Autopsy Study Links Parkinsonian Diagnosis, Genetics, and Pathology

Key Takeaways

• Clinicopathologic discordance affected roughly one in 10 to one in 5 movement-disorder diagnoses, and dementia with parkinsonism aligned more strongly with Lewy body pathology.
• Mixed pathology was common, with Alzheimer disease copathology in Lewy body disease and Lewy pathology in some neurologically normal controls.
• Greater Lewy body burden was observed in GBA1 carriers, and pathological diagnoses varied by genetically inferred ancestry independent of GBA1 and LRRK2 status.

Autopsy confirmation in a large brain bank cohort showed that movement-disorder diagnoses diverged from underlying pathology in about 10% to 20% of cases. Within that overall pattern, dementia with parkinsonism aligned more closely with Lewy body pathology than Parkinson disease without dementia. Mixed pathology and variable biologic signatures recurred across the cohort.

In an online article in JAMA Neurology, researchers reported findings from a multicenter, retrospective, autopsy-confirmed cross-sectional brain bank study. Donors were enrolled between 1985 and 2024 at 11 academic brain banks in the UK, US, and Australia. The analysis included 3353 eligible donors from 5648 brain donors with available genetic data; mean age at death was 76.8 years (SD, 10.6), and 2072 donors were male (61.8%). Clinical categories included Parkinson disease, Parkinson disease dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal syndrome, multiple system atrophy, and neurologically normal controls. The cohort allowed comparison of clinical syndromes with autopsy-confirmed pathology and genetic background.

Compared with autopsy findings, dementia with parkinsonism showed a stronger association with Lewy body pathology than Parkinson disease without dementia. In this analysis, dementia with parkinsonism included Parkinson disease dementia and dementia with Lewy bodies. The comparative estimate was OR 1.96, 95% CI 1.30-3.04, P = 7.2 × 10-4. Lewy pathology was also identified in 33 of 745 neurologically normal controls (4.4%). Alzheimer disease copathology was present in 426 of 1064 cases with Lewy body disease (40.0%), showing overlap in neuropathologic processes across the cohort.

GBA1 variant carriers had greater Lewy body burden than noncarriers, with OR 1.94, 95% CI 1.24-3.03, P = .01. They also had greater burden than LRRK2 variant carriers, with OR 7.44, 95% CI 2.16-25.64, P = .01. Pathological diagnoses also differed by genetically inferred ancestry overall, with χ2 = 35.5 and P < .001. South Asian donors were more likely to have progressive supranuclear palsy pathology, whereas Ashkenazi Jewish donors were more likely to have Lewy body disease. These differences were independent of GBA1 and LRRK2 variant status.

The investigators concluded that integrating genetic and pathological data could improve diagnostic accuracy and support biologically informed diagnostic tools. They also linked the high prevalence of Alzheimer disease copathology and ancestry-associated pathology differences to future therapeutic trials tied to biomarker correlation. The framework they outlined emphasized genetically and pathologically stratified approaches, with correlation of pathology and in vivo biomarkers in future therapeutic trials. Their interpretation centered on closer alignment between diagnosis, pathology, and in vivo biomarkers.