Shared Genetic Liability Observed for Schizophrenia, Psychosis in Alzheimer Disease

The study examined 3 psychotic phenotypes: psychosis wide, psychosis narrow, and delusions narrow.

Psychosis in Alzheimer disease (AD) may share genetic liability with schizophrenia, according to an article published in Translational Psychiatry. The study raises the prospect of a transdiagnostic approach to psychotic symptoms across the lifespan.

Byron Creese, PhD, a senior research fellow at the University of Exeter Medical School in the United Kingdom, led study efforts to calculate schizophrenia polygenic risk scores (PRS) from Psychiatric Genomics Consortium data in patients with AD and psychotic symptoms. Clinical and genotype data from 3111 patients with AD were abstracted from 11 cohort studies conducted in Europe and the United States with validated, standardized tools.

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Psychotic symptoms for all patients were assessed with the Neuropsychiatric Inventory. The study examined 3 psychotic phenotypes: psychosis wide, psychosis narrow, and delusions narrow. After quality control and imputation procedures, a total of 4,895,913 single nucleotide polymorphisms (SNPs) were available to compute PRS, and after clumping, 76,213 independent variants were used. PRS was calculated at 10 genome-wide association study P-value thresholds (PT). Logistic regression was used to test the association between PRS and AD with psychosis, both for individual cohorts and in the pooled sample.

Across the 11 cohorts (mean age at baseline range, 75-87 years; 26%-59% men), the majority of patients were in the mild-moderate stages of dementia at first assessment, and cohorts with greater dementia prevalence also experienced more psychosis. Of 3111 screened individuals, 1116 (36%) tested positive for psychosis wide or the general phenotype for psychosis. The study excluded 879 patients who had not yet reached a moderate stage of dementia. Delusions narrow, comprising patients without hallucinations, were observed in 936 patients.

Per random effects meta-regression, schizophrenia PRS was associated with psychosis in AD, with the largest effect sizes observed at PT =.01. Schizophrenia PRS was significantly associated with symptom status for the psychosis wide group (odds ratio [OR], 1.14; 95% CI, 1.05-1.23; P =.003). In analyses with the modified control group, the association between schizophrenia PRS and psychosis symptom state persisted in both the psychosis narrow (OR, 1.16; 95% CI, 1.06-1.28; P =.004) and delusions narrow (OR, 1.18; 95% CI, 1.06-1.30; P =.001) groups.

As study limitations, investigators noted the variability inherent in using several study cohorts rather than a single sample. In addition, results may not be generalizable to patients without European ancestry, given the largely homogenous genetic makeup of the study cohorts.

Overall, the study found a particularly strong relationship between genomic factors for delusions in AD and schizophrenia. The study authors wrote, “This provides a strong rationale for further work to build a clearer clinical and biological understanding of the psychosis syndrome in AD, an urgently needed step for better management and treatment development.”

Disclosure: Two study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Creese B, Vassos E, Bergh S, et al. Examining the association between genetic liability for schizophrenia and psychotic symptoms in Alzheimer’s disease. Transl Psychiatry. 2019;9(1):273.