Association Between Psychosis Phenotype and APOE Genotype on the Clinical Profiles of Alzheimer's Disease

Background: Psychosis is a common phenomenon in Alzheimer's disease (AD). The APOE epsilon 4 allele is the strongest genetic risk factor for the development of AD, but its association with psychosis remains unclear. Objective: We investigated the associations between psychosis, subdivided into delusions and hallucinations, as well as APOE epsilon 4 allele on cognitive and functional outcomes. Secondarily, we investigated the associations between APOE epsilon 4, Lewy bodies, and psychosis. Methods: Data from the National Alzheimer's Coordinating Center (NACC) were used. Nine hundred patients with a confirmed diagnosis of AD based on the NIA-AA Reagan were included in the analysis. Global cognition was assessed using the Mini-Mental State Exam (MMSE) and functional status was assessed using the Functional Activities Questionnaire (FAQ). Psychosis status was determined using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Factorial design was used to assess the effects of psychosis and APOE epsilon 4, as well as their interaction. Results: Psychosis and the presence of APOE epsilon 4 were both associated with lower MMSE scores, while only psychosis was associated with higher FAQ scores. Furthermore, patients with hallucinations had lower MMSE and higher FAQ scores than patients with only delusions. There was a significant interaction effect between psychosis and APOE epsilon 4 on MMSE scores, with APOE epsilon 4 negatively affecting patients with hallucinations-only psychosis. APOE epsilon 4 was positively associated with the presence of Lewy body pathology, and both were found to be more prevalent in psychotic patients, with a stronger association with hallucinations. Conclusion: Psychosis in AD was associated with greater cognitive and functional impairments. Patients with hallucinations-with or without delusions-conferred even greater deficits compared to patients with only delusions. The APOE epsilon 4 allele was associated with worse cognition, especially for patients with hallucination-only psychosis. APOE epsilon 4 may mediate cognitive impairment in the hallucinations phenotype through the development of Lewy bodies. Our findings support that subtypes of psychosis should be evaluated separately.