Abstract Details

To evaluate the impact of GBA variants on cognitive status in a population-based series of ALS patients.

We included 751 ALS patients with full genetic and neuropsychological data, diagnosed in Piemonte and Valle d’Aosta, Italy, between 2007 and 2015, and 677 healthy controls (HC). Patients were classified as: ALS with normal cognition (ALS-CN); ALS with intermediate cognitive deficits; ALS with FTD (ALS-FTD). A single-variant association test was used to compare the frequency of GBA variants between ALS cases and HC. A binomial test evaluated the prevalence of GBA mutations across cognitive groups. Linear mixed-effects models and gene-based rare-variants association test investigated the associations between GBA genotype and cognitive functioning.

We identified three common GBA polymorphisms (p.E365K, p.T408M, p.N409S), which are known risk factors for Lewy Body Dementia and cognitive impairment in Parkinson’s Disease. These variants were found in 18 ALS patients (2.3%) and 15 HC (2.2%). The single-variant analysis confirmed that GBA variants are not a risk factor for ALS. We detected seven other GBA variants. Among ALS patients carrying GBA variants, 72.2% were cognitively impaired, compared to 47.1% among non-carriers (p=0.03). A linear mixed-effects model, controlling for sex, age, site of onset, bulbar signs at diagnosis, ALSFRS-R decline and C9orf72 status, confirmed the association (p=0.02). Collapsing tests revealed enrichment of rare disruptive GBA variants in cognitively impaired ALS patients (p=0.02).

GBA variants were associated with an increased risk of cognitive impairment in ALS patients, supporting the role of lysosomal impairment in the underlying neurodegenerative process.