Parkinson's disease is usually associated with neuron loss and brain atrophy, but what makes some people more vulnerable and others not remained unclear. Genetic studies have identified many risk-increasing variants, but their impact on brain structure in healthy people is only beginning to be studied. This work stands apart from neighboring studies: those deal with dementia, tremor, virtual brain modeling, and tumors, whereas here, for the first time, polygenic Parkinson's disease risk is combined with detailed neuroimaging data in thousands of healthy adults and children.
The researchers used UK Biobank data: 46,349 participants without neurological disease who had MRI, genetics, and behavioral measures. For each, they calculated a polygenic risk score (PRS) for Parkinson's disease based on the latest GWAS data. The brain was measured across six modalities: cortical thickness and surface area, subcortical structure volumes, fractional anisotropy and mean diffusivity of white matter, and quantitative susceptibility mapping (QSM) of 16 nuclei. Associations were sought using linear regression adjusted for age, sex, scanning site, and genetic principal components. Additionally, they performed Mendelian randomization, developmental gene expression analysis (BrainSpan), gene set enrichment (MAGMA), and genetic correlations (LDSC). The results were replicated in the pediatric ABCD cohort (ages 10–16).
Polygenic Parkinson's disease risk was positively correlated with cortical surface area in all regions (pFDR<0.001), with the volume of all 14 subcortical structures (pFDR<0.001), and with fractional anisotropy in 35 of 73 white matter tracts. The correlation with cortical thickness was negative but limited to frontal, temporal, and limbic regions. QSM in the substantia nigra, putamen, and caudate nucleus was reduced, indicating an absence of subclinical degeneration. The effects explained up to 0.92% of the variance in subcortical volume and 0.74% of cortical surface area. Mendelian randomization showed a potentially causal influence of greater cortical surface area and subcortical gray matter volume on disease risk (IVW p<0.001). In the pediatric cohort, the same associations with cortical surface area and subcortical volume were replicated at all four time points. Partitioning the PRS by pathway showed that the effect on brain size is carried by genes outside the mitochondrial-lysosomal-autophagy (Mito-ALP) set; these genes are expressed more highly before birth and are enriched in cell division and microtubule organization processes.
The work changes how we think about the nature of Parkinson's disease vulnerability: part of the genetic risk acts not through early degeneration but through enhanced brain growth during development. This sets it apart from neighboring studies that focus on atrophy or clinical symptoms. For the first time, it has been shown that polygenic Parkinson's disease risk is linked to an increase, not a decrease, in brain structures, and that this link can be traced back to childhood. This conclusion is supported by Mendelian randomization and gene expression analysis, making it more convincing than a simple correlation.
The topic may evolve toward studying the cellular mechanisms that link neural progenitor proliferation to subsequent vulnerability of dopamine neurons. Researchers may investigate how synapse density and the energy demands of a large brain contribute to the spread of alpha-synuclein. Another promising avenue is the study of how genetic risk interacts with environmental factors at different periods of life.
The results will affect the epidemiology of Parkinson's disease, the interpretation of associations with smoking and socioeconomic status, and the search for early biomarkers. They are also important for understanding the differences between Parkinson's and Alzheimer's diseases with respect to cognitive reserve.
The next step is to test whether a larger brain really does accelerate the spread of pathological alpha-synuclein in models and in patients. It is also necessary to study how neurodevelopmental genes interact with mitochondrial and lysosomal pathways throughout life.
For neuroscience, the key unsolved problem is why some neural systems are selectively vulnerable to neurodegeneration. This work links that vulnerability to features of early development, echoing the hypothesis of the "cost" of a large brain. It remains an open question exactly how an increased number of neurons and connections leads to the accumulation of toxic proteins specifically in dopamine neurons.
Polygenic Parkinson's disease risk turned out to be linked to higher levels of education, income, and even less smoking, that is, to traits usually considered protective for brain health.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.