GBA Variants Impact Cognitive Status in Amyotrophic Lateral Sclerosis

Variants in the glucocerebrosidase (GBA) gene are associated with an increased risk for cognitive impairment in patients with amyotrophic lateral sclerosis (ALS), according to study findings presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, held from April 2 to April 7 in Seattle, Washington, and virtually from April 24-26, 2022.

GBA polymorphisms represent “known risk factors for Lewy Body Dementia [LBD] and cognitive impairment Parkinson disease [PD],” the researchers explained. The objective of the current study was to assess the impacts of GBA variants on the cognitive status of patients with ALS.

The study population consisted of 751 patients with ALS and full genetic and neuropsychological data who were diagnosed in Piemonte and Valle d’Aosta, Italy, between 2007 and 2015. Additionally, the researchers included 677 healthy control individuals in the analysis set.

Patients with ALS were classified as having ALS with normal cognition (ALS-CN), ALS with intermediate cognitive deficits, or ALS with frontotemporal dementia (ALS-FTD). The researchers performed a single-variant association test to compare the frequency of GBA variants between patients with ALS and healthy control individuals. Additionally, the researchers performed a binomial test to assess the prevalence of GBA mutations across cognitive status groups. To investigate the associations between GBA genotype and cognitive functioning, the researchers used a linear mixed-effects models and gene-based rare-variants association test.

They identified 3 common GBA polymorphisms: p.E365K; p.T408M; and p.N409S. According to the researchers, these GBA polymorphisms are known risk factors for LBD as well as cognitive impairment in PD. The identified variants were observed in 18 patients with ALS (2.3%) and 15 healthy control individuals (2.2%).

In the single-variant analysis, the researchers confirmed that the GBA variants were not a risk factor for ALS. They also subsequently identified 7 other GBA variants. In patients with ALS who carried GBA variants, approximately 72.2% had cognitive impairment vs 47.1% in patients who didn’t carry these variants (P =.03).

The association between GBA variants and cognitive impairment in ALS was confirmed in a linear mixed-effects model that controlled for sex, age, site of onset, bulbar signs at diagnosis, decline in the revised ALS Functional Rating Scale, and C9orf72 status (P =.02). According to collapsing tests, enrichment of rare disruptive GBA variants were found in cognitively impaired patients with ALS (P =.02).

The researchers stated that the findings of an association between GBA variants and an increased risk of cognitive impairment in patients with ALS support “the role of lysosomal impairment in the underlying neurodegenerative process.”

Reference

Chio A, Grassano M, Moglia C, et al. GBA variants influence cognitive status of ALS patients. Presented at: the 2022 AAN Annual Meeting; April 2-7, 2022; Seattle, Washington; April 24-26, 2022; Virtual Meeting. Abstract S11.004.