I serve as Director of the Genetics and Aging Research Unit at MGH, which focuses on the molecular genetics of Alzheimer's disease (AD), as Vice Chair of Neurology and Co Director of the McCance Center for Brain Health. We played key roles in discovering three genes that cause early onset familial AD, including the amyloid protein (A4) precursor (APP), and the presenilin genes (PSEN1 and PSEN2). In 1993, we discovered the Wilson's disease gene, and over the past 25 years, I have directed the Alzheimer’s Genome Project, in which we have identified several novel AD genes, including ADAM10 and CD33. We have elucidated the mechanism of action by which CD33 initiates neuroinflammation in AD with TREM2. Most recently, my laboratory used whole exome and whole genome sequencing data from to identify rare functional variants influencing risk for AD. Since 2000, we have developed the field’s leading gamma secretase modulators, leading a clinical trial candidate. More recently, we characterized the GSMs in a novel AD model that recapitulates both plaque and tangle pathology using human stem cell derived neurons and glia grown in a three dimensional cell culture system (dubbed “Alzheimer’s in a Dish”).