The brain as a house built too spacious: lovely to live in, but expensive to maintain. Parkinson's disease is usually pictured as the destruction of that house, with neurons dying and structures shrinking. However, a new study of data from 46,349 healthy people in the UK Biobank paints a different picture: in those whose genes predispose them to the disease, the brain turns out to be larger from the start, not smaller.
The scientists calculated a polygenic risk score for Parkinson's disease for each participant (the combined contribution of many genetic variants) and compared it with detailed MRI measurements. It turned out that high risk is associated with a larger cortical surface area in all regions, a larger volume of all 14 subcortical structures, and more organized white matter fibers (higher fractional anisotropy in 35 out of 73 tracts). Cortical thickness, on the other hand, is sometimes smaller, but this is not atrophy; rather, it is a developmental feature: thin cortex with a large area is often found in people with high intelligence.
To check whether the association might be coincidental, the researchers used Mendelian randomization (a method for assessing causality through genetic variants). The result: a larger cortical area and a larger volume of subcortical gray matter potentially causally increase the risk of the disease. In other words, the genes that make the brain grow more also make it more vulnerable to Parkinson's in old age.
Why does this happen? Breaking down genetic risk by biological pathways showed that the effect on brain size is carried by genes not related to the mitochondrial-lysosomal-autophagy set (Mito-ALP), which is usually blamed for the disease. These genes are more active before birth and are responsible for cell division and microtubule organization. It appears that vulnerability is established in the womb, when the brain builds too many neurons and connections.
A house built with a surplus requires more energy and maintenance. A large brain has more neurons and synapses, meaning more places where the toxic protein alpha-synuclein, characteristic of Parkinson's disease, can accumulate. Perhaps it is precisely the excessive density of connections in dopamine neurons that makes them selectively vulnerable. This explains why the disease affects specific systems rather than the whole brain uniformly.
So we return to the original image: a spacious house is beautiful, but it is expensive to maintain. Genes that helped the brain grow large and efficient become a risk in old age. For now this is pure knowledge, with no applications in sight, but it helps us understand why epidemiological data on Parkinson's disease are so contradictory, and it suggests that early biomarkers should be sought not in atrophy but in developmental features.
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.