Lifestyle and genetics interact during the presymptomatic stage of ALS

Researchers identified lifestyle differences in amyotrophic lateral sclerosis (ALS) patients that were dependent on the mutation status of open reading frame 72 (C9orf72) of chromosome 9 in a case-control study published in Lancet Neurology.

Data from the ongoing population-based prospective ALS study in the Netherlands (PAN) were analyzed. The study researchers compared patients with a C9orf72 mutation (C9 +) and without (C9-) with participants in the control group for lifestyle characteristics. They matched patient groups according to age and gender. Mendelian randomization was performed to assess which group differences were potentially responsible for the occurrence of ALS symptoms and the functional decline.

A total of 143 patients were C9 +, 1322 C9- and 1322 participants in the control group. Members of the C9 + group were more likely to be diagnosed with frontotemporal dementia (8.5% vs. 2.9%; P = 0.0073) and more rapid ALS functional decline (P = 0.023).

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Compared to the participants in the control group, the C9 + cohort had lower lifelong alcohol consumption (mean difference [MD], -5388; 95% CI, -9113 to -1663 units; P = 0.0046, consumed more cigarette pack years (MD, 3.15; 95% CI, 0.36-5.93; P = 0.027), had a lower median body mass index (BMI) during the presymptomatic stage ( MD, -0.69; 95% CI, -1.24 to -0.13; P = 0.015) and consumed more energy every day (MD, 712; 95% CI, 212-1213 kJ; P = 0.0053) .

Compared to the C9 cohort, the C9 + patients had a lower BMI in the presymptomatic stage (MD, -0.92; 95% CI, -1.48 to -0.37; P = 0.0011) and had lower metabolic equivalent values for leisure activities (MD, -502; 95% CI, -921 to -82; P = .019) and professions (MD, -516; 95% CI, -968 to 65; P = .025).

Over time, the BMI in the C9 group tended to increase between 49 and 23 years before the onset of ALS symptoms and decreased 10 years before the onset of the ALS symptoms, and for the C9 + cohort, the BMI was 36 years ago the occurrence of symptoms was significantly lower and increased more slowly.

Leisure time and occupational physical activity increased faster in the C9 cohort from 31 to 35 years of age before symptoms began. No difference in activity was observed between the participants in the control group and the C9 + group.

Cigarettes were consumed more frequently in the C9 and C9 + cohorts from 47 and 24 years of age, respectively, prior to symptoms than the control group participants.

Genetic variants were associated with BMI (n = 826), tobacco consumption (n = 107), and alcohol consumption (n = 46), but not with energy intake. There was no evidence of a causal or preventive effect for the variants associated with the BMI. The results showed a causal effect for smoking in the C9 group (P.[Q|x] instrumental variable analysis [IVA]-neutral, 0.5703; IVA-informative, 0.9859) and for alcohol consumption under 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 could contain some recall bias based on retrospectively reported data.

These data indicated that environmental and genetic factors are likely to interact during the presymptomatic phase of ALS. Additional studies are needed to assess whether lifestyle changes can alleviate or delay the onset of ALS symptoms.

Disclosure: A study author stated links with biotech, pharmaceutical, and / or device companies. For a full list of the author’s disclosures, see the original reference.


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

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