Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and a burgeoning unmet medical need that will only worsen as the average lifespan continues to increase. The prevalence of AD increases with every decade after the age of 60 and ~ 20% of the population can expect to get this devastating disease in their lifetime given the current average lifespan of ~78 years. AD is strongly influenced by inherited factors. In fact, after age, the greatest risk factor for AD is family history. Studies of several thousand pairs of twins have revealed that at least 80% of Alzheimer’s disease involves the inheritance of risk-conferring gene defects—either gene mutations that directly cause the disease, or gene variants that increase susceptibility. To date, we know the identity of four AD genes. Over the last two decades, studies of these four genes, and particularly the three early-onset AD genes co-discovered by Cure Alzheimer’s Fund Research Consortium Chairperson, Dr. Rudy Tanzi, have guided virtually all laboratory research aimed at understanding AD and developing novel therapeutics. As invaluable as the known AD genes have been to solving the mystery of AD and guiding new therapeutic interventions, these four genes account for only 30% of the inheritance of Alzheimer’s disease. While the three early onset AD genes (APP,PSEN1, and PSEN2) account for roughly half of familial early-onset AD, for the most common late-onset (>60 years) form of AD, only one gene has thus far been established to increase susceptibility. This gene is known as the apolipoprotein E (APOE) gene. Since the discovery of the association between AD risk and the E4 variant of the APOE gene, increasing evidence indicates that this variant is neither sufficient nor necessary to cause the disease. We know that APOE works together with other genes to influence one’s inherited risk for AD. To date, the identity of the additional AD genes, which account for 70% of the genetic basis of AD, has remained unknown.