Search for Modifying Factors in the Genetic Risk of Alzheimer's Disease

Findings from epidemiology, genetics, and molecular and cell biology suggest that the development of Alzheimer's disease is characterized by a pathologic change in the normal processing of certain proteins. Yet the risk factors identified so far, though intriguing, explain only a small proportion of the observed phenotypic variation. In particular, one of the directly observable hallmarks of Alzheimer's disease --the density of amyloid plaques-- is only weakly correlated with the severity of dementia, while such plaques are also present in most elderly people. Using data from 227 late-onset families with 493 affected and 114 unaffected siblings, all of whom genotyped with respect to 222 polymorphic markers in a genome-wide scan, we addressed the question of the extent to which genetically predisposed factors may modify the development of Alzheimer's disease in terms of onset and severity of illness. Our novel multivariate genotype-to-phenotype search strategy was based on a genetic similarity function that allowed us to quantify the inter-individual genetic distances d(xi,xj) between feature vectors xi, xj made up by the allelic genotype patterns of any two subjects i, j with respect to n loci l1, l2, .. ln. Thus, we were able to assess the within-family genetic similarities on the basis of oligogenic models. Specifically, we searched for a multivariate configuration of marker loci for which the between-sib genetic similarity in affected sib pairs deviated from the between-sib similarity in pairs discordant for the disease. Such deviations were expected if the oligogenic model contained marker loci close to vulnerability genes or protective genes. Of particular interest were those loci that contributed to a significant oligogenic configuration while displaying significant dissimilarities in the discordant pairs. Our algorithm yielded a configuration of 7 marker loci that may be associated with factors that modify the development of Alzheimer's disease. The reproducibility of this marker configuration is currently being investigated using a multiple random splitting approach.

Key words: Alzheimer's disease, molecular genetics, genetic diversity, population admixture

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