Offering the possibility of a simple blood test that could help predict Alzheimer's, a study found that elderly people with high levels of the amino acid homocysteine have nearly twice the risk of developing the disease.
Currently there is no good way to predict a person's risk of developing the brain-destroying disease.
But that might eventually become possible by testing for homocysteine and a bad gene that doubles the risk of Alzheimer's, plus reviewing a patient's family history of longevity and Alzheimer's, said Dr. Sudah Seshadri, a Boston University neurologist who led the study.
Previous studies have shown that people with Alzheimer's and other forms of dementia have higher levels of homocysteine in their blood than others. The new study is the first to document high levels in people years before they developed Alzheimer's.
Homocysteine levels can be lowered by getting more folic acid and related B vitamins. But scientists said more research is needed to show whether lowering homocysteine levels can, in fact, ward off Alzheimer's.
Researchers already know that elevated homocysteine levels can raise the risk of heart disease and stroke, and stroke can increase the risk of dementia.
"So it was sort of the next step to look at whether elevated homocysteine leads to an increased risk of dementia," Seshadri said.
The study was reported in the New England Journal of Medicine.
The researchers studied 1,092 elderly people who have been part of the Framingham Heart Study since its inception in 1948. That highly regarded study, like the new research, is funded by the National Institutes of Health.
The Framingham study has uncovered key risk factors for heart disease by following several thousand people in the Massachusetts community with check-ups and surveys about their diet, exercise, smoking and other habits.
Seshadri and colleagues examined data from checkups on the 1,092 people in the late 1980s and eight years before, including their homocysteine levels and neurological exams showing they did not have Alzheimer's. The patients, now 76 on average, were followed through 2000.
By then, 83 had been diagnosed with Alzheimer's and 28 others had other forms of dementia.
The 25% with the highest homocysteine levels were 1.9 times more likely to have developed some form of dementia than the others.
"The higher your homocysteine is, the greater the risk is," Seshadri said.
The Alzheimer's Association estimates up to 4 million Americans have Alzheimer's and roughly 2 million have other forms of dementia.
Dr. Bill Thies, the association's vice president for medical and scientific affairs, said the "impeccable" study makes it clear homocysteine level is an important risk factor for Alzheimer's.
"What it doesn't tell us is whether it's a modifiable risk factor," he said.
Homocysteine levels in Americans' blood have been dropping since 1990, when the government required cereal and bread makers to fortify their products with folic acid to prevent a serious brain malformation in fetuses.
Dr. Artiss Powell, associate professor of neurology at University of Medicine and Dentistry of New Jersey in New Brunswick, said it is unclear whether the findings apply to the entire U.S. population because the Framingham study participants are mostly white.
Powell also said several factors besides homocysteine and genes are believed to affect the risk of Alzheimer's, including levels of mentally stimulating activity and gender. Alzheimer's is about three times more common in women. Thies warned people against taking vitamin supplements to lower their homocysteine without consulting a doctor. Seshardi said people would be better off eating more green, leafy vegetables and fruits, which contain folic acid.
"In addition to reducing your risk of heart attack and stroke, it's probably going to reduce your risk of Alzheimer's," she said.
February 13, 2002 - People with elevated levels of homocysteine in the blood had nearly double the risk of developing Alzheimer's disease (AD), according to a new report from scientists at Boston University. The findings, in a group of people participating in the long-running Framingham Study, are the first to tie homocysteine levels measured several years before with later diagnosis of AD and other dementias. The report, which appears in the February 14, 2002, issue of The New England Journal of Medicine, provides some of the most powerful evidence yet of an association between high plasma homocysteine and later, significant memory loss.
The relationship between AD and the amino acid homocysteine is of particular interest because blood levels of homocysteine can be reduced, for example, by increasing intake of folic acid (or folate) and vitamins B6 and B12. The therapeutic use of these compounds is being explored as scientists try to understand better homocysteine's role in AD or other types of dementia as well as its possible link to various forms of heart disease.
The dementia/AD study is being conducted by Philip A. Wolf, M.D., Boston University (BU), and colleagues at BU and Tufts University, who authored the new findings. The study was supported by the National Institute on Aging (NIA), part of the National Institutes of Health (NIH). The researchers were also funded by NIH's National Institute of Neurological Disorders and Stroke (NINDS). The Framingham Heart Study is supported by the NIH's National Heart, Lung, and Blood Institute (NHLBI).
"The Framingham population gave us the perfect opportunity to look at homocysteine levels in a group of people without memory problems over a period of several years, well before any evidence of dementia," Wolf pointed out. "This is the clearest demonstration yet of the relationship between elevated homocysteine levels and dementia," he noted.
"The evidence is beginning to mount regarding homocysteine's role in dementia," according to Neil Buckholtz, Ph.D., chief of the Dementias of Aging program at the NIA. "The good news is that we may have found a potential risk factor for AD that is modifiable. We don't know yet whether reducing homocysteine levels will reduce dementia risk, but this is something that can and will be tested in clinical trials." Buckholtz noted that the NIA-sponsored Alzheimer's Disease Cooperative Study, a nationwide consortium of research centers, is already planning a clinical trial of folate and vitamins B6 and B12 to test whether reducing homocysteine levels with high doses of these vitamin supplements can slow the rate of cognitive decline in people diagnosed with AD.
Wolf and colleagues followed 1,092 people in a "dementia-free" group of the Framingham cohort. Participants in this group, whose average age was 76, were enrolled in the study between 1976 and 1978. Plasma homocysteine levels were measured between 1979 and 1982 and between 1986 and 1990. Researchers also considered age, sex, vascular risk factors other than homocysteine, and plasma levels of folate and vitamins B6 and B12 of the participants. Information from the participants was also available on the late-onset AD genetic risk factor APOE-e4.
From the 1986-1990 examinations through December 2000, some 111 people developed dementia, including 83 diagnosed specifically with AD. Elevated homocysteine levels (defined as greater than 14 mmol/liter) doubled the chance that a participant would develop AD and each 5 mmol/liter elevation increased the risk of AD by 40 percent. The analysis showed further that people with consistently high levels of homocysteine throughout the period of the study were at highest risk for dementia and AD. The researchers also examined whether the earlier levels of homocysteine, measured between 1979 and 1982, had any relationship to the development of dementia or AD later on; this analysis, too, linked elevated levels at least 8 years prior to a later diagnosis of dementia and AD. The association between homocysteine and AD was found to be strong and independent of other factors, such as age, gender, APOE genotype, and other known or suspected risk factors for dementia and AD.
There was no direct association in this study between the serum levels of folate and vitamins B6 and B12 and the development of dementia among the participants. As the relationship between these B vitamin levels, homocysteine, AD, and cardiovascular disease continues to be studied, scientists speculate that consuming adequate amounts of B vitamins by diet or supplementation might help reduce levels of homocysteine in some individuals. Findings from the NHLBI-supported DASH (Dietary Approaches to Stop Hypertension) study suggest that a diet rich in green leafy vegetables, low-fat dairy products, citrus fruits and juices, whole wheat bread, and dry beans can significantly lower levels of homocysteine. The Food and Drug Administration (FDA) now requires the addition of folic acid to enriched breads, cereals, flours, corn meals, pastas, rice, and other grain products. "Although there is no evidence that actually reducing homocysteine levels will prevent AD or cardiovascular disease, a healthy diet low in fat and rich in nutrients is always a good idea," says BU's Wolf.
The National Institute on Aging is a component of the National Institutes of Health, U.S. Department of Health and Human Services.
