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
Alzheimer's disease is
now the fourth leading cause of death in adults. Almost 4 million Americans, and
8 million more worldwide, have it. Unless effective methods for prevention and
treatment are developed, Alzheimer's disease will reach epidemic proportions,
afflicting an estimated 22 million people worldwide by 2025.
Age is the biggest risk
factor for Alzheimer's. The number of cases of Alzheimer's doubles every five
years in people over 65 until by age 85 almost half of all people are afflicted.
People with a family
history of the disease are at higher than average risk for Alzheimer's. [
See Genetic Factors under What Causes Alzheimer's Disease.]
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
studies have been conducted on differences among population groups.
African Americans and Hispanics may have a higher risk than Caucasian Americans.
Alzheimer's disease occurs less frequently in the Native American Crees and Cherokees and in Asians than in the general American population.
Genetic factors are at
work in all groups but the same genes may have different effects depending on
the ethnic population. Environmental factors also most likely play a role. For
example, a study of Japanese men showed that their risk increased if they
emigrated to America. And, the disease is rare in West Africa although African
Americans share the same or higher risk with Caucasians Americans.
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.)
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.
Researchers are finding
specific biologic factors involved with Alzheimer's disease. Various
environmental and genetic players appear to contribute to or trigger the process
by which these factors destroy nerve cells leading to this disease.
abnormalities occur in brains of people affected by Alzheimer's:
Twisted nerve cell fibers, known as neurofibrillary tangles.
A sticky protein called beta amyloid .
Other factors also play
The Effects of
Neurofibrillary Tangles and Beta Amyloid in Alzheimer's. These biologic
factors appear to be involved in the development Alzheimer's disease in the
Neurofibrillary tangles 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 the tau protein, which in its healthy version helps in the assembly of the microtubule structure. The defective tau, however, appears to block the actions of the normal version.
Beta Amyloid (also called A beta) is the second significant finding. This insoluble protein accumulates and forms sticky patches called neuritic plaque, which are found surrounded by the debris of dying nerve cells in the brains of Alzheimer's victims.
Beta amyloid is a fragment of amyloid precursor protein (APP). APP is actually a large nerve-protecting protein that, in Alzheimer's, appears to be snipped into beta amyloid pieces by enzymes, particularly those called gamma-secretases. This process is controlled by factors called presenilin proteins. (Genetic abnormalities that affect APP or presenilin proteins occur in some inherited cases of early onset Alzheimer's.)
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.
Researchers have now identified other important proteins in the areas of the
brain affected by Alzheimer's disease.
ERAB (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 beta amyloid.
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.
Major research targets
in Alzheimer's are the factors responsible for beta amyloid build-up and
concentration in certain people and not in others. Genetic factors are believed
to play a role in many cases.
The ApoE Gene and
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:
ApoE4. Studies have reported the greatest deposits of beta amyloid in people with ApoE4, which is now believed to be a major risk factor for late-onset Alzheimer's. Some experts theorize that one function of the ApoE protein is to remove beta amyloid and that the ApoE4 variant does so less efficiently than other ApoE genetic types. (ApoE4 has been studied for years as a risk factor for coronary artery disease, although the relationship between heart disease and Alzheimer's is uncertain. Some studies have found a higher risk for heart disease in people with Alzheimer's disease who carry two copies of the ApoE4 genotype.)
ApoE3. Fewer beta amyloid deposits have been observed in people with the ApoE3 gene. Some research indicates that ApoE3 in combination with ApoE4 may induce changes in beta amyloid that trigger the inflammatory response in the brain.
ApoE2. The fewest deposits have been observed in people with ApoE2, which may actually be protective.
People inherit a copy
of one type from each parent, but 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:
People without ApoE4 have an estimated risk for developing Alzheimer’s by age 85 of between 9% and 20%.
In people 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 suspects
that some specific variation of the ApoE4 gene may be the actual culprit, since
many people carry the ApoE4 and exhibit no signs of Alzheimer's.
Factors in Late-Onset Alzheimer's. Most people with late-onset Alzheimer’s
disease 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. Some under investigation are the following:
An apolipoprotein called Apo(a) may be involved in amplifying the effects of ApoE4.
Researchers have detected mutations in the proteins amyloid precursor protein (APP) and ubiquitin-B (Ubi-B), which may account for some cases of late- and early-onset Alzheimer's. Such mutations are not inherited, however, but appear to be genetic mistakes that occur during transcription, the coding process in which DNA establishes the pattern for the production of its proteins and other molecules.
One 2000 study of an Arab community with a high incidence of Alzheimer's has found evidence for a recessive gene, which means that both parents must carry it in order for the disease to be passed on. (Surprisingly, the ApoE4 gene showed up in this population at the lowest levels on record.)
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.
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 accelerate beta amyloid plaque formation and apoptosis, a natural process by which cells self-destruct.
Genetic mutations in the genes that control amyloid precursor protein (APP) are also being targeted as causes of early-onset Alzheimer's. The genetic disease Down's syndrome, for example, overproduces beta-amyloid precursor protein (APP), the source of beta amyloid, and almost always leads to early Alzheimer's. Other APP mutations are being identified.
Researchers are also
attempting to discover why beta amyloid is so toxic to nerve cells. Some
researchers are focusing on two processes in the body that may be involved with
Alzheimer's disease: oxidation and the inflammatory process . One
scenario for their role in Alzheimer's is as follows:
As beta amyloid breaks down it releases unstable chemicals called oxygen-free radicals. Once released, oxygen-free radicals bind to other molecules through a process called oxidation.
Oxidation is the result of many common chemical processes in the body, but in certain circumstances it can trigger harmful events, including even affecting genetic material in cells (its DNA). 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 result of oxidation is the so-called inflammatory response, in which the immune system produces factors intended to fight harmful agents or to manage injuries. In excess, however, these factors can actually damage the body's own cells themselves.
Inflammatory factors of specific interest in Alzheimer's research are the enzyme cyclooxygenase (COX) and its products called prostaglandins. Excess amounts of these factors may increase levels of glutamate.
Glutamate is an amino acid that excites nerves and, when overproduced, is a powerful nerve-cell killer.
Also of interest to
researchers are the environmental factors (eg, viruses, metals, or dietary
factors) that may trigger oxidation, inflammation, and the disease process,
particularly in people with genetic susceptibility to Alzheimer's.
Virus and Bacteria.
Slow, infectious viruses cause a number of other degenerative neurologic
diseases, such as kuru and Creutzfeldt-Jakob disease. Although no specific virus
has been linked to Alzheimer's, some researchers theorize that people with a
genetic susceptibility to Alzheimer's may be vulnerable to the actions of
certain viruses, particularly under circumstances when the immune system may be
weakened. Studies that help support this theory are as follows:
In one study the risk for Alzheimer's was very high in people with both ApoE4 and evidence of herpesvirus (HSV) 1 (a form of herpes that can invade the central nervous system). The risk was normal in those with only one of these factors. Furthermore, research is finding that parts of the HSV1 protein strongly resemble beta amyloid and, in laboratory studies, even have been observed to kill brain cells and develop sticky plagues.
Another suspect is Chlamydia pneumoniae , a bacterium that causes respiratory infections. Researchers have found evidence of it 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.)
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.
Fields. Some 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.
Some studies have found an association between serious head injuries in
early adulthood and the development of Alzheimer's. It is not yet known if such
injuries directly cause Alzheimer's or simply accelerate the disease in people
who are already susceptible to it.
Malnutrition. According to one study, poor nutrition in childhood may render
the brain more susceptible to mental impairments later in life, including
Vitamin B Deficiencies. Some studies suggest that deficiencies of the B vitamins B12 and folate may be a risk factor for Alzheimer's. Such vitamins are related to nerve protection.
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.
Estrogen and Hormone
Replacement Therapy. Estrogen, the primary female hormone, appears to have
properties that protect against the memory loss and lower mental functioning
associated with normal aging. Among its effects on the brain are the following:
Estrogen, the primary
female hormone, appears to have properties that protect against the memory loss
and lower mental functioning associated with normal aging. Among its effects on
the brain are the following:
Laboratory studies suggested that estrogen may help block production of beta-amyloid, the source of the sticky plaques found in Alzheimer's brains.
Estrogen may trigger the temporary growth of nerve pathways in the memory portion of the brain.
Estrogen may stimulate production of the neurotransmitters acetylcholine and serotonin, which are depleted in Alzheimer's patients.
Estrogen also appears to smooth, relax, and open blood vessels, which may help blood flow in the brain.
Estrogen is also an antioxidant. That is, it helps clean up free-oxygen radicals, the unstable particles thought to play a role in Alzheimer's.
Positive Benefits on the Brain. Researchers, then, have been investigating
whether hormone replacement therapy can actually help prevent Alzheimer's
disease in women after menopause. The following are some results of studies
weighing in for the brain-protective benefits of hormone replacement therapy
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.
Five studies suggested a 40% to 60% reduction in the risk of Alzheimer's in women who have taken supplemental hormones. Even brief exposure was associated with a delay in Alzheimer's onset. These were population studies, however, and not controlled trials
One 2000 study reported fewer age-related changes in the brains of people on estrogen compared to those not taking it. To complicate matters, however, another 2000 study reported that women taking HRT tended to have signs of central brain atrophy (reduction in size) compared to those not taking estrogen. The greatest harm, however, was observed in current users compared to past users or non-users. And, past users performed best on mental exams and nonusers performed worse.
Studies Showing No
or Negative Benefits on the Brain. Women who take HRT, however, tend to be
healthier and better educated to begin with. Some studies have reported no
One study of young women who had hysterectomies found no association between natural estrogen levels and mental functioning. Another found no association between differing levels of natural estrogen levels and better or worse mental functioning in older women.
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.
One 2000 study on Japanese women found modest benefits from unopposed estrogen therapy but not greater mental decline with combined therapies containing progestin and estrogen.
A 2001 study reported no association with a lower risk for Alzheimer's disease in women taking either estrogen or estrogen-progestin combination therapies.
Estrogen replacement therapy is being investigated as a treatment for Alzheimer's, but too date it has no had no benefits on improving symptoms or slowing progression. Such studies do not prove, however, that estrogen would not be protective against the disease in the first place. And, some experts believe that the negative effects were due to a devastating effect of sudden estrogen exposure on brains that had been estrogen deprived for years.
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. [ For more information, see the Well-Connected
Report, Menopause, Estrogen Loss, and Their Treatments.]
One small study suggested that 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.
Anti-Inflammatory Drugs. Common nonsteroidal anti-inflammatory drugs
(NSAIDs), such as aspirin, ibuprofen (Advil, Motrin), and naproxyn, have
properties that block specific factors in the inflammatory response believed to
play a major role in nerve-cell degeneration. Long-term studies are reporting
that regular use of even low-dose NSAIDs may be protective against Alzheimer's.
(Note: acetaminophen (Tylenol) is not an anti-inflammatory drug and has no
effect on this disease.)
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.
Special Warning on NSAIDs
Long-term use of NSAIDs can cause bleeding and ulcers in the gastrointestinal tract. Combinations of NSAIDs and stomach-protective agents, such as diclofenac and misoprostol (Arthrotec), may reduce this risk considerably. Still, no one should take NSAIDs for protection against Alzheimer's disease without the recommendation of a physician.
considerable interest are 1999 and 2000 studies reporting a significantly lower
risk (60% to 73%) for Alzheimer's disease in people who were taking cholesterol
lowering drugs known as statins. The most positive results to date are with
lovastatin (Mevacor) and pravastatin (Pravachol). Oddly, in one study, patients
taking simvastatin (Zocor), which is very similar to the others, did not appear
to have a lower risk for Alzheimer's compared to the other two.
Some small studies have reported some protection from H2 blockers, common
drugs used to treat heartburn. They include famotidine (Pepcid AC), cimetidine
(Tagamet), ranitidine (Zantac), and nizatidine (Axid). (It should be noted that
omeprazole, an agent called a proton pump inhibitor that is also used to treat
heartburn, has been associated with a higher risk for Alzheimer's.) More
research is needed on these agents.
Fats and Oils.
Some population studies have reported an association between low-fat diets
and a lower incidence in Alzheimer's. For example, in China and Nigeria, where
fat intake is low, the risk of developing Alzheimer's is 1% at age of 65
compared to 5% in the US. Conversely, a study in the Netherlands reported an
association between dementia and diets high in total fat, saturated fat, and
cholesterol. A high-fat diet in people who carry the ApoE4 gene may confer a
particularly high risk. In one 2000 study of Americans between the ages of 40
and 50, those who carried the ApoE4 gene and whose diet consisted of 40% fat
calories had 29 times the risk for Alzheimer's compared to non-ApoE4 carriers on
the same high-fat diet. Some dietary tips concerning fat intake are as follows:
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.
The recommended dietary goal is to limit total fat intake to 30% or fewer calories from fat. [ For more information, see the Well-Connected Report, Heart Healthy Diet.]
Supplements and Foods. Much research on Alzheimer's disease has indicated
that oxidation (release of damaging unstable particles) may play an important
role in the disease process. Some reports have suggested, then, that dietary
antioxidants, such as vitamins C and E, selenium and other food
chemicals, may be protective against mental decline.
Vitamin E and vitamin C are important antioxidants, but studies have not provided any evidence that they can prevent Alzheimer's. In one study, a combination of these supplements was associated with a lower risk for dementia in older people (although not of Alzheimer's itself).
According to several studies, eating plenty of darkly colored fruits and vegetables may slow brain aging. Of interest was a 1999 study on animals, in which extracts taken from blueberries and strawberries actually reversed age-related decline in brain function. Blueberries were the most effective. Dark-colored fruits and vegetables are recommended in any case for good health.
Some studies on wine have reported a lower risk but they have not been consistent. One suggested that wine may have some protective properties for noncarriers of ApoE4 but actually increase the risk for carriers of the gene.
Soy has estrogen-like properties and might be protective. Of some concern, however, was a study reporting greater decline in mental function among older people who had a high intake of soy. Some experts suggest that the plant estrogens in soy may interfere with natural protective estrogens in the brain. This was one small study, however, and more are needed to confirm these results.)
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. Educational Levels and Alzheimer'sA 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.
Concluding that education helps protect against Alzheimer's, however, is under
An ongoing study of nuns found 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 speculate that learning itself may stimulate more neurons to grow and thus create a larger reserve in the brain so that it takes longer for brain cells to be destroyed. This study was very small, however, and when cases outside the study were assessed using the same criteria, the same results did not occur.
A 2000 study found no differences in educational levels between patients with Alzheimer's and those without dementia.
Some experts believe that the link between lower education levels and Alzheimer's are due to their common association with certain environmental assaults, such as high-fat diets and toxins, which are observed in lower socioeconomic populations.
A 2001 study reported
that older people who regularly exercised had lower rates of mental
deterioration, Alzheimer's and dementia of any type.Investigative VaccinesOf
great interest is the investigation of vaccines that use antibodies to attach to
beta amyloid molecules. Antibodies are immune factors that target and attack
specific molecular invaders in the body. Researchers hope that these antibodies
will alert the immune system to attack and destroy the beta amyloid molecules,
which are considered to be the building blocks of the nerve-destroying deposits
in Alzheimer's brains. Animal studies are promising, and clinical trials on
humans are now underway.What Are the Symptoms of Alzheimer’s Disease?Mild
impairment in thinking is now believed to be a significant sign of early-stage
Alzheimer's in older people. The early symptoms of Alzheimer’s disease may be
overlooked because they resemble signs of natural aging. These symptoms include:
Loss of concentration.
Unexplained weight loss.
Motor problems, including mild difficulties in walking.
In healthy individuals,
similar symptoms can result from a number of common aging problems:
Grief or depression.
Vision or hearing loss.
The use of alcohol or certain medications.
Simply the burden of too many details to remember at once.
DIFFERENCES BETWEEN NORMAL SIGNS OF AGING AND DEMENTIA
Early Signs of Alzheimer’s
Memory And Concentration
Memory And Concentration
Periodic minor memory lapses or forgetfulness of part of an experience.
Occasional lapses in attention or lapses in attention or concentration.
Misplacement of important items.
Confusion about how to perform simple tasks.
Trouble with simple arithmetic problems.
Difficulty making routine decisions.
Confusion about month or season.
Mood And Behavior
Mood And Behavior
Temporary sadness or anxiety based on appropriate and specific cause.
Increasingly cautious behavior.
Unpredictable mood changes.
Increasing loss of outside interests.
Depression, anger, or confusion in response to change.
Denial of symptoms.
Later Signs of Alzheimer’s Disease
Language And Speech.
Language And Speech.
Unimpaired language skills.
Difficulty completing sentences or finding the right words.
Inability to understand the meaning of words.
Reduced and/or irrelevant conversation.
Increasing caution in movement.
Slower reaction times.
Visibly impaired movement or coordination, including slowing of movements, halting gait, and reduced sense of balance.
Source: Alzheimer's Disease: Early Warning Signs and Diagnostic Resources. The Junior League of NYC, Inc, 1988
Many medical and
psychological conditions can also cause Alzheimer's symptoms. About 20% of
suspected Alzheimer’s cases, in fact, turn out to be some other disorder, half
of which are potentially treatable or controllable. [ See How Is
Alzheimer’s Disease Diagnosed?, below.]
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. There are now three known major causes
for dementia in the elderly:
Vascular dementia (abnormalities in the vessels that carry blood to the brain).
Lewy bodies variant (LBV), also called dementia with Lewy bodies.
As yet, it is very
difficult to differentiate among these dementias. Other diseases, many common in
the elderly, can also cause symptoms that resemble Alzheimer's disease.
Lewy Bodies Variant.
Lewy bodies are abnormalities found in the brains of patients with both
Parkinson's disease and Alzheimer's. They can also be present in the absence of
either disease; in such cases, the condition is called Lewy bodies variant
(LBV). In all cases, the presence of Lewy bodies is highly associated with
dementia. LBV was defined in 1997 and some experts believe it may be responsible
for about 20% of people who have been diagnosed with Alzheimer's. One study
reported that patients with LBV may be more likely than Alzheimer's patients to
have hallucinations and delusions early on, to walk with a stoop, and to perform
better on verbal recall but less well organizing objects.
Vascular dementia is primarily caused by wither multi-infarct dementia
(multiple small strokes) or Binswanger's disease (which affects tiny arteries in
the midbrain). One analysis of a number of studies suggests that patients with
vascular dementia have 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. In general, dementia
caused by stroke is rarely reversible.
Impairment. 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.
that Cause Similar Symptoms. A number of conditions, including many
medications, can produce symptoms similar to Alzheimer's:
Parkinson’s disease. This is a common neurologic disease in the elderly and may cause dementia. It often occurs along with Alzheimer's, which confuses the diagnosis of each. [ See Well-Connected report Parkinson's Disease.]
Severe vitamin B12 deficiency.
Hydrocephalus (excessive accumulation of spinal fluid in the brain).
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.
Testing. A number of psychologic tests are used or being developed to assess
difficulties in attention, perception, and memory and problem-solving, social,
and language skills.
Two commonly used tests that are very useful in identifying individuals who may be at risk for Alzheimer's are the Mini-Mental State Exam (MMSE) and the Mattis Dementia Rating Scale. One study suggests that missing recall items on the MMSE in combination with a cluster of other symptoms, including difficulty in calculation, repetition, getting lost while driving, forgetting relatives' names, and poor judgment, may provide an accurate way to diagnose Alzheimer's at an early stage.
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.
(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.
(CT), magnetic resonance imaging (MRI), and positron-emission tomographic (PET)
are sometimes used in confirming a diagnosis of Alzheimer's in patients with
other indications. Positron-emission tomographic (PET) is a more advanced
technique that can show brain activity and may eventually detect early
Alzheimer's before symptoms occur. For example, in one study PET scans revealed
higher brain activity in older APOE4 carriers who were undergoing memory tasks
than noncarying peers. These results suggest that the genetically susceptible
people find such tasks more demanding. (Blood tests alone for ApoE4 gene are not
useful for diagnosing Alzheimer's.) Such scans can also be used to detect the
presence or rule out multi-infarct dementia, stroke, blood clots, tumors, or
High blood levels of a
substance called p97 may prove to help detect the presence of Alzheimer's, but
more research is needed. Other blood tests may rule out metabolic abnormalities.
Of interest was a study
in which individuals with mild mental impairments were given a "scratch and
sniff" test and asked to distinguish between about 40 different odors. About 40%
of those who had a significantly difficult time distinguishing between smells
went on to develop Alzheimer's over a 20 month period. (Most of them believed
they had a good sense of smell). None of the people who could distinguish odors
developed the 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:
The presence of high blood pressure.
Signs of loss of motor control and coordination.
Loss of appetite.
Accompanying sensory problems, such as hearing loss and a decline in reading ability.
General physical debility.
Most drugs currently
being used or that are under investigation to treat Alzheimer's are aimed at
slowing progression. To date, none are cures. In fact, the improvements from
some of these drugs may be so modest that even the patients and their families
are not aware of them. Even in these cases, however, the drugs 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
The standard drugs used
for Alzheimer's are designed to protect the cholinergic system, which is
essential for memory and learning and is progressively destroyed in Alzheimer’s.
The benefits of these drugs 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. All drugs have gastrointestinal side
effects, including nausea. Many experts have reservations about developing more
drugs that affect the cholinergic system since, at best, they only slow
progression, but will never cure the disease.
Tacrine. Tacrine (THA or Cognex) was the first cholinergic protective drug. It needs to be taken four times a day, has only modest benefits, and has no benefits for patients who carry the ApoE4 gene. In high doses, it can also injure the liver. In general, newer cholinergic protective drugs that do not pose as great a risk for the liver are now used for Alzheimer's.
Donepezil. Donepezil (Aricept) is one of the drugs of choice for Alzheimer's in the US. It is taken once a day and has only modest benefits but it does help slow loss of function and reduce caregiver burden. It works equally in patients with or without ApoE4.
Rivastigmine. Rivastigmine (Exelon) is the other drug of choice in the US. It is taken twice a day. This agent may be particularly beneficial for patients with rapidly progressing disease. Improvements with this drug have been observed even in patients with advanced disease. (Rivastigmine may cause significantly more side effects than donepezil, including nausea, vomiting, and headache.) As with all anticholinergics, the drug is not a cure.
Metrifonate. Metrifonate is taken once daily and has improved mental and physical functioning as well as behavior in patients with mild to moderate Alzheimer's.
Galantamine (Reminyl). Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. [See also Nicotine and Related Agents below.] Trials are showing that it may both improve memory and delay the loss of functioning and the emergence of behavioral symptoms.
Comparative studies are
needed to determine which of these agents are most beneficial with least side
are being studied for treatment as well as prevention of Alzheimer's.
Nonsteroidal anti-inflammatory drugs (NSAIDs), ranging in potency from over-the-counter remedies (aspirin and ibuprofen) to more potent forms (eg, indomethacin) are under intense scrutiny for both preventing and treating Alzheimer's. Such agents block prostaglandins, which are inflammatory factors that appear to contribute to Alzheimer's. One 2000 study found that the long-term use of NSAIDs enhanced mental performance but did not stop progression of the disease itself.
COX-2 inhibitors (sometimes referred to as super aspirins) are newer NSAIDs that block coenzyme-2 (COX-2), a substance that may regulate specific inflammatory factors involved in Alzheimer's. They also do not appear to have such negative effects on the intestinal lining as standard NSAIDs. Celecoxib (Celebrex), rofecoxib (Vioxx), and meloxicam (Mobic) are currently approved in the US but more are under investigation.
Of note, corticosteroids, the most potent anti-inflammatory agents, are not research targets. Such agents can actually cause memory loss over time. In addition, they do not block prostaglandins as NSAIDs do.
Ginkgo biloba is a
common herb that has antioxidant properties and appears to increase blood flow
to the brain. Some studies have suggested that ginkgo biloba may slightly
improve the memory of Alzheimer's patients. Small studies have indicated that
the effects in the brain were comparable to those of tacrine and donepezil and
that ginkgo 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. (The website www.naturaldatabase.com compares brands by quality.)
The agent poses a small risk for bleeding, which may increase in combination
with other medications, such as warfarin or high-doses of vitamin E.
Nicotine enhances the
actions of the cholinergic system (which is depleted in Alzheimer's disease) and
is known to improve concentration and memory in the short term. Some studies
have suggested that nicotine may protect nerve cells and help prevent the
formation of beta amyloid.
Researchers are investigating nicotine replacements and a number of
nicotine-like drugs or agents that act on the receptors for nicotine in the
brain. Research to date, however, has found no strong evidence of improvement
with the nicotine patches or other nicotine replacement methods.
is no evidence that smoking is protective against Alzheimer's. In fact, some
research suggests it may slightly increase the risk for dementia. One study
indicated that smoking might help protect against Alzheimer's disease in
carriers, but not noncarriers, of the ApoE4 gene. In any case, smoking is never
recommended for either prevention or treatment. (Nicotine itself, unlike
smoking, does not appear to cause cancer.)
A number of other
agents are being investigated and show promise in early or late trials. Intense
areas of research are focusing on agents that prevent beta amyloid build-up, its
toxic effects on nerve cells, or other mechanisms of the disease process. Among
them are the following:
Propentofylline has nerve-protective properties and may enhance metabolism in the brain. The drug is showing promise in improving symptoms and slowing disease progression.
Citicoline is an agent that affects the cholinergic system and has been used for treating head injury and stroke and might be a useful agent in Alzheimer's disease.
Nerve growth factors are agents that stimulate nerve activity in the brain. Cerebrolysin, for example, is one such agent showing promise. It is produced from purified brain proteins and mimics a natural growth factor. In one study, over 60% of patients reported improved memory and concentration.
A particularly exciting target of research is nerve growth factor that is produced by genetically modified cells, which are injected into the brain. Animal studies are very hopeful and a very small human trial is underway.
Memantine blocks N-methyl-D-aspartate (NMDA), a substance that binds to glutamate (an amino acid that excites nerves and, when overproduced, is a powerful nerve-cell killer). Early small studies report that it reduces severe dementia and improves function.
Leteprinim potassium (Neotrofin) reduces cell-levels of beta amyloid in laboratory studies. Early human trials are suggesting that it may have positive effects on memory and behavior.
In Japan, researchers are working on an extract of the guarana tree that appears to protect cells from the harmful effects of beta amyloid.
Melatonin, a natural hormone involved in sleep regulation, is of interest. It is an antioxidant, it may break down beta amyloid, and it is able to pass through blood-brain barrier.
Some investigation is targeting the role of insulin, specifically insulin growth factors, in treatment of Alzheimer's.
Researchers investigating the use of the antibiotic clioquinoline, which binds to metals in beta amyloid plaques. Studies on mice were promising and human trials are underway.
Certain procedures are
being tested for Alzheimer's.
Transcutaneous electrical nerve stimulation (TENS) is a well-known treatment that uses low-level electrical pulses. Some studies suggest that TENS may produce improvement in depression, sleep, memory, and functioning in early Alzheimer's. It does not appear to have much benefits for later stages.
Low-flow ventriculoperitoneal shunts are implanted devices that drain cerebrospinal fluid from the brain. The theory is that a low flow clearance will also carry off beta amyloid as well. Early studies show some promise, although the procedure is invasive.
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.
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.
Psychosis (Wandering, Irritability, Aggression, and Hallucinations).
Verbally or physically aggressive behavior, wandering, and hallucinations
have been traditionally treated with standard antipsychotic drugs, such as
haloperidol (Haldol), but they have severe side effects. 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.
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
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.
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
Mood and Emotional
Behavior. Alzheimer’s patients display abrupt mood swings and many 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
recommendations for caregivers may help reduce agitation:
Keep environmental distractions and noise at a minimum if possible. (Even normal noises, such as people talking outside a room, may seem threatening and trigger agitation or aggression.)
Speak clearly. Most experts recommend speaking slowly to an Alzheimer’s patient, but some caregivers report that Alzheimer’s patients respond better to clear, quickly spoken, short sentences that they can more easily remember.
Limit choices (such as clothing selection).
Offer a diversion, such as a snack or car ride, if the patient starts shouting or exhibiting other disruptive behavior.
Simply touching and talking may also help.
Maintain as natural an attitude as possible. Alzheimer’s patients can be highly sensitive to the caregiver’s underlying emotions and react negatively to patronization or signals of anger and frustration.
Showing movies or videos of family members and events from the patient's past may be comforting.
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 and even enjoying
such states may bring some comfort to a caregiver.
There is no single
Alzheimer’s personality, just as there is no single human personality. All
patients must be treated as the individuals they continue to be, even after the
social selves have vanished.
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. 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.
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, the following precautions are recommended:
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.
The caregiver should contact organizations, such as Alzheimer's Association or Medic Alert, for identification supplies and procedures that help locate patients who wander away from home and become lost. [See Where Else Can Help Be Found for Alzheimer's Disease?, below.]
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.
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.
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.