Association between schizophrenia polygenic score and psychotic symptoms in Alzheimer’s disease: meta-analysis of 11 cohort studies

Background Psychosis (delusions and hallucinations) is common in Alzheimer’s disease (AD) and associated with worse clinical outcomes including accelerated cognitive decline and shorter time to nursing home admission. Atypical antipsychotics have limited efficacy which, along with emerging genomic research, suggests some overlapping mechanisms with other disorders characterized by psychosis, like schizophrenia. In this study, we tested whether polygenic risk score (PRS) for schizophrenia was associated with psychotic symptoms in AD. Methods Schizophrenia PRS was calculated using Psychiatric Genomics Consortium data at 10 GWAS p-value thresholds ( P T ) in 3,173 AD cases from 11 cohort studies. Association between PRS and AD psychosis status was tested by logistic regression in each cohort individually and the results meta-analyzed. Results The schizophrenia PRS was associated with psychosis in AD at an optimum P T of The strongest association was for delusions where a one standard deviation increase in PRS was associated with a 1.17-fold increased risk (95% CI: 1.07-1.3; p=0.001). Conclusion These new findings point towards psychosis in AD – and particularly delusions – sharing some genetic liability with schizophrenia, and support a transdiagnostic view of psychotic symptoms across the lifespan.