Quantitative pathology and APOE genotype reveal dementia risk and progression in Lewy body disease

Abstract

Abstract Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ɛ4 genotype, and co-pathology, including concomitant Alzheimer’s disease pathology and hypoperfusion related to orthostatic hypotension. However, the relative impact of these factors remains unclear. To address this, we analysed 399 post-mortem brains from LBD cases comprising Parkinson’s disease, Parkinson’s disease dementia and dementia with Lewy bodies, and controls, integrating APOE genotype, clinical data and assessment of ischaemic pathology alongside large-scale digital pathology quantification. We established an image analysis pipeline using machine learning to enable automated, standardized measurement of α-synuclein, amyloid-β and phosphorylated tau burden across multiple brain regions. Quantitative pathology was strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ɛ3 and ɛ4 carriers showed distinct dementia risk profiles. APOE ɛ3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ɛ4 carriers, although overall dementia risk was dominated by ɛ4 genotype, consistent with ɛ4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ɛ3 carriers with low Lewy and Alzheimer’s proteinopathy burden, and male sex further modulated dementia risk for this subgroup. The Subtype and Stage Inference (SuStaIn) algorithm identified four trajectories of Lewy pathology progression. Two corresponded to recognized patterns: (i) brainstem first; and (ii) with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement: (i) with early cingulate cortex involvement together with brainstem pathology; and (ii) starting in the neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-β, phosphorylated tau or α-synuclein and showed that Lewy subtypes follow two propagation trajectories in opposite directions. Together, these findings demonstrate that integrating quantitative pathology with genotype and clinical data reveals distinct yet overlapping pathways to dementia in LBD, refining disease progression models and providing a basis for genotype- and pathology-informed patient stratification in therapeutic trials.