Integrated clinical and postmortem profiling in schizophrenia reveals a cognitive subtype linked to cerebrovascular...

Cognitive impairment is a core feature of schizophrenia with an unknown neuropathological basis. In older adults with schizophrenia, contributions of Alzheimer's pathology and cerebrovascular disease (CVD) to specific neurocognitive deficits remain largely unexplored. This study investigated the relationship between postmortem neuropathology and neuropsychological performance in 55 older adults with schizophrenia (mean age 78.2 years), providing the most detailed clinicopathologic correlation study in schizophrenia to date. Overall, 70% of the sample met criteria for cognitive impairment, but remarkably nearly half of this cognitively impaired group lacked neuropathological autopsy findings that could explain their symptoms. While the prevalence of postmortem Alzheimer's pathology (35.1%) was similar to rates in the general population, CVD pathology was more frequent (84.2%) and associated with lower Mini-Mental State Examination (MMSE) scores (p < 0.001). No other pathology-cognition relationships were observed. Clustering analysis based upon cognitive testing scores alone identified three subgroups (NCOG_1, NCOG_2, and NCOG_3) with distinct cognitive profiles despite similar postmortem neuropathology findings. NCOG_2 exhibited relatively spared cognition (mean MMSE = 26/30) and a significantly younger age at death. Interestingly, at our level of sample depth, the MMSE-CVD association was specific to only the NCOG_3 cluster, which exhibited more selective impairments, implicating vascular pathology in at least one distinct cognitive phenotype of schizophrenia. Our data suggest a novel clinicopathologic association between CVD pathology and cognitive impairment in schizophrenia and that targeted interventions to reduce cardiovascular risk may offer meaningful cognitive benefits in a specific schizophrenia patient subgroup.