Family-based approaches led to the identification of disease-causing Alzheimer’s Disease (AD) variants in the genes encoding amyloid-beta precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2). Subsequently, the identification of these genes led to the Aβ-cascade hypothesis and recently to the development of drugs that target that pathway. In this proposal, we will identify rare risk and protective alleles. In a recent study, we identified a rare coding variant in TREM2 with large effect size for risk for AD, confirming that rare coding variants play a role in the etiology of AD. We will use sequence data from families densely affected by AD, because we hypothesize that these families are enriched for genetic risk factors. We already have access to sequence data from 695 families (2,462 individuals), that combined with the ADSP data will lead to a very large family-based dataset: more than 805 families and 4,512 participants. Our preliminary results support the flexibility of this approach and strongly suggest that protective and risk variants with large effect size will be found. The identification of those variants and genes will lead to a better understanding of the biology of the disease.