The goal of this study is to identify the genetic determinants of late-onset Alzheimer's disease (AD). The proposed study uses Perlegen Sciences' high-density oligonucleotide array-based genotyping platform to genotype over 1.5 million single nucleotide polymorphisms (SNPs) across the genome in the context of a whole-genome association study of late-onset AD. Late-onset AD is a devastating neurodegenerative disease, characterized by the formation of pathogenic plaques in the brain, which affects as many as 10% of people 65 or older. The disease is complex, likely to involve the interaction of a number of genes, including apolipoprotein E, which increases risk and lowers age of onset. Studies aimed at identifying additional late-onset AD-susceptibility genes are ongoing. Using Perlegen Sciences' high-density array technology, SNPs associated with late-onset AD will be identified by measuring SNP allele frequency differences between 400 individuals with late-onset AD (cases) and 400 matched unaffected controls from samples in the NIMH AD Genetics Initiative collection. The initial 1.5 million SNP scan will be performed using separately pooled case and control DNA samples. A subset of these SNPs will be selected for verification based on the largest estimated allele frequency differences, haplotype structure and biological relevance. Genotyping the individual case and control samples, as well as a replicate population will verify the association of these SNPs with late-onset AD. The number of SNPs to be analyzed in this study is orders of magnitude higher than in previously published case-control studies, rendering this the most comprehensive search for genetic loci involved in AD. In addition to providing further evidence regarding the role of previously identified candidate loci, the study may also identify novel associations with unsuspected loci. Identification of new genetic factors associated with AD will lead to a better understanding of the molecular mechanisms underlying the disease and provide a basis for new approaches to treatment and prevention.
