Understanding Lewy Body Diseases and related movement disorders through the integration of Clinical, Genetic and Pathological data

Hypokinetic movement disorders, including Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), progressive supranuclear palsy (PSP), corticobasal syndrome/degeneration (CBS/D) and multiple system atrophy (MSA) are clinically, pathologically and genetically heterogeneous. Post-mortem studies are often limited to small sample sizes, which limits statistical power. To address this limitation, I established the MD-GAP database—the first aim of my PhD—integrating genetic, clinical, and neuropathological data from autopsy-confirmed cases. It is designed to facilitate large-scale analyses and meta-analyses with other existing cohorts across the world. The second aim was to identify genetic risk alleles associated with dementia in PD, PDD and DLB . Using a large genome-wide association study comparing PDD/DLB to cognitively normal PD cases, I confirmed APOE4 as the strongest risk allele and identified protective variants at SNCA-AS1 and LRRK2. Subsequent validation using autopsy data associated SNCA-AS1 to lower Lewy pathology burden, supporting its role in mitigating dementia risk and underscoring the value of integrative resources like MD-GAP. The third aim assessed diagnostic accuracy, the burden of co-pathology and pathological features related to genetic variations. I found persistent clinical misdiagnosis rates across these parkinsonian disorder cases. Additionally, 40% of LBD cases had Alzheimer's disease (AD) co-pathology, which was associated with dementia. I also found GBA1 variants associated with more extensive Lewy body pathology, and LRRK2 pathogenic mutation carriers showed lower Lewy body pathology burden and longer survival than non-carriers. Together, this work emphasises the need to include AD and alpha-synuclein biomarkers to better stratify patients in clinical trials. The final aim explored genetic determinants of pathology distribution. I found APOE4 strongly associated with cortical Lewy bodies, likely via AD pathology. My findings support two distinct mechanisms of LB spread: one AD-dependent and one AD-independent, potentially involving lysosomal or synaptic genes. Future work will 3 explore rare variants in a larger sample size and polygenic risk scores to further dissect these pathways.