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NIMH Genetics Initiative Study Steers Alzheimer’s Disease Research in New Direction

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NIMH investigators have found in a sample of Alzheimer’s disease (AD)-prone families that the Apolipoprotein E-4 (apoE-4) gene may exert its most marked effect in those in whom the disease develops at age 70 or younger. However, in this largest genetic study of AD to date, the gene remained a significant risk factor even at later ages.

The apoE-4 gene confers increased risk of developing AD, suggesting that it plays a significant role in the disease process. One copy of apoE-4 moderately increases an individual’s risk of developing AD, while two copies confer a higher risk. At least one copy of the apoE-4 gene is borne by about one-half of those with AD in general population-based surveys, and by only about one-quarter of those without the disease.

The findings from the new report reaffirm the importance of this gene in conferring risk for AD and suggest that it asserts its maximal effect before age 70, at least in the families studied in this project. Combined results of large population-based studies will be necessary to determine the overall age-related risk conferred by the apoE-4 gene.

This study is the latest to suggest that additional genetic factors likely play a role in later onset forms of the disease. Steven E. Hyman, M.D., Director of the National Institute of Mental Health, whose Genetics Initiative funded the study, said, “These results should steer scientists to look for additional genetic clues to the later onset, more common form of this terrible, mind-destroying disease.”

The newly published research is remarkable for its sample size of 679 individuals in 310 families, which was large enough for the researchers to separate out individuals by age at onset of AD symptoms. Rudolph E. Tanzi, Ph.D., of Harvard’s Massachusetts General Hospital, the senior author of the study, said, “It remains critical to search for additional genes involved in the development of late-onset AD.”

The newly published research also shows that in the studied families, several individuals over 80, who were Alzheimer’s-free, carried two copies of the apoE-4 gene. So, said Dr. Tanzi, it seems premature to offer apoE testing as the sole predictive test for AD. This position is consistent with that of two national panels that examined the practical considerations regarding genetic assessment for AD using apoE-4. However, said Dr. Tanzi, genetic research carries the greatest promise to ultimately clarify mechanisms leading to the development of AD. “In the future, reliable genetic tests for AD could be used to identify those who are most likely to develop the disease,” he said. “In this complex disease, such genetic tests might have to take into consideration the combined effects of multiple risk factor’ genes and, perhaps, other non-genetic risk factors.”

Dr. Tanzi’s Harvard collaborators on the study, published in the January issue of Neurology, were lead authors, Deborah Blacker, M.D., Sc.D., and Jonathan Haines, Ph.D., along with principal investigator Marilyn S. Albert, Ph.D.

Source: National Institute of Mental Health

Press Release

April 24, 1997

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