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
dementia. "
Preface
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
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.
-----------------------------
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
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.
-----------------------------
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 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
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.
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).
-----------------------------
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.
-----------------------------
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.
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.
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.
-----------------------------
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.
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.
-----------------------------
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
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.
-----------------------------
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.
-----------------------------
Investigating Treatments
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.
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
Moderate Symptoms
- Difficulty with activities of daily living, such as feeding
and bathing
- Anxiety, suspiciousness, agitation
- Sleep disturbances
- Wandering, pacing
- Difficulty recognizing family and friends
Source:
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 replacement
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
memory.
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.
-----------------------------
Calcium regulators
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
the disease.
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.
-----------------------------
Antioxidants
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.
-----------------------------
Anti-inflammatory drugs
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.
Managing Symptoms
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
before walking."
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 sym | 
