Table 1.

A summary of the reports 2009–21, investigating whether PA is an environmental risk factor for ALS

Publications	Summary conclusion: positive association
Daneshvar et al.23	Significantly higher incidence and mortality with ALS among NFL players than the US population. Also a direct link with increased length of NFL career.
Raymond et al.24	Participants involved in vigorous PA ≥3 times per week more likely to develop ALS and at a younger age.
Gamez et al.25	Mean age of onset of ALS was younger in Spanish professional/semi-professional football players by 23.7 years compared to the general European population.
Russell et al.26	Neurodegenerative disease risk in soccer players was highest in defenders and players that had played for >15 years.
Julian et al.27	MR evidence supported a relationship between genetic liability to frequent strenuous leisure-time exercise and ALS. Transcriptomic analysis showed that genes altered in response to acute exercise are enriched with known ALS risk genes. A positive relationship found between age of onset of G4C2-repeat expansion C9orf72-ALS and strenuous, leisure-time exercise.
Westeneng et al.28	Daily energy intake at symptom onset in C9-positive group and C9-negative group higher versus controls. Concluded that exercise increases the risk of ALS.
Canosa et al.29	18F-FDG-PET demonstrated that in a group of ALS patients expressing the same level of disability, hypermetabolism was found in the subgroup that did not exercise, suggesting that this hypermetabolic group could potentially adapt better to the neurodegenerative process.
Fang et al. 30	Examining a large cohort of cross-country skiers, as a high endurance exercise, the authors reported that the fastest skiers had a 4-fold increased risk of developing ALS. Participants who had been involved in over four races compared to a single race were also at increased risk.
Harwood et al.31	The use of the HAPAQ questionnaire showed that the level of total PA throughout adulthood is significantly associated with the risk of developing ALS.
Pasquinelli et al.32	ALS patients with Gly482Ser allelic variant in PGC1α show increased exercise-related oxidative stress. ALS participants had significantly increased advanced oxidation protein products, decreased ferric reducing ability and thiol groups in comparison to controls.
Lehman et al.33	Neurodegenerative mortality from ALS and Alzheimer’s disease was increased 4-fold in professional footballers’ versus the general US population.
Turner et al.34	The was concordance for side of onset and handedness in upper limb-onset ALS patients, implying a higher exercise demand can trigger the site of onset of ALS.
Summary conclusion: negative association
Korner et al.35	In a cohort study, ALS patients did not report increased PA at leisure or occupation versus controls.
Venkataramni et al.19	There was no statistically significant difference in the risk of long-term all-cause mortality among career NFL players versus NFL replacement players who participated in the NFL during a three-game league-wide player strike in 1987.
Janssen et al.18	American varsity high-school football players had an increased risk of medically documented trauma, but did not have increased risk of neurodegenerative disease overall.
Savica et al.16	In high school football players, there was no increased risk of Alzheimer’s dementia, Parkinson’s disease or ALS.

See Supplementary Table 1 for further critical analysis. HAPAQ = historical adulthood physical activity questionnaire; NFL = National Football League.