Pre-dementia clinical trajectories associated with neuronal α-synuclein neuropathologic change: a retrospective cohort study
Biological definitions of neuronal α-synuclein disease are advancing diagnosis beyond traditional clinical syndromes, but the trajectories preceding dementia and the influence of concomitant Alzheimer’s disease neuropathologic change (ADNC) remain uncertain. We analyzed longitudinal data from 1,543 participants without dementia at baseline who underwent repeated cognitive, functional, neuropsychiatric, and motor assessments and had neuropathological characterization at autopsy. Participants were classified as having neuronal α-synuclein neuropathologic change (NSNC), ADNC, or both. NSNC without intermediate or high ADNC was associated with the greatest motor burden. Among participants without mild cognitive impairment at baseline, concomitant ADNC was associated with earlier cognitive impairment and faster cognitive decline; mixed NSNC/ADNC also showed faster functional worsening than NSNC alone. Across participants with NSNC, baseline mild cognitive impairment, neuropsychiatric manifestations and concomitant ADNC predicted progression to dementia, whereas prespecified motor signs did not. These findings reveal heterogeneous pre-dementia trajectories and support combining α-synuclein detection with Alzheimer biomarkers, cognitive staging and multidomain clinical measures to improve prognosis and trial design.