Alzheimer's disease is known to have a strong genetic basis, but it is not well understood. Prior work on families with dominantly inherited Alzheimer's disease significantly advanced our understanding of the role of beta-amyloid in the disease. This paved the way to a broader understanding of how Alzheimer's disease develops not only in individuals from these rare families but in those with common forms of the disease. Ultimately, these insights have guided the development of new therapies to halt or slow the progression of this devastating and relentless disease, which are ongoing. Our study seeks to find additional therapeutic targets by identifying new genetic mechanisms of disease. We aim to identify new genetic causes of Alzheimer's disease in a large family with highly penetrant, dominantly inherited late-onset Alzheimer's disease. This family has been recruited over the last 11 years by researchers at the NIA-funded Emory Alzheimer's Disease Research Center. We currently have recruited 143 individuals, including 112 who have donated biological specimens, who span 10 generations from the original founders in 3 major branches. Genetic screening revealed no family member with an AD-causing mutation. In our proposal, we marry cutting-edge technology and classical genetic techniques to discover the AD-causing gene in a large multi-generational family. Because individuals in this pedigree are distantly related but continue to transmit AD as a dominantly inherited trait, we hypothesize that they share a rare or previously described AD-causing mutation. To test this hypothesis, we propose to identify all rare or previously described genetic variants among 12 distantly related affected members of this kindred using whole-exome sequencing. Next, we will test whether variants that are shared among the 12 affected individuals co-segregate with AD in the entire pedigree. Because there are approximately 10 generations separating affected individuals any variant that co-segregates with AD in the entire pedigree is likely causal since it is highly unlikely that a variant would co-segregate with AD ove that many generations by chance alone. To better understand the role of the gene containing the co-segregating variant in AD, we will examine the (1) expression of the gene in post- mortem tissue and (2) determine the genetic contribution of the gene to AD using an independent cohort.