GBA variants influence cognitive status in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive degenerative disease of upper and lower motor neurons. Approximately 15% of patients display clinical features consistent with frontotemporal dementia (FTD) and 35% display milder degrees of cognitive and behavioural impairment at some stage during their illness.1 Several genes have been reported to cause both ALS and FTD. Nevertheless, it remains unclear why some patients with ALS develop cognitive impairment, while other cases, often within the same family, remain unaffected. The GBA gene (OMIM *606463) encodes glucocerebrosidase (GCase), a lysosomal enzyme that converts glucocerebroside into glucose and ceramide. Heterozygous GBA mutations increase the risk of Parkinson’s disease (PD) and the risk of cognitive impairment in patients with PD.2 It is increasingly recognised that variants in genes causing Mendelian neurodegenerative diseases may exhibit pleiotropic effects and impact the phenotypic heterogeneity of those disorders. Moreover, lysosomal dysfunction has recently been associated with both Dementia with Lewy Bodies and FTD spectrum (online supplemental table 1). Based on this, we postulated that GBA variants may influence the cognitive status of patients with ALS. ### Supplementary data [jnnp-2021-327426supp001.pdf] We examined the GBA variants’ association with the risk of cognitive impairment in 751 patients with ALS from the population-based Piemonte and Valle d’Aosta Register for ALS that had undergone both a detailed neuropsychological evaluation and a whole-genome sequencing screening.3 Patients were classified as ALS with normal cognitive function (ALS-CN), ALS-FTD and ALS with intermediate cognitive deficits. The characteristics of the study population and a detailed description of neuropsychological testing and genetic screening are reported in online supplementarl materials in the Methods section. A mutational screening of GBA exonic variants was performed and their frequencies were compared with an internal control cohort (see online supplemental methods, Subjects). To assess whether pathogenic rare variants (minor allele frequency