Lifestyle and Genetics Interact During Presymptomatic Stage of ALS

Investigators aimed to assess lifestyle during the presymptomatic phase of ALS, stratified by C9orf72 mutation, and examine evidence about whether lifestyle factors are causative factors.

Researchers identified lifestyle differences among patients with amyotrophic lateral sclerosis (ALS) dependent on chromosome 9 open reading frame 72 (C9orf72) mutational status in a case control study published in Lancet Neurology.

Data from the ongoing population-based Prospective ALS study in the Netherlands (PAN) were analyzed. Study researchers compared patients with a C9orf72 mutation (C9+) and without (C9-) with control group participants for lifestyle features. They matched patient groups for age and gender. A Mendelian randomization was performed to assess which group differences were potentially causal for ALS symptom onset and functional decline.

A total of 143 patients were C9+, 1322 were C9-, and 1322 were control group participants. The members of the C9+ group were more likely to be diagnosed with frontotemporal dementia (8.5% vs 2.9%, respectively; P =.0073) and to have more rapid ALS functional rating decline (P =.023).

Compared with control group participants, the C9+ cohort had less lifetime alcohol consumption (mean difference [MD], -5388; 95% CI, -9113 to -1663 units; P =.0046), consumed more cigarette pack-years (MD, 3.15; 95% CI, 0.36-5.93; P =.027), had lower median body mass index (BMI) during presymptomatic stage (MD, -0.69; 95% CI, -1.24 to -0.13; P =.015), and consumed more energy daily (MD, 712; 95% CI, 212-1213 kJ; P =.0053).

Compared with the C9- cohort, the C9+ patients had lower BMI during the presymptomatic stage (MD, -0.92; 95% CI, -1.48 to -0.37; P =.0011) and had lower metabolic equivalent scores for leisure time activities (MD, -502; 95% CI, -921 to -82; P =.019) and occupations (MD, -516; 95% CI, -968 to 65; P =.025).

Over time, BMI tended to be increased between 49 to 23 years before ALS symptom onset and decreased 10 years before onset among the C9- group and for the C9+ cohort, BMI was significantly lower 36 years before symptom onset, increasing more slowly.

Leisure and occupational physical activity increased more quickly among the C9- cohort starting 31 to 35 years before symptom onset. No difference in activity between control group participants and the C9+ group was observed.

Cigarettes were consumed more than control group participants starting at 47 and 24 years before symptoms among the C9- and C9+ cohorts, respectively.

Genetic variants were associated with BMI (n=826), tobacco use (n=107), and alcohol consumption (n=46), but not for energy intake. No evidence supported a causal or preventive effect for the variants associated with BMI. Findings indicated a causative effect for smoking among the C9- group (P[Q|x] instrumental variable analysis [IVA]-neutral, 0.5703; IVA-informative, 0.9859) and for alcohol consumption among the C9- (P[Q|x] IVA-neutral, 0.6832; IVA-informative, 0.9347) and C9+ cohorts (P[Q|x] IVA-neutral, 0.7604).

This study may have included some recall bias because of retrospectively reported data.

These data indicated environmental and genetic factors likely interact during the presymptomatic phase of ALS. Additional studies are needed to assess whether modification of lifestyle habits may mitigate or delay ALS symptom onset.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.


Westeneng HJ, van Veenhuijzen K, van der Spek RA, et al. Associations between lifestyle and amyotrophic lateral sclerosis stratified by C9orf72 genotype: a longitudinal, population-based, case-control study. Lancet Neurol. 2021;20(5):373-384. doi:10.1016/S1474-4422(21)00042-9