Alpha-synuclein propagation trajectories in a population-based postmortem cohort

Abstract Parkinson’s disease and dementia with Lewy bodies are defined neuropathologically by the accumulation of α-synuclein. Postmortem studies have led to theories that pathology propagates systematically along anatomical brain networks. Yet, existing staging systems present conflicting patterns of pathology distribution. Recent work suggests that these discrepancies may reflect heterogeneous “brain-first” and “body-first” subtypes, but prior studies are largely based on clinical cohorts that underrepresent incidental pathology in the general aging population. Previous studies have also rarely examined spinal cord involvement, useful for distinguishing routes of propagation from the body. Using data-driven disease-progression modelling in a population-based cohort of 304 individuals aged 85 years and older, we identify three distinct α-synuclein propagation trajectories. We find a “body-first” subtype (26.8%) originating in the lower brainstem, and two divergent “brain-first” subtypes (73.2%) initiating in the olfactory bulb, one spreading toward the brainstem and the other preferentially targeting the amygdala. The amygdala-directed trajectory is strongly associated with Alzheimer’s co-pathology, APOE ε4 genotype, and poorer cognitive outcomes. These findings reconcile discrepancies among prior staging frameworks by demonstrating substantial spatial heterogeneity even within brain-originating pathways, and they establish the biological distinctness of these trajectories in an unselected, community-dwelling population. Moreover, we show that the spatial extent of α-synuclein pathology contributes to cognitive impairment independently of comorbid Alzheimer’s disease or transactive response DNA-binding protein 43 (TDP-43) pathology. Together, these results provide a framework for patient stratification and for linking α-synuclein propagation patterns to clinical trajectories from prodromal to late stages. Abbreviated Summary Using data-driven modelling in a population-based cohort (Vantaa 85+), Khalafi et al. identify three distinct α-synuclein propagation trajectories: one originating in the lower brainstem and two initiating in the olfactory bulb with divergent downstream targets. The trajectory preferentially involving the amygdala is strongly associated with Alzheimer’s co-pathology and cognitive decline, independent of other comorbid pathologies.