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Presence of Genetic Variation Appears to Accelerate Onset of Alzheimer Disease

CHICAGO The APOE epsilon 4 allele (variation in a certain gene that has been linked with Alzheimer disease) appears to be a powerful risk factor for developing Alzheimer disease (AD), and may accelerate the onset of AD in some persons, but not all, according to an article in the May issue of The Archives of General Psychiatry, one of the JAMA/Archives journals.

According to background information in the article, the incidence of AD increases with age, but little is known about the cumulative incidence of AD over a very long lifetime (100 years) or its relationship to the APOE epsilon 4 allele, a genetic variation that has been identified as a strong genetic risk factor for AD. The prevalence of AD may reach 45 percent or higher after 85 years of age, the article states.

The Cache County, Utah population has been extensively studied for the occurrence of AD. The population is one of the longest-lived in the United States, and includes 719 individuals older than 85 and 249 individuals 90 years and older. Additionally, 97 percent of the population has donated DNA for analysis of the APOE allele.

Ara S. Khachaturian, Ph.D., of Khachaturian and Associates, Inc., Potomac, Md., and colleagues estimated the occurrence of AD as it relates to age, and the number of APOE epsilon 4 alleles in 3,308 elderly participants in the Cache County Study.

The researchers entered their data into a model that estimated the 100-year lifetime incidence of AD was 72 percent, implying that 28 percent of individuals would not develop AD over any reasonable life expectancy. The researchers confirmed that the onset of AD was accelerated in individuals with one and especially with two, APOE epsilon 4 alleles.

"These analyses support our previous observation that APOE genotype primarily influences when, and not whether, individuals will develop AD," the researchers write.

"Our findings do not dispute the importance of APOE as a risk factor for AD. They do, however, suggest a different role for APOE than is sometimes discussed. Through its effects on the timing of disease expression, the gene appears to influence the age-specific risk of AD onset," write the authors. They write that the presence of one, and especially two APOE epsilon 4 alleles "translates to a strongly increased age-specific risk of AD, especially in early old age."

(Arch Gen Psychiatry. 2004;61:518-524. Available post-embargo at archgenpsychiatry.com)

Editors Note: This study was supported by a grant from the National Institutes of Health, Bethesda, Md. (Dr. Breitner) and a grant from the National Institute of Mental Health (Dr. Zandi).

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