ArticlemedRxiv : the preprint server for health sciences2026
Pathology and genetics in a global cohort of Parkinsonian Disorders.
Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Importance: Accurate diagnosis of neurodegenerative movement disorders is challenging because of a lack of Objective: To evaluate clinicopathological correlation, diagnostic accuracy, genetic association with pathology, and ancestry-related differences in a multi-ancestry brain bank cohort. Design: Multicentre retrospective autopsy cohort study on donors enrolled between 1985 - 2024. Setting: 11 academic brain banks in the UK, US and Australia. Participants: Brain donors identified from participating brain banks with available brain tissue and a clinical diagnosis of Parkinson's disease, Parkinson's disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls. Exposure: Genetic variant carrier status and clinical diagnostic category. Main outcome: Clinical diagnostic accuracy; Lewy body and Alzheimer's disease pathology burden; survival; association with genetic variants and genetically inferred ancestry. Results: We studied 3,353 brain donors (1281 [38.2%] female, mean [SD] age at death, 76.8 [10.6] years). Misdiagnosis rates for movement disorders ranged approximately from 10%-20%. Clinical diagnoses of dementia with parkinsonism (PDD/DLB) were more strongly associated with Lewy body pathology than Parkinson's disease without dementia (OR = 1·96, 95% CI = 1·30 - 3·04, p = 7·2e-04). Lewy pathology was identified in 4% of neurologically normal controls. Alzheimer's disease co-pathology was present in 40% of cases with Lewy body disease. Conclusion and Relevance: Our findings highlight the value of integrating genetic and pathological data to improve diagnostic accuracy. The high prevalence of Alzheimer's disease co-pathology and ancestry-related differences in pathology point to the need for biologically informed diagnostic tools. These results support the integration of genetically and pathologically stratified approaches, correlating pathology with Funding: Medical Research Council, Global Parkinson's Genetic Program/Aligning Science Across Parkinson's.
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