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
"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
a visit," says Freed.
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
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 and caregivers."
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
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
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 forming."
"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,
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
Today, AD can be diagnosed conclusively only by examining the brain after
death. But physicians can make a probable diagnosis on living patients by
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
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)
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 with
None of the studies performed with the anti-inflammatory drugs to date
are definitive, cautions Katz, and these drugs would need to be studied
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
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
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
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
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
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
research studies so that they learn about the illness and are
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."