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March 2000WHAT IS ALZHEIMER'S DISEASE?
Alzheimer's disease is a
degenerative disease of the brain from which there is no recovery.
Slowly and inexorably, the disease attacks nerve cells in all parts of
the cortex of the brain, as well as some surrounding structures,
thereby impairing a person's abilities to govern emotions, recognize
errors and patterns, coordinate movement, and remember. At the last,
an afflicted person loses all memory and mental functioning.
WHO GETS ALZHEIMER'S DISEASE
About half of the people in
nursing homes and almost half of all people over 85 have Alzheimer's
disease. It is now the fourth leading cause of death in adults. Almost
4 million Americans have Alzheimer's disease, and unless effective
methods for prevention and treatment are developed, it will reach
epidemic proportions by the middle of the next century, afflicting
between 8 and 14 million people. In addition to the elderly, people at
higher than average risk are those who have a family history of the
disease. [ See Genetic Factors under What Causes
Alzheimer's Disease.] Nearly all patients who inherit Down's syndrome
develop changes in the brain that resemble Alzheimer's if they live
into their 40s, although onset varies and can occur as late as age 70.
Women under the age of 35, but not older mothers, who give birth to
children with Down's syndrome are also at much higher risk for
Alzheimer's. A number of studies suggest that women are more likely to
develop Alzheimer's, while one reported that men are more likely to
suffer age-related brain damage. Studies are not consistent, however.
Few well-conducted studies have been conducted on differences among
population groups. The disease is rare in West Africa, but
African-Americans have the same risk as white Americans, possibly even
a higher one. Hispanics may also have a higher risk than Caucasian
Americans. Genetic factors are at work in all groups but the same
genes may have different effects depending on the ethnic population.
Alzheimer's disease occurs less in the Native American Crees and
Cherokees and in Asians than in the general American population. A
study of Japanese men, however, showed that their risk increased if
they emigrated to America. Chronic high blood pressure is associated
with mental deterioration in older people, including increased risks
for short-term memory and attention, Alzheimer's disease, and
dementia. The higher the blood pressure the greater the risk for
mental impairment. (Controlling blood pressure may help ward off
memory loss to begin with and treating blood pressure in older
patients can reduce the risk of dementia in elderly patients with
elevated systolic pressure.)
WHAT CAUSES ALZHEIMER'S DISEASE?Biologic Factors in the Brain
Two significant abnormalities
occur in brains of people affected by Alzheimer's: twisted nerve cell
fibers, known as neurofibrillary tangles, and a sticky protein
called beta amyloid . Other factors also play a role.
Neurofibrillary Tangles. The
tangled fibers are the damaged remains of microtubules, the support
structure that allows the flow of nutrients through the neurons (nerve
cells). A key component in these tangled fibers is an abnormal form of
a protein known as tau. Some experts believe that this defective
version blocks the activity of normal tau proteins, which help in the
assembly of a healthy microtubule
structure.
Beta Amyloid. The second
significant finding is a high concentration of an insoluble protein
known as beta amyloid (also called A beta), which is a fragment of a
larger protein called amyloid precursor protein (APP). (APP itself
appears to be important for nerve protection.) Peseniline proteins
appear to regulate enzymes (or actually are the enzymes) involved in
snipping amyloid precursor protein (APP) into fragments so that beta
amyloid is formed. (Genetic abnormalities that affect these proteins
occur in some inherited cases of Alzheimer's.) Beta amyloid forms
sticky patches called neuritic plaques. These plaques are found
outside the nerve cells surrounded by the debris of dying neurons.
High levels of beta amyloid are associated with reduced levels of the
neurotransmitter acetylcholine. Neurotransmitters are chemical
messengers in the brain. Acetylcholine is part of the cholinergic
system, which is essential for memory and learning, and which is
progressively destroyed in Alzheimer's patients. Beta amyloid may also
disrupt channels that carry sodium, potassium, and calcium; these
elements serve the brain as ions, producing electric charges that must
fire regularly in order for signals to pass from one nerve cell to
another. If the channels that carry ions are damaged, an imbalance can
interfere with nerve function and signal transmission.
Other Proteins. Researchers
have now identified other important proteins in the areas of the brain
affected by Alzheimer's disease. . E RAB (endoplasmic-reticulum
associated binding protein) appears to combine with beta amyloid,
which in turn attracts new beta amyloid from outside the cells. High
amounts of ERAB may also enhance the nerve-destructive power of this
protein partner. AMY plaques resemble beta amyloid so closely that
researchers were able to detect them only with the use of highly
sophisticated techniques. Elevated levels of a protein called prostate
apoptosis response-4 (Par-4) may cause nerve cells to self-destruct.
Other Neurotransmitters. Although
studies have emphasized acetylcholine, other neurotransmitters,
including serotonin and norepinephrine levels, are also affected in
Alzheimer's disease.
Inflammatory Response
Some researchers think that beta
amyloid may break into fragments that release oxygen-free radicals.
These are unstable chemicals in the body that, through a process
called oxidation, bind to other molecules and cause damage by
affecting DNA and triggering other harmful processes. Oxidation is
known to play a role in many serious diseases, including coronary
artery disease and cancers, and experts believe it may also contribute
to Alzheimer's. One of its effects is the so-called inflammatory
response, in which the immune system overproduces factors normally
intended to fight harmful agents, but in excess, they can actually
injure the body's own cells. Of specific interest is cyclooxygenase
(COX), which produces prostaglandins, substances important in the
inflammatory response and which, in Alzheimer's, may increase levels
of glutamate, an amino acid that is a powerful nerve-cell killer.
Genetic Factors
Genetic Factors for Late-Onset
Alzheimer's. The major target in genetic research on late-onset
Alzheimer's disease has been apolipoprotein E (ApoE), which plays a
role in the movement and distribution of cholesterol for repairing
nerve cells during development and after injury. The gene for ApoE
comes in three major types: ApoE2, ApoE3, and ApoE4. People inherit a
copy of one type from each parent. Studies have reported greatest
deposits of beta amyloid in people with ApoE4, fewer in ApoE3, and
lowest in those with ApoE2. Some research indicates that ApoE3 and
ApoE4 may induce changes in beta amyloid that trigger an inflammatory
response in the brain. ApoE2 appears, on the other hand, to have
protective qualities. It should be noted that although the ApoE4 gene
increases susceptibility to Alzheimer's, it does not appear to
regulate the disease process itself.
Alzheimer's disease is not
inevitable even in people with two copies of the ApoE4 gene. Reports
vary widely in estimating the extent of risk. In people without ApoE4,
estimates for the risk of developing Alzheimer's by age 85 range from
9% to 20%; in those with one copy of the gene, the risk is between 25%
and 60%; in people with two copies, the risk ranges from 50% to 90%.
Only 2% of the population carry two copies of the ApoE4 gene. Some
research indicates that a specific variation of the ApoE4 gene may be
the primary culprit in the development of Alzheimer's, which would
explain why many people with ApoE4 exhibit no signs of Alzheimer's. A
number of studies also indicate that ApoE4 gene occurs in about 20% of
cases of vascular dementia, which is dementia caused by blockage in
blood vessels to the brain. ApoE4 has been studied for years as a risk
factor for coronary artery disease, but the relationship between the
genetic type, heart disease, and Alzheimer's is inconclusive. Some
studies have found a higher risk for heart disease in people with
Alzheimer's disease who also carry two copies of the ApoE4 genotype.
Most people with Alzheimer's
disease, however, do not carry the ApoE4 gene. Increasingly,
researchers believe that many cases of late-onset Alzheimer's disease
are a result of a collaboration of genetic factors that participate in
the process of producing or degrading beta amyloid. Another
apolipoprotein called Apo(a) may be involved in amplifying the effects
of ApoE4. Other research has identified genetic abnormalities in the
mitochondria (the source of energy within cells) in about 20% of
people with late-onset Alzheimer's; such defects are passed only from
mother, not father, to child. Researchers have detected mutations in
proteins called beta amyloid precursor protein (BAPP) and ubiquitin-B
(Ubi-B), which may account for some cases of late- and early-onset
Alzheimer's. Such mutations are not inherited, but appear to be
genetic mistakes that occur during transcription, the coding process
in which DNA establishes the pattern for the production of proteins
and other molecules.
Genetic Factors for Early-Onset
Alzheimer's. Scientists are coming closer to identifying defective
genes responsible for early-onset Alzheimer's, an uncommon, but
extremely aggressive form of the disease. Research has found that
mutations in genes known as presenilin-1 (PS1) and presenelin-2 (PS2)
account for most cases of early onset inherited Alzheimer's disease.
The defective genes appear to cause Alzheimer's by accelerating beta
amyloid plaque formation and apoptosis, a natural process by which
cells self-destruct. People with Down's syndrome, who almost always
develop Alzheimer's, overproduce beta-amyloid precursor protein (APP),
which, in turn, manufactures beta amyloid.
Environmental and Other Factors
Genetics factors play a major role
but do not offer a complete answer to the development of Alzheimer's.
Other factors, then, are involved with nerve destruction in many of
these patients.
Virus and Bacteria. Because
a slow, infectious virus causes a number of other degenerative
neurologic diseases, such as kuru and Creutzfeldt-Jakob disease,
researchers are exploring the viral route as one possible cause of
Alzheimer's disease. No evidence exists that Alzheimer's is
transmittable, but a possible scenario is a genetic susceptibility
coupled with a breakdown of the immunologic system that leaves a
person vulnerable to a virus. One study has indicated that herpesvirus
1 may provide this link. The study's results found that the risk for
Alzheimer's was very high in people with both ApoE4 and evidence of
this virus, but risk was normal in those with only one of these
factors. Another study detected Chlamydia pneumoniae , a
bacterium that causes respiratory infections in parts of the brain
affected by late-onset Alzheimer's, but not in unaffected parts. The
presence of the bacterium may have been the result of Alzheimer's
disease rather than its cause, but the finding warrants more research.
Metals. Some laboratory
studies have associated the formation of amyloid plaques with
excessive amounts of metal ions such as zinc, copper, aluminum, and
iron. Such ions may also change the chemical architecture of beta
amyloid making it more harmful. A mildly acidic environment appears to
be important in the process that binds these metals to beta amyloid.
Experts observe that such conditions (acidic environment and higher
levels of zinc and copper) commonly occur as part of the inflammatory
response to local injury.
Electromagnetic Fields. Some,
but not all, studies on people exposed to intense electromagnetic
fields have reported a higher incidence of Alzheimer's. Some
researchers believe that magnetic fields may interfere with the
concentration of calcium inside cells, and others believe that they
may increase production of beta amyloid.
Head Injury. Injury to the
head can accelerate the development of Alzheimer's in people who are
already susceptible to it.
Childhood Malnutrition and
Vitamin Deficiencies. According to one study, poor nutrition in
childhood may render the brain more susceptible to mental impairments
later in life, including Alzheimer's disease. Other recent studies
suggest an elevated homocysteine level may be a risk factor for
Alzheimer's. Homocysteine is a substance in the blood that increases
with deficiencies of vitamins B12 and folate. No evidence exists that
supplements of these vitamins offer any protection against Alzheimer's
disease.
HOW CAN ALZHEIMER'S DISEASE BE PREVENTED?
There have been no proven methods
for preventing Alzheimer's disease since the cause of it is still
unknown. Still, certain factors are showing some evidence of reducing
risk.
Male and Female Hormones
Estrogen. Estrogen, the
primary female hormone, appears to have properties that protect
against the memory loss and lower mental functioning associated with
normal aging. A number of studies have reported that women taking
hormone replacement therapy (in various combinations and even for
brief periods) score better on verbal memory than women not on HRT.
However, one study of young women who had hysterectomies found no
association between estrogen levels and mental functioning. Another on
older women found no association between differing levels of natural
estrogen and better or worse mental functioning, and an analysis of
major studies reported that the largest and more rigorously-conducted
one found no benefits from estrogen supplements on mental functioning
in healthy postmenopausal women.
Studies continue to report,
however, an association between estrogen replacement therapy and
protection against both Alzheimer's and dementia in Parkinson's
disease. Five studies suggested a 40% to 60% reduction in the risk of
Alzheimer's in women who have taken supplemental hormones. In
addition, estrogen may enhance the benefits of such drugs, including
Tacrine, which are used to treat Alzheimer's, but these data are
preliminary. Recent laboratory studies suggested that estrogen may
help ward off Alzheimer's by blocking the production of the
beta-amyloid peptides, which are the primary culprit in causing this
disease. Estrogen may also trigger the temporary growth of nerve
pathways in the memory portion of the brain and stimulate production
of the neurotransmitters acetylcholine and serotonin, which are
depleted in Alzheimer's patients. And because estrogen may reduce the
risk of atherosclerosis (the build-up of plaque in blood vessels),
some doctors hypothesize that it may improve blood flow to the brain.
While taking estrogen may prove to reduce the risk of Alzheimer's, its
use for this purpose is still unproven, and women should not choose
hormone replacement therapy solely to prevent Alzheimer's disease.
Testosterone. One small
study suggested testosterone might be helpful in reducing levels of
beta amyloid. More research is warranted to determine if testosterone
supplements may be protective in elderly men.
Nonsteroidal Anti-Inflammatory Drugs
Common nonsteroidal
anti-inflammatory drugs (NSAIDs), such as aspirin, ibuprofen (Advil,
Motrin), and naprosyn, have properties that block specific factors in
the inflammatory response believed to play a major role in nerve-cell
degeneration. A long-term study found that people who took ibuprofen
for two years or more had a 50% reduction in the incidence of
Alzheimer's compared to those who did not take the drug. In the same
study, long-term use of aspirin appeared to confer no benefit, perhaps
because the dose was often very low. Long-term use of NSAIDs can cause
bleeding and ulcers in the gastrointestinal tract. Combinations of
NSAIDS and gastro-protective agents, such as diclofenac and
misoprostol (Arthrotec), may reduce this risk considerably. Still,
NSAIDS are not necessarily appropriate for all patients and should not
be taken without the recommendation of a physician. Newer NSAIDs
called COX-2 inhibitors (Vioxx, Celebrex) may have nerve-protecting
properties without as severe side effects, but long-term studies are
needed to determine this. Acetaminophen (Tylenol) is not an
anti-inflammatory drug and has no effect on this disease.
Statin Drugs. Of
considerable interest was a preliminary 1999 study that reported a
significantly lower risk (63% to 73%) for Alzheimer's disease in
people who were taking cholesterol lowering drugs known as statins.
The statins noted in the study were lovastatin (Mevacor) and
pravastatin (Pravachol).More Studies are needed.
Diet
Fats and Oils. A
preliminary analysis of dietary habits in eleven countries suggests
that a low-fat diet might reduce the risk of Alzheimer's. In countries
with low-fat diets, such as China and Nigeria, the risk of developing
Alzheimer's is 1% at age 65 compared to 5% in the US. A study in the
Netherlands reported an association between dementia and diets high in
total fat, saturated fat, and cholesterol. Saturated fats (found in
animal products) and trans-fatty acids (found in fast foods and
commercial baked goods) should be avoided. Some fats, however, such as
omega-3 fatty acids, which are found in fish such as salmon, halibut,
swordfish, and tuna are essential for the development of the nervous
system. These fatty acids also may help protect against mental decline
in old age. Some reports have suggested that certain dietary
antioxidants, such as vitamin C, E, and selenium may be protective
against mental decline.
Antioxidant-Rich Supplements
and Foods. Much research on Alzheimer's disease has indicated that
oxygen-free radicals may play an important role in the disease
process. These particles are released during normal chemical processes
and after injuries and can cause great dramage. Vitamin E is an
important antioxidant and is of particular interest. Most foods are
not rich in this vitamin, but it can be obtained in vegetable oils
(particularly wheat germ oil), sweet potatoes, avocados, nuts,
sunflower seeds, and soy beans. According to several studies, eating
plenty of darkly-colored fruits and vegetables may slow brain aging;
they are recommended in any case for good health. In a 1999 study on
animals, extracts taken from blueberries and strawberries actually
reversed age-related decline in brain function. Blueberries were the
most effective. Such foods are rich in antioxidants. Red wine, which
also contains powerful antioxidants, has also been associated with a
lower risk for Alzheimer's.
Calorie Restriction. Caloric
intake itself may play a role in brain health. In one study on
animals, restricting calories below normal (but above starvation
levels) helped prevent age-related nerve degeneration. It should be
pointed out, however, that in patients with existing Alzheimer's,
weight loss is a strong indicator of mental decline.
Continuing Education and Mental Acuity
A number of studies have reported
a higher risk for Alzheimer's disease in people with less education
and a lower risk for dementia and Alzheimer's in those who remain
mentally active. A few experts speculate that learning itself
stimulates more neurons to grow and thus may create a larger reserve
in the brain so that it takes longer for brain cells to be destroyed.
Others believe that socioeconomic forces, such as diet and
environmental toxins, may make less educated people more susceptible
to Alzheimer's. A 2000 study found no differences in educational
levels between patients with Alzheimer's and those without dementia.
An ongoing study of nuns also found no association between education
and Alzheimer's, but did find a high risk for Alzheimer's among those
whose youthful writings showed a paucity of ideas and a low risk in
those whose writings were idea-rich. Some experts postulate that this
study offers evidence that Alzheimer's is lifelong, beginning at a
young age and that continuing education is not protective. This study
was very small, however, and when cases outside the study were
assessed using the same criteria, the same results did not occur. In
any case, staying mentally active and interested in life is always
good advice.
WHAT ARE THE SYMPTOMS OF ALZHEIMER'S DISEASE?
The early symptoms of Alzheimer's
disease may be overlooked because they resemble signs of natural
aging. These symptoms include forgetfulness, loss of concentration,
unexplained weight loss, and motor problems, including mild
difficulties in walking. In healthy individuals, similar symptoms can
result from fatigue, grief or depression, illness, vision or hearing
loss, the use of alcohol or certain medications, or simply the burden
of too many details to remember at once. But when memory loss worsens,
family and friends perceive that more serious problems exist. [ See
Table , Differences between Normal Signs of Aging and Dementia, below.]
One clue to differentiating Alzheimer's from normal aging may be the
patient's inability to understand the meaning of words. Accompanying
sensory problems, such as hearing loss and a decline in reading
ability, as well as general physical debility in newly diagnosed
Alzheimer's patients, indicate shorter survival time. A number of
other disorders may be causing these extreme symptoms and must be
ruled out before a diagnosis of Alzheimer's disease can be certain. [ See
How Is Alzheimer's Disease Diagnosed? below.] About 20% of
suspected Alzheimer's cases turn out to be some other disorder, half
of which are potentially treatable or controllable. Strictly speaking,
a definitive diagnosis of Alzheimer's can only be made at autopsy
after death.
HOW IS ALZHEIMER'S DISEASE DIAGNOSED?Diagnosing Alzheimer's Disease
Ruling Out Other Causes Memory
Loss or Dementia. A definitive test to diagnose Alzheimer's
disease even in patients showing signs of dementia has not yet been
devised, so the first step is to rule out other conditions that might
be causing memory loss or dementia. Some elderly people have a
condition called mild cognitive impairment, which involves more severe
memory loss than normal but no other symptoms of Alzheimer's.
There are now three known major
causes for dementia in the elderly: Alzheimer's disease, vascular
dementia (abnormalities in the vessels that carry blood to the brain),
and Lewy bodies variant (LBV), also called dementia with Lewy bodies.
As yet, it is very difficult to differentiate among these dementias.
LBV was defined in 1997 and is now believed to be responsible for
about 20% of people who have been diagnosed with Alzheimer's. It is
often hard to distinguish these neurologic disorders. One analysis of
a number of studies suggested that patients with vascular dementia had
better long term verbal memory than Alzheimer's patients but poorer
executive function (less ability to integrate and organize). Experts
currently believe that 60% of cases of dementia are due to
Alzheimer's, 15% to vascular injuries, and the rest are a mixture of
the two. Vascular dementia is primarily caused by multiple small
strokes (called multi-infarct dementia) or Binswanger's disease, which
affects tiny arteries in the midbrain. In general, dementia, whether
caused by Alzheimer's or stroke, is rarely reversible. LBV may cause
more mental disturbances related to visual processing but less memory
impairment than Alzheimer's. For example, in one study, patients with
LBV performed worse than Alzheimer's patients on "design"
tasks, such as arranging pictures or assembling objects, but they did
better with word recall and tests that scored verbal memory.
Parkinson's disease is a common
neurologic disease in the elderly and may also cause dementia. Other
disorders that cause reversible delirium, which might account for
symptoms of dementia, include severe depression, drug abuse, or
certain medications. Less common conditions that cause dementia or
delirium are thyroid disease, severe vitamin B12 deficiency, blood
clots, hydrocephalus (excessive accumulation of spinal fluid in the
brain), syphilis, Huntington's disease, Creutzfeldt-Jakob disease, and
brain tumors. It is important that the physician recognize any
treatable conditions that might be causing symptoms or worsening
existing dementia caused by Alzheimer's or vascular abnormalities.
Psychological Testing. A
number of psychologic tests are used or being developed to assess
difficulties in attention, perception, memory, and problem-solving,
social, and language skills. Two commonly used tests that are very
useful are the Mini-Mental State Exam and the Mattis Dementia Rating
Scale. One small study reported that a so-called ten-point clock test
might help identify Alzheimer's patients. The patient is given a piece
of paper with a circle on it and first asked to write the numbers in
the face of a clock and then to show "10 minutes after 11."
The score is based on spacing between the numbers and the positions of
the hands. In the study, scoring 8 or less identified 71% of
Alzheimer's patients and correctly ruled out 82% of subjects without
the disease.
Electroencephalography.
Electroencephalography (EEG) traces brain-wave activity; in some
Alzheimer's patients this test reveals "slow waves."
Although other diseases may evidence similar abnormalities, EEG data
helps distinguish a potential Alzheimer's patient from a severely
depressed person, whose brain waves are normal.
Imaging Tests. Computerized
tomography (CT) or magnetic resonance imaging (MRI) scans can detect
the presence of multi-infarct dementia, stroke, blood clots, tumors,
or hydrocephalus. Vascular dementia is more likely if the onset of
dementia was abrupt and if the physician finds signs that
abnormalities exist in specific locations in the brain. MRI and PET
(positron emission tomography) scans and other advanced imaging
techniques may eventually be able to diagnosis Alzheimer's by
identifying changing blood flow patterns in the brain or predict
severity of existing disease.
Blood Test for ApoE4. A
blood test for the ApoE4 gene may be useful for confirming a diagnosis
in patients who have symptoms and other indications of Alzheimer's,
although finding evidence of ApoE4 is still not definitive. Other
blood tests may also rule out metabolic abnormalities.
Determining Severity of Existing Alzheimer's Disease
Once a diagnosis has been made,
some experts observe that certain factors at the time of diagnosis
indicate a higher risk for a more rapid decline: older age, being
male, high blood pressure, signs of loss of motor control and
coordination, tremor, social withdrawal, loss of appetite, and
problems walking.
WHAT ARE THE LATEST DRUG TREATMENTS FOR ALZHEIMER'S DISEASE?
Most drugs currently being used or
that are under investigation to treat Alzheimer's are aimed at slowing
progression; there is no cure. In fact, the improvements from some of
these drugs that are considered significant in studies may not even be
noticed by the patients or their families, but they may delay the need
for admission to nursing homes. Since nearly all the studies are
conducted on Alzheimer's patients in mild to moderate stages of the
disease, it is important to seek out clinical drug trials as soon as
Alzheimer's disease is diagnosed. Caregivers need to be available to
help patients comply with any experimental therapies.
Drugs that Protect the Cholinergic System
Drugs have been designed to
increase the amount of acetylcholine in the brain. Tacrine (THA or
Cognex) was the first of these drugs; donepezil (Aricept) is a more
recently approved one. Both drugs have modest benefits; patients
taking either drug usually show improvement in functioning and
behavior. Tacrine appears to have no effect on patients who carry the
ApoE4 gene; the presence of the gene does not affect donepezil.
Typical side effects of both drugs include nausea and diarrhea.
Donepezil appears to be better tolerated than tacrine, however, and
may be more effective in improving mental functioning and for more
people than tacrine. It also does not seem to be as harmful to the
liver as tacrine, which has been found to have severe effects in high
doses. Discontinuing the drug reverses liver problems. Tacrine needs
to be taken four times a day, but donepezil only needs to be taken
once a day. The benefits of these and other drugs that protect the
cholinergic system are far from dramatic, however; about half of
patients with mild to moderate disease show slight improvement, and
when they go off the drugs the deterioration continues. In fact,
tacrine's effect on the liver coupled with its few benefits makes it
unlikely to continue to be used very much.
Other cholinergic protective drugs
showing promise in trials include rivastigmine (Exelon), metrifonate,
and physostigmine (Synapton). In one 1998 study, rivastigmine improved
performance on a standard scoring system for Alzheimer's patients by
nearly five points, which were the best results at that time of any
similar drug. Improvement was seen even in patients with advanced
disease. Metrifonate is a long-acting drug that only needs to be taken
once a day; in trials it has improved mental functioning and behavior.
None of these newer drugs have the harmful effects on the liver that
tacrine has. One study on physostigmine also reported some improvement
or slowing of progression in mental decline but drop-rates were high
because of severe stomach and intestinal side effects. Many experts
have reservations about developing more drugs that affect the
cholinergic system because such drugs, at best, only slow progression
but will never cure the disease.
Anti-Inflammatory Drugs
Because the inflammatory process
may play a role in Alzheimer's, a number of anti-inflammatory drugs
are being studied. Nonsteroidal anti-inflammatory drugs (NSAIDs),
which include aspirin and ibuprofen, are under intense scrutiny.
Corticosteroids are the most often-prescribed anti-inflammatory drugs,
but long-term use may actually cause memory loss, and they do
not appear to effect prostaglandins, substances that appear to be
factors in the development of Alzheimer's and which are targets of
NSAIDs. Other anti-inflammatory agents being considered include
corticotropin releasing factor (CRF), thalidomide, and tenidap.
Estrogen and Other Hormones
Estrogen replacement therapy d is
being studied as a treatment for the disorder, but A 2000 study
reported that it had no effect on progress or symptoms of the disease
in 120 women with mild to moderate Alzheimer's disease. [ See
How Can Alzheimer's Be Prevented? above.] Results to date are
mixed on its effectiveness.
Antioxidants
One study found that two daily
doses of vitamin E (1000 IU each dose) or of selegiline (5 mg each)
delayed the progression of the disease or its symptoms. These two
agents appeared to provide equal benefits, but combining them did not
add any advantage.
Vitamin E. High doses of
vitamin E can cause nausea and cramping, and may increase the risk for
bleeding in patients with coagulation abnormalities or who are taking
blood-thinning drugs.
Selegiline. Selegiline,
also called deprenyl (Eldepryl), is a selective monoamine oxidase B
(MAO-B) inhibitor, a class of drugs that can cause a number of side
effects including a sudden drop in blood pressure upon standing,
drowsiness, dizziness, sexual dysfunction, and insomnia. The most
serious side effect is severe hypertension, which can be brought on by
eating certain foods having a high tyramine content. Such foods
include aged cheeses, most red wines, sauerkraut, vermouth, chicken
livers, dried meats and fish, canned figs, fava beans, and
concentrated yeast products. MAOIs can have serious interactions with
a number of drugs, including some common antidepressants and
over-the-counter cough medication and decongestants.
Ginkgo Biloba. Ginkgo
biloba is a common herb that has antioxidant properties and appears to
increase blood flow to the brain. New studies have suggested that
ginkgo biloba may slightly improve the memory of Alzheimer's patients,
although it is not clear if the improvement is significant. Small
studies have indicated that the effects in the brain of a dried-leaf
ginkgo extract manufactured in Germany (where standards have been
established) were comparable to those of tacrine and donepezil and
that gingko has only minimal side effects. The herb is available over
the counter, but there are no standards in the US to regulate its
quality or effectiveness. No one should take this herb for Alzheimer's
disease without consulting a physician; there is a small risk for
bleeding, which may increase in combination with other medications,
such as warfarin or high-doses of vitamin E.
Investigative Agents and
Procedures
Nerve-Growth Factors. Nerve
growth factors are agents under investigation. One, AIT-082, is
showing promise in early trials.
Nicotine. Nicotine acts on
receptors in the cholinergic system in the brain that are depleted by
the Alzheimer's disease process. Some studies have suggested that
nicotine may protect nerve cells and help prevent the formation of
beta amyloid. Nicotine itself, unlike smoking, does not appear to
cause cancer. In a 1999 study, patients with mild to moderate
Alzheimer's experienced improved attention after four weeks on the
nicotine patch, although it did not seem to have any effect on other
aspects of the disease, including memory and behavior. Researchers are
investigating a number of nicotine-like drugs that may protect nerve
cells. The effects of smoking itself on Alzheimer's have been unclear.
In any case, smoking is never recommended for either prevention or
treatment.
Other Drugs. Propentofylline
has nerve-protective properties and may enhance metabolism in the
brain. The drug is showing promise in improving symptoms and slowing
disease progression. Alzheimer's disease is associated with insulin
resistance, a condition in which insulin, a hormone essential in the
metabolism of sugar, becomes ineffective. Some research has suggested
that increasing insulin levels may help improve memory. Researchers
are investigating vaccines made from beta amyloid that may some day
help prevent or slow progression of Alzheimer's. Researchers hope that
the vaccine will produce antibodies, proteins in the blood that attack
foreign matter, which would attach to beta amyloid molecules. The
antibodies would alert the immune system to attack and destroy the
beta amyloid molecules considered to be the building blocks of the
brain deposits. This study is in its infancy and requires more
investigation, but researchers believe that this vaccine will show
similar benefits in Alzheimer's patients. Studies on mice are
promising, but even if effective, use of such vaccines in humans is
years away. In Japan, researchers are working on an extract of the
guarana tree that appears to protect cells from the harmful effects of
beta amyloid. There have been claims that the Chinese herbal medicine
HupA helps prevent brain cell death, but no studies have confirmed
this.
Investigative Procedures
Transcutaneous electrical nerve
stimulation (TENS) is a well-known treatment that uses low-level
electrical pulses to suppress chronic pain; patients are barely aware
of the sensation. Some interesting studies observed that TENS produced
improvement in memory and functioning in Alzheimer's patients. An
experimental surgical technique being tested on animals employs small
plastic implants in the brain that release a powerful nerve growth
factor that may prevent nerve-cell death.
Treating Symptoms of Alzheimer's
Depression. Major
depression with dementia that occurs in elderly people may be an early
sign of Alzheimer's; in such cases, it precedes Alzheimer's by two
years or less. Some experts believe that disease progression may even
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