Genetics of Alzheimer Disease
Alzheimer disease (AD) is a progressive neurodegenerative disorder of later life with a complex etiology and a strong genetic component. While genetic risk factors for AD clearly exist, defining them has been difficult. Since the description of the three autosomal dominant early-onset genes (APP, PS1, and PS2) and the strong risk associated with APOE, progress has been slow, even though more than 50% of the genetic effect in AD remains unexplained. Although linkage regions, most notably on chromosomes 9, 10, and 12, have been reported, no single gene has been consistently implicated as contributing to AD risk in these regions. In addition, more than 100 functional candidates have been explored for involvement in AD risk, again with no consistent resolution. Uncovering the identity of these additional genetic factors will require an integrated and comprehensive approach. One solution to this growing data flood is genomic convergence, which combines existing, yet disparate information (such as genetic linkage data, allelic/genotypic/haplotypic association data, existing candidate gene results, and gene expression data) to prioritize candidate genes for intensive analysis. We have already demonstrated the utility of this approach with the identification of the GSTO1 gene. Alternate solutions include phenotypic subsetting using clinical variables to characterize clinically homogeneous subsets of patients that may represent underlying genetic heterogeneity, such as Ordered Subset Analysis based on age at onset to identify a novel linkage region on chromosome 2 and the fine mapping of chromosome 12q. Updated application of these various approaches to current problems in AD genetics will be presented and discussed.