Quantitative pathology and APOE 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 {varepsilon}4 genotype, co-pathology including concomitant Alzheimers 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 Parkinsons disease, Parkinsons 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 -synuclein, amyloid-{beta}, 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 {varepsilon}3 and {varepsilon}4 carriers showed distinct dementia risk profiles. APOE {varepsilon}3 carriers developed dementia at lower quantitative -synuclein and amyloid-{beta} thresholds than {varepsilon}4 carriers, although overall dementia risk was dominated by {varepsilon}4 genotype, consistent with {varepsilon}4 both promoting greater pathology accumulation and modifying the threshold for dementia onset. Orthostatic hypotension and ischaemic pathology increased dementia risk only in {varepsilon}3 carriers with low Lewy and Alzheimers proteinopathy burden, while male sex further modulated dementia risk for this subgroup. A data-driven progression model (SuStaIn) identified four trajectories of Lewy pathology: two corresponding to recognised patterns, one brainstem-first and the other with early amygdala involvement, and two representing novel cortical-onset patterns, one with early cingulate cortex involvement and the other starting in neocortex before limbic and brainstem involvement. Co-pathology progression modelling identified subtypes with early predominance of amyloid-{beta}, phosphorylated tau, or -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 uncovers 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.