Alzheimer's Disease
Unraveling The Mystery
Table of Contents
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.
About using this
booklet
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 booklet.
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 Lydia Kibiuk.
"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 common..."
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.
Basics
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 neurons die.
Graphical
Representation -- The Brain and Alzheimer's Disease
[illustration] The
Brain and Alzheimer's Disease--Shows the cerebral cortex, involved
in conscious thought and language; the basal forebrain, which
has large numbers of neurons containing acetylcholine, a chemical
important in memory and learning; the hippocampus, which is
essential to memory storage; neuritic plaques; and neurofibrillary
tangles. Alzheimer's disease attacks nerve cells (neurons) in
several regions of the brain. The earliest signs of Alzheimer's
are found in the nearby entorhinal cortex (not shown). Hallmarks
of Alzheimer's disease include neuritic plaques (outside neurons),
and neurofibrillary tangles (inside neurons).
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 a journal.
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 care.
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.
Definitions
- 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.
Progress
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 future.
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.
Further Reading
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.
Sources:
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 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
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
Alzheimer's disease.
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 and reasoning.
Graphical
Representation -- How Neurons Communicate
[illustration] How
Neurons Communicate--Shows cell bodies, axons, and dendrites
of two neurons, the synapse between them, receptors, and vescicles
containing neurotransmitter molecules; how neurotransmitters
are released from the axon, cross the synapse, and bind to receptors
on the surface of another neuron; and how electrical impulses
pass along the axon.
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 in balance.
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).
Graphical Representation -- Across the Synapse
[illustration] Across
the Synapse--Problems in the membrane, or inner structures of
the neuron receiving the message, may be involved in Alzheimer's
disease. Shows a spiral shaped receptor, the neuron membrane,
the phospholipid bilayer, mitochondria, cytoplasm, and membrane
channels.
The Proteins
Beta amyloid.
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 fragment.
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 the
protein.
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 attack
neurons.
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.
[photograph] A researcher
seeks clues for how beta amyloid affects concentrations of other
substances inside and outside neurons.
Tau.
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.
Graphical
Representation -- Neurofibrillary Tangles
[illustration] Compares
a normal neuron and its microtubules with a neuron with 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.
The 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.
Graphical
Representation -- Chromosomes and Genes
[illustration] Chromosomes
and Genes--Shows a nerve cell, chromosomes, genes, double DNA
strands, bases, and a nucleus. 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 population.
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 apoE4 gene.
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.
[photograph] A researcher
uses an automated DNA sequencer to study genes involved in aging
and Alzheimer's disease.
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 active.
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.
Graphical
Representation -- Brain Metabolism in Alzheimer's Disease (PET
Scans)
[illustrations] 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 neuron.
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 in Alzheimer's.
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 the cell.
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
of calcium.
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.
Environmental Suspects
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.
Aluminum.
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 tissue.
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 disease.
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.
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.
Foodborne poisons.
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 finding.
- 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.
Sources:
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.
Further Reading
Cotton P. Constellation
of Risks and Processes Seen in Search for Alzheimer's Clues,
Journal of the American Medical Association 271:89-91, 1994.
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.
The Proteins
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; pp 305-316.
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.
The Genes
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.
Metabolism
Beal MF. Energy, Oxidative
Damage, and Alzheimer's Disease: Clues to the Underlying Puzzle,
Neurobiology of Aging 15(Suppl. 2):S171-S174, 1994.
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, 1993.
Calcium
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 23:1247-1260, 1992.
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, 1994.
Environmental Suspects
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.
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 group."
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 percent
accuracy.
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.
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 lead.
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
Guidelines).
Diagnostic
Tools
- 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 environment.
- 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.
Biological Markers
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.
Imaging.
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 radioactive
markers.
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 Alzheimer's disease.
[photograph] Studies
searching for early signs of Alzheimer's disease use PET scans,
such as the one in progress here.
Further Reading
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.
Cognitive Markers
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, 1991.
Zonderman AB, Giambra
LM, Kawas CH. Changes in Immediate Visual Memory Predict Cognitive
Impairment, Archives of Clinical Neuropsychology (in press).
Biological Markers
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.
Graphical
Representation -- How THA Works
[illustration] 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.
Neurotrophic factors.
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 is remembering.
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.
Mild Symptoms
- Confusion and
memory loss
- Disorientation;
getting lost in familiar surroundings
- Problems with
routine tasks
- Changes in
personality and judgment
Severe Symptoms
- Loss of speech
- Loss of appetite;
weight loss
- Loss of bladder
and bowel control
- Total dependence
on caregiver
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