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Objective  Variants in  GBA  are associated with Lewy Body (LB) pathology. We investigated whether variants in other lysosomal storage disorder (LSD) genes also contribute to disease pathogenesis.    Methods  We performed a genetic analysis of four LSD genes including  GBA ,  HEXA ,  SMPD1 , and  MCOLN1  in 231 brain autopsies. Brain autopsies included neuropathologically defined LBD without Alzheimer Disease (AD) changes (n = 59), AD without significant LB pathology (n = 71), Alzheimer disease and lewy body variant (ADLBV) (n = 68), and control brains without LB or AD neuropathology (n = 33). Sequencing of  HEXA ,  SMPD1 ,  MCOLN1  and  GBA  followed by ‘gene wise’ genetic association analysis was performed. To determine the functional effect, a biochemical analysis of  GBA  in a subset of brains was also performed. GCase activity was measured in a subset of brain samples (n = 64) that included LBD brains, with or without  GBA  mutations, and control brains. A lipidomic analysis was also performed in brain autopsies (n = 67) which included LBD (n = 34), ADLBV (n = 3), AD (n = 4), PD (n = 9) and control brains (n = 17), comparing GBA mutation carriers to non-carriers.    Results  In a ‘gene-wise’ analysis, variants in  GBA ,  SMPD1  and  MCOLN1  were significantly associated with LB pathology ( p  range: 0.03–4.14 x10 -5 ). Overall, the mean levels of GCase activity were significantly lower in  GBA  mutation carriers compared to non-carriers ( p <0.001). A significant increase and accumulation of several species for the lipid classes, ceramides and sphingolipids, was observed in LBD brains carrying  GBA  mutations compared to controls ( p  range:  p <0.05- p <0.01).    Interpretation  Our study indicates that variants in  GBA ,  SMPD1  and  MCOLN1  are associated with LB pathology. Biochemical data comparing  GBA  mutation carrier to non-carriers support these findings, which have important implications for biomarker development and therapeutic strategies.

Gene-Wise Association of Variants in Four Lysosomal Storage Disorder Genes in Neuropathologically Confirmed Lewy Body Disease