Dementia in Severe Schizophrenia

Importance: Dementia develops in individuals with schizophrenia 4- to 20-fold more frequently than in the general population, but its etiology remains unexplained. Objective: To characterize the cognitive, clinical, and genetic features of dementia in individuals with severe, extremely treatment-resistant schizophrenia (SETRS). Design, Setting, and Participants: This retrospective cohort study among individuals with SETRS was conducted at New York state hospitals from December 2017 through July 2019. All participants met DSM-5 schizophrenia criteria and were continuously hospitalized for 5 years or more. Exclusion criteria included forensic hospitalization, known medical causes of psychosis, or recent substance abuse. Cognitive, clinical, and genetic data were compared to data from individuals from the National Alzheimer Coordinating Center dataset, including those with Alzheimer disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), or vascular dementia (VD), along with healthy controls. Data were analyzed from January 2025 through December 2025. Main Outcomes and Measures: Multiple regression was used to analyze the effects of demographic, clinical, and genetic factors on the Montreal Cognitive Assessment (MoCA). Results: In this study's cohort of 155 individuals with SETRS (mean [SD] age, 59.3 [10.3] years; 56 female participants [36.1%]), 153 of 155 (98.7%) scored below the cutoff of 26 for mild cognitive impairment, and 73 of 155 (47.1%) scored below the cutoff of 10 for severe dementia (mean [SD] MoCA score, 9.8 [6.4]). At the item level, the MoCA profile of SETRS differed from those of AD and FTD but paralleled that of community-dwelling individuals with schizophrenia (Pearson r = 0.86; P < .001). No participants carried pathogenic variants in mendelian dementia genes; APOE4 allele frequency was significantly lower in SETRS (14.4%) than in AD (33.6%; odds ratio [OR], 0.33; 95% CI, 0.20-0.53; P < .001) or LBD (24.7%; OR, 0.51; 95% CI, 0.29-0.89; P = .01). Cognitive impairment was not attributable to premorbid intellectual disability, poor effort, medications, cardiometabolic risk factors, or institutionalization. Conclusions and Relevance: In this cohort study of 155 individuals with SETRS, none of the commonly proposed explanations for schizophrenia dementia (eg, comorbid Alzheimer disease or cardiovascular risk factors) proved viable. The pattern of cognitive impairments differed from those of Alzheimer disease, frontotemporal dementia, and Lewy body dementia, but recapitulated and intensified that of community-dwelling schizophrenia.