Co‐pathology in Alzheimer's disease and Lewy body disease and its association with neuropsychiatric symptoms

Mixed neuropathology is common in dementia, but the clinical implications for neuropsychiatric symptoms (NPSs) are not well characterized. In a population-based post mortem study, cases with Alzheimer's disease neuropathological change (ADNC) and Lewy body disease (LBD) were identified with any comorbid neuropathology (limbic-predominant age-related transactive response DNA-binding protein 43 encephalopathy neuropathological change (LATE-NC), cerebrovascular disease, LBD, and ADNC, respectively). Post mortem interviews collected information regarding NPSs and cognition to explore associations between each co-pathology and NPSs across the whole cohort, as well as in participants without dementia. Co-existing neuropathology was frequent, even among individuals without clinical dementia. In cases with ADNC, comorbid neocortical LBD pathology was associated with hallucinations, regardless of cognitive status. However, ADNC co-pathology in LBD was linked to a greater NPS burden in the full cohort but not in individuals without dementia. Lewy bodies are associated with hallucinations independent of cognitive impairment, whereas ADNC co-pathology may contribute to NPS only when widespread and associated with cognitive dysfunction. Neuropathological heterogeneity is high even in clinical stages without dementia. Neocortical but not limbic or brainstem LBD co-pathology is associated with hallucinations. LBs are associated with hallucinations independent of cognitive status. ADNC co-pathology is not associated with NPSs in LBD without dementia. LATE co-pathology is associated with increased risk of dementia but not NPS. Vascular co-pathology is associated with increased risk of delusions in ADNC.