Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer Disease (AD + Psychosis, AD+P), affecting ~ 40% to 60% of individuals with AD. Psychosis is a marker for a subtype of AD associated with more rapid cognitive and functional decline, poor outcomes including premature institutionalization, and elevated caregiver distress. Current treatments for AD+P have limited efficacy and cause excess mortality. It is thus imperative to develop a translational approach to promote discovery regarding the biology of AD+P and identify opportunities to intervene to prevent its adverse trajectory. We initially reported that AD+P aggregates in families with a heritability of ~61%, findings since replicated in independent cohorts. These observations, and additional findings from our genetic studies, led us in the current funding interval to hypothesize that AD+P results from a set of risk alleles that includes risk alleles for schizophrenia (Sz), but not risk alleles for AD. Our findings during the current funding interval have further illuminated the genetic architecture of AD+P: 1) We have independently replicated our finding of the association of common genetic variation with AD+P; 2) We have similarly replicated our prior finding of a significant association of AD+P with polygenic variation associated with Sz, including our prior, biologically intriguing, observation that the direction of most allelic effects on risk are opposite for Sz and AD+P; 3) Contrary to our hypothesis, we found that polygenic variation at loci associated with AD risk associate with psychosis risk in AD, and this polygenic contribution is independently additive with the contribution of Sz risk variants; 4) We have developed novel methods to map individual cognitive and cognitive-behavioral trajectories that incorporate genetic variation in predicting the probability of transition to psychosis. These findings have led us to a revised hypothesis: AD+P results from risk alleles that include unique AD+P risk alleles and subsets of alleles associated with Sz and AD; these alleles combine to yield a more rapidly deteriorating cognitive trajectory and an increased probability of transition to psychosis. We will now test our hypothesis by first performing an unbiased survey of the genome, including the use of innovative analytic methods that we and others have developed to further identify genetic variants associated with AD+P (Aim 1); then leveraging advances in the genomics of AD and Sz to refine the contribution of polygenic risk for these disorders to AD+P (Aim 2); and validating across cohorts the prediction of the adverse cognitive and behavioral trajectory of AD+P by variants identified in the preceding Aims (Aim 3). By identifying genetic variants that predict psychosis onset in AD, upon completion, these studies may provide a means to identify individuals at risk for the poor outcomes associated with AD+P so they can be targeted for ad...