Probable Risk Factors for Alzheimer's Disease

Disease Considerable research evidence strongly suggests that the following factors increase Alzheimer's risk, but experts do not yet consider them well-established:

Presence of Apolipoprotein E-e4. The gene for apolipoprotein E (APOE) is located on chromosome 19. Several recent studies show that its natural variations correlate well with risk of Alzheimer's disease. (Nat. Inst. on Aging/Alzheimer's Association Working Group. "Apolipoprotein E Genotyping in Alzheimer's Disease," Lancet (1996) 347:1091.)

The APOE gene comes in three varieties, called alleles (ah-LEELS), designated with a lower-case "e": e2, e3, and e4. Everyone's APOE gene has two of these three alleles, so there are six possible combinations in any individual's DNA. The e2 allele is associated with decreased risk of Alzheimer's disease. The e3 allele is associated with average risk. Even one e4 allele approximately doubles risk, while two e4 alleles boosts risk eight- to ten-fold.

Scientists have long been aware of the APOE gene and the protein it instructs the body to make, apoE, because this protein plays a role in the metabolism of cholesterol, a key risk factor for heart disease. Recently, researchers discovered that apoE also binds to amyloid, the peptide associated with the senile plaques of Alzheimer's. The various alleles of APOE affect amyloid differently. The e4 allele appears to increase deposition of amyloid in the brain. The mechanism remains a mystery, but is the focus of a great deal of research.

Genetic testing for APOE alleles is currently possible, but it is not widely available because it currently has little predictive value. Despite the increased risk of having two e4 APOE alleles, many people with these two alleles live into their 80s with no sign of Alzheimer's. Currently, genetic testing for APOE alleles only suggests increased risk; it does not predict development of Alzheimer's. But once drugs are developed that can prevent Alzheimer's disease, then APOE testing would make more sense to identify those who would benefit from preventive medication.

Infrequent Use of Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Some years ago, researchers noticed that people with severe arthritis have strikingly low rates of Alzheimer's disease. More recently, Japanese researchers noted a similar unusually low rate of Alzheimer's disease in people being treated for leprosy. Treatment of both leprosy and arthritis involves large doses of medications known as non-steroidal anti-inflammatory drugs (NSAIDS). These drugs include such common, over-the-counter medications as aspirin, ibuprofen (Motrin, Advil), and naproxen (Naprosyn)--but not acetaminophen (Tylenol).

Meanwhile, researchers discovered that inflammation of brain tissue plays a key role in the development of neurofibrillary tangles and beta-amyloid plaques, the anatomical hallmarks of Alzheimer's disease.

These observations strongly suggested that NSAIDs might prevent, or at least delay Alzheimer's disease, or help treat it.

Powerful evidence of NSAID protection against Alzheimer's comes from the 38-year Baltimore Longitudinal Study of Aging. Researchers from the National Institute on Aging assessed NSAID use in 1,828 elderly, 110 of whom developed Alzheimer's from 1980 to 1995. Every two years, all subjects filled out extensive food and drug surveys, and were given a battery of cognition and memory tests. People who took NSAIDs more than occasionally for at least two years were 30 to 60 percent less likely to develop Alzheimer's disease. As duration of NSAID use increased, Alzheimer's risk decreased. All NSAIDs other than aspirin significantly reduced risk. Aspirin did not reach statistical significance, but there was a trend toward lower risk with increased duration of more-than-occasional aspirin use. (Stephenson, J. "More Evidence Links NSAIDs, Estrogen with Reduced Alzheimer's Risk," Journal of the American Medical Association (May 8, 1996) 275:1389.)

NSAIDs also slow cognitive decline in people who have Alzheimer's. Researchers at the Johns Hopkins Alzheimer's Disease Research Center tested 210 Alzheimer's sufferers over time to see how rapidly they lost cognitive ability. Some showed rapid mental deterioration, while others declined more slowly. Then the researchers reviewed everyone's medical records to see who had been taking NSAIDs. They found that as NSAID use increased, the rate of mental deterioration decreased. (Rich, JB et al. "Nonsteroidal Anti-Inflammatory Drugs in Alzheimer's Disease," Neurology (1995) 45:51).

The main problem with NSAIDs is that they carry a significant risk of stomach distress, and gastrointestinal bleeding, which can become serious.

According to studies to date, many different NSAIDs have Alzheimer's-protective effects, among them: ibuprofen (Motrin, Advil, Nuprin), naproxen (Naprosyn), indomethacin (Indocin), meclofenamate (Meclomen), and possibly aspirin.

In Women, No Use or Brief Use of Post-Menopausal Estrogen Replacement Therapy. Compared with men, women are at greater risk of developing Alzheimer's disease. However, several recent studies show that postmenopausal hormone replacement therapy helps prevents--or at least delay--Alzheimer's disease. Estrogen also helps treat the disease.

Several studies show that women who take estrogen after menopause have an unexpectedly low rate of Alzheimer's disease. Among women with Alzheimer's, those taking estrogen suffer less severe symptoms and slower mental deterioration. In addition, animal studies show that estrogen improves blood circulation through the brain, and stimulates nerve cell growth in areas of the brain affected by Alzheimer's.

These findings are summarized in a report published in the July 1996 Journal of the American Geriatric Society by Stanley Birge, M.D., a geriatrician at the Washington University School of Medicine in St. Louis. Birge calls these estrogen findings "terribly exciting" and potentially "among the most promising recent discoveries about treating Alzheimer's."

Estrogen boosts the production of acetylcholine, a key chemical (neurotransmitter) involved in the transmission of nerve impulses across the tiny gaps between nerve cells (synapses). Estrogen also impedes the deposition of beta-amyloid, the protein involved in the characteristic plaques of Alzheimer's disease. In addition, estrogen improves blood flow through the brain, and enhances verbal abilities of postmenopausal women who take hormone replacement therapy. Estrogen also helps maintain the integrity of the hippocampus, an area of the brain involved in memory. (Kawas, C. et al. "Treating Alzheimer's Disease: Today and Tomorrow," Patient Care, Nov. 15, 1996, 62-83.)

Several lines of evidence suggest that estrogen has value against Alzheimer's disease:

Several epidemiological studies show that taking estrogen reduces women's risk of Alzheimer's disease. (Paganini-Hill, A. et al. " Estrogen Deficiency and Risk of Alzheimer's Disease," American Journal of Epidemiology (1994) 140:256.) In one notable report, New York City researchers investigated risk of Alzheimer's among 1,124 elderly women. During the follow-up period, Alzheimer's disease developed in 14.9 percent of the women. Among women who had never used estrogen, the figure was 16.3 percent, while only 5.8 percent of estrogen users developed Alzheimer's. Among estrogen users, risk decreased with hormone use for longer than one year. (Tang, MX et al. "Effect of Estrogen During Menopause on Risk and Age at Onset of Alzheimer's Disease," Lancet (1996) 348:429.)

As part of the 38-year Baltimore Longitudinal Study of Aging, researchers from the National Institute on Aging assessed 16 year's worth of medical records for 514 postmenopausal women. They found that compared with women who had never taken estrogen, those who had were 54 percent less likely to develop Alzheimer's disease. (Stephenson, J. "More Evidence Links NSAID, Estrogen Use with Reduced Alzheimer's Risk," Journal of the American Medical Association (May 8, 1996) 275:1389.)

Estrogen also helps treat Alzheimer's disease in women. In a 30-week study of 318 women with mild to moderate Alzheimer's disease, all participants took tacrine (Cognex), one of only two drugs currently approved to treat the disease, and some also took estrogen replacement therapy. Compared with those on tacrine only, the women taking tacrine plus estrogen fared better on a number of cognitive measures. (Schneider, LS et al. "Effects of Estrogen Replacement Therapy on Response to Tacrine in Patients with Alzheimer's Disease," Neurology (1996) 46:1580.)

In addition to helping prevent and treat Alzheimer's disease, a great deal of research shows that the sex hormone also helps prevent heart disease, women's leading cause of death, and osteoporosis, bone-thinning that can lead to serious fractures.

But for all its benefits, estrogen also carries some risks. It increases breast cancer risk an estimated 20 to 30 percent, and also increases uterine cancer risk if the woman takes it without another sex hormone, progesterone. If you'd like to take postmenopausal discuss it with your physician, who can help you weigh your risks of heart disease, osteoporosis, Alzheimer's disease, and breast cancer.

Estrogen helps only women reduce their risk of Alzheimer's disease. The female sex hormone is rarely given to men.

Deficiency of Antioxidant Nutrients. We humans need oxygen to live, but oxygen also has a downside. In the body, some oxygen molecules become so highly chemically reactive that they disrupt other body processes. These troublemaker molecules are called "free radicals," and many scientists believe that the damage they inflict (oxidative damage) is at the root of both cancer and heart disease. (Smoking and a high-fat diet greatly increase the number of free radicals in the blood.)

Free radicals also contribute to the development of Alzheimer's disease.

Fortunately, certain nutrients--antioxidants--can prevent the oxidative damage free radicals cause. Antioxidant nutrients include: vitamin A, vitamin C, vitamin E, the mineral selenium, and vitamin A's close chemical relatives, the carotenoids, among them beta-carotene. These nutrients are abundant in plant foods, and many studies show that as fruit and vegetable consumption increases, risk of every cancer decreases.

A few studies have investigated the effects of antioxidants on Alzheimer's disease. Results to date have been intriguing:

Czech researchers gave the antioxidant drug selegiline to 173 people with mild to moderate Alzheimer's disease. After six months, their memory improved significantly. In another study, selegiline enhanced the benefits of tacrine (Cognex), the only drug currently approved for Alzheimer's treatment. (Kawas, C. et al. "Treating Alzheimer's Disease: Today and Tomorrow," Patient Care (Nov. 15, 1996) pp. 62-83.)

Head injuries. Some evidence suggests that head injuries resulting in loss of consciousness increase risk of Alzheimer's disease. (Duara, R. "Unlocking the Mysteries of Alzheimer's Disease," Patient Care (Nov. 15, 1996) pp. 44-61.)

Heart disease, stroke, and high blood pressure (hypertension). These diseases damage blood vessels including vessels in the brain. This damage contributes to the death of brain cells, increasing risk of Alzheimer's disease. (Skoog I. et al. "15-Year Longitudinal Study of Blood Pressure and Dementia," Lancet (1996) 347:1141)

Family history of Down syndrome. Having a close relative with Down appears to increase risk.


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