Project 3 Project Summary Aging populations worldwide, particularly in developed countries, face an increasing burden of neurodegenerative diseases. The most common neurodegenerative disease is Alzheimer disease (AD), which is characterized by protein misfolding and aggregation. One intriguing characteristic is the broad spectrum of age at onset, even within specific risk groups (i.e, mutation carriers). Furthermore, the existence of resilient individuals (individuals who are positive for known biomarkers or have a high burden of genetic risk variants but do not exhibit symptoms), suggests that there are protective and disease-modifying genetic factors. The goal of this Project is to identify variants and genes that confer resilience as well as novel protective and modifying factors. We will use genetic data (GWAS, Exome-chip, Whole Exome Sequencing and Whole Genome Sequencing) from resilient individuals and compare them with matched affected individuals to identify protective and modifying genetic factors. The multi-factorial etiology and heterogeneity of AD may reveal itself in racial or ethnic differences in overall AD risk and in putative risk or protective factors or in the progression of neuropathology. For this reason, we will also determine if the modifier and protective variants, genes and pathways also play a role in other races, especially in African Americans.