Pathology and Genetics in a Global Cohort of Parkinsonian Disorders

Introduction

Neurodegenerative movement disorders such as Parkinson’s disease (PD) and related Parkinsonian syndromes pose substantial challenges for accurate diagnosis due to the lack of definitive in vivo biomarkers, overlapping clinical symptoms, and delayed appearance of characteristic pathological features. Enhancing diagnostic precision is critical for patient management and development of targeted treatments.

This global study investigates the clinicopathological correlations, diagnostic accuracy, genetic associations with pathology, and ancestry-related pathological differences in a large, multi-ancestry cohort from multiple brain banks. It provides key insights into the complex relationships between clinical presentation, underlying brain pathology, and genetic variants, paving the way for improved diagnosis and personalized therapeutic approaches.

Study Design and Cohort Characteristics

The study was a multicenter, retrospective, and cross-sectional analysis of brain donors enrolled between 1985 and 2024 from 11 academic brain banks located in the United Kingdom, United States, and Australia. A total of 5,648 brain donors with available genetic data were screened, with 3,353 eligible cases included based on clinical diagnoses of Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies (DLB), progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, or neurologically normal controls.

The average age at death was 76.8 years with a majority of male donors (61.8%). This large diverse dataset allowed examination of clinicopathological patterns across multiple neurodegenerative entities and genetic backgrounds.

Clinical Diagnostic Accuracy and Pathological Findings

The study found misdiagnosis rates for movement disorders ranged from approximately 10% to 20%, highlighting the diagnostic challenges facing clinicians. Clinical diagnoses of dementia with parkinsonism (including Parkinson disease dementia and DLB) correlated more strongly with the presence of Lewy body pathology compared to Parkinson disease without dementia, with an odds ratio (OR) of 1.96. This underscores the relevance of Lewy body accumulation in cognitive decline accompanying parkinsonism.

Interestingly, 4.4% of neurologically normal control brains showed Lewy body pathology, suggesting subclinical or preclinical pathology may be more common than expected. Additionally, Alzheimer disease (AD) copathology was present in 40% of cases with Lewy body disease, indicating a significant overlap of pathological processes in these disorders.

Genetic Associations with Pathology

Carriers of the GBA1 gene variant exhibited a greater burden of Lewy body pathology compared with both noncarriers and carriers of the LRRK2 variant. Specifically, the odds ratio for greater Lewy body burden in GBA1 carriers was 1.94 compared to noncarriers and 7.44 compared to LRRK2 variant carriers, indicating strong genetic influence on underlying pathology.

These findings support previous literature linking GBA1 mutations to more aggressive Lewy body pathology and more severe clinical manifestations of Parkinsonian disorders. Understanding these genotype-pathology relationships is critical for stratifying patients in clinical trials and tailoring therapeutic strategies.

Kaplan-Meier (KM) Survival Curve in Individuals With GBA1 and LRRK2 Variants and Those Without Known Variants.

Ancestry-Related Differences in Pathology

Pathological diagnoses significantly varied according to ancestry. South Asian donors were more likely to exhibit progressive supranuclear palsy pathology, whereas donors of Ashkenazi Jewish descent had a higher likelihood of Lewy body disease. This association was independent of GBA1 and LRRK2 variant status, highlighting ancestry-specific risk factors beyond these commonly studied mutations.

This evidence supports the need to consider genetic background and ancestry in diagnostic evaluations and clinical trial design, ensuring that diverse populations are properly represented and therapeutic approaches are appropriately tailored.

Implications for Clinical Practice and Research

The study findings emphasize the value of integrating genetic and pathological data to enhance clinical diagnostic accuracy in Parkinsonian disorders. The high prevalence of Alzheimer copathology among Lewy body disease cases points to the complexity of neurodegeneration, suggesting that multifaceted biomarker panels that capture these overlapping pathologies are needed.

Furthermore, this study advocates for the development and use of biologically informed diagnostic tools that incorporate genetic, pathological, and biomarker data. Such an approach promises better disease stratification, allowing more precise prognostic predictions and personalized interventions in clinical practice and research settings.

For future therapeutic trials, it is recommended to support genetically and pathologically stratified study designs, correlating pathological findings with in vivo biomarkers to enhance understanding of disease mechanisms and treatment responses.

Conclusion

This large-scale, multi-ancestry brain bank study provides critical insights into the complexities of Parkinsonian disorders. The integration of comprehensive genetic and pathological evaluations reveals diagnostic challenges, significant genotype-pathology correlations, and ancestry-associated variations in disease pathology. These findings underscore the urgency of developing sophisticated, biologically informed diagnostic and therapeutic paradigms to improve outcomes for patients worldwide.

Reference:

Wu LY, du Toit T, Georgiades T, Stafford EJ, Levine K, Fang ZH, Jasaityte S, Martinez AG, Cullinane P, De Pablo-Fernandez E, Blauwendraat C, Singleton AB, Scholz SW, Traynor BJ, Wood N, Hardy J, Chinnery P, Houlden H, Cain R, Troakes C, Chelban V, Serrano GE, Gveric D, McLean C, Love S, King A, Robinson AC, Roncaroli F, Shepherd C, Halliday G, Parkkinen L, Morris CM, Smith C, Beach TG, Gentleman S, Warner TT, Lashley T, Jaunmuktane Z, Real R, Morris HR; Global Parkinson’s Genetic Program (GP2). Pathology and Genetics in a Global Cohort of Parkinsonian Disorders. JAMA Neurol. 2026 Aug 1;83(8):798-807. doi: 10.1001/jamaneurol.2026.1634. PMID: 42258190; PMCID: PMC13247843.