Dementia risk in Parkinson's disease is associated with interhemispheric connectivity loss and determined by regional gene expression.

Parkinson's dementia is a common and devastating part of Parkinson's disease. Whilst timing and severity vary, dementia in Parkinson's is often preceded by visual dysfunction. White matter changes, representing axonal loss, occur early in the disease process. Clarifying which white matter connections are affected in Parkinson's with visual dysfunction and why specific connections are vulnerable will provide important mechanistic insights. Here, we use diffusion tractography in 100 Parkinson's patients (33 low visual performers) and 34 controls to identify patterns of connectivity loss in Parkinson's with visual dysfunction. We examine the relationship between regional transcription and connectivity loss, using the Allen Institute for Brain Science transcriptome atlas. We show that interhemispheric connections are preferentially affected in Parkinson's low visual performers. Interhemispheric connection loss was associated with downweighted genes related to the smoothened signalling pathway (enriched in glutamatergic neurons) and upweighted metabolic genes. Risk genes for Parkinson's but not Alzheimer's or Dementia with Lewy bodies were over-represented in upweighted genes associated with interhemispheric connection loss. Our findings suggest selective vulnerability in Parkinson's patients at highest risk of dementia (those with visual dysfunction), where differences in gene expression and metabolic dysfunction, affecting longer connections with higher metabolic burden, drive connectivity loss.