Genetics of psychosis in AD

 
   Lead Investigator:    Rob Sweet
   Institution      :    University of Pittsburgh
   E-Mail           :    SweetRA@upmc.edu
   Proposal ID      :    482


   Publications:


1  DeMichele-Sweet M, Weamer EA, Klei L, Vranag DT, Hollingshead DJ, Seltman HJ, Sims R, Foroud T, Hernandez I, Moreno-Grau S, T^{unicode 00E1}rraga L, Boada M, Ruiz A, Williams J, Mayeux R, Lopez OL, Kamboh MI, Devlin B, Sweet RA
   Genetic Risk for Schizophrenia and Psychosis in Alzheimer Disease
   Journal Article  Mol Psychiatry,23:963-972,2018,PMC5668212

   PUBLISHED





   Proposal Description:
   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, cause excess mortality detectable after even short-term treatment, and may worsen the more rapid cognitive and functional decline. 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.  To address this goal, we have exploited our initial observation of the familial aggregation of AD+P, now replicated in two independent cohorts. We have completed the first Genome-Wide Association Study (GWAS) of AD+P, finding strong preliminary evidence for association with novel loci and with psychosis risk loci shared with schizophrenia. In contrast we have found that AD+P is not associated with several established risk genes for neurodegeneration, including APOE. Finally, we have clarified that the adverse cognitive trajectory of AD+P emerges within the earliest stages of AD, and have developed innovative analytic methods to chart personal trajectories of cognitive decline and test the impact of genetic variation on them.      From Mary Ann DeMichele-Sweet:    Psychotic symptoms, defined as the occurrence of delusions or hallucinations, are frequent in Alzheimer Disease (AD + Psychosis, AD+P), aggregate in families and are heritable. We hypothesize that AD+P results from risk alleles that include unique AD+P risk alleles and subsets of alleles associated with schizophrenia (Sz) and AD these alleles combine to yield a more rapidly deteriorating cognitive trajectory and an increased probability of transition to psychosis.  We will perform an