Highlight
1. Anticholinergic burden (AChB) from medications is linked to poorer cognitive performance and decreased total gray matter volume in individuals with psychosis spectrum disorders.
2. Polygenic scores (PGSs) for cognition and psychiatric disorders modify the impact of AChB on cognitive outcomes and brain structure, demonstrating significant gene-by-environment interactions.
3. Cognitive impairment associated with AChB may be partially mediated by reductions in gray matter volume, with effects moderated by composite psychiatric genetic risk.
Study Background
Psychotic disorders, including schizophrenia and bipolar disorder with psychotic features, are characterized by enduring cognitive deficits and brain structural abnormalities that contribute to functional impairments. Medications with anticholinergic properties, commonly prescribed for various psychiatric and somatic indications in this population, have been implicated as a modifiable risk factor exacerbating cognitive dysfunction. However, inter-individual variability in cognitive responses to medication burden remains poorly understood, with genetic predispositions emerging as potential modulators. This study addresses a critical gap by investigating how polygenic liability to cognitive function and psychiatric illnesses interact with anticholinergic burden to influence cognition and brain morphology in psychosis spectrum disorders.
Study Design
The authors recruited 1,704 individuals aged 18–65 years diagnosed with psychosis spectrum disorders from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) consortium, encompassing diverse ancestry groups. Participants underwent comprehensive cognitive testing using the Brief Assessment of Cognition in Schizophrenia (BACS), structural magnetic resonance imaging to quantify total gray matter volume, genotype analysis to derive polygenic scores, and meticulous medication history review.
Anticholinergic burden was quantified using the CRIDECO Anticholinergic Load Scale, reflecting cumulative exposure to scheduled medications with anticholinergic effects. Polygenic scores were generated separately for cognition, schizophrenia, bipolar disorder, and major depression, then combined into a composite psychiatric polygenic score. Multivariable linear regression models examined interactions between AChB and each PGS concerning cognitive and brain structural outcomes, controlling for clinical covariates and multiple testing via false discovery rate adjustments. Furthermore, hypothesis-driven moderated mediation analyses explored whether gray matter volume mediated cognitive effects of AChB, moderated by genetic risk.
Key Findings
The study found that higher anticholinergic burden was strongly associated with reduced cognitive performance as measured by the BACS composite score. Concurrently, greater AChB correlated with diminished total gray matter volume, underscoring its deleterious impact on brain structure.
Importantly, the adverse cognitive effects of anticholinergic burden were amplified in individuals with higher polygenic scores for cognitive ability. This suggests a gene-by-environment interaction wherein genetic predisposition to cognition modulates susceptibility to medication-related cognitive decline.
Conversely, participants with lower composite psychiatric polygenic scores exhibited more pronounced gray matter volume reductions associated with AChB, indicating differential vulnerability based on psychiatric genetic risk profiles.
Moderated mediation analyses revealed that gray matter volume partially mediated the negative effect of anticholinergic burden on cognition, with this pathway itself influenced by composite psychiatric PGS. These findings highlight a complex interplay between genetics, medication exposure, brain structure, and functional outcomes.
Expert Commentary
This investigation advances the field by integrating genomic data with pharmacologic exposure to elucidate mechanisms underlying cognitive impairment in psychosis. It highlights the importance of considering polygenic risk and cumulative anticholinergic load in clinical decision-making to minimize cognitive adverse effects. The differential patterns of vulnerability—enhanced cognitive deficits in those genetically predisposed to higher cognition versus greater brain volume susceptibility in those with lower psychiatric risk—invite further mechanistic studies.
Limitations include cross-sectional design limiting causal inference and potential residual confounding from unmeasured factors such as illness severity or lifestyle variables. Additionally, the broad CRIDECO scale may not capture nuances of individual drug pharmacodynamics. Replication in longitudinal cohorts and intervention studies targeting medication optimization are warranted.
Conclusion
This study provides compelling evidence that genetic predispositions significantly interact with anticholinergic drug burden to influence cognition and brain structure in psychosis spectrum disorders. These gene-by-environment interactions elucidate heterogeneity in cognitive impairment and consolidate the rationale for personalized medication management to preserve cognitive and brain health. Future research should explore targeted strategies to reduce anticholinergic load and consider genetic profiling as part of comprehensive risk assessment in psychotic disorders.
