50 Important Health Topics
Alzheimer's: Searching for a Cure
It was 1997 when an alarm went off in Vivian Freed's head. She
knew something was wrong with her 85-year old mother, who had
always planned her trip to celebrate Thanksgiving with her children
down to the last detail. But that year, she got the airline tickets
for the wrong days. Freed also found out that her mother had been
missing doctors' appointments and social engagements, so she flew
from her home in Rockville, Md., to her mother's home in Florida
to check on her.
"Everything that she had done perfectly before was a mess,"
says Freed. The bills weren't paid, and the medications that her
mother had been giving to her ailing father weren't right. "We
realized we needed to do something," says Freed, after a
doctor diagnosed her mother with Alzheimer's disease.
Freed's sister, Annette Heller, later "adult-napped"
her parents and moved them to Maryland under the pretense of just
visiting." They didn't really notice that she was packing
up more things than they would need for just a visit," says
Her parents were fiercely independent and would have objected
to moving. "It would have been much nicer to give them closure,
but it wasn't possible," Freed says.
Not long after Freed moved her parents into an assisted living
facility in Maryland, her father passed away. "The day after
he died, Mom remembered what happened, but never did again,"
she says. "Mom kept asking, 'Where's Daddy?'"
As her mother's mental and physical health continued to deteriorate,
Freed moved her into a small group home where she got 24-hour
care. Alzheimer's disease, along with worsening vision, prevented
her mother from recognizing Freed. "It was a very slow demise,"
she says. Her mother died at age 90 in 2002.
"Ultimately, Alzheimer's is fatal," says William Thies,
Ph.D., vice president of medical and scientific affairs at the
Alzheimer's Association in Chicago. "Until research provides
the answers, Alzheimer's will continue to exact a terrible toll
on those with the disease, as well as on their families, friends
But an explosion of Alzheimer's research in the last 10 years
and its continuing momentum hold out hope for potential preventions
and treatments for this devastating disease.
Health care costs for the roughly 4.5 million Americans with
Alzheimer's disease (AD) exceed $100 billion a year, according
to the Alzheimer's Association. As baby boomers age during the
next few decades, the number of victims and the dollar costs of
care are expected to almost quadruple.
As age increases, so does the risk of getting AD. For each five-year
age group beyond 65, the percentage of people with AD doubles,
according to the National Institute on Aging (NIA). Nearly half
of those over age 85 have it. A small number are diagnosed with
"early-onset Alzheimer's," which can strike people in
their 30s, but most AD cases are among older people. A person
with AD lives an average of eight years after the onset of symptoms,
but some live as long as 20 years.
A Disease of the Brain
AD is a brain disorder that occurs gradually. It starts with
mild memory loss, changes in personality and behavior, and a decline
in thinking abilities (cognition). It progresses to loss of speech
and movement, then total incapacitation and eventually death.
It is normal for memory to decline and the ability to absorb complex
information to slow as people get older, but AD is not a part
of normal aging.
Researchers aren't exactly sure what causes AD, but they do
know that people with the disease have an abundance of two abnormal
structures in the brain: plaques and tangles. Plaques are
dense, sticky substances made up of accumulations of a protein
called beta-amyloid. Tangles are twisted fibers caused by changes
in a protein called tau. The beta-amyloid plaques reside
in the spaces between the billions of nerve cells, or neurons,
in the brain, and the neurofibrillary tangles clump together inside
the neurons. Plaques and tangles block the normal transport of
the electrical messages between the neurons that enable us to
think, remember, talk and move. As AD progresses, nerve cells
die, the brain shrinks, and the ability to function deteriorates.
Treating the Symptoms
There is no cure for AD, but there are drugs to treat some of
the symptoms. The Food and Drug Administration has approved four
prescription drugs for people with mild-to-moderate AD: Cognex
(tacrine), Aricept (donepezil), Exelon (rivastigmine), and Reminyl
(galantamine). "All of them work by the same mechanism,"
says Russell Katz, M.D., director of the FDA's Division of Neuropharmacological
Drug Products. The drugs increase the level in the brain of acetylcholine--a
chemical that nerves use to communicate with each other. "People
with AD are deficient in this neurotransmitter, and the drugs
work by inhibiting an enzyme called cholinesterase that breaks
down the acetylcholine," says Katz. "These cholinesterase
inhibitors have an effect on the symptoms, but we have no evidence
that they have any effect on the underlying progression of the
disease. During treatment, as far as we know, the nerve cells
are still dying and the various plaques and tangles are still
"There's healthy debate about whether these drugs actually
affect the course of the illness," says Trey Sunderland,
M.D., chief of the Geriatric Psychiatry Branch of the National
Institute of Mental Health (NIMH). According to the data, says
Sunderland, "If people are on the cholinesterase inhibitors,
they tend to go to nursing homes later than people who are not
on the inhibitors." Some researchers have reported a delay
of up to 22 months in going to nursing homes, he adds.
Another drug, Namenda (memantine), is approved to treat people
with moderate-to-severe Alzheimer's disease. This drug is thought
to work by blocking the action of glutamate, a brain chemical
that may be overactive in people with AD.
Treating the Disease
Scientists continue to search for treatments to slow the progress
of AD and to hold the disease off as long as possible. "If
you could delay the onset of symptoms by five years, the total
number of new cases projected into the future would be cut in
half," says Steven Ferris, Ph.D., director of the Alzheimer's
Disease Center at the New York University School of Medicine.
"Within the next five to 10 years, we will at least be able
to slow down the disease in people who already have symptoms and
do a much better job at identifying people at high risk of getting
Alzheimer's who do not yet have symptoms," Ferris predicts.
And once new treatments come along to slow down the disease, those
treatments may be given to people at high risk, he adds, so a
growing number of people will live longer but not long enough
to get AD.
Scientists are uncovering clues to better diagnose the disease
and to determine who is at risk. "It is my hope that in time
for the baby boomers, there will be both a prognostic test, as
well as at least one therapeutic strategy," says Sunderland.
"Both prognostic and therapeutic options are needed. If you
had a preventative drug that potentially had toxicity associated
with it, you wouldn't want to give it to everybody--only the subpopulation
at greatest risk."
Today, AD can be diagnosed conclusively only by examining the
brain after death. But physicians can make a probable diagnosis
on living patients by taking a complete medical history, administering
neurological and psychological tests, and doing a physical exam,
blood and urine laboratory tests, and a brain-imaging scan. Once
symptoms begin, the disease can be diagnosed with up to 90 percent
accuracy by experienced physicians, according to the NIA.
But do people start getting AD before symptoms show themselves?
"That's the big question in Alzheimer's disease: When does
it really begin?" says Sunderland. No one knows for sure,
he says, but research "suggests that the illness may predate
clinical symptoms by years and maybe decades."
Advances in neuroimaging--taking pictures of the brain to measure
its structure and activity--may allow researchers to see the accumulation
of plaques and tangles at various points in time. Neuroimaging
may one day prove useful in monitoring the progression of the
disease and assessing people's responses to drug treatment.
Another early indication of AD could be found in a person's
spinal fluid, which, like the brain, carries beta-amyloid and
tau proteins. In a study at the NIMH, Sunderland's team
of researchers was able to diagnose AD in most cases by measuring
the levels of these proteins in spinal fluid. These measurements,
or biomarkers, may help scientists identify people at risk for
AD, says Sunderland. "By establishing a person's baseline
and tracking levels over time, we might be able to interpret gradual
changes as a sign that he or she is developing the disorder."
Sunderland's study, which included physical examination of more
than 200 participants and an analysis of over 50 similar studies,
is reported in the April 23, 2003, issue of the Journal of
the American Medical Association (JAMA). While work in this
area is currently investigational in nature, spinal fluid testing
may become a valuable routine diagnostic tool in the future.
Delaying the Disease
Some studies hint that a variety of existing drugs and supplements
may be useful in delaying AD or stopping its progression. These
studies are preliminary, and their findings would need to be demonstrated
in adequately designed and conducted studies before their conclusions
can be considered proven, says Katz.
Cholesterol-lowering drugs, anti-inflammatory drugs, antioxidants,
and estrogen are some of the substances that have been studied,
but study results have been conflicting. These studies don't prove
causation, warns Thies of the Alzheimer's Association. "All
they really tell us is it's a good place to start doing clinical
trials." And researchers are doing just that.
The Heart and Head Connection
Studies have shown a link between known risk factors for heart
disease--high blood pressure, high cholesterol levels, and diets
high in saturated fats and trans fats--and an increased
risk for AD. There is also evidence that an elevated level of
homocysteine, an amino acid in the blood, presents a risk for
both heart disease and AD. Further, taking cholesterol-lowering
drugs (statins) is associated with a lower occurrence of AD.
"What is good for the heart may be good for the head,"
says Thies, and healthy lifestyle behaviors such as exercising,
eating healthily, and managing blood pressure and cholesterol
may be of value in protecting people from AD.
Large-scale clinical trials are being conducted to clarify the
link between cardiovascular risk factors and AD. In addition to
statins, substances being tested for slowing and preventing AD
are folate (a form of B vitamin) and vitamins B6 and B12, which
may lower homocysteine levels.
People who take large doses of non-steroidal anti-inflammatory
drugs (NSAIDs), commonly used to reduce joint inflammation and
pain, have a reduced likelihood of developing AD, according to
some studies. NSAIDs, which include over-the-counter aspirin and
ibuprofen, as well as some prescription drugs, such as Celebrex
(celecoxib), may reduce the inflammation in the brain associated
None of the studies performed with the anti-inflammatory drugs
to date are definitive, cautions Katz, and these drugs would need
to be studied in scientifically rigorous trials before the effects
of these drugs on AD could be accepted. One of these trials, the
Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT),
was launched in 2001 to test the effectiveness of some NSAIDs
in preventing AD. The study of more than 2,500 healthy participants
age 70 and over is sponsored by the NIA and is scheduled to run
between five and seven years.
Researchers are also looking at antioxidants to possibly prevent
cognitive decline. Antioxidants, such as vitamin E, vitamin C
and carotene, may help break down "free radicals"--cell-damaging
compounds that are byproducts of normally functioning cells. The
natural defenses of cells protect against these compounds, but
these protective mechanisms decline as a person ages.
Some study results have suggested that antioxidants may protect
against cell damage and lessen the likelihood of getting AD. But
a four-year study of nearly 1,000 older people conducted at Columbia
University found that consuming carotenes or vitamins C and E
either through the diet or by supplements did not decrease the
risk of developing AD. "This large-scale study is at variance
with earlier indications that these supplements are effective
as a treatment for Alzheimer's," says Thies. "This tells
us that more work needs to be done before we completely understand
the value of these agents." The results of this study are
published in the February 2003 issue of Archives of Neurology.
"There are virtually shelf-fuls of compounds capable of
acting in an antioxidant fashion," says Thies. One of these,
Ginkgo biloba, used for thousands of years in Chinese herbal medicine,
has been shown in a small study to result in a modest improvement
in cognition, social behavior and performing activities of daily
living, such as dressing and eating. A larger study (about 3,000
participants) funded by the National Institutes of Health (NIH)
is currently investigating the effectiveness of Ginkgo in preventing
or delaying cognitive decline in older adults.
The FDA cautions consumers that some supplements may interact
with prescription and over-the-counter medicines and cause serious
harm. Check with your doctor or health care provider before taking
any dietary supplement, including herbs.
Several epidemiological studies have linked the female hormone
estrogen to improved memory and possible delay or prevention of
AD in women. But a large, long-term clinical trial sponsored by
the NIH has provided evidence to the contrary. In the trial, part
of the Women's Health Initiative Memory Study (WHIMS), women 65
and over taking estrogen combined with another hormone, progestin,
had twice the rate of dementia, including AD, than those women
not taking the hormones. The study, published in the May 28, 2003,
issue of JAMA, also found that the hormone combination
did not protect against the development of mild cognitive impairment,
a form of mental decline less severe than dementia.
New Drug Development
New drugs are emerging from the basic science laboratories and
moving toward testing in human trials. "The ones furthest
along are based on the amyloid hypothesis," says Thies. The
hypothesis is that AD starts with the accumulation of amyloid
plaques, and that limiting this accumulation will change the progress
Scientists have isolated enzymes called secretases, which are
thought to lead to the formation of beta-amyloid. Secretases are
categorized as proteases, the same type of enzymes that are targeted
by protease inhibitors to treat AIDS. Drugs called secretase inhibitors
are being developed to block beta-amyloid formation, and some
of these drugs are now being tested.
Another approach to plaque attack is to stimulate the body's
immune system to destroy the beta-amyloid. Scientists developed
a vaccine that put amyloid into the blood in the hopes of making
antibodies to destroy the plaques. The vaccine was successful
in transgenic mice--special mice that were injected with human
genes that caused them to develop AD-like plaques. But when tested
in a human trial, some people showed inflammation of the brain
(encephalitis). Further vaccination was stopped, but study participants
continue to be followed. Although this particular vaccine may
be disappointing, many scientists believe that the strategy of
fighting AD by stimulating the immune system still remains an
important potential avenue to slow or prevent the disease.
"We are still searching for the sequence of events where
we can intervene and cure the disease without causing harm,"
says Marcelle Morrison-Bogorad, Ph.D., associate director of the
NIA's Neuroscience and Neuropsychology of Aging Program. Morrison-Bogorad
notes that scientists may someday be able to inject a substance
into the blood to draw amyloid from cerebral spinal fluid and
the brain. "This can happen in transgenic mice--we don't
know whether it happens in humans yet."
The two biggest risk factors for getting AD are age and genetics,
neither of which is in our control, says Thies. Scientists have
identified several genes that play a role in early-onset AD, a
rare form of the disease that strikes people as young as in their
30s. For late-onset AD, defined as showing symptoms after age
65, a gene that produces a protein called apolipoprotein E (ApoE)
appears to play a role. The gene comes in several forms, or alleles.
Having the ApoE4 allele increases the risk for getting AD, according
to the NIA.
About 40 percent of people with AD have the ApoE4 allele, but
inheriting it doesn't mean a person will definitely get AD. Some
people with the gene never get the disease, and some without it
do develop AD. Once researchers know more about how genetics affects
AD, people could be genetically screened and then treated based
on their genetic factors.
Some studies have shown that participating in mentally stimulating
activities, such as reading books, doing crossword puzzles, or
going to museums, may be associated with a reduced risk of AD.
Researchers speculate that repetition might improve certain cognitive
skills, making them less susceptible to brain damage.
This "use-it-or-lose-it" theory may have value, but
further study is needed, says Morrison-Bogorad. AD may actually
cause people to stop doing mentally challenging activities because
the disease makes it harder to do them, she says. "It's impossible
to tease out the cause and effect in these studies. We can only
say it's correlative--not causal." Morrison-Bogorad does
encourage mental activity. "It keeps you nimble--whether
it helps prevent Alzheimer's, we don't know."
No cure or prevention for Alzheimer's disease exists yet, but
experts offer some advice to help prolong mental health:
"The best thing people can do is to try to plan for their
later years and try to remain as functional as possible,"
says William Thies, Ph.D., vice president of medical and scientific
affairs at the Alzheimer's Association in Chicago. "And stay
connected to the world, because the literature suggests that social
isolation is a contributor to unhealthy aging."
Steven Ferris, Ph.D., director of the Alzheimer's Disease Center
at the New York University School of Medicine, makes three recommendations:
Stay mentally active. "The more you challenge the brain,
the more you'll be able to maintain it," says Ferris. "When
you're stimulating the brain, you're growing more interconnections
and maybe even growing new neurons. The more brain cells and
connections you have, the longer you'll be able to function
well, even if you get Alzheimer's."
Stay physically active. Physical exercise improves brain
function as well as benefiting the rest of your body.
Have a healthy diet and stay in good physical health. These
are essential for maintaining good brain function.
Trey Sunderland, M.D., chief of the Geriatric Psychiatry Branch
of the National Institute of Mental Health, encourages people
to participate in Alzheimer's research studies so that they learn
about the illness and are followed carefully for any incremental
change that might occur in their health. "Our volunteers
have found that they actually get reassured by being in a study,"
says Sunderland. "For the most part, we're telling them--in
our long-term follow-up studies--that they continue to be normal."