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Brain size links neurodevelopment to neurodegeneration in Parkinson's disease

Azizi, H.; Abbasi, N.; Liu, L.; Pastor-Bernier, A.; Tremblay, C.; Pourmajidian, M.; Senkevich, K.; Morys, F.; Vo, A.; Moqadam, R.; Rajimehr, R.; Yu, E.; Savadjiev, P.; D Markello, R.; Shafiei, G.; Khatibi, N.; Jahanshad, N.; M. Thompson, P.; Poline, J.-B.; Gan-Or, Z.; Misic, B.; Zeighami, Y.; Dagher, A.

2025-12-11 neurology
10.64898/2025.12.09.25341901 medRxiv
Show abstract

Genetic studies have advanced our understanding of Parkinsons disease (PD) pathogenesis, establishing a role for autophagy and lysosomal dysfunction. However, how genetic risk translates into neuronal vulnerability remains mostly unknown. Using recent genome-wide association studies and neuroimaging data from UK Biobank, we show that higher polygenic risk score of PD correlates with greater cortical surface area, white matter fractional anisotropy and subcortical volumes. Mendelian randomization supports a causal relation from increased brain size to PD, and cortical regions showing the greatest polygenic expansion in surface area show the greatest atrophy in PD. Lifespan gene expression and pathway-specific analyses identify autophagy-lysosomal and neurodevelopmental pathways as separate mechanisms of vulnerability. We show that a portion of PD susceptibility originates from neurodevelopmental processes that regulate neuronal proliferation. Genetically-determined increases in brain size confer vulnerability to PD in later life, supporting the existence of shared neurobiological pathways between brain development and neurodegeneration.

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