The Indianapolis-Ibadan Dementia Project has now demonstrated that incidence rates for Alzheimer disease (AD) and dementia are significantly lower in Yoruba than in African Americans. In our new application we are proposing to study intensively risk factors which may explain the differences in incidence rates. As these risk factors are likely to be multiple, complex, involving genetic, environmental as well as genetic-environmental interactive influences, larger cohorts than those we currently possess will be required. We propose to enrich our current surviving cohort of 800 subjects in each site by recruiting an additional 2000 African Americans and 2000 Yoruba, 70 years and over, for a total of 2800 subjects at each site. With this enlarged sample we propose to measure ApoE genotypes and ApoE promoter haplotypes on all subjects in both cohorts. As exploration of site differences suggest that factors associated with increased vascular risk may be a productive line of investigation, we will also measure a number of biochemical values known to be associated with cardiovascular risk. We will continue to collect our current clinical, neuropsychological and socio-demographic data. With these new data we propose to test the following hypotheses. 1) Possession of the e4 allele of ApoE will be a stronger risk factor for AD in African Americans than in the Yoruba. The ApoE 2 allele will be protective for AD in the African Americans but not in the Yoruba. 2) Vascular risk factors increase the risk of dementia, AD and cognitive decline within each population site. The lower prevalence of these factors accounts for some of the differences in rates of AD and dementia between sites. 3) The interaction between ApoE genotypes and vascular risk factors alter the strength of the association between the ApoE 4 and 2 alleles and AD and account for some of the variation in AD rates between the populations. Our secondary aims are, 1) to continue to develop measurements of social engagement and activity levels which can be applied validly across sites; 2) to continue to evaluate natural history of cognitive and social functioning in two community-dwelling cohorts and to identify factors which may predict decline in cognitive and social function; 3) to determine if ApoE promoter haplotype is a risk factor for AD and correlate this risk with promoter transcriptional activity; and 4) to store blood, plasma and DNA samples for future genetic and biological studies.
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