Alzheimer's disease (AD) causes severe cognitive and social impairment and is the most common cause of dementia in the elderly, affecting approximately five million people in the United States and 30 million people worldwide. Three highly penetrant genes have been identified that can harbor mutations causing most Mendelian forms of AD, although such familial cases account for only 5% of the AD burden in the population. For the remaining sporadic cases of AD, the e4 allele of the APOE gene has been identified as the most important genetic risk factor. However, over one-third of AD patients lack the e4 allele and less than one third of e4 heterozygotes surviving to age 80 years develop AD, implying that other genetic and environmental risk factors influence AD susceptibility. Several candidate genes have been evaluated to assess their role in AD, but none have been confirmed as having an impact on AD risk. The research proposed herein will use a well-characterized collection of unrelated Caucasian and African American AD cases and non-demented, age-matched controls to carry out a large-scale association study using 100,000 single nucleotide polymorphisms (SNPs) located within 34,237 (96%) of known or predicted genes. This study will employ a cost effective, high-throughput method of SNP analysis that relies on DNA pooling and chip-based mass spectrometry to compare allele frequencies among AD cases having at least one e4 allele, AD cases lacking e4, and non-demented controls. This design will allow us to identify genes that influence 1) overall risk of AD and 2) risk of AD in the presence or absence of e4. Results for the most strongly associated SNPs will be verified by genotyping. In subsequent steps, genetic associations will be verified by replication in an independent collection of AD cases and controls and discordant sibships, and elaborated by targeted SNP discovery and haplotype analysis in conserved genomic regions.