It would be of considerable value to develop predictoors of susceptibility to drug-induced cognitive toxicity in the elderly, since centrally acting medications, such as the benzodiazepines, continue to be widely prescribed in this population and older individuals may be more sensitive to some of the adverse central effects. Moreover, normal age-related decline in cognitive functions may accentuate the significance of drug-induced deficits. Our preliminary data from studies examining the acute effects of various benzodiazepines (diazepam, alprazolam, and lorazepam) on performance of cognitively intact normal volunteers suggest that possession of the ApoE-oplison4 allele may increase susceptibility to drug-induced cognitive toxicity. Buschke total and delayed recall were imparied in subjects with the oplison4 allele but not in those without this allele. This relationship between impairment and the presence of the opsilon4 allele was found despite the inclusion of younger subjects in the study, and only one subject homozygous for the e4 allele, in a group of participants who were not selected on the basis of family history of Alzheimer's disease (AD). The proposed research will more directly assess whether the epsilon4 allele is associated with increased susceptibility to drug-induced cognitive toxicity in normal cognitively intact older persons. We will study the cognitive effects of one of the benzodiazepines in the population most at risk for the deleterious effects of the opsilon4 allele on brain function: older, non-demented cognitively intact individuals who have a documented history of AD in a first degree relative and are homozygous for the epsilon4 allele (ApoE epsilon4/epsilon4 genotype). They will be compared with an appropriate, age-matched control group without the epsilon4 allele.
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