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

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.

NIMH is one of the 18 institutes that make up the National Institutes of Health, part of the Public Health Service within the Department of Health and Human Services.

THE NIMH GENETICS INITIATIVE

The National Institute of Mental Health launched the broad and multifaceted Genetics Initiative in 1989 to provide a national resource for research on families containing multiple individuals affected by Alzheimer's Disease, schizophrenia or bipolar disorder. The primary goal of this initiative is to establish a data bank with potential for linking genetic and clinical/diagnostic information for research by qualified investigators in the scientific community. For the Initiative, NIMH established several sites which, following a common protocol, identify families that contain at least two individuals affected with the disorder under study. Diagnostic, demographic, and clinical information is collected in a standardized fashion from affected individuals and their relatives, and maintained in a central computerized database. Blood samples are sent to a central cell repository that creates tissue cultures from which DNA can be extracted. As new genetic markers are identified in the future, scientists can easily obtain a new sample of DNA to examine each subject's genetic profile. All clinical, diagnostic and biological data collected for the Initiative have been rendered anonymous through removal of all personal identifiers -- to safeguard the rights, welfare and confidentiality of subjects who participate in the Initiative.

The report published in the February issue of Neurology was funded by the NIMH Genetics Initiative. Samples for this study came from three sites: Massachusetts General Hospital, affiliated with Harvard Medical School in Boston; the University of Alabama School of Medicine in Birmingham; and The Johns Hopkins Medical School in Baltimore.

For this study of Alzheimer's Disease, families were recruited from memory disorder clinics, nursing homes, and the communities surrounding the three sites. They were required to contain at least two living blood relatives with memory problems. One member of the pair was required to meet standard criteria for probable AD, and the other for possible or probable AD. Autopsies, which are the only way to definitively diagnose AD, have been performed on 113 of the initial subjects, with 112 (99.1%) meeting neuropathologic criteria for definite AD.

Steven O. Moldin, Ph.D., Chief, Genetics Research Program and Scientific Coordinator, NIMH Genetics Initiative has said, "Given our lack of knowledge of exactly how many genes are involved in AD and how they interact, it becomes very difficult to determine exactly how large a genetic sample should be. Experience with schizophrenia and bipolar disorder as well as with other genetically complex disorders like type I diabetes, suggests that sample sizes of at least 400 to 500 families ultimately may be required. The NIMH is currently exploring the various options for the growth and enrichment of this scientific resource."

Genetic research offers an opportunity to determine how AD develops and to develop a genetic test to identify individuals with the disease. Identification of persons with mild cognitive complaints who are at risk for AD would allow physicians to apply existing antidementia treatments before extensive brain damage develops, thereby slowing the progression of AD and substantially reducing the number of years of disability associated with the disease. This is especially important because no currently foreseeable treatment for AD would reverse permanent neuronal damage. Early detection strategies can provide reassurance to people whose age-related memory complaints are benign or help in the diagnosis of other more treatable causes of dementia. In addition, patients may wish to know their prognoses while their mental faculties are intact so that they can plan for their future care. The currently available genetic test involving the gene apoE-4 has been deemed an unreliable predictor of AD, emphasizing the need for more research into the genetics of this complex disorder.