Alzheimer's Disease - Unraveling the Mystery
Alzheimer's disease is one of the most
common causes of the loss of mental function known broadly as
Over the past few decades, Alzheimer's disease has emerged from
obscurity. Once considered a rare disorder, it is now recognized
as a major public health problem having a severe impact on millions
of Americans and their families. Research on Alzheimer's disease
has grown accordingly. The small group of pioneers who conducted
research on the disease in the 1970's has expanded to thousands
of scientists in laboratories, institutions, and communities all
over the world.
At the National Institutes of Health (NIH), several institutes
conduct and sponsor studies on Alzheimer's disease, including
the National Institute of Neurological Disorders and Stroke, the
National Institute of Mental Health, and the National Institute
of Nursing Research. The lead agency for Alzheimer's research
at NIH is the National Institute on Aging (NIA), which launched
an Alzheimer's disease program in 1978. Since then the study of
this disease has become one of NIA's major priorities.
In the private sector, the Alzheimer's Association and other
groups are working to combat this disease. They fund research,
contribute to public policy decisions, inform and educate the
public, and provide services to people with Alzheimer's disease
and their families. Their support for research is critical in
the effort to understand and defeat this disorder.
Thanks to these many groups, the study of Alzheimer's disease
is moving ahead rapidly. Based on the pace of research over the
past two decades, many scientists now think that effective treatments
are not far in the future. The purpose of this booklet is to describe
what we have learned to date and where research is now headed
in the search for answers about Alzheimer's disease.
This booklet was written for people who are interested in research
on Alzheimer's disease. Technical terms, if italicized in the
text, are defined in a glossary. The booklet covers numerous areas
of research briefly; for those who want to pursue a specific topic,
each chapter ends with a list of review articles and other materials
that provide more detail on the studies mentioned in the text.
More information on Alzheimer's disease research is also available
from the publications and organizations listed at the end of the
Many people contributed to this booklet. The NIA extends special
thanks to the managers and residents of Sunrise of Arlington for
the photographs by Richard Nowitz; and to researchers in NIA's
Laboratory of Neuroscience for the photographs by Kay Chernush.
This booklet was written by Caroline McNeil, Public Information
Office, NIA; designed by Beth Singer Design; and illustrated by
What Is Alzheimer's Disease?
"With Alzheimer's people, there's no such thing as having a
day which is like another day. Every day is separate....it's as
if every day you have never seen anything before like what you're
seeing right now." -- Cary Henderson
This excerpt from the journal of a man with Alzheimer's disease
offers a glimpse of what it's like to be one of the 4,000,000
people in the United States who have this progressive, degenerative
brain disorder. Cary Henderson, a history professor in Virginia,
was diagnosed with Alzheimer's disease at age 55.
Alzheimer's disease is one of the most common causes of the
loss of mental function known broadly as dementia. This type of
dementia proceeds in stages, gradually destroying memory, reason,
judgment, language, and eventually the ability to carry out even
the simplest of tasks.
"You just feel that you are half a person," Henderson says in
his narrative, which was dictated on a tape recorder in the early
stages of the disease. "And you so often feel that you are stupid
for not remembering things or for not knowing things... Just the
knowledge that I've goofed again or I said something wrong or
I feel like I did something wrong or that I didn't know what I
was saying or I forgot--all of these things are just so doggone
Such personal accounts inevitably make one ask, why? What causes
this disease? Can't anything be done to stop it? To prevent it?
Scientists ask essentially the same questions, and this booklet
describes their search for answers. It provides a brief overview
of dozens of paths that are bringing us closer to ways of managing,
and eventually defeating, Alzheimer's disease.
A report like this one would not have been possible 20 years
ago, when very little was known about Alzheimer's disease. But
it is by no means a new disease. Ancient Greek and Roman writers
described symptoms similar to those of Alzheimer's disease. In
the 16th century, Shakespeare wrote about very old age as a time
of "second childishness and mere oblivion," suggesting that the
symptoms of Alzheimer's disease, or something quite similar, were
known and recognized then.
These characteristic symptoms acquired a name in the early part
of the 20th century when Alois Alzheimer, a German physician,
described the signs of the disease in the brain. Alzheimer had
a patient in her fifties who suffered from what seemed to be a
mental illness. But when she died in 1906, an autopsy revealed
dense deposits, now called neuritic plaques, outside and around
the nerve cells in her brain. Inside the cells were twisted strands
of fiber, or neurofibrillary tangles. Today, a definite diagnosis
of Alzheimer's disease is still only possible when an autopsy
reveals these hallmarks of the disease.
Plaques and tangles remained mysterious substances until the
1980's, when neuroscientists--the scientists who study the brain--discovered
the proteins that make up these telltale anomalies. As research
progresses, it is turning up clues to how plaques and tangles
develop and how they relate to other changes in the brain.
In the meantime, much more about the disease has come to light.
We now know that Alzheimer's begins in the entorhinal cortex and
proceeds to the hippocampus, a waystation important in memory
formation. It then gradually spreads to other regions, particularly
the cerebral cortex. This is the outer area of the brain, which
is involved in functions such as language and reason. In the regions
attacked by Alzheimer's, the nerve cells or neurons degenerate,
losing their connections or synapses with other neurons. Some
The course of the disease.
As the hippocampal neurons degenerate, short-term memory falters.
Often the ability to perform routine tasks begins to deteriorate
as well. Henderson describes the difficulty and frustration he
feels when he tries to open a can of food for the family's dog.
"...the best I could do was to try to dig a hole, make a little
perforation and see if I could extend the side of it--and it was
something like a panic...I'm too clumsy because of the Alzheimer's....
Right now, the doggie seems to be in fairly good shape. I'm not
too sure I am."
As Alzheimer's disease spreads through the cerebral cortex,
it begins to take away language. "Lately, I've had trouble with
words (practically have to play charades)" says Letty Tennis,
a North Carolina woman with Alzheimer's disease who also kept
Tennis talks about how her judgment is changing and refers to
the emotional outbursts that are common in this disease. "We had
a great time shopping, but...I bought everything in sight....My
poor dear husband didn't stop me very much unless it was too outrageous
and then I'd get very angry. I bought a pair of boots--galoshes
really...and I told George it's something I've always wanted so
we bought them and when we got home I had no memory of buying
them--they were awful and cost $40...I used to be the sensible
one in the family."
Disturbing behaviors, such as wandering and agitation, beset
many people as the disease progresses. In its final stages Alzheimer's
disease wipes out the ability to recognize even close family members
or to communicate in any way. All sense of self seems to vanish,
and the individual becomes completely dependent on others for
Patients often live for years with this condition, dying eventually
from pneumonia or other diseases. The duration of Alzheimer's
disease from time of diagnosis to death can be 20 years or more.
The average length is thought to be in the range of 4 to 8 years.
Dementia: A group of symptoms characterized by a decline in
intellectual functioning severe enough to interfere with a person's
normal daily activities and social relationships.
Alzheimer's Disease: The most common cause of dementia
among older people. It is marked by progressive, irreversible
declines in memory, performance of routine tasks, time and space
orientation, language and communication skills, abstract thinking,
and the ability to learn and carry out mathematical calculations.
Other symptoms of Alzheimer's disease include personality changes
and impairment of judgment.
Age-Associated Memory Impairment: A decline in short-term
memory that sometimes accompanies aging; also called benign senescent
forgetfulness. It does not progress to other cognitive impairments
as Alzheimer's disease does.
Senile Dementia: An outdated term once used to refer
to any form of dementia that occurred in older people.
This bleak picture is countered by the continued, rapid pace
of research. Many neuroscientists think that a means to prevent
or treat Alzheimer's disease will be found in the foreseeable
Studies of Alzheimer's disease can be divided into three broad,
interacting categories. The first is research on causes, the second
is diagnosis, and the third is treatment, which includes caregiving.
The following chapters give a brief overview of what is known
about each topic. They highlight some key findings to date, the
clues researchers are now pursuing, and the paths that are expected
to lead to answers about Alzheimer's disease.
Henderson C. "Musings," The Caregiver: Newsletter of the Duke
Family Support Program, 12(2):6-12, 1994.
Khachaturian ZS and Radebaugh TS. Alzheimer's Disease: Progress
Toward Untangling the Mystery, Encyclopaedia Britannica: 1995
Medical and Health Annual, Chicago: Encyclopaedia Britannica,
Inc., 222-228, 1994.
Tennis L. "Alzheimer's Diary: I Have What!" The Caregiver: Newsletter
of the Duke Family Support Program 12(1):6-13, 1992.
Tennis L. "More From Letty's Diary," The Caregiver: Newsletter
of the Duke Family Support Program 12(3):8-10, 1992.
The Public Health Impact of Alzheimer's Disease
How Many People... It is estimated that about 4,000,000 people
in the United States have Alzheimer's disease. This is a very
rough estimate. Alzheimer's disease is not reported on death certificates,
so estimates of prevalence (how many people have a disease at
any one time) are based on surveys in different communities, and
their findings vary. Most surveys have found the percentage of
people age 85 and older who have any kind of dementia, including
Alzheimer's, to be in the range of 25 to 35 percent. One study
in Boston, however, found that the percentage of people with Alzheimer's
disease alone was 47.2 percent in people age 85 and over.
One problem in getting accurate figures lies in the lack of
a single definition of either dementia or Alzheimer's disease.
Different surveys use different criteria for determining whether
a person falls into one category or another. This is one reason
their findings can be different. Another problem is that in all
populations studied, a large proportion of people are unable or
unwilling to participate in surveys of dementia.
Although there is still no agreement on the exact percentage
of people with Alzheimer's disease or other dementia, all studies
do project one picture clearly--the exponential rise of this disease
with age. After age 65, the percentage of affected people approximately
doubles with every decade of life, regardless of how a survey
defines dementia or Alzheimer's disease.
It is also clear that as America's older population grows, the
number of people with Alzheimer's will rise. If current population
trends continue and no cure is found, the actual number of people
with the disease could double every 20 years.
...And How Much It Costs. Alzheimer's disease has been estimated
to cost the nation $80 to $90 billion a year. This figure includes
both direct financial outlays, such as for nursing care, as well
as indirect costs, such as lost productivity on the part of patients
and the family members who care for them.
Caring for a patient with Alzheimer's disease costs more than
$47,000 a year whether the person lives at home or in a nursing
home, according to a recent study in northern California. This
study found that the families of Alzheimer's disease patients
living at home spent about $12,000 annually, per family, for formal
services, such as physician care and home health aides. But when
the researchers added the estimated cost of unpaid, informal care
provided by family members, the total annual cost was $47,049--comparable
to the cost of nursing home care.
Evans DA. Estimated Prevalence of Alzheimer's Disease in the
United States, The Milbank Quarterly 68(2): 267-289, 1990.
Rice D, Fox PJ, Max W, et al. The Economic Burden of Alzheimer's
Disease Care, Health Affairs, 12(2):164-176, 1993.
The Search for Causes
The brain has hundreds of billions of neurons, any one of which
can have thousands, even hundreds of thousands, of connections
with other neurons. Within and among their extensive branches
travel dozens of chemical messengers--neurotransmitters, hormones,
growth factors, and more--linking each neuron with others in a
vast communications network.
Somewhere in this complex signaling system lies the cause of
Alzheimer's disease. In the past two decades, neuroscientists
have combed through it in search of defects that might explain
what goes wrong in this disease. One of their earliest findings
came from studies of neurotransmitters, the chemicals that relay
messages between neurons.
Neurotransmitters reside in tiny sacs at the ends of axons,
the long tube-like extensions of neurons. Released when electrical
impulses pass along the axon, the chemicals cross a minute space
called the synapse and bind to a molecule (a receptor) sitting
in the membrane of the next neuron. The neurotransmitters then
either break down or pass back into the first neuron, while other
substances inside the second neuron take up and relay the message.
In the mid 1970's, scientists discovered that levels of a neurotransmitter
called acetylcholine fell sharply in people with Alzheimer's disease.
The discovery was intriguing for several reasons. Acetylcholine
is a critical neurotransmitter in the process of forming memories.
Moreover, it is the neurotransmitter used commonly by neurons
in the hippocampus and cerebral cortex--regions devastated by
Since that early discovery, which was one of the first to link
Alzheimer's disease with biochemical changes in the brain, acetylcholine
has been the focus of hundreds of studies. Scientists have found
that its levels fall somewhat in normal aging but drop by about
90 percent in people with Alzheimer's disease. They have turned
up evidence linking this decline to memory impairment. And they
have looked for ways to boost its levels as a possible treatment
for Alzheimer's disease.
Other neurotransmitters have also been implicated in Alzheimer's
disease. For example, serotonin, somatostatin, and noradrenaline
levels are lower than normal in some Alzheimer's patients, and
deficits in these substances may contribute to sensory disturbances,
aggressive behavior, and neuron death. Most neurotransmitter research,
however, continues to focus on acetylcholine because of its steep
decline in Alzheimer's disease and its close ties to memory formation
On the Other Side of the Synapse
Once the message carried by a neurotransmitter has crossed the
synapse it passes into another territory, where neuroscientists
are beginning to find more clues to Alzheimer's disease. The gateways
to this new territory are the receptors, coil-shaped proteins
embedded in neuron membranes. They interest Alzheimer's researchers
for two reasons.
First, these molecules have chemical bonds with molecules of
fat, called phospholipids, that lie next to them in the membrane.
Several studies have detected phospholipid abnormalities in neurons
affected by Alzheimer's disease. These abnormalities might change
the behavior of neighboring receptors and garble the message as
it passes from neuron to neuron.
Second, researchers have uncovered several types of receptors
for acetylcholine and are now exploring their different effects
on message transmission. It may be that the shapes and actions
of the receptors themselves, independent of their neighboring
phospholipids, play a role in Alzheimer's.
But the receptor is just the starting point of the cell's communications
system. When a neurotransmitter binds to a receptor, it triggers
a cascade of biochemical interactions that relay the message to
the neuron's nucleus, where it activates certain genes, or to
the end of the axon, where it passes to other cells.
This messaging system involves a number of proteins, and abnormalities
in these proteins or dysfunction at the relay points could block
or garble the message. So could other events and processes in
the cell, such as problems with the system that turns food into
energy (metabolism) or the mechanisms that keep calcium levels
Drug therapies aimed at these various postsynaptic events are
now being explored, although most are still in the very earliest
phases of testing. Two of them, vitamin E and deprenyl, are currently
in clinical trials (studies of people).
When Alois Alzheimer observed the plaques now known as a hallmark
of this disease, he could say little about them. No one knows
still what role they play in the disease process, but scientists
have learned that plaques are composed of a protein fragment called
beta amyloid mixed with other proteins. Beta amyloid is a string
of 40 or so amino acids snipped from a larger protein called amyloid
precursor protein or APP.
Scientists also know something about how beta amyloid is formed.
Its parent protein, APP, protrudes through the neuron membrane,
part inside and part outside the cell. There only for a moment,
it is continually replaced by new APP molecules manufactured in
the cell. While it is embedded in the membrane, enzymes called
proteases snip or cleave it in two, creating the beta amyloid
What happens to the beta amyloid segment once it separates from
APP is less clear. A number of studies have centered on how beta
amyloid is processed, searching for abnormalities that could explain
what goes wrong. Others are seeking clues in the environment surrounding
For instance, certain other substances in the neighborhood of
beta amyloid protein may normally bind to it and thus keep it
in solution. But in Alzheimer's disease, according to one theory,
something causes the beta amyloid to drop out of solution and
form the insoluble plaques.
Other areas of research center on how beta amyloid affects neurons--if
at all. In one laboratory study, hippocampal neurons died when
beta amyloid was added to the cell culture, suggesting that the
protein is toxic to neurons. Another recent study suggests that
beta amyloid breaks into fragments, releasing free radicals that
The precise mechanism by which beta amyloid might cause neuron
death is still a mystery, but one recent finding suggests that
beta amyloid forms tiny channels in neuron membranes. These channels
may allow uncontrolled amounts of calcium into the neuron, an
event that can be lethal in any cell.
Other recent studies suggest that beta amyloid disrupts potassium
channels, which could also affect calcium levels. Still another
study links beta amyloid to reduced choline concentrations in
neurons; since neurons need choline to synthesize acetylcholine,
this finding suggests a link between beta amyloid and the death
of cholinergic neurons.
Another set of clues centers on a protein called tau, the major
component of neurofibrillary tangles.
Neurofibrillary tangles resisted analysis until the late 1980's,
when researchers discovered they were associated with neurons'
internal structures, called microtubules. In healthy neurons,
microtubules are formed like train rails, long parallel tracks
with crosspieces, that carry nutrients from the body of the cells
down to the ends of axons. In cells affected by Alzheimer's, this
structure has collapsed. Tau normally forms the crosspieces between
microtubules, but in Alzheimer's it twists into paired helical
filaments, like two threads wound around each other. These are
the basic constituents of neurofibrillary tangles.
Having identified beta amyloid and tau, researchers would now
like to find out what they do in the brain and in Alzheimer's
disease. Some ideas about their functions may come from studies
of certain genes.
Located along the DNA in the nucleus of each cell, genes direct
the manufacture of every enzyme, hormone, growth factor, and other
protein in the body. Genes are made up of four chemicals, or bases,
arranged in various patterns. Each gene has a different sequence
of bases, and each one directs the manufacture of a different
protein. Even slight alterations in the DNA code of a gene can
produce a faulty protein. And a faulty protein can lead to cell
malfunction and eventually disease.
Genetic research has turned up evidence of a link between Alzheimer's
disease and genes on three chromosomes--14, 19, and 21. The apoE4
gene on chromosome 19 has been linked to late-onset Alzheimer's
disease, which is the most common form of the disease.
Chromosomes contain DNA, or deoxyribonucleic acid, a large double-stranded
molecule that includes genes. Every cell in the body contains
a nucleus which has 23 pairs of chromosomes. Genes are made up
of bases arranged in certain sequences.
ApoE4 and Alzheimer's disease.
The apoE4 gene came to light through long, patient detective
work topped off by the serendipity that sometimes occurs in science.
Alzheimer's researchers knew there were families in which many
members developed the disease late in life. And therefore they
knew there had to be a gene that the affected family members had
in common. Searching for this gene, they combed through the DNA
from these families and by 1992 had narrowed the search down to
a region on chromosome 19.
In the same laboratory, another group of researchers were looking
for proteins that bind to beta amyloid. They were disappointed
at first. One version of a protein called apolipoproteinE (apoE)
did bind quickly and tightly to beta amyloid, but apolipoproteinE
was well known as a carrier of cholesterol in blood. No one suspected
that it could have anything to do with Alzheimer's disease.
But by coincidence, or so it seemed, the gene apoE, which produces
the protein, was also on chromosome 19. Moreover, it was on the
same region of chromosome 19 as the Alzheimer's gene for which
they had been searching.
The two groups of scientists decided to see if the apoE gene
and the still missing Alzheimer's gene could be one and the same,
and what they found made headlines: The apoE gene was identical
to the gene they had been seeking. ApoE, it turned out, is much
more common among Alzheimer's patients than among the general
More precisely, one version of apoE is more common among Alzheimer's
patients. Like some other genes, the one that produces apoE comes
in several forms or alleles. The apoE gene has three different
forms--apoE2, apoE3, and apoE4. ApoE3 is the most common in the
general population. But apoE4 occurs in approximately 40 percent
of all late-onset Alzheimer's patients. Moreover, it is not limited
to people whose families have a history of Alzheimer's. Patients
with no known family history of the disease, cases of so-called
sporadic Alzheimer's disease, are also more likely to have an
Since that finding, dozens of studies around the world have
confirmed that the apoE4 allele increases the risk of developing
Alzheimer's disease. People who inherit two apoE4 genes (one from
the mother and one from the father) are at least eight times more
likely to develop Alzheimer's disease than those who have two
of the more common E3 version. The least common allele, E2, seems
to lower the risk even more. People with one E2 and one E3 gene
have only one-fourth the risk of developing Alzheimer's as people
with two E3 genes.
What does the apoE4 gene do? On one level, all genes function
by transcribing their codes into proteins, so when we ask what
a gene does, we are really asking what its protein product does.
Many laboratories are now exploring what the apoE4 product does,
and they have several clues.
Some of these clues point to beta amyloid. While the apoE4 protein
binds rapidly and tightly to beta amyloid, the apoE3 protein does
not. Normally beta amyloid is soluble, but when the apoE4 protein
latches on to it, the amyloid becomes insoluble. This may mean
that it is more likely to be deposited in plaques. Studies of
brain tissue suggest that apoE4 increases deposits of beta amyloid
and that it directly regulates the APP protein from which beta
amyloid is formed.
Other clues, however, point to tau as the pivotal protein. As
the crosspiece in the microtubule, tau's function seems to be
to stabilize the microtubule structure. One hypothesis suggests
that the apoE4 protein allows this structure to come undone in
some way, leading to the neurofibrillary tangles.
While still controversial and far from proven, the hypotheses
surrounding apoE4 are driving new research. One next step is to
see how tau and beta amyloid react with apolipoprotein in its
several forms in living cells. Other experiments will attempt
to determine the actions and role of the protein. Once these are
clear, it should be easier to see how they might be affected by
drugs. For instance, if apoE2 does turn out to be beneficial,
then substances that mimic its effects might be designed to help
prevent or slow the progress of Alzheimer's disease.
The theories surrounding apoE4 are not confined to the proteins.
One finding that intrigues neuroscientists is that Alzheimer's
patients with the apoE4 gene have neurons with shorter dendrites--the
branchlike extensions that receive messages from other neurons.
Researchers speculate that the dendrites have been pruned back
by some unknown agent, limiting the neuron's ability to communicate
with other neurons. Although this pruning can also occur in people
without the apoE4 allele, it happens 20 or 30 years earlier in
people with apoE4.
Will the genetic information available now ever be used in screening
for Alzheimer's disease? Probably not. One of the puzzles surrounding
apoE4 is why some people with the gene do not develop Alzheimer's
disease and why, conversely, many people develop the disease even
though they do not have the gene. ApoE4, in other words, is not
a consistent marker for Alzheimer's.
This is one reason that few people advocate widespread screening
for apoE4. Screening would miss a large percentage of those who
will develop Alzheimer's and falsely identify others as future
Alzheimer's patients. Some scientists suggest, however, that testing
for the gene may someday help in the diagnosis of Alzheimer's.
Genes in early-onset Alzheimer's disease.
Two families in Belgium can count back six or seven generations
in which some members developed Alzheimer's disease in their 30's
and 40's. A Japanese family has 5 members who developed the disease
in middle age; a Hispanic family has 12 members; a French-Canadian
family, 23; a British family, 8. In families descended from Volga
Germans--a group of German families that settled in the Volga
River valley in Russia in the 1800s--dozens of descendants have
developed Alzheimer's disease in middle age.
Alzheimer's strikes early and fairly often in these and other
families around the world--often enough to be singled out as a
separate form of the disease and given a label: early-onset familial
Alzheimer's disease or FAD. Combing through the DNA of these early-onset
families, researchers have found a mutation in one gene on chromosome
21 that is common to a few of the families. And they have linked
a much larger proportion of early-onset families to a recently-identified
gene on chromosome 14. The gene on chromosome 21 occurs less often
in people with FAD than the chromosome 14 gene, which codes for
a membrane protein whose function is not yet known.
The chromosome 21 gene carries the code for a mutated form of
the amyloid precursor protein, APP, the parent protein for beta
amyloid. The discovery of this gene supports the theory that beta
amyloid plays a role in Alzheimer's disease, although the mutation
occurs in only about 5 percent of early-onset families.
The chromosome 21 gene intrigues Alzheimer's researchers also
because it is the gene involved in Down syndrome. People with
Down syndrome have an extra version of chromosome 21 and, as they
grow older, usually develop plaques and tangles like those found
in Alzheimer's disease.
Few researchers think that the search for Alzheimer's genes
is over. The Volga Germans, for one thing, have neither the chromosome
14 nor the chromosome 21 abnormality. Most investigators are convinced
that there are several genes involved in Alzheimer's disease and,
moreover, that other conditions must also be present for the disease
to develop. One of these conditions may be a problem with the
way in which neurons turn sugar, or glucose, into energy, a process
known as glucose metabolism.
Every few months, Alzheimer's patients travel to the National
Institutes of Health outside of Washington, D.C., and to other
centers around the country to take part in research studies. One
of the tests they take measures brain activity using special techniques,
such as PET (short for positron emission tomography).
PET works on a simple principle. Brain activity, whether one
is looking at a picture, working out a problem in calculus, or
simply observing the surroundings, requires energy. Neurons produce
energy through metabolism, a chain of biochemical reactions that
uses large amounts of glucose and oxygen. PET can track the flow
of glucose and oxygen molecules in the bloodstream to the parts
of the brain producing energy, thus revealing which areas are
A patient having a PET scan rests on a long low platform as
the scanner tracks the flow of glucose or oxygen. The data the
scanner collects are fed into a computer program which translates
it into multicolor images: red and orange for areas of high activity,
yellow for medium, blue and black for little or none.
By deciphering these patterns, Alzheimer's researchers can chart
the progress of the disease. Glucose metabolism declines dramatically
as neurons degenerate and die. Scientists are also using PET to
learn how changes in brain activity match up with changes in skills,
such as the ability to do arithmetic or to remember names of objects.
PET scans show differences in brain activity between a normal
brain and a brain affected by Alzheimer's disease. Blue and black
denote inactive areas.
No one knows whether the decline in glucose metabolism causes
neurons to degenerate or whether neuron degeneration causes metabolism
to decline. In the effort to find out, scientists have examined
glucose molecules at every step of the way from bloodstream to
The route is complex. It begins as glucose-laden blood flows
through the capillaries, the tiny blood vessels that carry the
blood past neurons. Specialized molecules capture glucose molecules
from blood and shuttle them into the neurons.
These transporter molecules come in several forms. One recent
study found that levels of two of them, GLUT1 and GLUT3, were
low in the cerebral cortex of people with Alzheimer's disease.
These reductions could be one reason glucose metabolism drops
Another key element in this scenario could be the condition
of the capillaries. The transport system could break down because
of thickening of the capillary walls, deposits of minerals, cholesterol,
and amyloid, or some injury to these microvessels.
Once inside the cell, glucose molecules are delivered to inner
structures, called mitochondria, where they are turned into energy
through metabolism. This process involves various enzymes and
other proteins, as well as glucose and oxygen. An alteration in
any of the ingredients could have a profound effect on the end
result, so investigating these enzymes is another important area
in Alzheimer's research. Studies have found, for instance, that
the enzyme cytochrome oxidase, important in glucose metabolism,
is produced at lower levels in cells affected by Alzheimer's.
Since its decline matches the declines in glucose metabolism,
it may play a role in the disease.
While the glitch in glucose metabolism has yet to be pinpointed,
its results are known to be devastating. Neurons depend wholly
on glucose for their sustenance and when glucose metabolism falters,
they suffer in various ways. For example, they cannot manufacture
as much acetylcholine as normal cells, which may be one reason
this neurotransmitter declines in Alzheimer's.
In addition, neurons having a problem with metabolism react
abnormally to another neurotransmitter, called glutamate. When
these neurons are stimulated by glutamate--even normal amounts
of glutamate--their regular mechanisms go awry and they are flooded
by calcium, with deadly consequences.
The Calcium Hypothesis
Calcium is an important substance in certain cells of the body,
the so-called excitable cells in muscles and the nervous system.
Muscle cells need calcium to contract, neurons to transmit signals.
Normally, the amount of calcium in a cell at any one time is carefully
regulated; calcium channels allow in certain amounts of calcium
at certain times, other proteins store the calcium within the
cell or remove it.
Too much calcium can kill a cell, and some neuroscientists suspect
that in the end, a rise in calcium levels may be precisely what
is killing neurons in Alzheimer's disease. According to one hypothesis,
an abnormally high concentration of calcium inside a neuron is
the final step in cell death. Several different series or cascades
of biochemical events could lead up to this last, fatal step.
What events might these be? One possibility is that an increase
in calcium channels could allow an excess of calcium into the
cell. Another possibility is that a defect develops in the structures
that store calcium inside the cell or those that pump it out of
Still another hypothesis suggests that calcium levels rise because
of an "energy crisis" in the neuron. In this scenario, chronically
high levels of the neurotransmitter glutamate disrupt energy metabolism,
leading to an influx of calcium. Glutamate is an excitatory neurotransmitter;
it triggers action in a neuron, stimulating the flow of calcium
into the cell. If it is produced in higher-than-normal levels,
it can overexcite a neuron, driving in too much calcium. Moreover,
glutamate can be dangerous to a neuron even at normal levels if
glucose levels are low. Thus a problem with glucose metabolism
could allow glutamate to overexcite the cell, allowing an influx
Another hypothesis, involving the hormones called glucocorticoids,
ties in with this theory. Glucocorticoids normally enhance the
manufacture of glucose and reduce inflammation in the body. They
came to the attention of Alzheimer's researchers when studies
in older animals showed that long exposure to glucocorticoids
contributed to neuron death and dysfunction in the hippocampus.
Now several laboratories are exploring mechanisms by which glucocorticoids
might lead to neuron death through their effect on glucose metabolism.
No one doubts that genetic and other biological factors are
important in Alzheimer's disease, but environmental factors could
also contribute to its development. The most studied of these
are aluminum, zinc, foodborne poisons, and viruses.
One of the most publicized and controversial hypotheses in this
area concerns aluminum, which became a suspect in Alzheimer's
disease when researchers found traces of this metal in the brains
of Alzheimer's patients. Many studies since then have either not
been able to confirm this finding or have had questionable results.
Aluminum does turn up in higher amounts than normal in some
autopsy studies of Alzheimer's patients, but not in all. Further
doubt about the importance of aluminum stems from the possibility
that the aluminum found in some studies did not all come from
the brain tissues being studied. Instead, some could have come
from the special substances used in the laboratory to study brain
Aluminum is a common element in the Earth's crust and is found
in small amounts in numerous household products and in many foods.
As a result, there have been fears that aluminum in the diet or
absorbed in other ways could be a factor in Alzheimer's. One study
found that people who used antiperspirants and antacids containing
aluminum had a higher risk of developing Alzheimer's. Others have
also reported an association between aluminum exposure and Alzheimer's
On the other hand, various studies have found that groups of
people exposed to high levels of aluminum do not have an increased
risk. Moreover, aluminum in cooking utensils does not get into
food and the aluminum that does occur naturally in some foods,
such as potatoes, is not absorbed well by the body. On the whole,
scientists can say only that it is still uncertain whether exposure
to aluminum plays a role in Alzheimer's disease.
Zinc has been implicated in Alzheimer's disease in two ways.
Some reports suggest that too little zinc is a problem, others
that too much zinc is at fault. Too little zinc was suggested
by autopsies that found low levels of zinc in the brains of Alzheimer's
disease patients, especially in the hippocampus.
On the other hand, a recent study suggests that too much zinc
might be the problem. In this laboratory experiment, zinc caused
soluble beta amyloid from cerebrospinal fluid to form clumps similar
to the plaques of Alzheimer's disease. Current experiments with
zinc are pursuing this lead in laboratory tests that more closely
mimic conditions in the brain.
Toxins in foods have come under suspicion in a few cases of
dementia. Two amino acids found in seeds of certain legumes in
Africa, India, and Guam may cause neurological damage. Both enhance
the action of the neurotransmitter glutamate, also implicated
in Alzheimer's disease.
In Canada, an outbreak of a neurological disorder similar to
Alzheimer's occurred among people who had eaten mussels contaminated
with demoic acid. This chemical, like the legume amino acids,
is a glutamate stimulator. While these toxins may not be a common
cause of dementia, they could eventually shed some light on the
mechanisms that lead to neuron degeneration.
The search for a virus
In some neurological diseases a virus is the culprit, lurking
in the body for decades before a combination of circumstances
stirs it to action. So for years researchers have sought a virus
or other infectious agent in Alzheimer's disease.
This line of research has yielded little in the way of hard
evidence so far, although one study in the late 1980's did provide
some data that have kept the possibility alive. A larger investigation
is now under way.
Alzheimer's Risk Factors and the Search for Causes
One tool in the search for causes of disease is the study of
risk factors. Similarities among people with a certain disease
may be risk factors, and they can provide clues to what is going
wrong. For example, when a sizable group of Alzheimer's patients
all come from the same family, epidemiologists suspect that a
gene is at fault.
Epidemiologic studies also search for environmental causes of
disease. For example, one current study is comparing a group of
Alzheimer's patients in Nigeria to a group of African-Americans
with Alzheimer's disease. If the prevalence is higher in one group
than another, the scientists will then look for some factor in
the environment that could explain the difference.
So far, only two risk factors have been linked to Alzheimer's
disease. Others are under investigation.
Known risk factors
Age: The risk of Alzheimer's rises exponentially with
age, doubling in each decade after age 65.
Family history/genetic disposition: People with relatives
who developed Alzheimer's disease are more likely to develop the
disease themselves. So far, scientists have discovered three genes
that help explain why family history is a risk factor.
Possible risk factors
Head injury: Some studies have found that Alzheimer's
disease occurs more often among people who suffered traumatic
head injuries earlier in life. A major survey of World War II
veterans is now looking for more evidence to corroborate this
Gender: Women may have a higher risk of the disease,
although their higher rates may only reflect the effects of age--women
have longer life spans on the average than men.
Educational level: Research suggests that the more years
of formal education a person has, the less likely he or she is
to develop Alzheimer's later in life. Thus lower educational levels
may increase the risk.
Gatz M, Lowe B, Berg S, et al. Dementia: Not Just a Search for
the Gene, The Gerontologist 34:251-255, 1994.
Khachaturian ZS and Radebaugh TS. Alzheimer's Disease: Progress
Toward Untangling the Mystery, Encyclopaedia Britannica: 1995
Medical and Health Annual, Chicago: Encyclopaedia Britannica,
Inc., 222-228, 1994.
A Disease With Many Causes?
The trails of clues that Alzheimer's leaves in its wake have
so far not converged. When they do, some scientists think that
this detective story will turn out to have a number of culprits.
One theory suggests that several factors act in sequence or in
combination to cause Alzheimer's disease, even though no single
factor is sufficient by itself. To explain this idea, scientists
use the metaphor of a light that requires several switches.
There might, for example, be just two switches, such as a gene
mutation and another event to trigger the gene. Or there might
be several. According to this idea, called the AND gate theory,
these events do not have to occur at the same time, but their
effects would have to linger and eventually coincide to bring
about Alzheimer's disease.
Cotton P. Constellation of Risks and Processes Seen in Search
for Alzheimer's Clues, Journal of the American Medical Association
Pennis E. A Molecular Whodunit: New Twists in the Alzheimer's
Mystery, Science News 145:8-11, 1993.
Neurotransmitters and Signaling
Davies P and Maloney AJ. Selective Loss of Central Cholinergic
Neurons in Alzheimer's Disease, Lancet 2:1403, 1976.
Geula C and Mesulam M. Cholinergic Systems and Related Neuropathological
Predilection Patterns in Alzheimer Disease. In Terry RD, Katzman
R, and Bick KL eds. Alzheimer Disease, New York: Raven Press,
1994; pp 263-292.
Horsburgh K and Saitoh T. Altered Signal Transduction in Alzheimer
Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease,
New York: Raven Press, 1994; pp 387-404.
Kosik KS. Alzheimer's Disease: A Cell Biological Perspective,
Science 256:780-783, 1992.
Lee VM, Balin BJ, Otvos L, and Trojanowski JQ. A68: A Major
Subunit of Paired Helical Filaments and Derivatized Forms of Normal
Tau, Science 251:675-678, 1991.
Cotman CW and Pike CJ. Beta-Amyloid and Its Contributions to
Neurodegeneration in Alzheimer Disease. In Terry RD, Katzman R,
and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994;
Kosik K and Greenberg SM. Tau Protein and Alzheimer Disease.
In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New
York: Raven Press, 1994; pp 335-344.
Hooper C. Research in Focus: Encircling a Mechanism in Alzheimer's
Disease, The Journal of NIH Research 4:48-54, 1992.
St. George-Hyslop PH. The Molecular Genetics of Alzheimer Disease.
In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease, New
York: Raven Press, 1994; pp 345-352.
Beal MF. Energy, Oxidative Damage, and Alzheimer's Disease:
Clues to the Underlying Puzzle, Neurobiology of Aging 15(Suppl.
Rapoport SI and Grady CL. Parametric In Vivo Brain Imaging During
Activation to Examine Pathological Mechanisms of Functional Failure
in Alzheimer Disease, International Journal of Neurosciences 70:39-56,
Landfield PW, Thibault O, Mazzanti ML, et al. Mechanisms of
Neuronal Death in Brain Aging and Alzheimer's Disease: Role of
Endocrine-Mediated Calcium Dyshomeostasis, Journal of Neurobiology
Khachaturian ZS. The Role of Calcium Regulation in Brain Aging:
Reexamination of a Hypothesis, Aging 1:17-34, 1989.
Khachaturian ZS. Calcium Hypothesis of Alzheimer's Disease and
Brain Aging, Annals of the New York Academy of Sciences 7471-7481,
Markesbery WR and Ehmann WD. Brain Trace Elements in Alzheimer
Disease. In Terry RD, Katzman R, and Bick KL eds. Alzheimer Disease,
New York: Raven Press, 1994; pp 353-368.
Gatz M, Lowe B, Berg S, et al. Dementia: Not Just a Search for
the Gene, The Gerontologist 34:251-255, 1994.
Research on Diagnosis
Ken Judy remembers vividly the first signs that something was
wrong. "Bernice began to forget appointments or what she had planned
for the day," he says. "She would lose her train of thought in
the middle of a sentence. She began to withdraw from society.
She didn't want to volunteer at the hospital or go to her church
Bernice Judy had a range of medical tests that suggested she
had Alzheimer's disease or a related disorder. The diagnosis,
in her case, turned out to be Pick's disease, another brain disease
that is similar in many ways to Alzheimer's.
Ten years earlier Bernice Judy's illness would probably have
been swept into a broad and ill-defined category labeled senile
dementia. But with the recognition of Alzheimer's as a distinct
and common disease, progress in diagnosing it has been rapid.
Alzheimer's researchers are still some way from their ultimate
aim--a reliable, valid, inexpensive, and early diagnostic marker--but
they now have the tools to diagnose the disease with 85 to 90
Despite the lack of a treatment for Alzheimer's, early diagnosis
has advantages. Twenty percent of suspected Alzheimer's cases
turn out to be something else, and it is often something that
can be treated or even reversed. Tumors, strokes, severe depression,
thyroid problems, medication side effects (or "drug intoxication"),
nutritional disorders, and certain infectious diseases can all
have effects that mimic those of Alzheimer's. Early diagnosis
increases the chances of treating these conditions successfully.
Even when the underlying cause of dementia turns out to be Alzheimer's,
there are advantages to finding out sooner rather than later.
One benefit is medical. The only drug now on the market to treat
the cognitive decline in Alzheimer's disease, THA, is more likely
to be effective in the early stages of the disease. The same may
be true of other drugs now being developed.
Other advantages to an early diagnosis are practical ones. The
sooner the patient and family know, the more time there is to
make future living arrangements, handle financial and legal matters,
and establish a support network.
Research on diagnosis falls into two categories. One major group
of studies is looking for early biological markers--changes in
blood chemistry or brain structures, for example. Another group
is searching for telltale changes in mental abilities and personality--the
so-called cognitive markers.
When Bernice Judy went to a doctor about her memory problems,
one of the tests consisted of 10 simple questions, such as: What
day is this? Where are we? Who is the President of the United
States? This brief mental status questionnaire is one way to look
for cognitive markers of Alzheimer's, but it is far from definitive.
More reliable cognitive markers are urgently needed. In the
search for them, scientists are studying a phenomenon known as
visual memory--the ability to remember and reproduce geometric
patterns, for instance. People who develop Alzheimer's disease
begin to lose immediate visual memory sooner than is expected
in normal aging and long before other markers of dementia appear,
according to some studies. Declines in verbal memory also may
be an early marker.
Followup studies are now looking for such markers in larger
groups of people. They are also using brain imaging techniques,
such as PET scans and MRI, to see if early cognitive markers can
be linked to early biological changes in the brain.
The familiar visual pattern of a clock forms the basis of one
experimental method of diagnosing Alzheimer's. In this test, the
patient draws the face of a clock, draws the hands to show certain
times, and reads the time when someone else draws the hands. So
far, findings suggest that the clock test may help differentiate
Alzheimer's from the effects of normal aging and perhaps from
other forms of dementia. Larger studies will follow up on this
Other researchers are searching for changes in personality that
may herald the onset of Alzheimer's. In normal aging, personality
does not change with age. In Alzheimer's, however, there is a
hint that two facets of personality may change early in the disease;
these are "conscientiousness," which declines and "vulnerability
to stress," which increases. These findings are far from conclusive,
but they do offer a lead. Researchers are following up by tracking
personality changes in a larger group.
Diagnosing Alzheimer's Disease: Current Tools
A definite diagnosis of Alzheimer's disease is still only possible
during autopsy when the hallmark plaques and tangles can be detected.
But with the tools now available, physicians and patients can
count on 85 to 90 percent accuracy, according to studies in which
clinical diagnosis was later confirmed by autopsy. Clinicians
diagnose "possible Alzheimer's disease" and "probable Alzheimer's
disease" using criteria established in 1984 by the National Institute
of Neurological and Communicative Disorders and Stroke and the
Alzheimer's Disease and Related Diseases Association (NINCDS/ADRDA
Patient history: A detailed description of how and when
symptoms developed; the patient's and family's medical history;
and an assessment of the patient's emotional status and living
Physical examination and laboratory tests: Standard medical
tests to help identify other possible causes of dementia.
Brain scans: Usually a computed tomography (CT) scan
or magnetic resonance imaging (MRI) to detect strokes or tumors
that could be causing symptoms of dementia.
Neuropsychological testing: Usually several different
tests in which patients answer questions or complete tasks that
measure memory, language skills, ability to do arithmetic, and
other abilities related to brain functioning.
The tantalizing possibility that somewhere outside the brain
there is a biological marker for Alzheimer's disease--an abnormal
protein, for instance, that shows up in blood as well as the brain--continues
to attract investigators.
Over the past decade, small preliminary studies have raised
hope--and headlines--for several different markers. So far none
has stood up under closer scrutiny. Still under consideration
is a marker that may show up during a simple eye test, according
to one study. In this study, a drug commonly used in eye examinations
to enlarge the pupils, called tropicamide, increased the pupil
size of suspected Alzheimer's disease patients in the study more
than in other older people. This study involved fewer than 20
patients. Again, the next step is larger studies.
Scans of the brain already help in diagnosing Alzheimer's disease
by ruling out other forms of dementia, such as tumors and signs
of stroke. But researchers also are using scans to search for
markers of Alzheimer's disease itself.
Their tools include PET, which traces blood flow and metabolism
in the brain and SPECT (single photon emission computed tomography)
which also measures blood flow. Another imaging technique, magnetic
resonance imaging (MRI), lets researchers view the brain's structure
in cross section.
New techniques available to PET and SPECT researchers allow
them to assess interactions among molecules in the brain, such
as neurotransmitters and their receptors. Another new technique,
magnetic resonance spectroscopy imaging or MRSI, lets neuroscientists
observe certain substances throughout the brain, without using
All of the imaging techniques--PET, SPECT, MRI, and MRSI--are
still primarily research tools. However, they hold the promise
of leading to an early and cost-effective method for diagnosing
Walker LC. Progress in the Diagnosis of Alzheimer's Disease,
Neurobiology of Aging 15:663-666, 1994.
McKhann G, Drachman D, Folstein M, et al. Clinical Diagnosis
of Alzheimer's Disease: Report of the NINCDS-ADRDA Work Group.
In Alzheimer's Disease and Related Dementias: Legal Issues in
ADRD Care and Treatment, Washington, DC: U.S. Department of Health
and Human Services, Advisory Panel on Alzheimer's Disease, 1994.
Bondi MW, Salmon DP, and Butters NM. Neuropsychological Features
of Memory Disorders in Alzheimer Disease. In Terry RD, Katzman
R, and Bick KL eds. Alzheimer Disease, New York: Raven Press,
1994; pp 41-64.
Siegler IC, Welsh KA, Dawson DV, et al. Ratings of Personality
Change in Patients Being Evaluated for Memory Disorders, Alzheimer's
Disease and Associated Disorders: An International Journal 5:240-250,
Zonderman AB, Giambra LM, Kawas CH. Changes in Immediate Visual
Memory Predict Cognitive Impairment, Archives of Clinical Neuropsychology
Budinger TF. Future Research in Alzheimer's Disease Using Imaging
Techniques, Neurobiology of Aging 15(Suppl. 2):S41-S48, 1994.
Resnick SM, Zonderman AB, Golski S, et al. Memory Change as
a Predictor of Regional Brain Structure and Function. In Kabota
and Matsuo DS eds. Recent Advances in Aging Research: From the
Molecule to the Human. Proceedings of the Fifth Joint Symposium
of the Tokyo Metropolitan Institute of Gerontology and the National
Institute on Aging, Tokyo:135-139, 1994.
The rapid pace of research on Alzheimer's disease over the past
20 years has opened numerous pathways that could lead to effective
treatments for the disease. Treatment research falls into two
general categories. First, neuroscientists have turned up an array
of substances in the brain that seem to be related to the disease
and these are potential targets for biomedical treatments.
A second group of studies focuses on management of the disease.
This area of research is looking for ways to treat the symptoms
of Alzheimer's disease and slow its progress, either through drugs
or behavioral approaches.
Potential Biomedical Treatments
Cholinergic replacement therapy
The discovery that the neurotransmitter acetylcholine declines
in Alzheimer's disease led naturally to the hypothesis that replacing
acetylcholine could stop the disease. Since that finding, many
scientists have looked for compounds that can either increase
the levels of acetylcholine, replace it, or slow its breakdown.
This search has taken them into a broader territory that includes
the cells that use acetylcholine and the enzymes and other proteins
that take part in its manufacture or activity--a grouping known
as the cholinergic system.
One member of the cholinergic system is acetylcholinesterase
(often referred to simply as cholinesterase), the enzyme that
breaks down acetylcholine after it crosses the synapse. Many of
the experimental Alzheimer's drugs developed to date are cholinesterase
inhibitors; that is, they are designed to suppress cholinesterase
so that acetylcholine will not be broken down as quickly.
One such cholinesterase inhibitor is THA or tetrahydroaminoacridine,
the only drug approved so far by the Food and Drug Administration
to slow the loss of cognitive ability in Alzheimer's disease.
THA has helped some patients, but its impact on the disease in
general has proved disappointing. However other cholinesterase
inhibitors that may be more effective are under development.
The discovery of acetylcholine deficits in Alzheimer's disease
also raised hope that choline and lecithin, if added to the diet,
could help in treating Alzheimer's disease. The body uses these
nutrients to synthesize acetylcholine. Trials with the two substances
have been disappointing so far, with choline supplements having
no effect on cognitive function and lecithin only a slight effect
in a few patients. Researchers are still interested in other substances
that may enhance the availability of acetylcholine.
How THA Works--Cholinesterase inhibitors (red) like THA, block
cholinesterase, giving the acetylcholine extra time to transmit
messages. Normally acetylcholine carries a message across the
synapse... and then is broken down by cholinesterase.
When a laboratory animal makes its way through a maze to get
to a reward, it makes a number of wrong turns the first time.
After that, its errors are fewer, and it makes more correct turns.
Scientists have various ways to explain what is happening in the
animal's brain in such experiments, but in simple terms, the animal
Some older rats (about 2 years old) take longer to negotiate
a maze or cannot seem to make memories of the correct turns at
all. In a study in the mid-1980's, scientists took several rats
with such memory impairment and gave them nerve growth factor
or NGF. The rats' ability to negotiate the maze improved, coming
close to the ability seen in older rats with no impairment. Because
of this study and several similar ones, NGF intrigues neuroscientists
as a possible treatment for Alzheimer's disease.
How NGF works is not completely clear, but it is known to be
one of several growth factors in the brain or, in neurobiologists'
terms, neurotrophic factors. Growth factors elsewhere in the body
promote and support cell division. Neurons cannot divide, but
they can regenerate after injury and neurotrophic factors promote
this regeneration. They also promote the growth of axons and dendrites,
the neuron branches that form connections with other neurons.
Other neurotrophic factors that may be implicated in Alzheimer's
include brain derived neurotrophic factor and neurotrophin-3.
Studies have turned up a number of clues that link NGF specifically
to the cholinergic neurons (those that use acetylcholine as a
neurotransmitter). In that early maze experiment, the rats whose
memories had improved not only had higher NGF levels but also
their cholinergic neurons had regenerated. In another study, NGF
promoted the survival of cholinergic neurons after injury.
Symptoms of Alzheimer's Disease
Alzheimer's is a progressive disease, the symptoms growing worse
with time. Yet it is also a variable disease. Symptoms progress
at different rates and in different patterns. Thus one patient
may begin to have problems with muscular coordination earlier
than another or retain some memories longer.
Researchers, who need to have some standard way to measure the
progression of symptoms, have devised several different scales.
One, the Clinical Dementia Rating (CDR), delineates five stages
in the disease, while another, the Global Dementia Scale (GDS),
has seven stages.
However most people who work with patients and families think
of the disease in three phases: mild, moderate, and severe. These
three stages can be viewed as follows, keeping in mind that the
divisions are approximate, that they overlap, and that the appearance
and progression of symptoms vary from one individual to the next.
- Confusion and memory loss
- Disorientation; getting lost in familiar surroundings
- Problems with routine tasks
- Changes in personality and judgment
- Loss of speech
- Loss of appetite; weight loss
- Loss of bladder and bowel control
- Total dependence on caregiver
- Difficulty with activities of daily living, such as feeding
- Anxiety, suspiciousness, agitation
- Sleep disturbances
- Wandering, pacing
- Difficulty recognizing family and friends
Gwyther LP. Care of Alzheimer's Patients: A Manual for Nursing
Home Staff, Chicago: American Health Care Association and Alzheimer's
Disease and Related Disorders Association, 1985.
Getting around the blood-brain barrier
The problem in testing NGF in humans is the difficulty getting
it into the brain. While substances pass easily from the bloodstream
to cells in other parts of the body, the brain has a complex set
of defenses that protect it from possible poisons. Known as the
blood-brain barrier, these defenses include physical barriers,
such as tightly opposed cells in the walls of the blood vessels.
Another defense is chemical--enzymes that act as gatekeepers,
escorting only certain substances into the inner compartments.
One way to circumvent the blood-brain barrier is through direct
injections into the brain, but there is little evidence that such
injections are effective. So researchers have been looking at
other ways to deliver drugs to the brain. Animal experiments with
the NGF gene show that it can be incorporated into skin cells
and then implanted in brains, where it has prevented the loss
and degeneration of cholinergic neurons. Other researchers are
looking at ways to package NGF and other neurotrophic factors
with substances that can cross the blood-brain barrier, in effect
smuggling these potential treatments into the brain.
Researchers are also investigating substances that interact
with NGF. One of these is estrogen, the female reproductive hormone
that falls sharply at menopause.
Estrogen made front page headlines in late 1993 when scientists
reported a possible link between it and Alzheimer's disease. In
a study of thousands of women in a southern California retirement
community, those who had taken estrogen after menopause had lower
rates of Alzheimer's disease than those who had not taken estrogen.
It was not the first time that neuroscientists had taken notice
of this hormone. Earlier studies sought connections between estrogen
and mental skills with mixed results. One study of 800 women found
that taking estrogen after menopause had no effect on later mental
functions. Another showed that estrogen did not seem to protect
intellectual function in general, although it did enhance verbal
Nonetheless, the California study and others have provided enough
evidence in favor of estrogen to spur much larger population studies
of postmenopausal estrogen therapy and its possible preventive
effect on Alzheimer's. A clinical trial of estrogen as a treatment
in early-stage Alzheimer's disease is under way.
In the meantime, biochemical studies have come up with a string
of related findings. Researchers have found that the cholinergic
neurons of the brain have numerous estrogen receptors, and they
occur on the same neurons that have receptors for nerve growth
factor; that estrogen in animals boosts levels of nerve growth
factor; and that estrogen injected in rats' brains strongly affects
neurons in the cerebral cortex and the hippocampus--regions affected
by Alzheimer's disease. These pieces of evidence have given rise
to the hypothesis that nerve growth factor and estrogen interact
in some way to protect cholinergic neurons from degenerating.
It is much too early, of course, to tell whether taking estrogen
does reduce the risk of Alzheimer's disease. Like the other areas
of treatment research, this one is still at a preliminary stage.
And since estrogen replacement therapy following menopause is
not recommended for all women, scientists have urged caution in
interpreting the findings to date.
The theory that a rise in calcium levels in neurons is the final
step in the biochemical pathway leading to Alzheimer's disease
has raised more treatment possibilities. A drug that could keep
this final step from taking place might prevent or help slow down
Drugs called calcium channel blockers, already in wide use to
treat high blood pressure and other problems, might fill this
role, say some researchers. Calcium enters and exits neurons through
several kinds of channels, so finding the right channel and channel
blocker may be a complex task. Currently one drug company is testing
a channel blocker in Alzheimer's patients and other calcium regulators
are being considered for trials.
Still another theory about calcium imbalance points to out-of-control
molecules known as oxygen free radicals and the agents that disarm
them, including antioxidants.
A free radical is a molecule with an unpaired electron in its
outer shell. Ordinarily an oxygen molecule, like other molecules,
has an even number of electrons in orbit. But the normal process
of turning food into energy--metabolism--produces oxygen radicals
with an odd number of electrons. The oxygen radical is extremely
reactive; it will latch readily onto another molecule--a part
of the membrane or a unit of DNA, for instance. When this happens,
it can set off a chain reaction, releasing chemicals that can
be harmful to the cell. Scientists theorize that damage from oxygen
radicals plays a role in aging as well as in diseases ranging
from glaucoma to cancer.
In Alzheimer's disease, free radicals are suspects for several
reasons. They attack phospholipids, the molecules of fat in neuron
membranes. Some researchers hypothesize that free radicals upset
the delicate membrane machinery that regulates what goes into
and out of a cell, such as calcium.
Free radicals may also have a connection with beta amyloid.
One study has found that in neuritic plaques, beta amyloid breaks
easily into fragments, releasing free radicals.
The body has certain lines of defense against oxygen free radicals.
Enzymes like superoxide dismutase (SOD) and catalase can disarm
the damaging oxygen molecules. And the vitamins in food known
as antioxidents--vitamins C and E and beta-carotene, which is
related to vitamin A--also counter free radicals.
Several proposed treatments for Alzheimer's hinge on the theory
that free-radical damage plays a key role in the disease and that
antioxidents, therefore, should be able to slow down its progression.
One clinical trial is testing vitamin E and deprenyl, a drug that
inhibits oxidation, to see if they can make a difference.
Another compound now in clinical trials, acetyl-L-carnitine,
may also slow Alzheimer's by reducing the production of free radicals.
This synthetic compound is very similar to a naturally occurring
molecule that can help neurons carry out the process of metabolism.
Acetyl-L-carnitine also may provide important constituents for
the synthesis of acetylcholine.
Alzheimer's rates may be lower among people who take anti-inflammatory
drugs than among those who do not. In a recent study of twins,
one member of each pair had Alzheimer's and one did not. Many
of the twins who did not have the disease had one thing in common:
they took anti-inflammatory drugs for arthritis. A clinical trial
is now testing whether the anti-inflammatory drug prednisone can
slow the progress of the disease in its early stages.
In The 36-Hour Day, one of the first books on Alzheimer's from
the caregiver's perspective, Nancy Mace and Peter Rabins devote
several chapters to coping with the symptoms of Alzheimer's disease.
"Some people fall when they first get out of bed," they write.
"Have the person sit on the edge of the bed for a few minutes
These chapters are about daily routines and problems. "If all
of the person's socks will go with all of his slacks, he doesn't
have to decide which is right to wear with what... Many families
have told us that a bath seat and a hand-held hose greatly reduce
the bath time crisis."
When the first edition of this book came out in 1981, it filled
a great void. Information on the symptoms of the disease was sparse
and guidance on managing them even sketchier. Throughout the 1980's,
other publications appeared, filled with informal observations
about symptoms and coping strategies.
Toward the end of the decade, more and more formal research
began to focus on this aspect of Alzheimer's disease. In contrast
to the biological research described earlier, the low-tech, behavioral
approach centers as much on family members and caregivers as on
the patients themselves. The rationale is that if the people who
care for Alzheimer's patients know how to cope with symptoms of
the disease, they can reduce the degree of disability associated
Current studies are looking at two kinds of caregiving strategies:
those that help the patient maintain independence in daily activities
as long as possible and those that help prevent disturbing behaviors.
Dressing, preparing simple meals, performing other household
tasks: These are all things that many Alzheimer's patients can
still do in the earlier stages of the disease. "If we go out,"
said Letty Tennis in her journal, "I still can fix my face and
hair perfectly but I forget basic steps and go by a little piece
of paper like do eyes, cheeks, lips, etc.... I never cook when
alone...but I still can microwave."
Maintaining independence has obvious advantages: The longer
the patient can function independently, the better his or her
quality of life and self esteem. Strategies that increase or maintain
independence as long as possible also lower the level of stress
for the spouse, child, or other caregiver.
Researchers are experimenting with several methods to slow the
loss of independence. Some are looking for ways to improve cognitive
functions. For instance, one research team has used mental stimulation
exercises for 1 hour each day in an attempt to improve cognitive
abilities. So far, the Alzheimer's patients who do these exercises
show improvement in comparison with a control group. Moreover,
the caregivers in the group who did the exercises reported lower
stress levels. Researchers are now testing mental exercises in
group settings outside the home.
Other studies are testing ways to improve patients' functional
abilities. This term encompasses the ability to carry out the
so-called activities of daily living (ADLs), such as dressing
and eating, as well as the more complex instrumental activities
of daily living (IADLs). The latter include tasks like shopping
Some findings show promise. Techniques that have been successful
in small studies of getting dressed include having the caregiver
demonstrate what to do, so that the patient can mimic the action
(the technical term is "modeling"). Another technique is laying
out clothes in the order that they should be put on ("stimulus
control"). Still another is "prompting." Verbal prompts are statements
like, "Pick up the shirt. Put your arm in the sleeve." Physical
prompts are when the caregiver uses touch to show the patient
which arm to use.
Researchers are now extending these strategies to other activities,
such as bathing and feeding. One of the most intriguing results
of such studies is the effect that the strategies have had on
other aspects of Alzheimer's disease. Improved functioning seems
to go along with a significant improvement in the behavioral problems
that afflict Alzheimer's patients and families.
In one of his journal entries, Cary Henderson commented: "I
think this disease does make us kind of irrational--sometimes
very irrational--and sometimes it's out of fear and sometimes
it's being left out of things."
As Alzheimer's disease makes inroads into memory and mental
skills, it also begins to alter emotions and behavior. An estimated
70 to 90 percent of Alzheimer's patients eventually develop behavioral
symptoms. One of the most common is agitation, which Letty Tennis
describes: "It's a feeling like no other--like your engine is
racing 100 mph and you can't go anywhere.... I'm getting cross
at people and I hate that. When my psychologist kept asking me
questions--the same ones over and over, I got so impatient inside
that I had a strange impulse to throw my purse on the floor or
better yet to bite him and say NO MORE!"
In addition to agitation, Alzheimer's patients often experience
feelings of anger, frustration, and depression. The disease can
also lead to wandering, pacing, and screaming. Behavioral symptoms
may become worse in the evening, a phenomenon called sundowning,
or during certain daily routines, especially bathing. These symptoms
of the disease and their effects on the family are thought to
be one of the most common reasons that Alzheimer's patients are
Drugs are one way to approach the behavioral symptoms of Alzheimer's
disease. Most often prescribed are anti-psychotics or antidepressants,
which were developed for use in psychiatry. They can have a tranquilizing
effect, although physicians and caregivers report varying results
with these drugs. Few scientific studies have tested their effectiveness
specifically in Alzheimer's disease.
One area of special interest is the effect of antidepressants
on cognitive function. Many antidepressants suppress activity
in the neurons that use acetylcholine. These are the same neurons
affected by Alzheimer's disease, so suppressed activity in these
neurons might make the cognitive symptoms, such as loss of memory,
even worse. Some studies show this may be true.
On the other hand, there is evidence that reducing depression
may improve functional ability in people with Alzheimer's disease.
In one study, for example, those patients who were more depressed
were less able to carry out the activities of daily living than
patients who were less depressed. The effects of depression on
functioning appeared to be over and above the effects of cognitive
impairment. This finding interests researchers because it raises
the possibility that treating depression may be one way to improve
The other approach to the behavioral side of Alzheimer's is
itself behavioral. That is, it relies on behavior management techniques
rather than drugs. Some behavior management techniques aim to
influence the entire spectrum of disturbing behaviors. One study,
for instance, is looking at the effects of bright lights and music
on all behavioral symptoms. Another is testing a daily schedule
of planned activities for patients and caregivers on the hypothesis
that regular routines can alleviate many disturbing behaviors
as well as reduce caregiver stress.
Other behavior management techniques have specific targets.
Aggressiveness and agitation commonly afflict patients during
bathing, for instance, so researchers are trying to pinpoint the
precise circumstances or events that trigger the problem. They
then will test methods of avoiding those triggers or alleviating
the patient's distress in other ways.
Wandering and pacing are also common among Alzheimer's patients.
One hypothesis suggests that if pacing and wandering can be accommodated
in some way, both patients and caregivers will benefit. To test
this idea, one researcher has arranged for Alzheimer's patients
in a nursing home to have access to an outdoor sheltered park
for pacing. In addition, the researchers have had stimulating
patterns painted on the floors. The study will compare the effects
of this approach to the effects of drugs and physical restraints,
the more traditional ways to manage pacing and wandering.
Screaming, also common among Alzheimer's patients, may be affected
by changes in the environment as well. Several researchers are
testing the effects of music. One is experimenting with videotapes
of the patient's relatives and direct social interaction, to see
if they have an effect on screaming.
Studies of behavior management techniques fall into two groups.
Many are still small descriptive studies. That is, their aims
are to establish a base of knowledge about the disturbing behaviors,
such as how prevalent they are and what circumstances trigger
Other studies are clinical trials of strategies that seem most
promising. One current trial is comparing the effects of non-drug
behavior management strategies to the effects of two different
medications, haloperidol and trazodone, in treating disturbing
"You don't know when it's going to end or what to expect."
"Your friends...will say we think of you, or we'll visit, but
they never do, because they don't know how to act around Alzheimer's."
"I must have looked at 30 different homes."
These quotes, culled from support groups and personal conversations,
express a few of the special problems that confront the wives,
husbands, children, and other family members who take care of
Formal research on caregiving, begun in the early 1980's, is
still young. The early studies documented that caregiving has
a severe impact on both the physical and mental health of the
caregiver. Fatigue, insomnia, and other physical symptoms are
frequent. Cardiovascular risk factors, such as high blood pressure,
may be affected. Studies also have linked the high levels of stress
in caregivers with depression, a sense of isolation, and strained
relationships with other family members.
Special Care Units for Alzheimer's Disease
Special care units or SCUs are separate areas for dementia patients
in nursing homes, assisted living residences, and other caregiving
facilities. They take different forms, but in general SCUs have
special architectural features and/or programs tailored to the
needs of dementia patients.
First appearing in the 1980's, SCUs have proliferated rapidly.
About 9.6 percent of all U.S. nursing homes with 30 or more beds
had SCUs by the end of 1990, according to the National Survey
of Special Care Units in Nursing Homes. The number may continue
to grow. A 1991/92 survey of Medicare/Medicaid nursing facilities
found that between 13 and 14 percent of certified facilities had
at least one SCU.
Aside from their dramatic growth, little is known about SCUs
as a group. What features do they offer? Which features, if any,
make a difference to patients, families, or staff? Ten research
teams are now studying SCUs in search of answers to questions
Early in these studies it became clear that SCUs vary widely.
Some offer only one special feature, such as a sheltered area
for pacing, perhaps, or staff training. Most have several special
features, such as family counseling, support groups, and therapeutic
activities for patients.
Still unknown is whether or not these special features make
a difference. To find out, investigators are studying both SCU
patients and dementia patients in traditional care settings, comparing
them in areas such as: mental function, frequency of disturbing
behaviors, degree of family involvement with the patient, staff
and family satisfaction with the SCU, and costs in relation to
The studies, begun in 1991 and completed in 1996.
Who are family caregivers?
Researchers have found that the greatest number of family caregivers
are wives and husbands; daughters come next. Many caregivers are
Researchers are now studying the experiences of caregivers from
various ethnic and racial groups to see if their approaches to
caregiving differ. African-American caregivers, according to several
studies, are less likely to see caregiving as a burden and more
likely to share it with a large number of extended family members,
when compared to white caregivers. Scientists are exploring these
differences to see if they can pinpoint the coping strategies
or other factors that affect how different racial and ethnic groups
What can be done to reduce the burden?
This is a critical research question. Scientists are testing
various methods (known in the language of research as interventions)
to help caregivers. These fall into three broad categories.
One major hypothesis is that social support can help reduce
stress and other caregiving problems. Support groups, individual
counseling, and family counseling all fall into this category,
and they are being studied in various ways. For example, one study
is comparing two different forms of social support--support groups
and home visits from professionals--to see if one is more effective
than the other in boosting caregiver well-being and reducing the
sense of burden.
To date, studies have generally shown a high level of satisfaction
with support groups, although it is not clear whether they also
help decrease caregivers' sense of burden. Individual counseling
has alleviated specific problems such as depression.
Help from community groups or professionals is another promising
way to ease the difficulties facing caregivers. Probably the most
common service, and the most studied so far, is respite care.
This is the broad term for a variety of situations in which someone
else cares for the patient for a period of time, giving the principal
family caregiver some temporary relief. Respite services are offered
in the home, in day care facilities, and even in institutions
where patients stay a limited time, usually a week or two. So
far studies of respite care show a very modest benefit, and current
research is looking for ways to increase its impact.
Knowledge and skills training
Another active hypothesis is that Alzheimer's caregivers will
benefit by learning more about the disease, including the resources
available to them and specific skills for coping with its symptoms.
Research projects, for instance, have trained caregivers in behavior
management techniques and other ways to resolve day-to-day problems.
The outcomes of many of these studies are positive, in that
caregiver behavior and sometimes patient behavior is changed.
In some cases, these studies have also demonstrated improvements
in caregiver stress, anxiety, and depression. On the other hand,
some of these studies show that decreased stress does not necessarily
translate into a reduced sense of burden.
A fourth category of interventions combines all three of these
approaches. Studies of such comprehensive efforts suggest that
the more components they have, the better the chance that they
will meet the needs of caregivers. However, questions remain about
the cost effectiveness of comprehensive interventions and about
the relative benefits of their individual components.
In the attempt to develop better interventions, researchers
are now trying to find and sort out the many factors that determine
caregiver stress. For instance, one study is looking at caregiver
personality, the degree of care needed, and resources available
to the caregiver. The study's goal is to see how these factors
interact to influence the caregiver's sense of burden.
Studies are also exploring when and how Alzheimer's caregivers
use formal services--adult day care or home health aides, for
instance. So far, the findings suggest that most caregivers delay
getting formal services until their situations are extremely stressful.
While finding services to help with family care may be difficult,
Alzheimer's families say that the decisions surrounding placement
in a nursing home can be even harder. Whether and when to turn
to a nursing home is the first and some say the most difficult
decision. Then come decisions on what type of care is best for
the patient and affordable for the family. An informal board and
care facility, where patients are supervised in a home setting?
An assisted living facility, where patients receive some help
with the activities of daily living? Or a traditional nursing
home? The options also include special care units within nursing
homes and assisted living facilities.
Research is now focusing on various kinds of institutional care.
For instance, one study is looking at 100 board and care homes
and 100 of their residents to see what factors affect the care
received in these facilities. Another study is focusing on nurses
aides in one New York City nursing home in an attempt to understand
how work situations affect their caregiving behavior. The overall
aim is to identify strategies that can lead to improvements in
the quality of care and lighten the burdens of caregiving.
Khachaturian ZS, Phelps C, and Buckholtz N. The Prospect of
Developing Treatments for Alzheimer Disease. In Terry RD, Katzman
R and Bick KL eds. Alzheimer Disease, New York: Raven Press, 1994;
Potential Biomedical Treatments
Barrett-Connor E and Kritz-Silverstein D. Estrogen Replacement
Therapy and Cognitive Function in Older Women, Journal of the
American Medical Association 269:2637-2641, 1993.
Breitner JC, Gau BA, Welsh KA, et al. Inverse Association of
Anti-Inflammatory Treatments and Alzheimer's Disease: Initial
Results of a Co-Twin Control Study, Neurology 44:227-232, 1994.
Burinaga M. Neurotrophic Factors Enter the Clinic, Science 264:772-774,
Tuszynski MH and Gage FH. Neurotrophic Factors and Neuronal
Loss: Potential Relevance to Alzheimer Disease. In Terry RD, Katzman
R, and Bick KL eds. Alzheimer Disease, New York: Raven Press,
1994; pp 405-418.
Knapp MJ, Knopman DS, Solomon PR. A 30-Week Randomized Controlled
Trial of High-Dose Tacrine in Patients With Alzheimer's Disease,
Journal of the American Medical Association 271:985-991, 1994.
Rapoport SI. Aging and the Blood-Brain Barrier, Neurobiology
of Aging 15:759-760, 1994.
Beck C, Heacock P, Mercer S, and Walton C. Decreasing Caregiver
Assistance With Older Adults With Dementia. In Funk SG, Tornquist
EM, Champagne MT, and Wiese RA, eds. Key Aspects of Elder Care,
New York: Springer, 1992.
Teri L, Rabins P, Whitehouse P, et al. Management of Behavior
Disturbance in Alzheimer Disease: Current Knowledge and Future
Directions, Alzheimer Disease and Associated Disorders: An International
Journal 6:77-88, 1992.
Bourgeois MS, Schulz R, and Burgio L. Intervention for Caregivers
of Patients with Alzheimer's Disease: A Review and Analysis of
Content, Process, and Outcomes, The International Journal of Aging
and Human Development (in press).
Holmes D, Ory M, and Teresi J. Special Dementia Care: Research,
Policy, and Practice Issues, Alzheimer Disease and Associated
Disorders: An International Journal 8(Suppl. 1), 1994.
Leon J and Siegenthaler LA. Perspectives on the Major Special
Care Units Surveys. In Special Dementia Care: Research, Policy,
and Practice Issues, Alzheimer Disease and Associated Disorders:
An International Journal 8(Suppl. 1): S58-S71, 1994.
Mace NL and Rabins PV. The 36-Hour Day, rev. ed., Baltimore:
The Johns Hopkins University Press, 1991.
Acetylcholine -- a neurotransmitter that plays an important
role in learning and memory.
Activities of daily living (ADLs) -- basic activities
that are important to self care, such as bathing, dressing, using
the toilet, eating, and getting in and out of a chair.
Amyloid -- See beta amyloid.
Amyloid precursor protein (APP) -- the larger protein
from which beta amyloid is formed.
Antioxidents -- substances that deactivate oxygen free
ApoE4 -- one form of the apoE gene, which produces the
protein apolipoprotein E4; this form of the gene occurs more often
in people with Alzheimer's disease than in the general population.
The other two forms of the gene, apoE2 and apoE3, may protect
against the disease.
ApolipoproteinE -- a protein that carries cholesterol
in blood and that appears to play some role in the brain.
Axon -- the tube-like part of a neuron that transmits
outgoing signals to other cells.
Behavioral symptoms -- symptoms of Alzheimer's disease
that are troublesome for family and professional caregivers, such
as wandering, pacing, agitation, screaming, and aggressive reactions.
Beta amyloid -- a protein found in dense deposits forming
the core of neuritic plaques.
Blood-brain barrier -- a group of mechanisms that keep
some substances in the bloodstream from entering cells in the
Calcium channel blocker -- a drug that stops calcium
from entering cells.
Capillaries -- the smallest blood vessels, which route
blood to individual cells.
Caregiver -- anyone who provides care to a physically
or cognitively impaired person, including both family and other
caregivers at home and professional caregivers in health care
Cell -- the smallest unit of a living organism that is
capable of functioning independently.
Cerebral cortex -- the part of the brain most involved
in learning, language, and reasoning.
Cholinergic -- pertaining to acetylcholine; the cholinergic
system includes the neurons that contain acetylcholine and the
neurons and proteins that are stimulated or activated by acetylcholine.
Chromosome -- a threadlike structure in the nucleus of
a cell. Humans have 23 pairs of chromosomes, one set from the
mother, one from the father. Chromosomes contain DNA, sequences
of which make up the genes.
Clinical trial -- a carefully controlled study designed
to test whether an intervention, such as a drug, is safe and effective
in human beings.
Cognitive functions -- all aspects of thinking, perceiving,
Computerized tomography scan (CT or CAT scan) -- a diagnostic
test that uses a computer and x-rays to obtain a highly detailed
picture of the brain.
Dementia -- a broad term referring to a condition in
which cognitive functions decline.
Dendrites -- the branchlike extension of neurons that
receive messages from other neurons.
DNA (deoxyribonucleic acid) -- a large double stranded
molecule within chromosomes; sequences of DNA make up genes.
Familial Alzheimer's disease (FAD) -- an early-onset
form of Alzheimer's disease that appears to be inherited. In FAD,
several members of the same generation in a family are often affected.
Free radicals -- see oxygen free radicals.
Gene -- the biologic unit of heredity, each gene is located
at a definite position on a particular chromosome and is made
up of a string of chemicals, called bases, arranged in a certain
sequence along the DNA molecule.
Gene mutation -- an abnormality in the sequence of bases
of a gene.
Glucose metabolism -- the process by which cells turn
food into energy.
Hippocampus -- a structure deep in the brain involved
in memory storage.
Magnetic resonance imaging (MRI) -- a diagnostic and
research technique that uses magnetic fields to generate a computer
image of brain anatomy. MRI can now also be used to measure brain
Magnetic resonance spectroscopy imaging (MRSI) -- a research
technique that allows scientists to measure concentrations of
substances in the brain.
Metabolism -- the normal process of turning food into
Mitochondria -- structures inside cells where glucose
metabolism takes place.
Nerve growth factor (NGF) -- a neurotrophic factor that
promotes the repair of cholinergic neurons.
Neuritic plaques -- deposits of amyloid mixed with fragments
of dead and dying neurons.
Neurofibrillary tangles -- collections of twisted nerve
cell fibers or paired helical filaments found in the cell bodies
of neurons in Alzheimer's disease.
Neuron -- a nerve cell in the brain.
Neuroscientist -- a scientist who studies the brain.
Neurotransmitter -- a chemical messenger between neurons;
a substance that is released by the axon of one neuron and excites
or inhibits activity in a neighboring neuron.
Neurotrophic factors -- a family of substances that promote
growth and regeneration of neurons.
Oxygen free radicals -- oxygen molecule with an unpaired
electron that is highly reactive, combining readily with other
molecules and sometimes causing damage to cells. See also antioxidents.
Paired helical filaments -- twisted fibers making up
PET scan - see positron emission tomography.
Phospholipids -- molecules of fat in cell membranes.
Positron emission tomography (PET) -- an imaging technique
that allows researchers to observe and measure brain activity
by monitoring blood flow and concentrations of substances such
as oxygen and glucose in brain tissues.
Protease -- an enzyme that splits a protein into smaller
Protein -- a molecule made up of amino acids arranged
in a specific order which is determined by a gene. Proteins include
neurotransmitters, enzymes, and hundreds of other substances.
Plaques -- see neuritic plaques.
Receptor -- a protein in a cell membrane that recognizes
and binds to chemical messengers, such as neurotransmitters.
Respite care -- temporary relief from the burden of caregiving
provided in the home, a nursing home, or elsewhere in a community.
Senile dementia -- an outdated term, previously used
for dementia in old age.
Single photon emission computerized tomography (SPECT)
-- an imaging technique that allows researchers to monitor blood
flow to different parts of the brain.
Special care unit -- a long-term care facility with environmental
features and/or programs designed for people with dementia.
SPECT -- see single photon emission computerized tomography.
Spectroscopy -- see magnetic resonance spectroscopy imaging.
Sundowning -- the tendency for the behavioral symptoms
of Alzheimer's disease to grow worse in the afternoon and evening.
Synapse -- the minute gap between nerve cells across
which neurotransmitters pass.
Tangles -- see neurofibrillary tangles.
Tau -- a protein that is a principal component of paired
helical filaments in neurofibrillary tangles.
For More Information
Alzheimer's Disease Progress Report -- Published annually by
the National Institute on Aging (NIA), this report summarizes
the year's findings, focusing on studies conducted at or sponsored
by the National Institutes of Health (NIH). Write or call the
Alzheimer's Disease Education and Referral Center (ADEAR). Free.
Brain Work: The Neuroscience Newsletter -- This bimonthly newsletter
from the Dana Institute reports on current brain research, including
Alzheimer's disease studies, for a general audience. Write the
Charles A. Dana Foundation, 1001 G Street NW, Suite 1025, Washington,
DC 20001-4545. Free.
Alzheimer's Disease: A Guide to Federal Programs -- A road map
to federally sponsored activities concerning Alzheimer's disease
and related disorders, this directory includes descriptions of
all programs and agencies that carry out or sponsor research.
Copies are available from ADEAR. Free.
On the Brain: The Harvard Mahoney Neuroscience Institute Letter
-- Written in non-technical language, this quarterly newsletter
describes current studies and findings in neuroscience. Write
to On the Brain, 1001 G Street NW, Suite 1025, Washington, DC
Report of the Council on Alzheimer's Disease -- The Council
on Alzheimer's Disease, part of the U.S. Department of Health
and Human Services (DHHS), coordinates research conducted by or
for Federal agencies. Its annual report to Congress covers progress
in research on services to Alzheimer's patients and families.
Copies are available from ADEAR. Free.
Report of the Panel on Alzheimer's Disease -- Published by the
Advisory Panel on Alzheimer's Disease, also in DHHS, this annual
report makes recommendations relating to services and encourages
support for promising biomedical research. Copies are available
from ADEAR. Free.
Alzheimer's Association -- The Alzheimer's Association issues
regular reports on its research grants and occasional research
updates, as well as many materials for families and caregivers.
A library provides reference service. Information on participation
in drug trials is also available. Contact a local chapter or the
Alzheimer's Association, 919 North Michigan Avenue, Suite 1000,
Chicago, IL 60611-1676; 312-335-8700 or 800-272-3900.
Alzheimer's Disease Education and Referral Center (ADEAR) --
Sponsored by the National Institute on Aging, ADEAR is a national
resource center for information on Alzheimer's disease including
research findings and participation in clinical trials. ADEAR
publishes Connections, a quarterly newsletter for professionals.
Write or call ADEAR Center, P.O. Box 8250, Silver Spring, MD 20907-8250;
Society for Neuroscience -- With more than 23,000 members, the
Society is the world's largest organization for basic scientists
and clinicians who study the brain and nervous system. Its annual
meeting, held in the fall, includes many presentations on Alzheimer's
disease research. Abstract volumes are available for purchase.
For information about obtaining publications, write or call Office
of Public Affairs, Society for Neuroscience, 11 Dupont Circle
NW, Suite 500, Washington, DC 20036; 202-462-6688.
National Institute of Neurological Disorders and Stroke (NINDS)
-- Part of the National Institutes of Health (NIH), NINDS conducts
and sponsors research on Alzheimer's disease and other neurological
disorders. Its Alzheimer's research focuses on the basic biology
and genetics of the disease, and its diagnosis and clinical management.
Write or call NINDS, Public Inquiries, Building 31, Room 8A-16,
Bethesda, MD 20892; 301-496-5751.
National Institute of Mental Health (NIMH) -- Part of NIH, NIMH
studies Alzheimer's disease in three principal areas: genetics
and neurobiology; clinical research; and psychosocial research
on the stress associated with caregiving. Write or call NIMH,
Public Inquiries, Parklawn Building, Room 15C05, 5600 Fishers
Lane, Rockville, MD 20857; 301-443-4513.
National Institute of Nursing Research (NINR) -- Part of NIH,
NINR supports and conducts research related to the diverse caregiving
responsibilities of nurses including the development of ways to
enhance mental functioning and independence. Write or call NINR,
Building 31, Room 5B-25, Bethesda, MD 20892; 301-496-0207.
National Institute on Aging (NIA) -- Part of NIH, NIA leads
the Federal effort on Alzheimer's disease and aging research.
NIA conducts and sponsors research on the epidemiology, cause,
diagnosis, and management of Alzheimer's disease. Write or call
NIA, Building 31, Room 5C-27, Bethesda, MD 20892; 301-496-1752.
Disease Education and Referral (ADEAR Center)
Alzheimer's Disease Society
Disease. Clinical Practice Guideline
The Boston Alzheimer's
Guideline for the Treatment of Patients With Alzheimer's
- Doctor's Guide to the Internet - The latest medical news and
information for patients or friends/parents of patients diagnosed
with Alzheimer's Disease.