Quantitative pathology and <i>APOE</i> genotype reveal dementia risk and progression in Lewy body disease

Dementia in Lewy body diseases (LBD) is common and arises through heterogeneous and incompletely understood pathways. Evidence suggests contributions from genetic factors, including APOE ε4 genotype, 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 utilising machine learning to enable automated, standardised measurement of α-synuclein, amyloid-β, and phosphorylated tau burden across multiple brain regions. Quantitative pathology strongly correlated with semi-quantitative ratings and outperformed conventional staging in predicting dementia. Across multiple analytical approaches, APOE ε3 and ε4 carriers showed distinct dementia risk profiles. APOE ε3 carriers developed dementia at lower quantitative α-synuclein and amyloid-β thresholds than ε4 carriers, although overall dementia risk was dominated by ε4 genotype, consistent with ε4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in ε3 carriers with low Lewy and Alzheimer's proteinopathy burden, while 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 recognised patterns, one brainstem-first and the other with early amygdala and concomitant brainstem involvement. Two further patterns showed early cortical involvement, one with early cingulate cortex involvement together with brainstem pathology and the other starting in 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.