The P&S Journal: Spring 1998, Vol.18, No.2
Alzeimer's and Genetics
Two studies, one published in February and one in March, bring into clearer focus the gene implicated in Alzheimer's disease. One study shows the limitations of genetic testing; the other suggests that the genetic factor affects races differently.
In one study, apolipoprotein-E (APOE) genotyping for Alzheimer's was shown to be of significant value in diagnosing the disease only when coupled with old-fashioned medicine-a thorough clinical evaluation.
The study, reported in the Feb. 18, 1998, issue of the New England Journal of Medicine, emphasizes that results from testing for the presence of the e4 form of APOE by itself is inconclusive and does not provide sufficient evidence to diagnose Alzheimer's disease. Researchers discovered that when the APOE test is administered along with a thorough examination, the validation of the clinical diagnosis of Alzheimer's disease could be greatly improved. The study is the largest cooperative investigation to date involving 26 federally funded Alzheimer's disease centers nationwide, including P&S researchers in collaboration with the National Institute on Aging.
"The apolipoprotein E genotype may be undeniable as a genetic risk factor for Alzheimer's disease, but its use as a diagnostic aid has received little attention until now," says Dr. Richard Mayeux, senior author and Gertrude H. Sergievsky Professor of Neurology, Psychiatry, and Public Health (epidemiology), and co-director of the Taub Center for Alzheimer's Disease Research.
Investigators, led by Dr. Mayeux, reviewed the eligibility of men and women referred to the 26 Alzheimer's disease centers for diagnosis of dementia. The study examined records of 1,108 women and 1,080 men. Each patient examined had a battery of clinical and behavioral tests, followed by numerous laboratory and brain imaging studies. The patients were followed throughout the course of their disease and their brains were examined after they died.
Based on autopsies, Dr. Mayeux found that 93 percent of the patients who were found to have Alzheimer's had been diagnosed by a physician as having the disease. However, 45 percent of individuals found to have other forms of dementia at the time of autopsy also had been diagnosed by physicians as having Alzheimer's. This high rate of false positive diagnoses shows the limitations of using recommended clinical criteria alone. But by testing for the APOE genotype only in patients who first met clinical criteria for Alzheimer's, the false positive diagnoses decreased from 45 percent to 16 percent.
Dr. Mayeux cautions that the study was done in a selected group of people who received treatment in specialized centers for Alzheimer's disease so the results may not apply to all individuals. "More broad-based study is needed before these results can be assumed to be universally applicable."
The study's other P&S authors were Dr. Steven Shea and Dr. Ming-Xin Tang.
The other study, reported in the March 11, 1998, issue of the Journal of the American Medical Association, examined the effect of the presence of APOE-e4 on increased risk of Alzheimer's disease among African-Americans and Hispanics. The study found that African-Americans and Hispanics have an increased risk of Alzheimer's disease whether or not they carry APOE-e4.
African-Americans and Hispanics with APOE-e4 have approximately the same risk of Alzheimer's disease as do whites with the allele, the study found. But African-Americans without the APOE-e4 genotype have four times the risk of developing Alzheimer's disease than do whites without the genotype, and Hispanics have 2.5 times the risk.
The study's lead author, Dr. Ming-Xin Tang, and colleagues determined the genotypes of approximately 1,000 elderly volunteers, all residents of Washington Heights. The researchers then monitored the health of the volunteers over five years to assess them for signs of Alzheimer's disease (all volunteers were free of any signs of disease at the start of the study). The researchers controlled for other factors that might affect risk for the disease, such as education levels. And to reduce the likelihood that the results might be swayed by a misdiagnosis of Alzheimer's, the researchers also calculated their results only among those who developed severe forms of the disease.
The researchers are not certain what causes the increased risk among the two minority groups. "It could be genetic or it could be due to environmental factors," says Dr. Tang, assistant professor of public health (biostatistics) in the Sergievsky Center. Researchers are planning a follow-up study.
Dr. Mayeux notes, "This research highlights an important point: When something is found to be true among whites, we can't automatically assume it will be true for other ethnic groups as well."
The study's other authors were Drs. Yaakov Stern, Karen Marder, Karen Bell, Barry Gurland, Rafael Lantigua, Howard Andrews, Lin Feng, and Benjamin Tycko. An NIH grant supported the study.