Neuropathology in genetic Parkinson's disease: a focused review of pathological and clinical findings.

Parkinson's disease (PD) is a neurodegenerative disorder with a complex interaction between genetic and environmental causal factors. The role of Lewy body (LB) pathology (Lewy bodies and neurites) in genetic PD remains unclear, as some gene mutations do not consistently present with alpha-synuclein aggregates or LB in postmortem studies. This review aims to evaluate neuropathological data from genetic PD cases, focusing on the prevalence of LB pathology and co-pathologies, as well as the relationship between neuropathological findings and relevant clinical features. Case reports, case series, and clinicopathological cohorts published between 1990 and 2024 were reviewed. Clinical information and data on LB pathology, tau pathology, amyloid-β deposition, and TDP-43 pathology were extracted. Among 243 genetic PD cases with autopsy data, LB pathology was present in 79% and varied by gene mutation. All SNCA and most GBA gene mutation cases (98%) exhibited LB pathology, while it was observed in 59% of LRRK2 cases and only 32% of PARKIN-related PD. LB pathology was associated with a later disease onset (54.6 vs. 44.7 years, p < 0.001), shorter disease duration (14.8 vs. 27.7 years, p < 0.001) and cognitive impairment (OR: 15.9, p < 0.001). Co-pathologies did not differ among gene mutations. LB pathology is not universally present in genetic PD, particularly in LRRK2 and PARKIN mutations, highlighting challenges for the development of synuclein-based biomarkers and the need for genetic considerations in clinical trials targeting alpha-synuclein.