Prediction of Psychosis in Alzheimer Disease

• Objectives of the proposed research:
To identify genetic correlates of psychotic symptoms, defined as the occurrence of delusions or hallucinations, in individuals with Alzheimer Disease (AD+Psychosis, AD+P)

• Study design:
Individuals who were analyzed in our genome-wide meta-analysis of psychosis in AD (https://www.medrxiv.org/content/10.1101/2020.08.07.20139261v1 and Mol Psychiatry, in revision) who have available whole exome or whole genome sequence data will be included. We will analyze the association of psychosis with the presence of missense, stop/gain/truncating, and canonical splice site mutations with the presence of psychosis at all loci in which our GWAS identified a suggestive (p<10-6) or a significant (p<5x10-8) association with psychosis.

• Analysis plan:
Analyses as described above will be conducted in individuals of European ancestry using Fisher’s exact test and the SKAT family of tests as appropriate. Psychosis presence/absence will be as defined in https://www.medrxiv.org/content/10.1101/2020.08.07.20139261v1. Covariates (sex, CDR score, age) will be included as appropriate.

• If applicable, a brief description of any planned collaboration with researchers at other institutions, including the name of the collaborator(s) and their institutions(s).
N/A

Individuals who develop psychotic symptoms such as delusions or hallucinations during Alzheimer disease (AD) have a more rapid deterioration and worse outcomes. We have found that the risk for developing psychosis during AD is influenced by genetic factors. In this proposed research plan, we build on our prior genome-wide association study (GWAS) of psychosis in the context of AD by asking if promising GWAS signal corresponds to association signal from whole-exome sequencing. To do so, we evaluate the correspondence between our GWAS association signals and those from whole-exome sequencing. We will also conduct an exploratory analysis of individuals with AD, with and without psychosis, for sequence variants that predispose to psychotic symptoms in Alzheimer disease.