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Cited by 10Amyotrophic Lateral Sclerosis ResearchDementia and Cognitive Impairment ResearchNeurogenetic and Muscular Disorders Research

Lifestyle and medical conditions in relation to ALS risk and progression—an introduction to the Swedish ALSrisc Study

Open access
Chourpiliadis, Charilaos, Seitz, Christina, Lovik, Anikó, Joyce, Emily E., Pan, Lu, Hu, Yihan, Kläppe, Ulf, Samuelsson, Kristin +3 more·2024·Journal of Neurology
DOI 10.1007/s00415-024-12496-wPMC PMC11319377
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Abstract

Background: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). Methods: We included 265 newly diagnosed ALS patients during 2016–2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. Results: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83–0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89–0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16–0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13–3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84–0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20–3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06–3.19), and hypertension (HR 1.76, 95%CI 1.03–3.01) were associated with higher risk of death, following ALS diagnosis. Conclusions: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.

AI snapshot

Written from the paper’s full text.

TL;DR

This introduction to the Swedish ALSrisc Study found that higher BMI and diabetes were associated with lower ALS risk, while hypercholesterolemia was associated with higher ALS risk. After diagnosis, higher BMI was associated with lower mortality, whereas smoking, hypercholesterolemia, and hypertension were associated with higher mortality.

Key findings

  • Higher BMI at recruitment was associated with lower ALS risk: unconditional OR 0.90 (95% CI 0.85–0.96) and conditional OR 0.89 (95% CI 0.83–0.95) per 1 kg/m². A one-unit increase in average BMI over the 3 decades before diagnosis was also associated with lower ALS risk (OR 0.94, 95% CI 0.89–0.99).
  • Diabetes mellitus was associated with lower ALS risk (OR 0.38, 95% CI 0.16–0.90), while hypercholesterolemia was associated with higher ALS risk (OR 2.10, 95% CI 1.13–3.90).
  • Among ALS patients, higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95% CI 0.84–0.98). The highest smoking exposure (>16 pack-years) (HR 1.90, 95% CI 1.20–3.00), hypercholesterolemia (HR 1.84, 95% CI 1.06–3.19), and hypertension (HR 1.76, 95% CI 1.03–3.01) were associated with higher risk of death.
  • In repeated ALSFRS-R analyses, faster functional decline was seen with the highest smoking pack-years (β −3.81, 95% CI −7.24 to −0.38), hypertension (β −4.55, 95% CI −7.22 to −1.89), and hypercholesterolemia (β −2.86, 95% CI −5.75 to 0.02).

Methods

  • The ALSrisc Study is an ongoing case–control study in Stockholm, Sweden. This analysis included 265 newly diagnosed ALS patients from March 2016 to May 2022 and 207 ALS-free controls (79 siblings and 128 partners), followed from diagnosis until death, invasive ventilation, or November 30, 2022.
  • Exposures were collected at recruitment via the Euro-MOTOR questionnaire: BMI, smoking status and pack-years, and history of head injuries, diabetes mellitus, hypercholesterolemia, or hypertension. C9orf72 mutation status came from a clinical genetic panel.
  • ALS risk was analyzed with unconditional and conditional logistic regression adjusted for age and sex; BMI over prior decades used generalized estimating equations. Prognosis used a joint longitudinal-survival model combining repeated ALSFRS-R measurements and survival, adjusted for age at diagnosis, sex, onset site, diagnostic delay, and BMI at diagnosis, with secondary Cox and linear mixed models.

Limitations

  • The paper states that exposure information was self-reported and retrospective, so recall bias may exist; BMI over prior decades may be non-differentially misclassified and could underestimate the true BMI effect.
  • The paper states little information was available on how well diabetes, hypercholesterolemia, and hypertension were controlled; the sample size was not large enough to study sibling and partner controls separately; and C9orf72 repeat length was not measured.
  • The paper states it focused on individual factors rather than synergistic effects. Evident from the text: controls were siblings and partners rather than a population-based sample, and some analyses had smaller numbers (e.g., BMI at recruitment in Table 3 included 146 cases/193 controls), which may limit precision and generalizability.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00415-024-12496-w

Cites

53 of 53 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

39 of 64 cited sources checked · 23 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    Observational studies indicate a higher level of total cholesterol among ALS cases than controls.

    “The association observed for a history of hypercholesterolemia and a higher risk of ALS in this study is consistent with Mendelian randomization studies suggesting a causal positive association between total cholesterol and low-density lipoprotein (LDL) and ALS risk [30, 31] as well as with observational studies indicating a higher level of total cholesterol among ALS cases than controls [32].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [32] Michels S, Kurz D, Rosenbohm A et al (2023) Association of blood lipids with onset and prognosis of amyotrophic lateral sclerosis: results from the ALS Swabia registry. J Neurol 270:3082–3090 source

      The Results section says total cholesterol concentrations were similarly distributed among ALS cases and controls, contrary to the claimed overall difference. The Case–control study subsection does find higher ALS odds in the top cholesterol quartile, but that does not establish higher cholesterol levels among cases overall. No page numbers are available in our copy. (LLM, conf=0.83)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
  • Premisecitation

    Some associations between environmental risk factors and ALS potentially vary by age, sex, and genetic factors.

    “with some of the associations potentially varying by age, sex, and genetic factors [11–15].”
    Quote in the paperSubstantial claim4 of 5 sources checked
    • cites [11] Nakken O, Meyer HE, Stigum H, Holmøy T (2019) High BMI is associated with low ALS risk: A population-based study. Neurology 93:e424–e432 source
    • cites [12] Alonso A, Logroscino G, Hernán MA (2010) Smoking and the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 81:1249–1252 source

      The Results (page not available in our copy) report that the smoking–ALS association varied by sex and was weakly associated with participants’ mean age. The paper does not report that genetic factors modify the association, and its analysis concerns smoking rather than environmental risk factors generally. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites [13] Batty GD, Gale CR (2021) Pre-Morbid Risk Factors for Amyotrophic Lateral Sclerosis: Prospective Cohort Study. Clin Epidemiol 13:941–947 source

      The Introduction discusses inconsistent findings for environmental risk factors and mentions genetic and non-genetic causes of ALS. The Results and Discussion identify age and sex as risk factors, but do not say that associations between environmental factors and ALS vary by age, sex, or genetics. Searches for interaction, effect modification, and stratification did not locate support for that claim; page numbers were not supplied. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
    • cites [14] Opie-Martin S, Jones A, Iacoangeli A et al (2020) UK case control study of smoking and risk of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 21:222–227 source

      The Discussion reports that a meta-analysis found a higher smoking–ALS association in women, supporting possible variation by sex. The Introduction notes both genetic and environmental contributions to ALS, but does not say genetic factors modify environmental associations. The paper adjusts for age rather than reporting that the association varies by age; no page numbers are available in our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [15] Peters S, Visser AE, D’Ovidio F et al (2020) Effect modification of the association between total cigarette smoking and ALS risk by intensity, duration and time-since-quitting: Euro-MOTOR. J Neurol Neurosurg Psychiatry 91:33–39 source

      The Introduction says environmental exposures may act on genetic predisposition, and the Neurodegeneration discussion reports a somewhat stronger smoking association after excluding cases with a C9orf72 repeat expansion. The Methods say age and sex were adjustment variables, but our copy does not report that the smoking–ALS association varies by either age or sex. No page numbers are available in the indexed passages. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
  • Premisecitation

    Exposure to certain environmental factors might modify the risk that monogenic ALS mutations confer.

    “as exposure to certain environmental factors might modify the risk the mutations confer [8].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Goutman SA, Hardiman O, Al-Chalabi A et al (2022) Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol 21:480–493 source

      The ALS epidemiology section discusses age, sex, and genetics as influences on ALS risk, while the section on ALS genes discusses mutations and clinical phenotype. Neither states that environmental exposures modify the risk conferred by ALS mutations; searches for environmental factors and genetic penetrance found no passage addressing that interaction. Page numbers were not available in our copy. (LLM, conf=0.73)

      Experimental — accuracy not yet measured
  • Premisecitation

    Monogenic ALS mutations may exhibit incomplete penetrance or delayed onset.

    “monogenic ALS mutations may still exhibit incomplete penetrance or delayed onset [8]”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [8] Goutman SA, Hardiman O, Al-Chalabi A et al (2022) Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis. Lancet Neurol 21:480–493 source

      The ALS epidemiology section (page unavailable) reports an age difference in ALS onset among C9orf72 expansion carriers, supporting variability in onset. The Conclusion (page unavailable) identifies penetrance as an unresolved question, but does not state that monogenic ALS mutations have incomplete penetrance. (LLM, conf=0.72)

      Experimental — accuracy not yet measured
  • Premisecitation

    The heritability of ALS is estimated to be around 50%.

    “the heritability of the disease is estimated to be around 50% [2]”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [2] Ryan M, Heverin M, McLaughlin RL, Hardiman O (2019) Lifetime Risk and Heritability of Amyotrophic Lateral Sclerosis. JAMA Neurol 76:1367–1374 source
  • Classified as probably not a substantial claim. 30
  • May combine two claims. 15

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Many environmental risk factors have been studied in relation to ALS.

    “Many environmental risk factors have been studied in relation to ALS [9, 10]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [9] Ingre C, Roos PM, Piehl F, Kamel F, Fang F (2015) Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol 7:181–193

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [10] Duan QQ, Jiang Z, Su WM et al (2023) Risk factors of amyotrophic lateral sclerosis: a global meta-summary. Front Neurosci 17:1177431 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Repeats of 24 or more hexanucleotides in C9orf72 are considered pathogenic, leading to earlier diagnosis of ALS.

    “Repeats of 24 or more hexanucleotides are considered pathogenic, leading to earlier diagnosis of ALS [6, 7].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [6] Iacoangeli A, Al Khleifat A, Jones AR et al (2019) C9orf72 intermediate expansions of 24–30 repeats are associated with ALS. Acta Neuropathol Commun 7:115 source

      The Discussion (page unavailable) proposes treating C9orf72 expansions of 24 or more repeats as pathogenic. The paper does not report that this threshold leads to earlier ALS diagnosis; its clinical analysis concerns age at onset and survival, not diagnostic timing. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Westeneng HJ, van Veenhuijzen K, van der Spek RA et al (2021) Associations between lifestyle and amyotrophic lateral sclerosis stratified by C9orf72 genotype: a longitudinal, population-based, case-control study. Lancet Neurol 20:373–384 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The contrasting findings on hypertension and ALS risk might be because systolic blood pressure is a risk factor and diastolic blood pressure is a protective factor for ALS.

    “The contrasting findings might be because the increment in systolic and diastolic blood pressure might eventually have opposite effects on the risk for ALS; namely, systolic blood pressure might be a risk factor, whereas diastolic blood pressure might be a protective factor, for ALS [46].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [46] Xia K, Zhang L, Tang L, Huang T, Fan D (2022) Assessing the role of blood pressure in amyotrophic lateral sclerosis: a Mendelian randomization study. Orphanet J Rare Dis 17:56 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A lower BMI at diagnosis and increased weight loss before diagnosis have been previously related to a higher risk of death after ALS diagnosis.

    “A lower BMI at diagnosis [21, 24–26] and an increased weight loss before diagnosis [27, 28] have been previously related to a higher risk of death after ALS diagnosis.”
    Quote in the paperNot a substantial claim3 of 6 sources checked
    • cites [21] Mariosa D, Beard JD, Umbach DM et al (2017) Body Mass Index and Amyotrophic Lateral Sclerosis: A Study of US Military Veterans. Am J Epidemiol 185:362–371 source
    • cites [24] Calvo A, Moglia C, Lunetta C et al (2017) Factors predicting survival in ALS: a multicenter Italian study. J Neurol 264:54–63 source
    • cites [25] Shimizu T, Nagaoka U, Nakayama Y et al (2012) Reduction rate of body mass index predicts prognosis for survival in amyotrophic lateral sclerosis: a multicenter study in Japan. Amyotr Lateral Scler 13:363–366 source
    • cites [26] Janse Van Mantgem MR, Van Eijk RPA, Van Der Burgh HK et al (2020) Prognostic value of weight loss in patients with amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry 91:867–875 source
    • cites [27] Marin B, Arcuti S, Jesus P et al (2016) Population-Based Evidence that Survival in Amyotrophic Lateral Sclerosis is Related to Weight Loss at Diagnosis. Neurodegener Dis 16:225–234 source
    • cites [28] Wolf J, Safer A, Wöhrle JC et al (2014) Factors predicting one-year mortality in amyotrophic lateral sclerosis patients–data from a population-based registry. BMC Neurol 14:197 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypermetabolism and weight loss have been previously shown among ALS patients.

    “Hypermetabolism and weight loss have been previously shown among ALS patients [18].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [18] Burg T, Van Den Bosch L (2023) Abnormal energy metabolism in ALS: a key player? Curr Opin Neurol 36:338–345 source

  • May combine two claims.

    Premisecitation

    A higher stage of chronic kidney disease and a lower concentration of cystatin C-based-eGFR have been associated with ALS risk.

    “A higher stage of chronic kidney disease and a lower concentration of cystatin C-based-eGFR have also been associated with ALS risk [48], indicating a potential explanatory mechanism for the link between hypertension and ALS.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [48] Nagel G, Kurz D, Peter RS et al (2023) Cystatin C based estimation of chronic kidney disease and amyotrophic lateral sclerosis in the ALS registry Swabia: associated risk and prognostic value. Sci Rep 13:19594 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Exposure to oxidative stress and neurotoxic chemicals might provide a plausible biological explanation for the association between smoking and ALS.

    “The exposure to oxidative stress and neurotoxic chemicals might provide a plausible biological explanation for this association [14].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Opie-Martin S, Jones A, Iacoangeli A et al (2020) UK case control study of smoking and risk of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 21:222–227 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Previous studies have suggested that a high circulating level of glucose and a higher energy balance can potentially counteract the energy deficit of ALS related to aberrant aggregations of proteins in neurons.

    “Previous studies have suggested several pathways potentially underlying the observed inverse association between diabetes mellitus type 2 and ALS risk; for instance, a high circulating level of glucose and a higher energy balance can potentially counteract the energy deficit of ALS related to aberrant aggregations of proteins in neurons [35].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [35] Jawaid A, Khan R, Polymenidou M, Schulz PE (2018) Disease-modifying effects of metabolic perturbations in ALS/FTLD. Mol Neurodegener 13:63 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    TDP-43 depositions have been found in animal models following head trauma and in cases of chronic traumatic encephalopathy.

    “Additional indications for a role of head trauma in neurodegeneration include the TDP-43 depositions found in animal models following head trauma and in cases of chronic traumatic encephalopathy [51, 52].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [51] Liu G, Ou S, Cui H et al (2021) Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis. Neuroepidemiology 2021:1–9 source
    • cites [52] Anderson EN, Gochenaur L, Singh A et al (2018) Traumatic injury induces stress granule formation and enhances motor dysfunctions in ALS/FTD models. Hum Mol Genet 27:1366–1381 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Other studies, including a meta-analysis, suggested that smoking is not associated with the risk for ALS or risk of death after ALS diagnosis.

    “Nevertheless, other studies, including a meta-analysis, suggested that smoking is not associated with the risk for ALS [11, 12] or risk of death after ALS diagnosis [13].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [11] Nakken O, Meyer HE, Stigum H, Holmøy T (2019) High BMI is associated with low ALS risk: A population-based study. Neurology 93:e424–e432 source
    • cites [12] Alonso A, Logroscino G, Hernán MA (2010) Smoking and the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 81:1249–1252 source
    • cites [13] Batty GD, Gale CR (2021) Pre-Morbid Risk Factors for Amyotrophic Lateral Sclerosis: Prospective Cohort Study. Clin Epidemiol 13:941–947 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A history of hypertension was previously linked to a higher risk of death among ALS patients.

    “In line with our results, history of hypertension was previously linked to a higher risk of death among ALS patients [43, 44].”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [43] Moglia C, Calvo A, Canosa A et al (2017) Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study. Amyotroph Lateral Scler Frontotemporal Degener 18:590–597 source
    • cites [44] Mandrioli J, Ferri L, Fasano A et al (2018) Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis. Eur J Neurol 25:861–868 source

  • May combine two claims.

    Premisecitation

    Some observational studies showed a positive association for current smoking but no association for former smoking with ALS risk.

    “Some observational studies showed a positive association for current smoking but no association for former smoking [7, 14, 15], while Mendelian Randomization studies have provided evidence for a causal link between smoking and risk for ALS [49].”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [7] Westeneng HJ, van Veenhuijzen K, van der Spek RA et al (2021) Associations between lifestyle and amyotrophic lateral sclerosis stratified by C9orf72 genotype: a longitudinal, population-based, case-control study. Lancet Neurol 20:373–384 source
    • cites [14] Opie-Martin S, Jones A, Iacoangeli A et al (2020) UK case control study of smoking and risk of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 21:222–227 source
    • cites [15] Peters S, Visser AE, D’Ovidio F et al (2020) Effect modification of the association between total cigarette smoking and ALS risk by intensity, duration and time-since-quitting: Euro-MOTOR. J Neurol Neurosurg Psychiatry 91:33–39 source

      The Neurodegeneration section reports a positive association for current smoking (OR 1.47, 95% CI 1.20–1.79). The Results give counts for former smokers, and the Discussion reports declining ALS risk with time since quitting, but the available passages do not establish that former smoking had no association with ALS risk compared with never smoking. No page numbers are provided in our copy. (LLM, conf=0.79)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Another study showed an inverse association of hypertension with ALS risk.

    “In contrast to our study, however, another study showed an inverse association of hypertension with ALS risk [45].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [45] Abdel Magid HS, Topol B, McGuire V, Hinman JA, Kasarskis EJ, Nelson LM (2022) Cardiovascular Diseases, Medications, and ALS: A Population-Based Case-Control Study. Neuroepidemiology 56:423–432 source

  • May combine two claims.

    Findingown data

    At the time of recruitment, compared to a BMI of 21, a lower BMI is associated with higher odds of ALS, whereas a higher BMI is associated with lower odds.

    “At the time of recruitment, compared to a BMI of 21, a lower BMI was associated with higher odds of ALS, whereas a higher BMI was associated with lower odds (Fig. 4).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Self-reported information on BMI, smoking, and history of medical conditions accurately reflects participants' true exposures and diagnoses.
    • Rests on an assumption: The controls (siblings and partners) are representative of the source population that gave rise to the ALS cases.
    • Rests on an assumption: The statistical models are correctly specified and no unmeasured confounding remains after adjustment for the included covariates.
    • Rests on an assumption: BMI at recruitment reflects BMI before disease onset and is not affected by preclinical ALS.

  • May combine two claims.

    Findingown data

    Cases had a slightly higher BMI than controls earlier in life, but they experienced a slower increase in BMI along with aging, resulting in lower BMI levels during the last decade before diagnosis.

    “Although cases had a slightly higher BMI than controls earlier in life, they experienced a slower increase in BMI along with aging, resulting in lower BMI levels during the last decade before diagnosis.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Self-reported information on BMI, smoking, and history of medical conditions accurately reflects participants' true exposures and diagnoses.

  • May combine two claims.

    Findingown data

    Current smoking is associated with a higher risk of death after ALS diagnosis, but the association is not statistically significant (HR 2.28, 95% CI 0.91-5.71).

    “Current smoking (HR 2.28; 95%CI 0.91–5.71) and the highest level of smoking in pack-years (HR 1.90, 95%CI 1.20–3.00) were both associated with a higher risk of death, although the association was only statistically significant for the latter.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The joint model was adjusted for age at diagnosis, sex, site of onset, diagnostic delay, and BMI at diagnosis.

    “The model was adjusted for age at diagnosis, sex, site of onset, diagnostic delay, and BMI at diagnosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The conditional logistic regression models used the family identifier as stratum to account for potential familial confounding due to shared early life environmental and genetic factors (between siblings) and adult-life environmental factors (between partners).

    “As a secondary analysis, we used conditional logistic regression models with the family identifier as stratum to account for potential familial confounding due to shared early life environmental and genetic factors (between siblings) and adult-life environmental factors (between partners).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    The proportional hazards assumption was tested using scaled Schoenfeld residuals, and interactions with time were introduced for any variables violating this assumption.

    “The proportional hazards assumption was tested using scaled Schoenfeld residuals, and interactions with time were introduced for any variables violating this assumption.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Reporting of the present study followed the STROBE guidelines.

    “Reporting of the present study followed the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guidelines (Supplementary File 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The GEE model for BMI during the 3 decades before recruitment was adjusted for age and sex.

    “The GEE model was adjusted for age and sex.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    None of the sibling controls tested positive for C9orf72 mutation and remained asymptomatic during the study.

    “None of these siblings tested positive for C9orf72 mutation and remained asymptomatic during the study.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The missingness level was low (5-10%) in variables with missing values; thus, complete case analyses were performed.

    “The missingness level was low (5–10%) in variables with missing values; thus, we performed complete case analyses.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Missing data are missing completely at random, so complete case analysis does not bias the results.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In both the unconditional and conditional logistic regression analyses, the models were adjusted for age at recruitment and sex.

    “In both analyses, we adjusted for age at recruitment and sex.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The most common monogenic mutation linked with ALS, especially in populations of European ancestry, is the repeat expansion of the GGGGCC hexanucleotide in the first intron of the C9orf72 gene.

    “The most common monogenic mutation linked with ALS, especially in populations of European ancestry, is the repeat expansion of the GGGGCC hexanucleotide in the first intron of the C9orf72 gene [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP (2017) Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 88:540–549 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The survival model was additionally adjusted for ALSFRS-R and progression rate at the time of diagnosis.

    “The survival model was additionally adjusted for ALSFRS-R and progression rate at the time of diagnosis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was approved by the Swedish Ethical Review Authority, and oral and written informed consent was collected from all study participants.

    “The study was approved by the Swedish Ethical Review Authority (DNRs: 2014–1815-31–4, 2018–1605-31, and 2021–06397-02). Oral and written informed consent was collected from all study participants.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The risk of ALS was three times as high for head injuries occurring less than a year before diagnosis.

    “The risk was three times as high for injuries occurring less than a year before diagnosis, indicating potentially reverse causation, considering that ALS is a disease with at least 1 year of diagnostic delay.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Liu G, Ou S, Cui H et al (2021) Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis. Neuroepidemiology 2021:1–9 source

  • May combine two claims.

    Study design and conductnone given

    The study included only incident ALS patients and had complete follow-up for all patients, alleviating concerns about selection bias due to recruitment of prevalent cases and loss to follow-up.

    “The strengths of the present study lie in the inclusion of only incident ALS patients and the complete follow-up for all patients, alleviating concerns on selection bias due to recruitment of prevalent cases (i.e., patients with better survival than average) and loss to follow-up.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Both severe and less severe head trauma were associated with an increased risk for ALS.

    “Both severe and less severe head trauma were associated with an increased risk for ALS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Liu G, Ou S, Cui H et al (2021) Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis. Neuroepidemiology 2021:1–9 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    For BMI during the decades before recruitment, both cases and controls may not have remembered accurately, introducing some degree of non-differential misclassification.

    “For BMI during the decades before recruitment, it is possible that both cases and controls did not remember accurately, introducing some degree of non-differential misclassification.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    If non-differential misclassification of BMI occurred, the observed effect of BMI on ALS risk might have underestimated the real effect.

    “If this is the case, the effect we observed might have underestimated the real effect of BMI on ALS risk.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    The study focused on the individual roles of the studied factors rather than their synergistic effects.

    “although we studied a rather extensive list of factors potentially related to the risk and prognosis of ALS, we focused on the individual roles of these factors.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    Exposure information was self-reported and obtained retrospectively, so some degree of recall bias might exist for cases and controls.

    “First, the information on exposure status was self-reported and obtained retrospectively. Thus, some degree of recall bias might exist for cases and the controls.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other studies have shown that a lower BMI is associated with a faster functional decline in ALS.

    “Other studies that considered ALSFRS-R score as a measure of disease progression have also shown that a lower BMI is associated with a faster functional decline [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Hannaford A, Byth K, Pavey N et al (2023) Clinical and neurophysiological biomarkers of disease progression in amyotrophic lateral sclerosis. Muscle Nerve 67:17–24 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A recent meta-analysis found a positive association between a history of head trauma and risk for ALS.

    “A recent meta-analysis by Liu et al. [51] found a positive association between a history of head trauma and risk for ALS.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Liu G, Ou S, Cui H et al (2021) Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis. Neuroepidemiology 2021:1–9 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Head injury has been suggested as a risk factor for several neurodegenerative diseases because head trauma may disrupt the permeability of the blood-brain barrier.

    “Head injury has been suggested as a risk factor for several neurodegenerative diseases as head trauma may for instance disrupt the permeability of the blood–brain barrier [51].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Liu G, Ou S, Cui H et al (2021) Head Injury and Amyotrophic Lateral Sclerosis: A Meta-Analysis. Neuroepidemiology 2021:1–9 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mendelian Randomization studies have provided evidence for a causal link between smoking and risk for ALS.

    “Some observational studies showed a positive association for current smoking but no association for former smoking [7, 14, 15], while Mendelian Randomization studies have provided evidence for a causal link between smoking and risk for ALS [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Zhan Y, Fang F (2019) Smoking and amyotrophic lateral sclerosis: A mendelian randomization study. Ann Neurol 85:482–484 source
38 of 38

  • The paper relies on this without support.

    Self-reported information on BMI, smoking, and history of medical conditions accurately reflects participants' true exposures and diagnoses.

    “Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment.”

  • The paper relies on this without support.

    The controls (siblings and partners) are representative of the source population that gave rise to the ALS cases.

    “We included 207 controls (79 siblings and 128 partners of the ALS patients) in the present study.”

  • The paper relies on this without support.

    Missing data are missing completely at random, so complete case analysis does not bias the results.

    “The missingness level was low (5–10%) in variables with missing values; thus, we performed complete case analyses.”

  • The paper relies on this without support.

    The statistical models are correctly specified and no unmeasured confounding remains after adjustment for the included covariates.

    “In both analyses, we adjusted for age at recruitment and sex.”

  • The paper relies on this without support.

    BMI at recruitment reflects BMI before disease onset and is not affected by preclinical ALS.

    “In the unconditional logistic regression, one-unit increase in BMI at recruitment was associated with 10% lower odds for ALS (OR 0.90, 95%CI 0.85–0.96) (Table 3).”

  • The authors state this as an assumption.

    Most participants reporting hypercholesterolemia had taken cholesterol-lowering medications, including statins.

    “Thus, even if we assume that most participants reporting hypercholesterolemia had taken cholesterol-lowering medications, including statins, the observed association of hypercholesterolemia with ALS risk might not be entirely explained by medication use.”

  • The paper relies on this without support.

    Siblings and spouses share genetic or non-genetic factors that might be common causes of the studied lifestyle and medical conditions and ALS.

    “because siblings and spouses share genetic or non-genetic factors that might be common causes of the studied lifestyle and medical conditions and ALS.”

  • The paper relies on this without support.

    ALS is a disease with at least 1 year of diagnostic delay.

    “considering that ALS is a disease with at least 1 year of diagnostic delay.”
8 of 8

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Authors
Chourpiliadis, C., Seitz, C., Lovik, A., Joyce, E. E., Pan, L., Hu, Y., Kläppe, U., Samuelsson, K., Press, R., Ingre, C., & Fang, F.
Affiliations
  • Karolinska Institutet (SE)
  • Leiden University (NL)
  • Karolinska University Hospital (SE)
Corresponding author
  • Ingre, Caroline
  • Fang, Fang
ORCID
Venue
Journal of Neurology
Publisher
Springer Science and Business Media LLC
Published
2024-06-15
Volume
271
Issue
8
Pages
5447-5459
ISSN
  • 0012-1037 (ISSN-L)
  • 0340-5354
  • 1432-1459
DOI
10.1007/s00415-024-12496-w
PMC
PMC11319377
OpenAlex
W4399705450
Semantic Scholar
7af70e3687a487afea8202d0d08b27bfba4e3c6d
Cited by
10
References
50
Citations by year
2026: 6 · 2025: 2 · 2024: 2
FWCI
2.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neurology (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Leiden Repository (Leiden University) (publishedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • Figshare (submittedVersion, cc-by)
Funders
  • European Research Council Starting Grant (MegaALS 802091)
  • US Center for Disease Control and Prevention (R01TS000324-01-00)
  • Swedish Research Council (2019-01088, 2023-02428)
  • Bjorklunds Fund
  • Ulla-Carin Lindquist Foundation
  • Neuro Sweden
  • Svenska Frimurar Orden
  • Karolinska Institute
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
Keywords
amyotrophic lateral sclerosis, ALS risk factors, disease progression, body mass index, diabetes mellitus, hypercholesterolemia, hypertension, smoking, traumatic brain injury, mortality, lifestyle factors
MeSH terms
Adult, Aged, Amyotrophic Lateral Sclerosis, Diabetes Mellitus, Female, Humans, Hypercholesterolemia, Hypertension, Life Style, Male, Middle Aged, Risk Factors, Smoking, Sweden, Body Mass Index, Disease Progression

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