, and indomethacin are associated with a decreased risk of AD. One
clinical trial designed to determine whether naproxen or rofecoxib (a new
selective cyclooxygenase, or COX-2, inhibitor) found that neither NSAID slowed
the rate of cognitive deterioration in people with mild to moderate AD. Researchers
hope that prevention trials underway will prove the effectiveness of NSAIDs
in preventing AD in people at risk, but not yet showing symptoms, of the
disease (Aisen et al., 2003).
agents and cognitive function - The mainstay of current AD treatment is
drugs that help to maintain levels of acetylcholine,
that is crucial in the formation of memories. These drugs have limited effectiveness,
however, so researchers also are exploring other therapeutic strategies.
Ongoing NCRR-supported investigations of the molecular substructure of central
nervous system nicotinic receptors, their accompanying pharmacology, and
the effects of nicotinic agents on cognitive function have suggested the
possibility that nicotinic cholinergic receptor stimulation may have beneficial
effects in AD and other neuropsychiatric disorders. Results from recent NCRR-supported
pilot clinical trials with nicotine and novel nicotinic agents suggest that
acute nicotinic stimulation in AD patients can transiently improve the acquisition
and retention of verbal and visual information and decrease errors in cognitive
tasks, as well as improve accuracy and response time (Newhouse et al., 2001).
treatments for psychiatric and behavioral problems in AD - Many people
with AD have periods of restless or irritable behavior
easily agitated. Agitation may be an expression of pain, anger, anxiety,
or depression, or it may be a still unexplained part of the disease. Whatever
the cause, it is a frequent and often difficult behavioral issue for people
with AD and their caregivers. An ADCS research team is now conducting a clinical
trial among 120 nursing home residents with severe AD to see whether divalproex
sodium (Valproate), an antiseizure medication, can help to ease agitation.
Other psychiatric and behavioral problems, such as delusions, mood changes,
and aggression, also are common in patients with Alzheimer's disease and
other dementias, and are disturbing to the person and his or her family.
A range of medications and non-medication approaches are used to help treat
these symptoms, but many questions remain about which treatments to use for
which symptoms and how to balance positive treatment effects against potential
side effects. The NIMH and NIA are supporting several clinical trials examining
the effectiveness of drugs used to treat aggression, psychosis, depression,
and other common behavioral problems in persons with AD (Pollock et al.,
2002; Schneider et al., 2001; Sultzer et al., 2001). Findings from this research
may lead to improved and more precise therapies for the behavioral and psychotic
disturbances associated with AD and other forms of dementia.
In addition to these ongoing or just completed trials, NIA is planning a
number of other innovative clinical trials over the next 5 years. These studies,
which will be conducted through the ADCS and other clinical sites, include:
project to develop sensitive and more effective methods for evaluating change
over time in cognitively healthy elderly
in a number of areas, such
as overall cognitive functioning, memory, ability to carry out activities
of daily life, and quality of life. These improved evaluation instruments
will then be used in AD prevention clinical trials to measure changes that
result from the interventions.
study to see whether low-doses of divalproex sodium (Valproate) can
delay or prevent agitation and psychosis from developing
in people with
mild to moderate AD, and also to see whether its possible neuroprotective
properties have any effect on slowing the rate of cognitive decline.
study to test the safety and tolerability of indole-3-propionic acid (IPA),
a highly potent, naturally occurring antioxidant that also inhibits
fibril formation by beta-amyloid. Investigators will measure levels of biological
markers related to oxidative damage and AD to assess the biological activity
of IPA and also determine whether this antioxidant has any beneficial short-term
effects on AD.
Research to Help Families and Caregivers
Although much of NIH's AD research effort is focused on the basic science
aspects of the causes, characteristics, diagnosis, and treatment of AD,
the Institutes have never lost sight of the enormous personal toll exacted
by AD on the families, friends, and caregivers of people with the disease.
Investigators supported by several Institutes, including NIA, the National
Institute of Nursing Research (NINR), and NIMH, are exploring the emotional,
psychological, and physical costs of caregiving, and they are investigating
ways to ease the burden.
A number of studies are examining the factors that contribute to stress and
depression in family caregivers of people with AD. In one study, Case Western
Reserve University investigators explored the relationship between depression
in the care recipient and in the caregiver (Neundorfer et al., 2001). They
found that the well-being of both people is closely related - the more depressed
the person with AD was, the more depressed the caregiver also was. Wives
of men with AD and caregivers who were themselves in poor health were at
particular risk of depression. The researchers concluded that interventions
for caregivers are needed early on in the family member's illness and that
further research is needed to understand what interventions will sustain
the quality of life and physical and mental well-being of the person with
AD as well as the caregiver.
A second study examined caregiving stress from a somewhat different angle.
We know that the chronic stress resulting from continuously caring for a
family member with dementia has been associated with depression, elevated
stress hormones, and increased vulnerability to influenza and poor wound
healing in older caregivers. However, only recently have the long-term effects
of this stressful period for caregivers after the death of the demented spouse
been investigated. This study, funded by NIA and NIMH and conducted by a
research group at the Houston Veterans Affairs Medical Center, examined the
psychological state of spousal caregivers for up to 4 years following the
death of the person with dementia (Robinson-Whelen et al., 2001). The former
caregivers were compared to a group of caregivers who were still caring for
their husbands or wives throughout the study, as well as to a group of non-caregiving
age-matched control participants. The investigators found that although former
caregivers experienced slight decreases in stress and negative mood after
their spouses had died, their emotional state and levels of depression and
loneliness had not returned to levels comparable to non-caregivers up to
3 years later. In fact, they remained similar to those of current spousal
caregivers, suggesting that the consequences of long-term caregiving may
be long-term as well. The investigators also found that social support after
the death of the spouse helped more to ensure a positive post-caregiving
outcome than support received during the caregiving years. Not surprisingly,
an inability to suppress thoughts of the caregiving years was negatively
associated with psychological well-being. Clearly, the needs of caregiving
spouses must receive long-term attention. Programs aimed at providing social
support and working through the persistent traumatic and stressful thoughts
of the prior years of spousal caregiving have the potential to help former
caregivers and boost their psychological and physical well-being.
A third study looked at ways to help family caregivers by building on previous
research showing that people who exercise benefit in various ways, including
reduced stress-induced high blood pressure and improved quality of sleep.
This study, conducted by Stanford University Medical School researchers,
is the first to examine the role that a regular moderate-intensity exercise
program plays in enhancing health and quality of life for women caring for
loved ones with dementia (King et al., 2002). A group of 100 women caregivers,
aged 49 to 82 years old, received either home-based, telephone-supervised
moderate-intensity exercise training or a nutrition education program. Exercise
consisted of brisk walking for four 30- to 40-minute sessions per week. Compared
with the nutrition education group, exercise participants showed significant
improvements in physical activity levels, stress-induced blood pressure reactions,
and sleep quality. The nutrition group also benefited through reducing the
percentage of total calories from fats and saturated fats and consuming fewer
fats, oils, sweets, and high-fat snacks. Both groups reported significant
reductions in psychological distress, including depressive symptoms and self-rated
stress. This research demonstrates that properly tailored health promotion
programs can improve the health and functioning of older women family caregivers.
A critical challenge remains: How best to tailor programs to the needs and
preferences of other populations of caregivers.
Outlook for the Future
The future builds upon the events and experience of the past and present.
That's certainly true for Alzheimer's disease research, for the explosion
of knowledge during the past 25 years has set the stage for a hopeful future
in which, one day, we may be able to prevent or even cure this terrible
disease, which robs our loved ones of their most precious faculty - their minds.
Here are just a few ways in which past and present research
findings are providing a foundation for the future:
years ago, we did not know any of the genes that could
cause AD, and we had only an inkling of the biological pathways
that were involved in the development of brain pathology.
we know the 3 major genes for early-onset disease and one of the
major risk factor genes for late-onset disease, and we are rapidly
expanding the research infrastructure to identify the other major
risk factor genes for late-onset AD (see the description of NIA's
Genetics Initiative in the genetics section). The known genes have
made major contributions to our extensive knowledge of pathways leading
development of AD's characteristic amyloid plaques in the brain.
Identification of the tau gene mutations causing frontotemporal dementia
with parkinsonism (FTDP-17), another late-onset dementia, is providing
clues to ways in which the formation of the characteristic intracellular
tangles in AD may be prevented.
years ago, we could not model Alzheimer's disease in animals.
transgenic mice are an invaluable resource for modeling amyloid plaque
development in the brain and in testing possible therapies (for more
on this work, see the beta-amyloid section and the immunization
sidebar in that section). Other animals also are now being effectively
used as models for age-related and disease-related changes in brain,
as well as models for testing promising interventions.
years ago, we had no ways of identifying people at high
risk for the disease and did not have any prevention clinical trials
scientists are identifying people at high risk of developing AD by
brain imaging, neuropsychological tests, and structured clinician
interviews, leading to insights into the preclinical phases of the
disease, such as MCI (see the neuroimaging section for more about
advances in neuroimaging). We have eight ongoing prevention clinical
and 11 clinical
trials that are aimed at slowing the progression of AD or alleviating
distressing symptoms such as agitation (for
more information on clinical trials, see the section on what can
be done to halt AD, slow its progress, or lessen its effects).
years ago, we did not understand the mechanism by which
plaques and tangles relate to each other.
as a result of developing the first double transgenic mouse that
produces both plaques and tangles, we know that plaques in the brain
can influence the development of tangles in brain regions susceptible
in AD (see the beta-amyloid section for more on the double transgenic
mouse). Recent findings also suggest that a number of neurodegenerative
have some common mechanisms of disease, and these findings will further
inform research in AD.
for the future is to predict the specific pilot and full-scale clinical
trials that are most likely to yield effective strategies for preventing
and treating AD in different populations. To facilitate this, we need to
develop new strategies for moving compounds that show promise in the laboratory
into animal studies to test for safety and efficacy and then into pilot
trials in people. The Alzheimer's Disease Prevention Initiative, a major
effort by NIH in collaboration with other Federal agencies and the private
sector, is providing a focus for AD researchers to meet this challenge
through support for current research on genetics, on the basic cellular
biology of AD-related pathways, and on the changes taking place in the
brains of people with mild cognitive impairment and early AD.
Results from animal model research and tantalizing hints of possible risk and
protective factors from epidemiologic studies will contribute further information.
Other studies will also provide valuable clues about the possible impact of
diseases such as cardiovascular disease and diabetes on AD-related dementia
in later life. The ultimate goal of this research is to develop and test a
variety of types of interventions, be they behavioral, dietary, or drug, to
determine whether they can ameliorate the cognitive and behavioral symptoms
of Alzheimer's disease, modify its course, or eventually delay the onset of
or prevent the disease entirely.
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Anne Brown Rodgers
Patricia D. Lynch and Karen M. Pocinki
National Institute on Aging
Rodney C. Williams and Brian Taylor
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