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

Abstract

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 0.01. 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.

Psychosis in Alzheimer’s Disease

“…CCNG1 may act to inhibit tau phosphorylation by cyclin-dependent kinases [39,40]. This study found that polygenic risk for schizophrenia was protective against psychosis risk in AD, although opposing findings exist which implicate genetic liability of schizophrenia [41]. It should be noted that neither study nor the majority of candidate gene association studies have found psychosis risk to be influenced by APOE4 genotype [42].…”

Psychosis as a Treatment Target in Dementia: A Roadmap for Designing Interventions

“…In the aforementioned GWAS, depressive symptoms were positively genetically correlated with psychosis, while bipolar disorder was negatively correlated. No genetic correlation was found with schizophrenia, but previous studies using schizophrenia polygenic risk scores to evaluate shared genetic liability have reported associations with psychosis in AD and in Huntington's disease, and with psychotic experiences in the general population [120][121][122][123].…”

Neuropsychiatric Symptoms and Functional Decline in Alzheimerʼs Disease and Lewy Body Dementia

“…Screening of NPSs may help identify patients with especially high risk of a more severe course. 36,37 These patients could be more vulnerable to polypharmacy, institutionalization, poor control of comorbidities, lack of mobility/immobilization, frailty, and isolation. Other potential explanations are more stress and disruption due to NPSs, leading to functional deterioration.…”

“…People with more severe NPSs showed a stronger association with functional deterioration. Screening of NPSs may help identify patients with especially high risk of a more severe course 36,37 . These patients could be more vulnerable to polypharmacy, institutionalization, poor control of comorbidities, lack of mobility/immobilization, frailty, and isolation.…”