There’s Still A Person In There

WHO’S AT RISK?

The cause of Alzheimer’s disease remains a mystery. But scientists have identified several risk factors that increase its likelihood. Some are well-established, and clearly play a role in Alzheimer’s. Others are less firmly established, but probably contribute to risk. And some are quite controversial. They may increase risk, or they may not.

Well-Established Risk Factors For
Alzheimer’s Disease

Increasing Age
This is the main risk factor. The older you grow, the greater your risk.

From age 65 to 74, an estimated 3 percent of the population has Alzheimer’s. From age 75 to 84, the figure rises to about 15 percent. And for those 85 and older, the disease afflicts some 30 to 40 percent.

Oddly, however, according to the Multi-Institutional Research in Alzheimer’s Genetic Epidemiology (MIRAGE) project based at Boston University School of Medicine, after age 90, Alzheimer’s risk declines. Currently, no one knows why.

Female Sex
The MIRAGE Study also shows that at all ages, women’s risk of Alzheimer’s disease is somewhat higher than men’s. By age 93, women’s risk is 13 percent higher. However, women can take something that reduces their risk—postmenopausal hormone replacement therapy (see below).

Family History
Finnish researchers have found that if one member of an identical-twin pair develops Alzheimer’s, the other’s risk is unusually high—40 to 50 percent—which argues for some genetic predisposition.

In addition, having any close relative who develops Alzheimer’s increases risk. MIRAGE project researchers tracked the lifetime risk of 12,971 people who had a first-degree relative (parent, sibling) with the condition. By age 80, people with Alzheimer’s disease in both parents had a 54 percent risk, 1.5 times the risk of the Alzheimer’s in people with just one affected parent, and 5 times the risk of people with two unaffected parents.

On the other hand, having a first-degree relative with Alzheimer’s does not mean that you are fated to develop the disease. In fact, most people with one affected parent don’t develop Alzheimer’s.

Genetics
The fact that Alzheimer’s often runs in families points to some genetic predisposition. The genetic mechanisms of familial Alzheimer’s remain largely unexplained, but a few genetic mutations—specific abnormalities on chromosomes 1, 14, and 21—have been identified that greatly increase risk in some families. The mutations on these chromosomes cause rare clusters of unusually early-onset Alzheimer’s disease in small numbers of families around the world. Along with observations about family history as a risk factor, these defects prove that Alzheimer’s has a genetic component.

Chromosome 21 also causes Alzheimer’s disease in people with Down syndrome. Normally, all cell nuclei (except sperm and egg cells) have two copies of each chromosome. But people with Down syndrome have an extra copy of chromosome 21, and as a result, an extra gene for a protein that plays a role in Alzheimer’s, the gene that codes for production of amyloid precursor protein (APP). If people with Down syndrome survive into their 40’s and 50’s, they almost always develop Alzheimer’s because their extra APP gene causes them to produce abnormally large amounts of amyloid precursor protein, which leads to unusually high levels of beta-amyloid peptide, the major component of the senile plaques of Alzheimer’s.

In addition, chromosome 19 has generated a great deal of interest among Alzheimer’s researchers. A gene on this chromosome plays a signficant role in the most prevalent type of Alzheimer’s, the one that strikes late in life. Chromosome 19 contains a gene that codes for apolipoprotein E (APOE), a protein involved in cholesterol metabolism. There are three natural variations (alleles) of the APOE gene, known as allele 2, 3, and 4. Everyone has two alleles, meaning that there are six possible combinations (2-2, 2-3, 2-4, 3-3, 3-4, and 4-4).

Alzheimer’s risk varies depending on the different allele combinations. In general, allele 2 is protective, while alleles 3 and 4 increase risk (except when they are paired with allele 2). The highest risk is associated with the 3-4 and 4-4 combinations, though many people with one of these combinations do not develop the disease. Recently, a research team led by biostatistician Lindsay Farrer, Ph.D., at Boston University School of Medicine, used sophisticated statistical techniques (meta-analysis) to combine the results of more than 40 studies of APOE allele effects. The results: People with Alzheimer’s are two to three times more likely than the general population to have at least one copy of allele 4, and six to 10 times more likely to have the 4-4 combination. The 3-4 combination also raises risk substantially. But allele 2 is powerfully protective. Even those with the 2-4 combination had a very low risk of Alzheimer’s.

APOE alleles are not evenly distributed throughout the population. In general, allele 3 is the most common (about 78 percent of all alleles), while alleles 2 and 4 are considerably less common (7 and 15 percent respectively) The most common combination, 3-3, occurs in 60 percent of Americans. The 2-2 combination occurs in 0.05 percent (1 per 200), and the 4-4 combination occurs in 2 percent of the population.

APOE alleles also influence age at Alzheimer’s diagnosis. People with the highest-risk 4-4 allele combination who develop Alzheimer’s tend to get diagnosed before age 70, while those with lowest-risk 2-2 pair who develop the disease tend to get diagnosed at around 90.

But unlike the mutations on chromosomes 1, 14, and 21 that cause Alzheimer’s in anyone who has them, APOE allele status does not reliably predict Alzheimer’s risk. Many people with the high-risk 3-4 and 4-4 combinations never develop the disease, and some people with the low-risk allele 2 combinations do. A test that determines APOE allele status is available to physicians, but it does not predict Alzheimer’s very well. Recently, officials of the Program in Genomics, Ethics, and Society at Stanford University released a report discouraging APOE allele testing as a mass screening tool for Alzheimer’s risk because of the combination of its cost, poor predictive value, and the fact that those with higher-risk combinations would suffer considerable anxiety, often unnecessarily.

On the other hand, when doctors evaluate people with suspected Alzheimer’s disease, they increasingly test for APOE allele status. Having even one copy of allele 4 can help make a diagnosis of Alzheimer’s. Without allele testing, clinicians currently diagnose Alzheimer’s correctly in about 90 percent of cases. But in a recent study, when people with suspected Alzheimer’s had at least one allele 4, diagnostic accuracy increased to 97 percent, according to Allen Roses, M.D., the Jefferson-Pilot Corporation professor of neurology and director of the Joseph and Kathleen Bryan Alzheimer’s Disease Research Center at Duke University School of Medicine.

There may also be a gene involved in late-onset Alzheimer’s disease on chromosome 12. Some studies suggest this, but the issue remains controversial.

Finally, Cherokee Indians appear to possess some as-yet-undetermined genetic resistance to Alzheimer’s disease. Scientists from the University of Texas Southwestern Medical Center in Dallas studied 52 members of the Cherokee Nation, who had varying degrees of Cherokee ancestry. Half of those studied had Alzheimer’s disease, and half did not. Using genealogical information supplied by the Cherokee Nation Tribal Registration Department, the researchers discovered that as the participants’ proportion of Cherokee ancestry increased, their Alzheimer’s risk decreased.

Ethnicity
The different racial and ethnic groups have slightly different genetics. One area of difference is the prevlence of high-risk APOE allele 4. African-Americans are most likely to have at least one allele 4 (19 percent), followed by whites (14 percent), Hispanics (11 percent), and Asian-Americans (9 percent).

However, even without an allele 4, African-Americans and Hispanics are two to four times more likely than whites to develop Alzheimer’s by age 90. This finding comes from a recent study by Columbia University neurologists of 1,079 elderly New Yorkers, who were tracked from 1991 to 1996. The researchers controlled for sex, education, family history, and blood pressure, so the differences in risk had nothing to do with any of those attributes.

It’s not clear why African-Americans and Hispanics might be at unusually high risk of Alzheimer’s. But the researchers point to two possibilities--an as-yet-undiscovered gene or environmental factors.

Environmental Factors
Ethnic differences in Alzheimer’s disease rates are only one indication that environmental factors play a role in the disease. The Finnish identical-twin study, mentioned earlier, provides even stronger evidence. That study shows that while genetic factors play an important role in Alzheimer’s, it also clearly shows that genetic identity is not destiny. Identical twins have the exact same genetic make-up, but Alzheimer’s disease develops in only about half of identical-twin pairs. In addition, when both members of an identical-twin pair develop Alzheimer’s, their ages at diagnosis often differ by as much as 15 years. These findings demonstrate that environmental factors also play a role in Alzheimer’s risk, even among those with clear genetic predisposition.

Additional support for environmental factors comes from a recent analysis of a long-term study of Japanese men living in Hawaii. Back in 1965, researchers from the National Institute on Aging recruited 4,000 middle-aged Japanese-American men, and have tracked their health ever since. Thirty years later, in 1995, 3,734 of the men, by then elderly, were still alive. The survivors had a rate of dementia from all causes of 9.3 percent, and 5.4 percent had Alzheimer’s. The researchers then compared the incidence of dementia and Alzheimer’s in a similar group of elderly Japanese men living in Hisayama, Japan. Only 3.2 percent showed dementia, and 1.5 percent had with Alzheimer’s—about one-third the risk.

The researchers did all they could to make sure that the same Alzheimer’s diagnostic criteria were used in both groups of men. The genetics of Japanese-Americans and native Japanese are quite similar, yet their rates of Alzheimer’s varied considerably. Clearly, environmental or cultural factors must play a role in the disease.

Probable Risk Factors For Alzheimer’s Disease

Considerable evidence shows that the following factors increase Alzheimer’s risk, but experts do not yet consider them well-established:

Meat-Based, High-Fat Diet
One clear difference between Japanese in Japan and Japanese-Americans is their diet. Compared with Japanese-Americans, native Japanese eat less meat, and a lower-fat, higher-fiber diet with more fish. Japanese-Americans, on the other hand, generally adopt the burger-fries-and-shake American diet—meat-based, high-fat, and low-fiber. High-fat, low-fiber diets have been persuasively linked to heart disease and many cancers. Recently, they have also been linked to increased risk of Alzheimer’s disease.

At Erasmus University in the Netherlands, researchers gave cognitive function tests to a large number of Dutch people, and asked 5,300 who were cognitively normal and over 55 to fill out diet questionnaires. Two years later, they retested them. Those with the poorest cognition scores had the diets highest in total fat, saturated (animal) fat, and cholesterol.

Meanwhile the more fish the participants ate, the higher their cognitive scores. In food folklore, fish has a reputation as a “brain food.” There may be something to this. Cold water fish, for example, salmon and mackerel, are high in omega-3 fatty acids, which help prevent the blood clots in the brain that cause most strokes. And as fish consumption increases, high-fat meat consumption—and the cognitive impairment linked to it—tend to decline.

Corroborating evidence of diet as a risk factor for Alzheimer’s comes from a study by Yorktown, Virginia, Alzheimer’s researcher William Grant, Ph.D. He compiled statistics from 11 countries around the world (in Africa, Asia, Europe, and North America), and found that the highest rates of Alzheimer’s occur in countries with the highest-fat diets. Alzheimer’s risk also correlated to total number of calories consumed.

He then zeroed in on the U.S., Canada, and five European countries: England, Italy, Spain, Finland, and Sweden. The populations of all these countries consume about the same proportion of total calories as fat, but the Finns and Swedes eat considerably more fish. They also have lower rates of Alzheimer’s disease.

Why would a meat-based, high fat diet raise Alzheimer’s risk? Because dietary fat causes “oxidative damage.” We humans need oxygen to live, but oxygen also has a major 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 a meat-based, high-fat diet floods the bloodstream with them. The emerging scientific consensus is that the damage free radicals inflict (oxidative damage) plays a significant role in the development of cancer, heart disease, and other illnesses, including, it now appears, Alzheimer’s.

The role of free radicals in Alzheimer’s risk was recently confirmed by a team of researchers led by Garret FitzGerald, M.D., chair of the department of pharmacology at the University of Pennsylvania Medical Center in Philadelphia. The autopsy study compared evidence of free-radical activity in the brain tissue of people who died with and without Alzheimer’s. Those with Alzheimer’s had double the free-radical activity in their frontal and temporal lobes, areas critical to memory and cognitive function.

Smoking also greatly increase the number of free radicals in the blood—see below.

Deficiency of Antioxidant Nutrients
Fortunately, certain nutrients—antioxidants—can, to a considerable extent, prevent the oxidative damage free radicals cause. Antioxidant nutrients include: vitamin A (and its close chemical relatives, the carotenoids, among them beta-carotene), vitamin C, vitamin E, and the mineral, selenium. These nutrients are abundant in plant foods, and many studies show that as fruit and vegetable consumption increases, risk of diseases linked to oxidative damage, notably cancer and heart disease, decreases. Antioxidants are also available as supplements. Researchers at Harvard and elsewhere have shown that a diet high in vitamin E, or daily consumption of 100 IU of a supplement reduces risk of heart attack risk by more than 30 percent.

Recent research has also shown that antioxidants, notably vitamin E and the antioxidant Parkinson’s drug, selegiline (Eldepryl), slow the rate of cognitive decline in Alzheimer’s disease (see Chapter 10).

Might antioxidants also reduce risk of Alzheimer’s? To date, no rigorous studies have investigated this issue. But it’s a good bet that the answer is yes. Oxidative damage contributes to the brain changes that result in Alzheimer’s, and antioxidants help treat the disease. It makes sense that deficiencies of these nutrients would be a risk factor for Alzheimer’s.

Cardiovascular Disease:
Heart Disease, Stroke, High Blood Pressure (Hypertension), and Diabetes
These diseases damage the blood vessels, including those in the brain. Given sufficient blood-vessel damage, enough brain cells can die to cause “vascular dementia” (“vascular” refers to the blood vessels). Stroke is the best-known cause of vascular dementia. In addition, a series of mini-strokes, medically known as transient ischemic attacks (TIA’s) can cause a similar type of vascular dementia (multi-infarct dementia, or MID). And recent research shows that chronic high blood pressure, cardiac arrest, and diabetes, which also damage the blood vessels and greatly increases risk of heart disease, are all risk factors for vascular dementia.

Until recently, researchers believed that vascular dementia and Alzheimer’s were two entirely different diseases. A person might have both (mixed dementia), but scientists considered Alzheimer’s a neurological condition, and vascular dementia a disease of the circulatory system. Then both vascular dementia and Alzheimer’s were linked to oxidative damage, and the line between them began to blur. Recently, Alzheimer’s was linked to activation of platelets, the blood cells that play a key role in clotting. The platelets are also involved in cardiovascular disease. The upshot is that Alzheimer’s and cardiovascular disease appear to have more and more in common. The underlying cause of cardiovascular disease is atherosclerosis, arterial narrowing by cholesterol-rich plaque deposits. Not surprisingly, the latest studies show that atherosclerosis also raises risk of Alzheimer’s.

At Erasmus University Medical School in Rotterdam, Dutch researchers discovered a correlation between atherosclerosis and Alzheimer’s disease. They studied 1,900 people, 207 of whom had Alzheimer’s. Using sophisticated ultrasound equipment to measure atheroscerlosis in the carotid arteries that carry blood into the brain, they discovered that as carotid atherosclerosis increased, so did risk of both MID and Alzheimer’s.

Stroke also raises risk of Alzheimer’s. In a study of elderly Roman Catholic nuns at the Sanders-Brown Center for Aging at the University of Kentucky, David Snowdon, Ph.D., and colleagues have discovered that even small strokes in certain areas of the brain dramatically increase risk of Alzheimer’s disease. They tested the cognitive function of 102 elderly nuns, age 76 to 100, and then performed brain autopsies after they died. Of the 61 nuns who showed autopsy evidence of Alzheimer’s disease, those who also had had strokes were significantly more likely to have developed Alzheimer’s before they died. And those with small strokes in certain specific areas of the brain were 20 times more likely to have developed Alzheimer’s.

Meanwhile, the APOE gene that plays a role in Alzheimer’s risk also appears to relate to dementia risk after a stroke. At Columbia University in New York, researchers analyzed the APOE allele status of 594 stroke survivors, 187 of whom had suffered significant dementia. Stroke survivors who became demented were significantly more likely to have at least one copy of high-risk allele 4. Compared with those who had two copies of allele 3, those with one allele 4 had twice the risk of post-stroke dementia, while those with two allele 4’s had seven times the risk.

Diabetes damages the blood vessels and substantially increases risk of heart disease. It also raises risk of Alzheimer’s, according to researchers at the Mayo Clinic in Rochester, Minnesota, and the Mayo Foundation in Scottsdale, Arizona. They followed 1,455 type 2 diabetics (people who did not inject insulin) for 14 years. Various types of dementia developed in 101 of them, of whom 77 were diagnosed with Alzheimer’s. Compared with nondiabetic controls, those with diabetes were 66 percent more likely to develop Alzheimer’s.

Finally, chronic high blood pressure (hypertension) raises risk of Alzheimer’s disease. Ingmar Skoog, M.D., an assistant professor of medicine at Goteborg University in Sweden, followed a group of elderly Swedes for 15 years, and found that a 10-year history of hypertension significantly increased their risk of both stroke and Alzheimer’s.

Smoking
Smoking is a disaster for the circulatory system. It boosts blood levels of free radicals, damages the blood vessels, raises blood pressure, contributes to atherosclerosis, and is a major risk factor for heart disease and stroke. It should come as no surprise, therefore, that smoking also increases risk of Alzheimer’s disease.

Back in 1990, the previously mentioned Alzheimer’s researchers at Erasmus University in Rotterdam surveyed 8,000 Dutch people over age 55 about their smoking habits. Five years later in 1995, they determined who among them had developed Alzheimer’s. The smokers were at significantly greater risk.

A 1998 study by the same group showed that compared with lifelong nonsmokers, women smokers are twice as likely to develop Alzheimer’s and men who smoke have six times the risk.

Ironically, nicotine, the addictive drug in cigarette smoke, boosts cognitive function in people with Alzheimer’s and is under investigation as a possible treatment for the disease (Chapter 10).

Infrequent Use of
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Some years ago, researchers noticed that people with severe arthritis have unexpectedly low rates of Alzheimer’s. More recently, Japanese researchers noted a similar unusually low rate of the disease in people being treated for leprosy. The medications used to treat both leprosy and arthritis are non-steroidal anti-inflammatory drugs (NSAID’s). Around the same time, researchers discovered that inflammation of brain tissue plays a key role in the development of the neurofibrillary tangles and beta-amyloid plaques of Alzheimer’s disease. These observations strongly implied that NSAID’s anti-inflammatory action might prevent, or at least delay Alzheimer’s, and possibly help treat it.

Several widely used over-the-counter drugs are NSAID’s: aspirin, ibuprofen (Motrin, Advil), and naproxen (Naprosyn). (However, acetaminophen (Tylenol) is not an NSAID. It is only a pain reliever. It has no anti-inflammatory action.) In addition, there are dozens of prescription NSAID’s.

Powerful evidence of NSAID protection against Alzheimer’s comes from the Baltimore Longitudinal Study of Aging (BLSA). Every two years for almost 40 years, BLSA participants have filled out extensive food, drug, and lifestyle questionnaires, and have taken a battery of cognition and memory tests. Recently, researchers from the National Institute on Aging assessed NSAID use in 1,828 people in the study, 110 of whom developed Alzheimer’s from 1980 to 1995.

As their frequency and duration of NSAID use increased, their Alzheimer’s risk decreased—by up to 60 percent. All NSAID’s (except aspirin) significantly reduced risk, including: ibuprofen, naproxen, indomethacin (Indocin), and meclofenamate (Meclomen). Aspirin’s effect did not reach statistical significance, but there was a trend toward lower risk with increased duration of more-than-occasional aspirin use.

NSAID’s also help slow cognitive deterioration in Alzheimer’s (Chapter 10).

Unfortunately, NSAIDs often cause side effects—abdominal distress, and potentially serious—even life-threatening—ulcers and gastrointestinal bleeding.

In Women, No Use or Brief Use of
Post-Menopausal Hormone Replacement Therapy
Compared with men, women are at somewhat greater risk of Alzheimer’s disease. However, several recent studies show that postmenopausal hormone replacement therapy (HRT), which contains the female sex hormone, estrogen, helps prevents—or at least delay—Alzheimer’s in women. In other words, little or no use of HRT is a risk factor for the disease.

Here’s the evidence:

• Animal studies show that estrogen improves blood circulation through the brain, and stimulates nerve cell growth in the parts of the brain affected by Alzheimer’s.

• Several epidemiological studies show that taking HRT—which is primarily estrogen—reduces women’s risk of Alzheimer’s disease. New York City researchers followed 1,124 elderly women for many years. Among those who had never used estrogen, 16.3 percent developed Alzheimer’s, but among women who had used HRT for at least one year, only 5.8 percent developed the disease.

• As part of the previously mentioned Baltimore Longitudinal Study of Aging (BLSA), Claudia Kawas, M.D., an associate professor of neurology at Johns Hopkins University and clinical director of Alzheimer’s research there, assessed 16 years of medical records for 514 postmenopausal women. Compared with women who had never taken HRT, those who had were 54 percent less likely to develop Alzheimer’s disease.

• In another study of BLSA participants, researchers tested the memories of 288 women, none of whom had Alzheimer’s. HRT had been used by 116 of them. The estrogen users had better memories. They made significantly fewer errors on the memory test.

• HRT use reduced Alzheimer’s risk 75 percent in a 1998 report by Marzia Baldereschi, M.D., of the Italian National Research Council in Rome. She analyzed HRT use by 2,816 women enrolled in the Italian Longitudinal Study. Ninety-two eventually developed Alzheimer’s, but only three of them had ever taken HRT.

• Tamoxifen, a close chemical relative of estrogen prescribed to treat breast cancer, also helps prevent Alzheimer’s disease, according to a recent (1998) study by New York researchers. Brenda Breuer, Ph.D., associate director of research at the Jewish Home and Hospital in New York, analyzed the medical records of all 93,031 women who resided in nursing homes in New York State in 1993. Among the 1,378 who had taken tamoxifen to treat breast cancer, 8 percent also had Alzheimer’s. Then, for each tamoxifen-user, Breuer identified up to four very similar nursing home residents who had not taken the estrogen drug. Among those 5,167, the prevalence of Alzheimer’s was 12 percent.

• Finally, in a 1998 analysis, a research team led by psychiatrist Kristine Yaffe, M.D., of the University of California Medical Center in San Francisco, amalgamated the results of 10 previous studies of HRT in postmenopausal women. Overall, HRT users were 29 percent less likely to develop Alzheimer’s.

Estrogen reduces risk of Alzheimer’s in several ways: It boosts production of acetylcholine, a brain chemical (neurotransmitter) involved in sending nerve impulses across the tiny gaps between nerve cells (synapses). It reduces production of the type of beta-amyloid that forms senile plaques. It improves blood flow through the brain. And it aids the function of the hippocampus, an area of the brain involved in memory. Stanley Birge, M.D., a geriatrician at the Washington University School of Medicine in St. Louis, calls these findings about estrogen’s ability to prevent Alzheimer’s “among the most promising recent discoveries about the disease.”

Estrogen also helps treat Alzheimer’s (Chapter 10).

Beyond Alzheimer’s, a great deal of research shows that HRT 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, HRT also increases breast cancer risk about 30 percent.

If you’re a postmenopausal woman, should you take HRT? This question has no easy answer. The best advice is to discuss the issue with your doctor, weighing your individual risk of heart disease, osteoporosis, Alzheimer’s, and breast cancer, and your own personal level of anxiety about each of these diseases.

Head Injuries
Some evidence suggests that head injuries resulting in loss of consciousness increase risk of Alzheimer’s disease and the cognitive problems that afflict about 20 percent of former boxers, notably, Mohammed Ali. But the research has been inconsistent and inconclusive. Recently, neurologists at New York-Hospital-Cornell Medical Center discovered that by themselves, blows to the head do not appear to raise risk of Alzheimer’s or other types of dementia. But in those with at least one copy of APOE allele 4, head injuries raise risk considerably.

The researchers studied 30 former boxers, all of whom had sustained countless blows to the head. Eleven showed normal cognitive function. Twelve showed minor deficits. Four were moderately impaired. Three were severely demented.

Risk of cognitive impairment increased with years of boxing, showing that number of blows to the head is, indeed, a risk factor for dementia.

But boxers with an APOE allele 4 showed significantly more mental impairment, and every boxer with severe dementia had at least one copy of allele 4.

Scientists cannot explain why the combination of head injuries and allele 4 conspire to cause Alzheimer’s-like dementia. They speculate that the head injuries trigger Alzheimer’s-type changes in the brain, and that APOE allele 4 prevents the body from repairing them.

Controversial Risk Factors For
Alzheimer’s Disease

Some research suggests that the following factors might raise Alzheimer’s risk, but as this book goes to press, they remain highly controversial:

Low Educational Level
Several studies show that intellectual pursuits—college education, recreational reading, taking classes for personal enrichment, doing crossword puzzles, etc.—helps preserve cognition. Or, to put it another way, lack of education is a risk factor for Alzheimer’s. But controversy surrounds the issue of education and Alzheimer’s.

The latest research casts substantial doubt on the notion that lack of education is a risk factor for Alzheimer’s. The problem, according to many prominent researchers, is not with the minds of those who have little education, but rather with the tests used to assess them. The tests, they say, are biased in favor of those with considerable education, and make those without it appear demented when they are actually cognitively normal.

A common test used in Alzheimer’s assessment is the Mini-Mental State Exam (MMSE). But according to F.M. Baker, M.D., a professor of psychiatry at the University of Maryland, several studies have shown that when African-Americans take the MMSE, if they have fewer than eight years of formal education, the test often produces false findings of dementia.

The same is true for Hispanic individuals. According to dementia researchers Marcel Ponton, Ph.D, of the department of psychiatry at UCLA and I. Maribel Taussig, Ph.D. of Naples, Florida, many studies “have shown convincingly that [on standard tests], less educated individuals tend to score much like brain-injured individuals. Education makes a significant difference in the performance of Spanish-speaking individuals on tests such as the MMSE.” Even when cognitive assessment tests are written and given in Spanish, they may produce false indications of impairment. One widely used test, the Wechsler Adult Intelligence Scale—Revised (WAIS-R) was translated in the mid-1960’s with the help of Puerto Rican Spanish speakers. Drs. Ponton and Taussig contend that it is of dubious value in testing elderly Spanish-speakers from Mexico or Central America almost 40 years later, especially if they are fairly recent immigrants. (As this book goes to press, the WAIS is being revised to increase its applicability to Spanish-speakers from Mexico or Central America.)

The situation is similar for elderly Asians, and probably applies to poorly educated whites as well.

Poor Linguistic and Writing Ability
In 1996, University of Kentucky researchers suggested that analysis of people’s writing ability during their 20’s could accurately predict their development of Alzheimer’s 60 years.

A team led by David Snowdon, whose work has been mentioned previously in this Chapter, studied 93 nuns who joined the Sisters of Notre Dame in the 1920’s. As part of their preparation, each wrote autobiographies, which the order archived. Sixty years later, by the 1980’s, almost one-third of the nuns, by then in their 80’s had been diagnosed with Alzheimer’s disease. Fourteen had died, and the researchers performed brain autopsies to look for the diseases’ characteristic abnormalities. Five had them.

The researchers then went back to the deceased nuns’ archived autobiographies to see if they might offer clues to their later development of Alzheimer’s. Without knowing who had written the essays, the researchers evaluated them for two aspects of language ability—grammatical complexity and idea richness. The scientists judged nine of the autobiographies to be grammatically complex and intellectually rich, that is, packed with ideas. They considered the other five to be idea-poor and grammatically simple. Finally, they linked each of the nuns to her autobiography. None of the nine whose writing was idea-dense and grammatically complex had developed Alzheimer’s. But all of those whose work was idea-poor and grammatically simple had succumbed. The researchers suggested that young-adult writing samples might predict later development Alzheimer’s with up to 90 percent accuracy. They wrote: “Our findings indicate that low linguistic ability early in life is a potent marker...of Alzheimer’s disease risk late in life.”

But other researchers have raised serious doubts about this study. One concerned the evaluation criteria. Grammar can be assessed objectively using standardized tests of sentence structure. It turned out that grammatical simplicity was not related to the nuns’ eventual development of Alzheimer’s. Meanwhile, the researchers’ conclusions were based largely on idea density, a subjective criterion.

The second objection concerned the study’s sample size—just five nuns out of 93 with autopsy-confirmed Alzheimer’s disease. Critics argued that such a small number of cases is not enough to conclude anything.

It’s possible that language ability during young adulthood may have something to do with developing Alzheimer’s later in life. But as this book goes to press, the nun study’s conclusion must be considered speculative.

A History of Seizures
Seizures are caused by electrical problems in the brain. Because Alzheimer’s disease also affects the brain, researchers have wondered if the two might somehow be connected.

Researchers at the Mayo Clinic in Rochester, Minnesota, compared 145 people suffering various forms of dementia with 290 similar people, age 55 and older, who were cognitively normal for their age. Compared with the controls, the people with Alzheimer’s were six times more likely to have suffered seizures as adults, and those with other forms of dementia were eight times more likely to have had at least one seizure.

This is a provocative finding, but it has yet to be replicated, so it must be viewed with caution.

Head Circumference
The smaller your head, the greater your Alzheimer’s risk, according to a study by researchers at Columbia University in New York. They measured head circumference of 649 residents of Manhattan who were participants in the North Manhattan Aging Project, and then correlated those measurements with their cognitive abilities, while controlling for potentially confounding factors: height, weight, ethnicity, education, and APOE allele status.

For both men and women, those whose head circumference was smallest had the greatest risk of Alzheimer’s disease. Compared with women who had the largest heads, women with the smallest had 2.9 times the risk. Men with the smallest heads had 2.3 times the risk.

A few other studies have suggested that as head size increases, Alzheimer’s risk decreases. Why would head size relate to Alzheimer’s risk? Because in general, people with larger heads have larger brains inside them.

A larger brain might protect against Alzheimer’s in any of several ways: The leading theory is that people with large brains have more brain tissue in reserve, so that the changes of Alzheimer’s disease don’t manifest as quickly or as severely. It’s also possible that a small brain might reflect a genetic predisposition to the disease, or result from exposure to environmental factors that increase risk.

At this writing, the role of head size in Alzheimer’s risk, if any, remains controversial.

Exposure to Large Amounts of Zinc
In a test-tube study, Australian researchers discovered that an unusually large intake of the essential trace mineral, zinc, promotes changes in brain cells similar to the senile plaques of Alzheimer’s disease. The study showed that beta-amyloid, which is found in soluble form in the healthy brain, forms plaque-like clumps at zinc concentrations only slightly higher than those typical of the normal brain.

The authors based their work on earlier trials in which people with Alzheimer’s disease were given zinc supplements, and appeared to show accelerated cognitive deterioration.

However, zinc is an antioxidant, and a good deal of research has shown that a diet high in antioxidants helps prevent Alzheimer’s (see Deficiency of Antioxidant Nutrients earlier in this Chapter). Indeed, other research has shown that Alzheimer’s disease may well be linked to a zinc deficiency. In a 1997 study, South African researchers gave 30 mg of zinc a day for a year to Alzheimer’s sufferers, and reported “modest cognitive improvement.”

The research on zinc is all over the map. As this book goes to press, it’s simply not clear what role, if any, zinc play in risk—or prevention—of Alzheimer’s.

Chlamydia Infection
Infection with a common bacteria, Chlamydia pneumoniae, may increase risk of Alzheimer’s accordng to researchers at Johns Hopkins. During brain autopsies, they found the bacteria in 17 of 19 Alzheiemr’s sufferers, but in only one of 19 similar people who had died of other diseases. In those who had Alzheimer’s, chlamydia infection was most likely to affect regions of their brains that also showed the characteristic abnormalities of the disease.

Chlamydia causes sinus infection, bronchitis, and other upper respiratory ailments. These infections can be treated with antibiotics.

Chlamydia can also enter the brain, and might conceivably play a role in triggering the inflammation that contributes to Alzheimer’s.

However, research focusing on the possible Chlamydia-Alzheimer’s connection is in its infancy. As this book goes to press, it remains unclear if the purported link is real, and if so, whether the infection is a cause of a result of Alzheimer’s.

Exposure to Aluminum
Aluminum is unusually abundant in the neurofibrillary tangles of Alzheimer’s disease. For years, rumors have circulated that aluminum cookware contributed to the disease. And for just as long, scientists have scoffed at this notion because aluminum is one of the most abundant elements on earth and everyone is exposed to a great deal of it.

French researchers compared the aluminum levels in the blood, urine, and cerebrospinal fluid (the fluid surrounding the brain and spinal cord) of 15 Alzheimer’s sufferers and 20 cognitively normal elderly individuals. They found no differences, and concluded that abnormally high absorption of aluminum is not a factor in Alzheimer’s disease. Findings by Spanish researchers tend to corroborate this. M.D. Zapatero and colleagues evaluated aluminum levels in the blood of 356 cognitively healthy people. Their levels increased with age, which suggests that brain-aluminum levels are related to age, not to Alzheimer’s.

But at least two studies have linked Alzheimer’s and aluminum. The same Spanish group measured aluminum levels in three groups of people: those with Alzheimer’s, those suffering from other dementias, and cognitively normal people of the same age. Those with Alzheimer’s had the highest levels. But the association shown in this study gives no clue about cause and effect. It’s possible that exposure to excess aluminum contributed to Alzheimer’s. It's also possible that for reasons that remain unclear, Alzheimer’s disease triggers aluminum accumulation in the body.

A more disturbing study, published in 1989 in the British medical journal, Lancet, showed an increased risk of Alzheimer’s disease among those whose drinking water contains more than 11 micrograms of aluminum per liter. Yet, in the decade since it was published, its results have not been corroborated, which tends to cast doubt on them.

At this writing, the consensus among Alzheimer’s experts is that exposure to aluminum is not a risk factor for the disease.

Nonetheless, if you’re concerned enough about aluminum to spend about $100 to have your water tested, the National Testing Laboratory of Cleveland includes aluminum in a 74-item test of water quality. They send you sampling test tubes. You fill them with your water, and send then to the lab in a special styrofoam-lined box. A week or so later, the lab sends you a report detailing what’s in your water. For more information, call 1-800-458-3330.