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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
be delayed by treating such people with both an antidepressant and a
drug, such as donepezil, currently used for Alzheimer's. The
antidepressants known as selective serotonin reuptake inhibitors
(SSRIs) may be particularly effective in relieving depression,
irritability, and restlessness associated with Alzheimer's.
Apathy. Depression is often
confused with apathy, which according to one study is more common than
depression in Alzheimer's patients and responds to stimulants, such as
methylphenidate (Ritalin), rather than antidepressants. An apathetic
patient lacks emotions, motivation, interest, and enthusiasm while a
depressed patient is generally very sad, tearful, and hopeless.
Wandering, Irritability, and
Aggression. Verbally or physically aggressive behavior and
wandering have been traditionally treated with standard antipsychotic
drugs, such as haloperidol (Haldol). Studies indicate that, although
effective, haloperidol has very severe side effects that impair motor
control and coordination. Newer, so-called atypical antipsychotics,
including risperidone (Risperdal) and olanzapine (Zyprexa), appear to
significantly decrease symptoms of psychosis and aggression while
posing a very low risk for severe side effects. Carbamazepine, an
anti-seizure drug, may also be effective for agitation and dementia.
Disturbed Sleep. Alzheimer's
patients commonly experience disturbances in their sleep/wake cycles.
Studies suggest that exposure to brighter-than-normal artificial light
during the day can reset these cycles and prevent nighttime wandering
and sleeplessness. This treatment is not effective for visually
impaired patients. Trials on melatonin, a natural hormone that helps
trigger sleep at night, are in progress.
WHAT ARE THE PHASES OF ALZHEIMER'S DISEASE AND ITS MANAGEMENT?
The remaining life span of an
Alzheimer's victim is generally reduced, although a patient may live
anywhere from three to twenty years after diagnosis. The final phase
of the disease may last from a few months to several years, during
which time the patient becomes increasingly immobile and
dysfunctional. Caregivers should understand the phases of this illness
in order to help determine their own capacities for dealing with this
painfully sad disease.
Home Treatment in Early Stages
Telling the Patient. Often
physicians will not tell patients that they have Alzheimer's. Studies
indicate that progression may be slowed down with intellectual effort
and most investigative drug trials are performed in early stages. If
an Alzheimer's patient expresses a need to know the truth, it should
be disclosed. Both the caregiver and the patient can then begin to
address issues of this disabling disease that can be controlled, such
as access to support groups and drug research.
Mood and Emotional Behavior. Alzheimer's
patients display abrupt mood swings and can become aggressive and
angry. Some of this erratic behavior is caused by chemical changes in
the brain. But certainly, it can also be attributed to the terrible
and real experience of losing the knowledge and understanding of one's
surroundings, causing fear and frustration that they can no longer
express verbally. It is important for the caregiver to control the
environment by keeping distractions and noise at a minimum and to
speak clearly. Most experts recommend speaking slowly to an
Alzheimer's patient, but some caregivers suggest that Alzheimer's
patients respond better to clear, quickly spoken sentences they can
more easily remember. Being offered too many choices (such as clothing
selection) or activities that are normal, but may feel threatening
(people talking outside the room) can trigger agitation and
aggression. Offering a distraction, such as a snack or car ride, in
response to shouting or other disruptive behavior may be helpful. One
study suggests that simply touching and talking may also help to
relieve anxiety and aggression. Caregivers should maintain as natural
an attitude as possible; many Alzheimer's patients are highly
sensitive to the caregiver's underlying emotions and react negatively
to signals of patronization, anger, and frustration. Although much
attention is given to the negative emotions of Alzheimer's patients,
some become extremely gentle, retaining an ability to laugh at
themselves or appreciate simple visual jokes even after their verbal
abilities have disappeared. Some appear not unhappy, but to be in a
drug-like or "mystical" state focusing on the present
experience as their past and future slip away. Encouraging this state
may bring some comfort to a caregiver. One study found that anxiety
and frustration may be relieved by watching movies or videos of family
members and events from the patient's past. Alzheimer's patients may
be delusional at times and must be reassured and redirected to other
activities. There is no single Alzheimer's personality, just as there
is no single human personality. Each patient must be treated as the
individual he or she continues to be even after the social self has
vanished.
Appearance and Cleanliness. For
the caregiver, grooming the Alzheimer's patient may be an alienating
experience. For one thing, many patients resist bathing or taking a
shower. Some spouses find that showering with their afflicted mate can
solve the problem for a while. Often the Alzheimer's patient loses the
sense of color and design and will put on odd or mismatched clothing.
This may be very frustrating to a loved one, particularly since
(certainly in the beginning) embarrassment is a common and painful
emotion experienced by the caregiver. It is important to maintain a
sense of humor and perspective and to learn which battles are worth
fighting and which ones are best abandoned.
Driving and Wandering. As
soon as Alzheimer's is diagnosed, the patient should be prevented from
driving. A Swedish study found that over half of elderly people
involved in fatal accidents had some degree of neurologic damage.
Another potentially dangerous trait is the Alzheimer's patient's
tendency to wander. At the point the patient develops this tendency,
many caregivers feel it is time to seek out nursing homes or other
protective institutions for their loved ones. For those who remain at
home, locks should be installed outside the door, which the
caregiver can open, but the patient cannot. Alarms might be installed
at exits. A daily exercise program should be implemented, which may
help tire the patient out; one study showed that walking 30 minutes,
three times a day also improved communication. A program offered by
the Alzheimer's Association provides a patient with an identification
bracelet with the Safe Return 800 number, clothing labels, and an ID
number. Personal and medical information about the patient and
critical phone numbers are stored in a central database. If a patient
is discovered missing, the police should be called first. Next, the
caregiver calls Safe Return and gives them the patient's ID number and
any appropriate information. An alert is then sent to law enforcement
agencies nationwide.
Sexuality. In many cases,
the Alzheimer's patient becomes uninhibited sexually; at the same
time, the patient's physical deterioration and receding capacity to
recognize the spouse as a known and loved individual can make sexual
activity despairing and repellent for the caregiving spouse. Other
patients may lose interest in sex. If sexual issues are a problem,
they should be discussed openly with the physician, and ways should be
found to maintain non-sexual physical affection that can bring comfort
to both the patient and the spouse.
Home Treatment During Later Stages
The Alzheimer's patient needs
24-hour a day attention. Even if the caregiver has the resources to
keep the Alzheimer's patient at home during later stages of the
disease, outside help is still essential.
Incontinence. An
Alzheimer's patient's incontinence is generally devastating to the
caregiver and a primary reason why many caregivers decide to seek
nursing home placement when the patient reaches this stage. When the
patient first shows signs of incontinence, the doctor should ascertain
that it is not caused by an infection. Urinary incontinence may be
controlled for some time by trying to monitor times of liquid intake,
feeding, and urinating. Once a schedule has been established, the
caregiver may be able to anticipate incontinent episodes and get the
patient to the toilet before they occur.
Immobility and Pain. As the
disease progresses, Alzheimer's victims become immobile, literally
forgetting how to move. Eventually, they become almost entirely
wheelchair-bound or bedridden. Bedsores can be a major problem. Sheets
must be kept clean, dry, and free of food. The patient's skin should
be washed frequently, gently blotted thoroughly dry and moisturizers
applied. The patient should be moved every two hours and the feet kept
raised with pillows or pads. Exercises should be administered to the
legs and arms to keep them flexible. One expert reported that 62% of
patients with mild to moderate dementia report pain, usually in
joints, yet very few patients in late-stage dementia receive pain
medication, even though there is no evidence that they are not
experiencing the same pain.
Eating Problems. Weight
loss and the gradual inability to swallow are two major related
problems in late-stage Alzheimer's and are associated with an
increased risk of death. Weight gain, however, is linked to a lower
risk of dying. The patient can be fed through a feeding syringe, or
the caregiver can encourage chewing action by pushing gently on the
bottom of the patient's chin and on the lips. The caregiver should
offer the patient foods of different consistency and flavor in case
the patient can handle one form better than another. Because choking
is a danger, the caregiver should learn to administer the Heimlich
maneuver, which may be taught by the local Red Cross. Dehydration can
also become a problem; it is essential to encourage fluid intake equal
to eight glasses of water daily. It should be noted that coffee and
tea are diuretics and will deplete fluid.
Care for the Caregiver
It is important for the caregivers
to receive counseling and support for themselves as well. The most
common difficulty reported by caregiving spouses from 15 different
European countries was the loss of communication with the partner.
According to one study, when caregivers took part in counseling and
support programs, institutionalization of the patient was delayed by a
year. Alzheimer's is a particularly devastating disease; the patient's
family endures two separate losses and grieves twice; first, for the
disappearance of the personality they recognize, and finally, for the
actual death of the person. No one should endure such agony alone. Few
diseases disrupt a patient and his or her family so completely or for
so long a period of time as Alzheimer's. The disease may even have
negative effects on the immune systems of the patients' partners.
Dealing with the Alzheimer's patient throughout the course of the
disease is like Alice's fall down the rabbit hole into Wonderland. No
sooner has the caregiver grappled with one set of problems, then the
patient's further deterioration creates new and more intractable ones.
Often, caregivers themselves begin to show signs of mental disorder or
ill health. Depression, empathy, exhaustion, guilt, and anger can play
havoc with a normally healthy individual faced with the care of a
loved one suffering from Alzheimer's. Often, adult children find they
have to care for the healthy parent as well as the parent affected by
Alzheimer's, particularly if the marriage was one in which the healthy
spouse was overly dependent on the other. Many books and pamphlets
seem to presume the possession of almost superhuman mental health and
physical strength on the part of caregivers. This is rarely the case.
The care-giving spouse is usually elderly, often frail. Children are
likely to be grown-up and may live far away. Forms of abuse, including
neglect, physical or emotional attacks, and financial exploitation,
are common with Alzheimer's patients. Although 96% of caregivers
interviewed in a survey stress the need for help, only 2% of
Alzheimer's families receive outside support services.
Nursing Homes and Other Outside ServicesA point comes when the most devoted caregiver will probably need to institutionalize the Alzheimer's patient. That point is determined not only by the caregiver's emotional endurance, but also by his or her physical strength and stamina, as an Alzheimer's adult typically takes on the random, undisciplined behavior of a very young child. Financial considerations in finding a nursing home are often paramount, but the kind of care is equally important. Although fully half of all nursing home patients are victims of Alzheimer's, not all nursing homes have programs specifically designed for them. Some institutions may claim that they do, but often they simply group patients together without offering any special programs. If a caregiver manages to find a facility that offers good services, it may be located far from home, making visits difficult. The caregiver must then decide whether superior care at a distant institution is worth seeing the patient less frequently, still one more painful issue. A hospice program, if it is available, offers a more humane and compassionate option than the nursing home or hospital during the final months of a terminal illness. Medicare coverage now includes hospice care for Alzheimer's patients.
Well-Connected reports are
written and updated by experienced medical writers and reviewed and
edited by the in-house editors and a board of physicians at Harvard
Medical School and Massachusetts General Hospital. The reports are
distinguished from other information sources available to patients
and health care consumers by their quality, detail of information,
and currency. These reports are not intended as a substitute for
medical professional help or advice but are to be used only as an
aid in understanding current medical knowledge. A physician should
always be consulted for any health problem or medical condition. The
reports may not be copied without the express permission of the
publisher.
Board of Editors
Harvey Simon, MD,
Editor-in-Chief, Massachusetts Institute of Technology; Physician,
Massachusetts
General Hospital
Stephen A. Cannistra, MD,
Oncology, Associate Professor of Medicine, Harvard Medical School;
irector, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center
Masha J. Etkin, MD, PhD,
Gynecology, Harvard Medical School; Physician, Massachusetts
General Hospital
John E. Godine, MD, PhD,
Metabolism, Harvard Medical School; Associate Physician,
Massachusetts
General Hospital
Daniel Heller, MD, Pediatrics,
Harvard Medical School; Associate Pediatrician, Massachusetts
General Hospital; Active Staff, Children's Hospital
Paul C. Shellito, MD, Surgery,
Harvard Medical School; Associate Visiting Surgeon, Massachusetts
General Hospital
Theodore A. Stern, MD,
Psychiatry, Harvard Medical School; Psychiatrist and Chief,
Psychiatric
Consultation Service, Massachusetts General Hospital
Carol Peckham, Editorial
Director
Cynthia Chevins, Publisher Lea Kling, Update Editor ฉ 2000 Nidus Information
Services, Inc., 41 East 11th Street, 11th Floor, New York, NY
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