Regional gene expression and brain atrophy in dementia with Lewy bodies: an imaging transcriptomics study

Regional brain atrophy has been observed in dementia with Lewy bodies (DLB), yet determinants of regional vulnerability remain unclear. Using imaging transcriptomics, we examined whether normative gene expression patterns relate to regional atrophy in DLB. We included 164 DLB patients (49 women) and 164 age- and sex-matched healthy controls from three European centres and the Mayo Clinic, USA. Volumetric atrophy was quantified from T1-weighted MRI across 58 left-hemispheric regions using w-scores. Normative expression of twelve genes implicated in alpha-synuclein, beta-amyloid, and tau pathology was extracted from the Allen Human Brain Atlas. DLB patients showed diffuse atrophy across most regions. In the full cohort, normative expression of MAPT, PINK1, and PSEN2 predicted regional atrophy after correction for spatial autocorrelation, although none survived multiple-testing correction. In the Mayo Clinic sub-cohort, expression of APP, BIN1, GBA, MAPT, PINK1, SNCA, and TMEM175 significantly predicted atrophy and survived multiple-testing correction. Random forest models did not outperform spatial null models in the full cohort, but PARK7, PINK1, and PSEN2 consistently emerged as important predictors. A significant global model was observed in the Mayo Clinic sub-cohort, driven by GBA, LRP1, and PINK1. These findings suggest that normative gene expression partially contributes to regional brain atrophy in DLB.