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In This Report

•	Highlights
•	Introduction
•	Causes
•	Risk Factors
•	Prevention
•	Symptoms
•	Diagnosis
•	Medications
•	Stages
•	Resources
•	References

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•	Depression

Encyclopedia

•	Dementia
•	Alzheimer’s disease

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Alzheimer's Disease

Highlights

Prevention

• The National Institutes of Health (NIH) suspended a large clinical trial investigating whether anti-inflammatory drugs such as naproxen and celecoxib could prevent AD. Study participants who took the nonsteroidal anti-inflammatory drug (NSAID) naproxen had a higher incidence of cardiovascular and cerebrovascular events. Safety concerns about the COX-2 inhibitor celecoxib have been raised in other trials. At the time of this report, celecoxib was still on the market.
• In contrast to prior retrospective research, several new prospective studies suggest that cholesterol-lowering statin drugs do not prevent AD.

Treatment

• Donepezil may have short-term benefits for patients with mild cognitive impairment by delaying progression to AD. Vitamin E shows no benefit for treatment.

Genetics

• Researchers have identified a second gene associated with Alzheimer's disease (AD). Variants of the gene ubiquilin 1 (UBQLN1) predict increased risk to AD. The ApoE4 gene was the first gene linked to late-onset AD.

Risk Factors

• New research suggests that diabetes may be a risk factor. High blood pressure and high cholesterol are also potential risk factors for AD.
• Estrogen-only therapy may slightly raise the risk of AD for women 65 years and older. Earlier research indicated that combination (estrogen plus progestin) hormone replacement therapy increased significantly a woman’s risk for developing AD.

Diagnosis

• The NIH launched the Alzheimer’s Disease Neuroimaging Initiative, a 5-year clinical trial, to see if MRI and PET scans, biomarkers, and neuropsychological tests can be combined to measure the progression of AD and mild cognitive impairment.
• The tracer molecule Pittsburgh compound B is showing promise for highlighting beta-amyloid protein deposits in PET scans.
• Researchers are using nanotechnology to develop a cerebrospinal fluid test that may be able to detect AD in its earliest stages.

Health Care Benefits

• Medicare expanded coverage of PET scans for beneficiaries who meet specific eligibility criteria.

Introduction

Alzheimer's disease (AD) is a degenerative disease of the brain from which there is no recovery. The disease slowly attacks nerve cells in all parts of the cortex of the brain and some surrounding structures, thereby impairing a person's abilities to govern emotions, recognize errors and patterns, coordinate movement, and remember. Ultimately, a person with AD loses all memory and mental functioning.

The major areas of the brain have one or more specific functions.

Causes

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.

Biologic Factors in the Brain

Imaging techniques in patients with Alzheimer's disease have found significant loss of cells and volume in the regions of the brain devoted to memory and higher mental functioning. Important abnormalities have specifically been observed during biopsies:

• Twisted nerve cell fibers, known as neurofibrillary tangles.
• A sticky protein called beta amyloid.

Other factors also play a role.

Click the icon to see an animation about Alzheimer's disease.

The Effects of Neurofibrillary Tangles and Beta Amyloid in Alzheimer's Disease. These biologic factors appear to be involved in the development Alzheimer's disease in the following ways:

• 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.
• Amyloid precursor protein (APP) is a large nerve-protecting protein that is the source of beta amyloid. In Alzheimer's certain enzymes, particularly those called gamma-secretases, snip APP into beta amyloid pieces. This process is controlled by factors called presenilin proteins. (Genetic abnormalities that affect either 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 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.

Click the icon to see an image of amyloidosis.

Other Proteins. 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.

Oxidation and the Inflammatory Response

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. There is some evidence that such events can begin decades before Alzheimer's disease actually develops. One scenario for their role in Alzheimer's is as follows:

The Role of Oxidation.

• 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 when oxidants are overproduced, they can cause severe damage in cells and tissue, 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.

The Inflammatory Response.

• One result of oxidation is the marshaling of immune factors to repair the cellular injuries it produces. Overproduction of some of these factors, however, produces the so-called inflammatory response, in which the immune process itself can actually damage the body's own cells themselves.
• Principle immune cells in the brain are called macrophage/microglia (M phi). In the healthy brain, they play an important protective role against invading organisms. However, when they are activated by beta amyloid oxidation, they release toxic molecules called cytokines, which are known to cause harm. For example, significantly high levels of interleukin-6, a specific cytokine, have been detected in people with Alzheimer's.
• Other 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.
• The inflammatory process has also been associated with the release of soluble toxins called amyloid beta derived diffusible ligands, which some investigators believe may prove to key players in the destructive process.

Genetic Factors

Major research targets in Alzheimer's disease 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. In 2003, the National Institute on Aging (NIA) launched the ambitious AD Genetics Initiative, a 3-year national project to bank genetic material from families who have at least two members with late-onset Alzheimer's.

The ApoE Gene and Late-Onset Alzheimer's. The major target in genetic research on late-onset Alzheimer's disease (called LOAD) 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 evidence suggests that the ApoE protein removes beta amyloid but the ApoE4 variant does so less efficiently than other ApoE types. (ApoE4 has also been studied for years as a risk factor for heart disease.)
• ApoE3 and ApoE2. Fewer beta amyloid deposits have been observed in people with the ApoE3, and 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 of between 9% and 20% for developing Alzheimer's by age 85.
• 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 researchers suspect that some specific variation of the ApoE4 gene or combinations with other genes are critical for the disease, since many people who carry the ApoE4 exhibit no signs of Alzheimer's. For example, evidence suggests that genetic factors play a role in a common subtype of late-onset Alzheimer's disease that also includes psychosis. An important 2002 genetic study has identified certain genetic linkages associated with ApoE4 that appear to play a strong role in this subtype.

Other Genetic 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 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:

• Researchers are now targeting chromosomes 9, 10, and 12 as possible locations for genetic factors involved with Alzheimer's disease. (The ApoE4 gene is on chromosome 19.) In 2005, researchers announced that mutations linked to the ubiquilin 1 (UBQLN1) gene, located on chromosome 9, might be associated with increased risk for late-onset Alzheimer's disease.
• 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 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.

Environmental Factors

Also of interest to researchers are the environmental factors (e.g., infections, metals, industrial or other toxins) that may trigger oxidation, inflammation, and the disease process, particularly in people with genetic susceptibility to Alzheimer's.

Infectious Organisms. Slow, infectious viruses cause a number of other degenerative neurologic diseases, such as kuru and Creutzfeldt-Jakob disease.

Click the icon to see an image of Creuztfeldt-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:

• Evidence in one British research center has suggested that presence of herpesvirus (HSV) 1 increases the risk for Alzheimer's disease in individuals who carry ApoE4. (HSV1 is a form of herpes that can invade the central nervous system). In one study, 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 plaques.Chlamydia pneumoniae is a common organism that causes respiratory infections. Researchers are finding that it may have very powerful inflammatory affects in blood vessels. And some studies (but not all) have found evidence of the organism in parts of the brain affected by late-onset Alzheimer's. More research is needed to determine the significance of these findings.

Click the icon to see an image of herpes.

Metals. Some laboratory studies have reported excessive amounts of metal ions such as zinc, copper in the brain of someone with Alzheimer's disease . Such ions may possibly change the chemical architecture of normal 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 studies on people exposed to intense electromagnetic fields (EMF) have reported a higher incidence of Alzheimer's. Various studies offer different reasons for the association. Some suggest that magnetic fields may lower the concentration of calcium inside cells or reduce levels of melatonin, which are both believe to help protect nerve cells. In any event, the association between EMF and Alzheimer's is very weak.

Risk Factors

Alzheimer's disease is now the fourth leading cause of death in adults. It affects an estimated 4.5 million Americans and eight million more people worldwide. Age is the biggest risk factor for Alzheimer's disease. The number of cases of Alzheimer's disease doubles every five years in people over 65. By age 85, almost half of all people are afflicted. People with the disease survive, on average, half as long as similarly aged adults without the disease.

With the increasing numbers of aging adults, unless effective methods for prevention and treatment are developed, Alzheimer's disease will reach epidemic proportions, afflicting an estimated 14 million Americans within 50 years. To date, evidence points to high blood pressure, cholesterol levels, and a family history of the disease as independent risk factors for Alzheimer's disease.

Gender and Estrogen Loss

Several studies have reported that women have a much higher risk for Alzheimer's disease than men. (Most of these studies have been on European and Asian populations, however. Some studies in the US have found no significant differences.) If there is a gender difference, it is likely to be due estrogen, the primary female hormone, which appears to have properties that protect against the memory loss and lower mental functioning associated with normal aging. Such actions include blocking production of beta amyloid, offering antioxidant protection, and regulating glucose (blood sugar) levels in the brain. The drop in estrogen levels after menopause, then, may explain that higher risk for Alzheimer's disease in older women than in men. (Some of testosterone, the male hormone, converts to estrogen, which may help protect them.) Studies have been mixed, however, on the association between the decline in natural estrogen levels and mental functioning in older women. For example, one 2001 study reported no association between lower risk for dementia in women who went into menopause at older ages. On the other hand, a 2002 study reported poorer mental status in women with lower levels of estrogen.

Family History and Populations Differences

People with a family history of the disease are at higher than average risk for Alzheimer's disease. Researchers are identifying important genetic factors, notably the ApoE4 gene, that may be responsible for late- and early-onset cases.

Few well-conducted studies have been conducted on differences among population groups. Some have observed the following:

• 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. Dietary and other cultural factors that increase the risk for hypertension and unhealthy cholesterol levels may also play a role. For example, a study of Japanese men showed that their risk increased if they emigrated to America. And the disease is much less common in West Africa than in African Americans, who share the same or higher risk with Caucasians Americans.

Risk Factors for Cardiovascular Disease

High blood pressure and unhealthy cholesterol levels -- the same important risk factors for heart disease and stroke -- may also be risk factors for Alzheimer's disease. In fact, they appear to be more important than ApoE4, the genetic factor most commonly associated with Alzheimer's disease.

Blood pressure is the force applied against the walls of the arteries as the heart pumps blood through the body. The pressure is determined by the force and amount of blood pumped and the size and flexibility of the arteries.

High Blood Pressure. Some studies have reported an association between Alzheimer's disease and systolic hypertension (the higher and first number in blood pressure measurement). Furthermore, some studies report a lower risk for Alzheimer's disease in patients whose blood pressure was reduced. Nevertheless, although hypertension is strongly linked to memory and mental difficulties, stronger evidence is needed to prove any causal relationship between hypertension and Alzheimer's disease. For example, some studies, including a large community study, report no relationship.

High Cholesterol Levels. There has been research suggesting an association between high cholesterol levels and Alzheimer's disease in some people. One theory is that cholesterol regulates the processing and accumulation of amyloid beta-protein. More research is needed.

Click the icon to see an image of cholesterol.

Diabetes. Patients with diabetes often have high blood pressure, lipid imbalances, and circulatory disorders that affect the heart and vascular system. Research suggests that diabetes can also affect cognitive function and increase the risk of developing Alzheimer's disease.

High Homocysteine Levels. Homocysteine is an amino acid that has been identified as a modest risk factor in heart disease. Now, it has also been associated with a higher risk for Alzheimer's disease. High levels are general due to deficiencies of the B vitamins B6, B12, and folate. Such vitamins are also related to nerve protection. Researchers theorize that homocysteine impairs the ability of DNA to repair nerve cells. The weakened cells are then more vulnerable to the harmful effects of oxidized beta amyloid.

Down Syndrome

Nearly all patients who inherit Down 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 syndrome are also at much higher risk for Alzheimer's. The National Institute on Aging is conducting a trial to determine if vitamin E, which has shown some benefit in slowing the progression of Alzheimer's, can help to slow cognitive decline in older patients with Down syndrome.

Other Risk Factors Associated with Alzheimer's Disease

Lower Education and Economic Groups. A number of studies have reported either a higher risk for Alzheimer's disease in people with less education or a lower risk for Alzheimer's disease in those who remain mentally active. 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. Some evidence suggests that early malnutrition, which is more likely to occur in lower income and educational groups, has been associated with smaller brains and with Alzheimer's disease in old age. Low-birth weight can cause problems in growth factors that could effect both mental and physical health later on in adulthood.

Small Head Size. The size of the skull is fixed by age 7. Brain size approximates the head size until old age, when it begins to shrink. Some evidence has reported an association between small head size (and therefore less brain volume) and Alzheimer's disease, possibly because people who start with larger brains can sustain more injury over time. For example, a 2002 study indicated that it was reduction in overall brain volume, not specific regions, that contributed to mental impairment in older healthy adults. Another 2002 study reported that people who had small heads plus the ApoE4 gene had 14 times the risk for Alzheimer's disease than those without this combination.Nevertheless, other studies have found no association between a small head size and Alzheimer's disease.

Some experts suggest that the relationship observed in other research may simply be due to social and economic factors, such as malnutrition or low birth weight, which have been associated with both Alzheimer's disease and small head size. Small head size independent of other factors, they argue, does not pose a higher risk for either Alzheimer's disease or low intelligence.(Of note, 30,000 years ago, the size of a human brain was 10% larger than it is now.)

Depression. There is a significant overlap between depression and dementia in the elderly. (In fact depression itself is often an early symptom of Alzheimer's disease.) In a 2002 study of Catholic nuns, for each of four depressive symptoms, the risk for developing Alzheimer's disease increased by an additional 19%. For example, for a woman with four depressive symptoms the risk increased by 76%. Some evidence suggests that there may even be common genetic factors in people who have both early depression and Alzheimer's disease.

Head Injury. 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.

Prevention

Although there is no strong evidence that any lifestyle change can prevent Alzheimer's disease, studies are showing that certain behaviors may help protect against mental decline. In particular, medications and lifestyle choices that protect the heart may be of specific importance. Other preventive agents are under investigation, including antioxidant and anti-inflammatory therapies.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) as Prevention

In December 2004, the National Institutes of Health (NIH) halted a large clinical trial that was investigating the use of anti-inflammatory drugs in preventing Alzheimer's disease. While prior data had confirmed that NSAIDs were not effective in treating AD, research continued to explore these drugs' potential preventive benefits.

The Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT) investigated whether long-term use of naproxen (Aleve) or celecoxib (Celebrex) could decrease the risk of developing AD. The NIH suspended this trial due to evidence that the NSAID naproxen was associated with increased incidence of cardiovascular and cerebrovascular events among participants. (The evidence is not uniform; other research has not implicated naproxen as a cardiovascular risk.) No adverse effects appeared during this trial for the COX-2 inhibitor celecoxib. However, safety concerns about this drug had been raised in other trials. Investigators did not believe that celecoxib's potential benefits outweighed its risks.

Heart-Protective Agents and Behaviors

The same lifestyle and medical choices that reduce risk factors for heart disease and diabetes may be important for reducing the risk for Alzheimer's disease. The following are some heart-protective medications that may also protect the brain.

Calcium-Channel Blockers and Other Anti-Hypertensive Agents. Some studies indicate that lowering high blood may reduce the risk of Alzheimer's disease in elderly patients with systolic hypertension. In one study, the calcium channel blocker nitrendipine was especially associated with protection. Studies are needed to determine if protection is derived from calcium channel blockers or if other blood-pressure lowering agents provide the same benefits. (Calcium-channel blockers are known to have nerve-protecting properties.) Preliminary research suggests that certain types of ACE inhibitors may also prevent cognitive decline in patients with Alzheimer's disease.

Statins. Statins are common drugs used to lower cholesterol levels. In the past several years, a number of studies reported a significantly lower risk for Alzheimer's disease in patients who took statins. However, the majority of these observational studies used a retrospective study design; patients had already been diagnosed with cognitive impairment and the researchers investigated whether they had used statin drugs in the past. Newer prospective studies have failed to prove that statins can help prevent Alzheimer's disease. In these prospective studies, large numbers of elderly people had their dementia assessed at baseline and then monitored over several years. The results indicated that statin use did not predict onset of AD. Prospective epidemiologic studies (which look ahead) are considered more reliable than retrospective studies (which look back). In the meantime, the NIH is conducting a randomized, placebo-controlled clinical trial to investigate whether simvastatin can slow the progression of AD. The Cholesterol Lowering Agent to Slow Progression (CLASP) trial is due to be completed at the end of 2005.

Male and Female Hormone Replacement Therapies

Hormone Replacement Therapy. Hormone replacement therapy (HRT) has been studied for years for health effects after menopause, including its effect on mental decline. Results have been mixed. In a 2002 study of women over 80, a history of HRT used for longer than 10 years appeared to reduce the risk for Alzheimer's disease, but HRT did not protect women who took it for less than ten years. A number of studies, including a major 2003 analysis, have found no differences in mental performance and no protection from Alzheimer's disease in women taking HRT compared to non-users. This trial, called the Women's Health Initiative Memory Study (WHIMS), enrolled 4,500 women over 65 years of age. The fact that most women who take HRT tend to be healthier and better educated to begin with may bias study results that favor HRT. Well-conducted studies are under way to resolve this important issue. It should be noted that long-term use of HRT may pose some health risks, including breast cancer, stroke, heart attack, and blood clotting, which a woman at risk for Alzheimer's should discuss with her physician.

The WHIMS study showed that older postmenopausal women who took combination HRT (estrogen plus progestin) had twice the risk of developing dementia than similarly aged women who received placebo pills. In addition to increasing the risk for dementia, (including Alzheimer's disease), combination HRT failed to prevent the development of mild cognitive impairment. Based on these results, the researchers from the National Institute on Aging (NIA) recommended against prescribing combination hormone therapy to older women for maintaining or improving cognitive function. Although a 2000 study indicated that estrogen replacement therapy was not effective in treating dementia in women with Alzheimer's who had undergone hysterectomy, the NIA continued research to determine whether estrogen-only therapy could prevent or delay the onset of Alzheimer's disease. Results released in 2004 indicated that older women (65 years and older) who took estrogen-only HRT had a slightly increased risk of developing dementia.

Testosterone. Some testosterone converts to estrogen, which may be a factor in the lower risk for Alzheimer's disease in older men than in women. Animal studies have also suggested that testosterone might be helpful in reducing levels of beta amyloid. There is also some evidence that low testosterone levels may be a particular risk factor in men with the APOE4 gene. Some experts believe that giving testosterone to elderly men and combinations of testosterone and estrogen to older women may prove to be protective. Side effects of testosterone in women include increased body hair, acne, fluid retention, anxiety, and depression. Long term benefits or serious adverse effects are unknown.

DHEA. Dehydroepiandrosterone (DHEA) is a male-like hormone in the body that declines with age. Some evidence suggests that it may help reduce mental decline in older women, but not in older men. Studies are under way. The hormone may, however, reduce HDL (the so-called good cholesterol) when taken in doses higher than 50 mg and its effect on cancer-cell growth is unknown, with some evidence indicating that high levels may increase the risk. In any case, DHEA is not regulated and brands vary widely in their content.

Dietary Factors

Because of differences in Alzheimer's disease rates among different populations, investigators are looking at dietary factors for protection. 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.

Fats and Oils. The following are some studies suggesting an association between fat and Alzheimer's disease.

• 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.
• A study in the Netherlands reported an association between dementia and diets high in total fat, saturated fat, and cholesterol.
• A number of studies are now suggesting that a high-fat high-calorie diet in people who carry the ApoE4 gene may confer a particularly high risk. For example, in one 2000 US study, adults 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.

It should be noted that fish oil, which contains omega-3 fatty acids, in particular the compound docosahexaenoic acid (DHA), may help protect the aging brain. In a 2002 eating fish at least once a week was associated with a lower risk for Alzheimer's disease. (In the same study, eating meat had no effect one way or the other.) These fatty acids are found in oily fish such as salmon, halibut, swordfish, and mackerel. People can also obtain DHA in supplements.

Omega-3 fatty acids, found plentifully in oily fish and flaxseed and canola oils, are beneficial to people afflicted with IBD (inflammatory bowel disease).

The recommended dietary goal is to limit total fat intake to 30% or fewer calories from fat. Everyone should avoid saturated fats found in animal products) and trans-fatty acids (found in fast foods and commercial baked goods). People should also eat fish twice a week and choose polyunsaturated and monounsaturated oils (canola and olive oil).

Dark-Colored Fruits and Vegetables. 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.

Soy. Soy has estrogen-like properties and animal studies suggest it may might be protective against Alzheimer's disease, particularly in postmenopausal women. Of some concern, however, were one population and a few animal studies suggest that the same estrogen-like effects of soy may actually pose a risk for greater mental among older men. More research is needed to confirm the effects of soy on the aging brain and to determine if there are gender differences.

Alcohol. Some studies have suggested that moderate intake of alcohol (one or two drinks a day) of any kind may protect the aging brain, possibly by releasing acetylcholine, the chemical in the brain that is deficient in Alzheimer's disease. Not all studies have been positive. One, for example, suggested that wine may have some protective properties for noncarriers of ApoE4 but actually increase the risk for carriers of the gene. In any case, heavy alcohol consumption offers no protection and is dangerous.

Caffeine. One study reported that women over 80 with a lifetime history of coffee intake had better performance on tests of mental function. (Coffee drinking in men and non-caffeinated drinking in either gender had no effect.)

Folate and Vitamin B12. Some studies suggest that deficiencies of vitamins B6, B12, and folate may be a risk factor for Alzheimer' diseases, possibly because deficiencies elevate homocysteine levels, which some research now associated with a higher risk for Alzheimer's disease. Both vitamins are added to cereal products Foods containing folate include avocados, bananas, oranges, asparagus, green leafy vegetables, and dried beans. B12 is found only in animal products. (Oily fish are very high in B12 and also have other nerve-protective properties.). People who are folate deficient may need supplements of folate (natural form) or folic acid (its synthetic from), which is twice as potent at folate. Some experts recommend 400 mcg of folic acid to reduce homocysteine, although one study suggested 800 mcg (.8 mg) a day is necessary to reduce homocysteine levels.

Click the icon to see an image of vitamin B12 sources.

Click the icon to see an image of folate sources.

Antioxidant Supplements. 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, including a large 2002 population study, have suggested that vitamin E intake, from food or supplements, may protect against mental decline. (One study suggested that the vitamin protected only those who carried the apoE4 gene. Most evidence on any benefits from other antioxidants come from a combination of the antioxidants, such as vitamins C and E and coenzyme Q-10 (but not the use of them separately). However, no strong evidence to date has found any protection from antioxidant supplements.

Other Health Behaviors

Exercise. Aerobic exercise (such as walking or jogging) is very important for helping to protect against mental decline during aging. A number of studies are reporting that regular exercise may protect specifically against Alzheimer's as well other forms of mental deterioration and dementia. And the more exercise, the better.

Social Behaviors and Stress Reduction. Lifelong learning, social engagements, and stress reduction are all useful in keeping the mind active and energized.

Symptoms

The early symptoms of Alzheimer's disease (AD) may be overlooked because they resemble signs of natural aging. Still, older adults who begin to notice a persistent mild memory loss of recent events may have a condition called mild cognitive impairment (MCI). MCI is now believed to be a significant sign of early-stage Alzheimer's in older people. Studies now suggest that older individuals who experience such mild memory abnormalities convert to Alzheimer's disease at a rate of about 10% to 15% per year.

Early symptoms of Alzheimer's disease include the following:

• Forgetfulness.
• Loss of concentration.
• Unexplained weight loss.
• Motor problems, including mild difficulties in walking.
• Incontinence
• Changes in sexuality;
• Psychiatric symptoms (depression, apathy, irritability). Such symptoms occur in about half of patients, and in most cases they occur very early on.

Between 40% and 60% of patients with late-onset Alzheimer's disease suffer from psychotic symptoms, which may include hallucinations, delusions, and dramatic verbal, emotional or physical outbursts. This is a severe form of Alzheimer's disease, possibly with a genetic basis, that has a more rapid and aggressive course.

It should be noted that many medical and psychological conditions can produce Alzheimer-like 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.

Diagnosis

A definitive test to diagnose Alzheimer's disease, even in patients showing signs of dementia, has not yet been devised. A number of expert groups have developed criteria to help diagnose Alzheimer's disease and rule out other disorders. Often a diagnosis involves answering the following questions about the patient:

• Do psychologic tests indicate dementia?
• Does the patient have deficits in two or more areas of mental functioning (such as language, motor skills, and perceptions)?
• Has memory and mental functions gotten progressively worse?
• Is consciousness disturbed? (It is not in Alzheimer's disease.)
• Is the patient over 40?
• Are other medical or physical conditions present that could account for the same symptoms?
• Are daily activity impaired or has the behavior changed?
• Is there a family history of Alzheimer's disease?
• Are there other symptoms, such as depression, insomnia, incontinence, delusions, hallucinations, dramatic verbal, emotional or physical outbursts, sexual disorders, and weight loss?

Other steps involved in making a decision include laboratory tests (EEG and possibly tests to rule out other diseases) and psychological testing to determine the presence of dementia.

Ruling out Conditions of Normal Aging that Can Cause Alzheimer's-like Symptoms

Although some memory impairment occurs in many people as they age, only some of these people develop Alzheimer's disease. Many similar symptoms can occur in healthy older individuals from other conditions associated with aging, such as the following:

• Fatigue.
• Grief or depression.
• Illness.
• Vision or hearing loss.
• The use of alcohol or certain medications.
• Simply the burden of too many details to remember at once.

Ruling Out Other Causes Memory Loss or Dementia

The first step in diagnosing Alzheimer's disease is to rule out other conditions that might be causing memory loss or dementia. There are a number of causes for dementia in the elderly:

• Alzheimer's disease.
• Vascular dementia (abnormalities in the vessels that carry blood to the brain).
• Lewy bodies variant (LBV), also called dementia with Lewy bodies.
• Parkinson's disease.
• Frontotemporal dementia

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 or caused by other factors. Specialists can usually clearly identify patients who have Alzheimer's by using criteria developed by expert groups. (It is much more difficult to diagnose a patient whose dementia is caused by a mixture of Alzheimer's disease and stroke-related injury.) Other diseases, many common in the elderly, can also cause symptoms that resemble Alzheimer's disease.

Vascular Dementia. Vascular dementia is primarily caused by either multi-infarct dementia (multiple small strokes) or Binswanger's disease (which affects tiny arteries in the midbrain). One major analysis 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).

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. They can be difficult to distinguish. Compared to Alzheimer's disease patients, those with LBV may be more likely to have hallucinations and delusions early on, to walk with a stoop (similar to Parkinson's disease), to have more fluctuating attention problems, and to perform better than Alzheimer's disease patients on verbal recall but less well with organizing objects.

Parkinson's Disease. Dementia is about six times more common in the elderly Parkinson patient than in the average older adult. It is most likely to occur in older patients who have had major depression. Unlike in Alzheimer's, language is not usually affected in Parkinson's related dementia. Visual hallucinations occur in about a third of people on long-term medications.

Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Part of the disease process develops as cells are destroyed in certain parts of the brain stem, particularly the crescent-shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to tissue located in both sides of the brain. There the cells release essential neurotransmitters that help control movement and coordination.

Frontotemporal Dementia (FTD). Once considered rare, FTD is now considered to be the second most common cause of early-onset dementia. People who develop this condition tend to be in their mid-fifties although it can develop later on. It results in greater behavioral impairment (e.g., apathy, reduced empathy, poor self-care, unrestrained behavior) than with Alzheimer's disease. It may also be marked by speech problems and early incontinence. Brain imaging scans can help diagnose this problem.

Other Conditions that Cause Similar Symptoms. 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. A number of conditions, including many medications, can produce symptoms similar to Alzheimer's:

• Severe depression.
• Drug abuse.
• Thyroid disease.
• Severe vitamin B12 deficiency.
• Blood clots.
• Hydrocephalus (excessive accumulation of spinal fluid in the brain).
• Syphilis.
• Huntington's disease.
• Creutzfeldt-Jakob disease.
• 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, and memory and problem-solving, social, and language skills. Experts are researching specific tests for mental impairment that may help identify early on people with mild memory impairment who are at high risk for Alzheimer's disease.

• 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. Still, these tests have limitations.
• A clock drawing test is also a good test for Alzheimer's disease. The patient is given a piece of paper with a circle on it and is 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 eight 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

Imaging tests include magnetic resonance imaging (MRI), positron-emission tomography (PET), and single photon emission computed tomography (SPECT). These tests are sometimes used to rule out other disorders such as multi-infarct dementia, stroke, blood clots, and tumors. Research is being conducted to determine if these tests can help to confirm a diagnosis of Alzheimer's disease and improve understanding of disease progression.

Click the icon to see an image of a MRI of the brain.

In 2005, the National Institute of Aging, in collaboration with industry partners, launched the $60 million Alzheimer's Disease Neuroimaging Initiative (ADNI). This landmark 5-year clinical trial, which will be conducted at 50 sites throughout the United States and Canada, will investigate whether neuroimaging techniques, such as MRI and PET scans, can be combined with biomarkers and neuropsychological tests to measure the progression of AD and mild cognitive impairment. In September 2004, Medicare expanded insurance coverage of PET scans for eligible beneficiaries who meet specific diagnostic criteria for both Alzheimer's disease and fronto-temporal dementia. Medicare will also cover the costs for patients enrolled in its agency-approved imaging clinical trials.

Research continues on Pittsburgh compound B, a tracer molecule used in PET brain scans to highlight beta-amyloid protein deposits. Results from this research may help to define potential drug targets and aid in the development of new Alzheimer's drugs.

Investigative Tests.

Blood Tests. Blood tests are currently used to check for anemia and other disorders that can produce dementia symptoms. Investigators are researching serum biomarkers, such as the iron transport protein p97, that might help detect the presence of Alzheimer's disease.

Cerebrospinal Fluid Test. Scientists are developing new nanotechnology screening methods that may eventually be used to identify Alzheimer's disease while it is still in its earliest stages and before plaque deposits accumulate. In 2005, a research team announced it had used a bio-barcode assay to detect tiny amounts of a protein called amyloid-beta-derived diffusable ligand (ADDL) in cerebrospinal fluid. ADDLs may be involved in cognitive decline and are a potential biomarker for early stage Alzheimer's disease. More research is needed. Tests for other proteins are also being developed.

Odor Test. Investigators are also using the impairment of smell in Alzheimer's disease to develop tests that require patients to distinguish between odors.

Determining Severity after a Diagnosis Has Been Made

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.
• The presence of high blood pressure.
• Signs of loss of motor control and coordination.
• Tremor.
• Social withdrawal.
• Loss of appetite and severe weight loss.
• Accompanying sensory problems, such as hearing loss and a decline in reading ability.
• General physical debility.

Medications

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 experimental therapies.

There are currently two drug classes that have been approved by the U.S. Food and Drug Administration (FDA) to treat the cognitive symptoms of Alzheimer's disease: cholinesterase inhibitors and N-methyl-D-aspartate (NMDA) receptor antagonists. Cholinesterase inhibitors are generally used to treat mild-to-moderate Alzheimer's. In October 2003, the FDA approved memantine (Namenda)-- an NDMA receptor antagonist-- the first drug of this class to be used for treating Alzheimer's and, more importantly, the first drug approved for the treatment of the moderate-to-severe stage of this disease.

Cholinesterase Inhibitors

Cholinesterase inhibitors are designed to protect the cholinergic system, which is essential for memory and learning and is progressively destroyed in Alzheimer's. These drugs work by preventing the breakdown of the brain chemical acetylcholine and are recommended for the treatment of mild-to-moderate Alzheimer's. The first cholinesterase inhibitor, tacrine, was approved in 1993 but is rarely prescribed today due to safety concerns. The three most commonly prescribed cholinesterase inhibitors are donepezil (approved in 1996), rivastigmine (approved in 2000), and galantamine (approved in 2001). Cholinesterase inhibitors may increase the risk for gastrointestinal bleeding or ulcers, and patients should be cautious about concurrent use of NSAIDs (which can also cause gastric irritation). Common side effects of cholinesterase inhibitors, especially when taken at higher doses, may include nausea, vomiting, diarrhea, and upset stomach.

• Donepezil. Donepezil (Aricept) 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. In a 2004 study, donepezil appeared to help improve memory and daily living ability in patients with moderate-to-severe Alzheimer's when taken in combination with memantine. Several trials, including an important 2005 New England Journal of Medicine (NEJM) study,  have found that donepezil may have short-term benefits for patients with mild cognitive impairment by delaying progression to AD. In the NEJM study, donepezil slowed progression during the first year of therapy, but demonstrated no benefits by the conclusion of the 3-year trial.
• Rivastigmine. Rivastigmine (Exelon) targets two enzymes (the major one, acetylcholinesterase, and butyrylcholinesterase). It is taken twice a day. This agent may be particularly beneficial for patients with rapidly progressing disease. This drug has slowed or slightly improved disease status 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.
• Galantamine (Reminyl). Galantamine not only protects the cholinergic system but also acts on nicotine receptors, which are also depleted during Alzheimer's. Studies report that it improves daily living, behavior, and mental functioning, including in patients with mild to advanced-moderate Alzheimer's disease and those with a mix of Alzheimer's disease and vascular dementia. Some studies have suggested that the effects of galantamine may persist for a year or longer and even strengthen over time.
• Tacrine. Tacrine (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.

About half of patients with mild to moderate disease show slight improvement. Comparative studies to date have reported little differences in effectiveness among them. All drugs have gastrointestinal side effects, including nausea. Of note, some of the drugs used often used in elderly Alzheimer's disease patients are known as anticholinergics and may offset the effects of the Alzheimer's disease pro-cholinergic agents. Such drugs include antihistamines, antipsychotic drugs, and some anti-incontinence drugs.

In any case, the benefits of these drugs are far from dramatic. In fact, many experts have reservations about developing any additional drugs that affect the cholinergic system, since, at best, they only slow progression and do not appear to affect the basic destructive disease process. When patients go off the drugs the deterioration continues. Some experts suggest that switching from one to another may be helpful for patients who do not respond to one. In 2005, the United Kingdom’s National Institute for Clinical Excellence (NICE) recommended against the use of donepezil, rivastigmine, galantamine, and memantine for Alzheimer’s disease treatment. The agency contended that the costs of these drugs outweigh their modest benefits. 

N-methyl-D-aspartate (NDMA) Receptor Antagonist

Memantine (Namenda) is the first NDMA receptor antagonist to be approved in the U.S. for the treatment of Alzheimer's disease. Marketed in Europe under the trade names Exira and Axura, memantine was first approved in Germany in 1982 for various neurological conditions, and was approved throughout Europe in 2002 for the treatment of Alzheimer's disease. It received its U.S. approval in October 2003, and has been commercially available since January 2004.

Memantine is the first drug indicated for the treatment of moderate-to-severe Alzheimer's disease (cholinesterase inhibitors are generally used to treat mild-to-moderate stages of the disease). By blocking NDMA receptors, memantine protects against the overstimulation of glutamate, an amino acid that excites nerves and, in excess, is a powerful nerve-cell killer.

In one study of effects on moderate-to-severe Alzheimer's, patients who received memantine showed a small but statistically significant benefit in cognitive function and performance of daily abilities compared with those patients who were given placebo. In another study, published in 2004, memantine was added to the drug regimen of patients with moderate-to-severe Alzheimer's who had taken donepezil for at least six months. In comparison to patients who took only donepezil, patients who received the combination donepezil-memantine therapy showed a greater improvement in measures of cognitive function, activities of daily living, and behavior parameters.

Although cholinesterase inhibitors and memantine are the best available medications for Alzheimer's, their benefits are, unfortunately, quite modest. More effective methods of prevention and treatment are urgently needed.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) as Treatment

There has been considerable controversy over whether NSAIDs may help in the treatment of Alzheimer's disease. As inflammation is involved in the destruction of brain cells, it has been postulated that anti-inflammatory drugs might be able to halt this process and thus slow the progression of the disease. In a rigorous 2003 study, patients with mild-to-moderate Alzheimer's were randomized to receive either the anti-inflammatories naproxen (Aleve) or rofecoxib (Vioxx) or placebo. After 12 months of treatment, patients in the anti-inflammatory groups did not show any difference in cognitive improvement compared to those patients who received placebo.

Results from another large study, published in 2004, also failed to demonstrate improvement in cognitive function for patients with mild-to-moderate Alzheimer's who were treated with rofecoxib. . Since the completion of these studies, rofecoxib was withdrawn from the market and the NIH suspended a clinical study assessing naproxen’s preventive benefits (see Nonsteroidal Anti-Inflammatory Drugs as Prevention). As mentioned earlier, patients should be cautious about taking NSAIDs in combination with cholinesterase inhibitors as they may increase the risk of gastrointestinal bleeding.

Nicotine Replacement

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. One study indicated that nicotine might help protect against Alzheimer's disease in carriers, but not noncarriers, of the ApoE4 gene. Another reported improvement in verbal recall and word retrieval in healthy relatives of Alzheimer's disease patients who wore a low-dose nicotine patch. Research to date, however, has found no strong evidence of improvement in Alzheimer's disease patients with nicotine replacement methods. No one should smoke to prevent or treat Alzheimer's disease.

Alternative Treatments

Ginkgo Biloba. Ginkgo biloba is a common herb that has antioxidant properties and appears to increase blood flow to the brain. The herb is available over the counter, although a 2002 study of healthy people who took over-the-counter ginkgo for six weeks reported no differences in memory or mental function. Studies are reporting that a ginkgo biloba extract, called Egb 761, may slightly improve the memory of patients with mild to moderate Alzheimer's disease. Ginkgo has only minimal side effects. The agent poses a small risk for bleeding, which may be hazardous in combination with other blood-thinning medications, such as warfarin or high-doses of vitamin E. (Although there are no standards in the US by which to regulate it, the website www.naturaldatabase.com compares brands by quality of ingredients.)

Turmeric. Interestingly, studies suggest that curcumin, a compound found in the spice turmeric, has properties that may protect against Alzheimer's disease process.

Melatonin. 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. Deficiencies have been observed in patients with Alzheimer's disease. A number of studies (but not all) report that melatonin may improve sleep habits in these patients. Some even reported some slower progression in mental impairment.

Other Investigative Agents

A number of other agents are being investigated for treatment and prevention of Alzheimer's disease. 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.

• Alzhemed. Alzhemed (NC-758) is an experimental drug designed to prevent beta-amyloid accumulation in the brain.
• Neramexane. Like memantine, neramexane is an NMDA receptor antagonist. This experimental drug inhibits the effects of the neurotransmitter glutamate.
• Xaliproden. Xaliproden (SR-57746A) is designed to increase the production of neurotrophins such as nerve growth factor.
• Vitamins. The homocysteine-reducing effects of vitamins B6 and B12 are being studied for delaying cognitive decline.
• Antioxidants. Vitamin E and selenium are being investigated for their preventive effects. Antioxidant treatment trials include circumin, (the yellow pigment found in turmeric spice), and a combination trial with fish oil and alpha-lipoic acid. A 2005 study found no benefit for Vitamin E treatment.
• Huperzine alpha. This Chinese herbal cholinesterase inhibitor is being studied for improvement of cognitive function.
• Antipsychotics/Anticonvulsants. The antipsychotic drug quetiapine (Seroquel) is being investigated for treatment of AD-associated agitation and psychosis. Valproate (Depakote), an anticonvulsant drug, is in trials for delaying emergence or slowing the progression of agitation and psychosis.
• Statins. Simvastatin, and other cholesterol-lowering drugs, are being investigated for slowing the progression of Alzheimer’s disease.

Investigative Procedures

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 in slowing progression of Alzheimer's disease, although the procedure is invasive. A large trial is under way.

Treating Symptoms Associated with 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. (It is, in fact, sometimes difficult to differentiate major depression from early stage Alzheimer's disease.) Antidepressants known as selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and sertraline (Zoloft), may be effective in relieving depression, irritability, and restlessness associated with Alzheimer's in some patients, particularly women with low aggression levels.

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.

Symptoms of Psychosis (Irritability, Aggression, and Hallucinations). Verbally or physically aggressive behavior, 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. They are now the drugs of choice. Carbamazepine or valproate, anti-seizure drugs, may also be effective for agitation and dementia.

Disturbed Sleep. Alzheimer's patients commonly experience disturbances in their sleep/wake cycles. Moderately short-acting sleeping agents such as temazepam (Restoril), zolpidem (Ambien), or zaleplon (Sonata) or sedating antidepressants such as trazodone (Desyrel, Molipaxin) may be useful in managing insomnia. Some research suggests that exposure to brighter-than-normal artificial light during the day for patients with normal vision may help reset wake/sleep cycles and prevent nighttime wandering and sleeplessness. Trials on melatonin, a natural hormone that helps trigger sleep at night, are in progress.

Stages

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 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 verbally.

The following recommendations for caregivers may help soothe patients and avoid 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.
• Use a combination of facial expression, voice tones, and words for communicating emotions. (One interesting study suggested that Alzheimer's patients may have difficulty in recognizing the meaning of facial expressions, particularly those signaling sadness, surprise, and disgust.)
• Limit choices (such as clothing selection).
• Offer diversions, 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 their 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. As soon as Alzheimer's is diagnosed, the patient should be prevented from driving. A Swedish study found that more than half of elderly people involved in fatal accidents had some degree of neurologic damage.

Wandering. A 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.
• Some experts are discussing the benefits versus the ethics of electronic tagging, which would emit a radio signal or alarm that allows the patient to be tracked using a detector.

Speech Problems. Some evidence suggests that speech therapy combined with Alzheimer's disease medications may be helpful for maintaining verbal skills patients with mild symptoms.

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 care-giving 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

An 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. If available, home visits by a health profession appear to have a favorable impact on survival and delay in needing a nursing home. Medicare is now covering many Alzheimer's services, and patients should be able to stay at home longer than previously.

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. Unfortunately, few patients in late-stage dementia receive pain medication.

Dehydration. Dehydration can 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.

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. In very late stages, some caregivers choose feeding tubes for the patient. They should be aware that feeding tubes have no measurable impact on survival.

Care for the Caregiver

About 80% of Alzheimer's patients are cared for by family members, who often lack adequate support, finances, or training for this difficult job. Few diseases disrupt a patient and his or her family so completely or for so long a period of time as Alzheimer's. The patient's family endures two separate losses and grieves twice:

• First, they must grieve for the ongoing disappearance of the personality they recognize. 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, when the patient's further deterioration creates new and more intractable ones.
• Finally, the caregiver must grieve the actual death of the person.

Often, caregivers themselves begin to show signs of mental disorder or ill health. The disease may even have negative effects on the immune systems of the patients' partners. Depression, empathy, exhaustion, guilt, and anger can play havoc with even a healthy individual faced with the care of a loved one suffering from Alzheimer's. And the care-giving spouse is usually elderly and often frail. Children are likely to have grown up and may live far away.

Although the great majority of caregivers have expressed their need for good information, in a 2001 study only 28% of caregivers believe they have received thorough and helpful information from their doctors. No one should endure such agony alone. It is important for the caregivers to receive counseling and support for themselves as well. Studies suggest that caregivers who are offered counseling on coping and handling stress experience fewer reactions to their patient's behavioral problems than those without such help. In one study in which caregivers took part in support programs, institutionalization of the patient was delayed by a year. National and local Alzheimer's associations are available and can provide important support and other services.

Nursing Homes and Other Outside Services

A 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.

Twelve Steps for Caregivers

1. Although I cannot control the disease process, I need to remember I can control many aspects of how it affects my relative.

2. I need to take care of myself so that I can continue doing the things that are most important.

3. I need to simplify my lifestyle so that my time and energy are available for things that are really important at this time.

4. I need to cultivate the gift of allowing others to help me, because caring for my relative is too big a job to be done by one person.

5. I need to take one day at a time rather than worry about what may or may not happen in the future.

6. I need to structure my day because a consistent schedule makes life easier for me and my relative.

7. I need to have a sense of humor because laughter helps to put things in a more positive perspective.

8. I need to remember that my relative is not being difficult on purpose; rather that his/her behavior and emotions are distorted by the illness.

9. I need to focus on and enjoy what my relative can still do rather than constantly lament over what is gone.

10. I need to increasingly depend upon other relationships for love and support.

11. I need to frequently remind myself that I am doing the best that I can at this very moment.

12. I need to draw upon the Higher Power, which I believe is available to me.

Source: The American Journal of Alzheimer's Care and Related Disorders & Research, Nov/Dec 1989

Resources

• www.alzheimers.org -- Alzheimer's Disease Education and Referral Center
• www.alz.org -- Alzheimer's Association
• www.alzforum.org -- Alzheimer's Research Forum
• www.alzfdn.org -- Alzheimer's Foundation of America
• www.alz.co.uk -- Alzheimer's Disease International
• www.ninds.nih.gov -- National Institute of Neurological Disorders and Stroke
• www.aan.com -- American Academy of Neurology
• www.medicalert.org -- Medic Alert
• www.eldercare.gov -- National Institute on Aging and Eldercare Locator
• www.ahaf.org -- American Health Assistance Foundation
• www.clinicaltrials.gov -- Find a clinical trial
• www.medicare.gov/NHCompare/Home.asp -- Find a nursing home

References

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