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Cited by 117Amyotrophic Lateral Sclerosis ResearchTraumatic Brain Injury ResearchAlzheimer's disease research and treatments

Association of ALS with head injury, cigarette smoking and APOE genotypes

Open access
Schmidt, Silke, Kwee, Lydia Coulter, Allen, Kelli D., Oddone, Eugene Z.·2010·Journal of the Neurological Sciences
DOI 10.1016/j.jns.2010.01.011PMC PMC2840700
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Abstract

Objective An increased risk of ALS has been reported for US veterans, but the cause is unknown. Since head injury and cigarette smoking are two previously implicated environmental risk factors that are more common in military than civilian study populations, we tested their association with ALS in a US veteran study population.Methods We used logistic regression to examine the association of ALS with head injury and cigarette smoking in 241 incident cases and 597 controls. Since APOE is a plausible ALS candidate gene, we also tested its main effect and its statistical interaction with these environmental exposures.Results Cigarette smoking was not associated with ALS in this predominantly male and Caucasian population. Veterans who had experienced head injuries during the last 15years before the reference date had an adjusted odds ratio of 2.33 (95% confidence interval 1.18-4.61), relative to veterans without any head injuries. This association was strongest in APOE-4 carriers.Conclusions Our results add to the body of evidence suggesting that head injuries may be a risk factor for multiple neurodegenerative diseases, including ALS. We hypothesize that the strength of association between head injuries and ALS may depend upon APOE genotype.

AI snapshot

Written from the paper’s full text.

TL;DR

In a US veteran case-control study, cigarette smoking was not associated with ALS, but head injury within the 15 years before the reference date was associated with higher ALS odds. The head-injury association appeared strongest among APOE-4 carriers, though the authors call for replication.

Key findings

  • Among 241 incident ALS cases and 597 controls, cigarette smoking was not associated with ALS, including analyses by never/former/current status, smoking duration, and pack-years.
  • Veterans with head injury in the last 15 years before the reference date had adjusted OR 2.33 (95% CI 1.18–4.61) for ALS relative to no head injuries.
  • The head-injury association was strongest in APOE-4 carriers: genotype-specific OR for injury within ≤15 years was 7.5 (95% CI 1.4–41.3) in APOE-4 carriers, versus 1.9 (0.8–4.4) in APOE 3/3 and 2.2 (0.8–5.6) in APOE-2 carriers.
  • APOE-2 carriage showed a non-significant elevated ALS risk (OR 1.32, 95% CI 0.88–1.98); APOE-4 carriage was not associated with ALS risk.

Methods

  • Case-control study within the GENEVA study of US veterans: 241 incident sporadic ALS cases with interviews and 597 veteran controls; APOE genotypes were available for 417 cases and 482 controls.
  • Structured telephone interviews assessed head injury and cigarette smoking; APOE genotypes were determined from rs7412 and rs429358.
  • Unconditional logistic regression estimated ALS associations adjusted for age, sex, race/ethnicity, and education, with gene-environment interaction tests between APOE, smoking, and head-injury interval.

Limitations

  • The authors state the study is not population-based, case and control enrollment methods were not identical, and case enrollment may have increased the proportion of more slowly progressing individuals.
  • The authors note control participation was 41%, they lacked detailed context/severity of head injuries, and genotype-specific categories were limited with wide confidence intervals requiring replication.
  • Evident from the text: the sample was predominantly male and Caucasian veterans, so generalizability to other populations is limited; exposure and injury data were self-reported, and the observational design cannot establish causality.

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

Integrity signals

Registry

Crossref · 10.1016/j.jns.2010.01.011

Cites

74 of 74 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 62 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    ALS was not significantly associated with smoking duration and cigarette pack-years.

    “Similarly, ALS was not significantly associated with smoking duration and cigarette pack-years.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Excluding smoking data reported within the last two years before the reference date is sufficient to remove smoking changes caused by early ALS symptoms.
  • Findingown data

    There was no association between ALS and cigarette smoking, analyzed as never vs. former vs. current smoking.

    “There was no association between ALS and cigarette smoking, analyzed as never vs. former vs. current smoking.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Excluding smoking data reported within the last two years before the reference date is sufficient to remove smoking changes caused by early ALS symptoms.
  • Findingown data

    Cigarette smoking was not associated with ALS in this predominantly male and Caucasian population.

    “Cigarette smoking was not associated with ALS in this predominantly male and Caucasian population.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Excluding smoking data reported within the last two years before the reference date is sufficient to remove smoking changes caused by early ALS symptoms.
  • Findingown data

    In the dataset, a higher proportion of individuals in the at-risk group than those not included had received imminent danger pay for active duty status in an area with imminent danger (55% vs. 34%).

    “a higher proportion (55% vs. 34%) had received imminent danger pay for active duty status in an area that presented an imminent danger of being exposed to hostile fire or explosion of hostile mines”
    Quote in the paperNot a substantial claim
  • Findingown data

    Carriage of the APOE-4 allele was not associated with ALS risk.

    “Carriage of the APOE-4 allele was not associated with ALS risk.”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 41
  • May combine two claims. 26
  • The quote only partly states this claim. 1

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

    Findingcitation

    The prevalence of cigarette smoking and head injuries was higher in GENEVA controls than in population-based studies of civilian controls of similar age.

    “As expected, the prevalence of both cigarette smoking and head injuries was higher in GENEVA controls than in population-based studies of civilian controls of similar age (ever vs. never smoking: 64.2% vs. 53.4% in (4); at least one head injury: 31.0% vs. 16.4% in (21)).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Nelson, 2000, Population-based case–control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption, Am J Epidemiol source
    • cites [21] Chen, 2007, Head injury and amyotrophic lateral sclerosis, Am J Epidemiol source

      Queued — the background check reaches it, usually within a day.

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

    Findingown data

    Restricting the analysis to non-Hispanic Caucasian subjects generated slightly lower ORs for APOE genotypes.

    “Restricting the analysis to non-Hispanic Caucasian subjects generated slightly lower ORs (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    More ALS cases than controls experienced head injuries during the last 15 years preceding the reference date, while intervals of the more distant past contained similar proportions of cases and controls, and controls somewhat outweighed cases for injuries reported more than 40 years ago.

    “Figure 1 shows that more ALS cases than controls experienced head injuries during the last 15 years preceding the reference date, while intervals of the more distant past contained similar proportions of cases and controls, and controls somewhat outweighed cases for injuries reported more than 40 years ago.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Excluding head injuries reported within two years of the reference date is sufficient to remove injuries caused by early ALS symptoms.
    • Rests on an assumption: The association between head injury and ALS is not due to unmeasured confounding.

  • May combine two claims.

    Findingown data

    Being a carrier of the APOE-2 allele was associated with a slightly elevated ALS risk, compared to homozygous carriers of the APOE-3 allele (OR 1.32, 95% CI 0.88-1.98), but this result did not reach statistical significance.

    “Being a carrier of the APOE-2 allele was associated with a slightly elevated ALS risk, compared to homozygous carriers of the APOE-3 allele (OR 1.32, 95% CI 0.88–1.98), but this result did not reach statistical significance.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Findingnone given

    Our predominantly male and Caucasian study population of US veterans has a higher head injury and smoking prevalence than comparable civilian cohorts and a larger sample size than most previous studies of ALS and environmental risk factors.

    “Our predominantly male and Caucasian study population of US veterans has a higher head injury and smoking prevalence than comparable civilian cohorts and a larger sample size than most previous studies of ALS and environmental risk factors.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Of the cases included in this analysis, 46.5% were identified through a search of VA databases, while 53.5% were enrolled solely via self-referral.

    “Of the cases included in this analysis, 46.5% were identified as potential Registry participants through a search of VA databases, while 53.5% were enrolled solely via self-referral.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was weak evidence for gene-environment interaction, since the association between ALS and the head injury variable was stronger in APOE-4 carriers (LRT 2.7 on 1 df, p=0.10) than in APOE-2 carriers (LRT 0.2 on 1 df, p=0.68).

    “there was weak evidence for gene-environment interaction, since the association between ALS and the head injury variable was stronger in APOE-4 carriers (LRT 2.7 on 1 df, p=0.10) than in APOE-2 carriers (LRT 0.2 on 1 df, p=0.68).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The ORs and 95% CIs for the first three intervals shown in Figure 1 were 1.62 (0.52, 5.08), 2.28 (0.59, 8.88) and 3.24 (1.15, 9.12), respectively.

    “The ORs and 95% CIs for the first three intervals shown in Figure 1 were 1.62 (0.52, 5.08), 2.28 (0.59, 8.88) and 3.24 (1.15, 9.12), respectively.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Excluding head injuries reported within two years of the reference date is sufficient to remove injuries caused by early ALS symptoms.
    • Rests on an assumption: The association between head injury and ALS is not due to unmeasured confounding.

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    The association between ALS and head injury was strongest in APOE-4 carriers; genotype-specific ORs for the shorter (<=15 years) interval were 1.9 (95% CI 0.8-4.4) for 3/3 genotypes, 2.2 (95% CI 0.8-5.6) for APOE-2 carriers, and 7.5 (95% CI 1.4-41.3) for APOE-4 carriers.

    “This association was strongest in APOE-4 carriers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The global tests of 'main effect plus interaction' indicated that the head injury variable had the greatest impact on the model fit (LRT 12.2 on 8 df), followed by APOE genotypes (LRT 8.8 on 8 df).

    “the global tests of “main effect plus interaction” indicated that the head injury variable had the greatest impact on the model fit (likelihood ratio test (LRT) 12.2 on 8 df), followed by APOE genotypes (LRT 8.8 on 8 df).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The 1 df test of interaction was slightly more significant when the sample was restricted to non-Hispanic Caucasians, but the confidence intervals for the genotype-specific ORs were approximately twice as wide due to a smaller sample size.

    “The 1 df test of interaction was slightly more significant when the sample was restricted to non-Hispanic Caucasians, but the confidence intervals for the genotype-specific ORs were approximately twice as wide due to a smaller sample size.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    To account for ALS cases stopping smoking due to early signs of disease, smoking data within the last two years before the reference date were excluded and smoking status was determined based on the reference date minus two years.

    “to account for the fact that ALS cases may stop smoking due to early signs of the disease, smoking data (duration, dose) reported within the last two years before the reference date were excluded and smoking status (former vs. current) was determined based on the reference date minus two years.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Excluding smoking data reported within the last two years before the reference date is sufficient to remove smoking changes caused by early ALS symptoms.

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

    Study design and conductcitation

    The control participation rate was 41%, slightly higher than the 36% reported by the Millennium Cohort Study and within the range reported for contemporary population-based case-control studies.

    “At the time of this analysis, 41% of eligible controls had consented to participate, which is a slightly higher rate than the 36% reported by the Millennium Cohort Study (42), and within the range reported for contemporary population-based case-control studies (43).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Ryan, 2007, Millennium cohort: enrollment begins a 21-year contribution to understanding the impact of military service, J Clin Epidemiol source
    • cites [43] Morton, 2006, Reporting participation in epidemiologic studies: a survey of practice, Am J Epidemiol source

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Unconditional logistic regression was adjusted for age, sex, race/ethnicity and education.

    “Unconditional logistic regression (SAS Institute Inc., Cary, NC) was used to estimate associations of ALS with the variables of interest, adjusted for age, sex, race/ethnicity and education.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The association between head injury and ALS is not due to unmeasured confounding.

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Cases and controls were frequency-matched on age (5-year age groups), gender, and use of VA health care.

    “An attempt was made to frequency-match cases and controls on age (5-year age groups, using age at ALS diagnosis for cases and age at interview for controls), gender, and use of VA health care”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Several studies have suggested that the association between Alzheimer's disease and head injury may be stronger in carriers of the APOE-4 allele.

    “several studies have suggested that this association may be stronger in carriers of the APOE-4 allele (30–32).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [30] Mayeux, 1995, Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease, Neurology source
    • cites [31] Katzman, 1996, Apolipoprotein-epsilon4 and head trauma: synergistic or additive risks?, Neurology
    • cites [32] Plassman, 2000, Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias, Neurology source

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

    Study design and conductown data

    A sensitivity analysis examined whether results were consistent regardless of whether PMA patients were included or excluded.

    “We performed a sensitivity analysis to examine whether the results were consistent regardless of whether PMA patients were included or excluded.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    There are reports of a potentially increased risk of ALS in US veterans.

    “Following reports of a potentially increased risk of ALS in US veterans (23–25), we are currently conducting a case-control study called GENEVA”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [23] Horner, 2003, Occurrence of amyotrophic lateral sclerosis among Gulf War veterans, Neurology source
    • cites [24] Haley, 2003, Excess incidence of ALS in young Gulf War veterans, Neurology source
    • cites [25] Weisskopf, 2005, Prospective study of military service and mortality from ALS, Neurology source

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

    Premisecitation

    A prospective study based on ALS mortality data found that an association with cigarette smoking was restricted to women.

    “A prospective study based on ALS mortality data found that an association with cigarette smoking was restricted to women (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Weisskopf, 2004, Prospective study of cigarette smoking and amyotrophic lateral sclerosis, Am J Epidemiol source

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

    Study design and conductnone given

    A telephone screener was used to verify the absence of ALS and other neurological disorders in controls.

    “A telephone screener was used to verify the absence of ALS and other neurological disorders.”
    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 study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Boards of the Durham VA and Duke University Medical Centers, and all participants provided informed consent.

    “The GENEVA study was conducted in accordance with the Declaration of Helsinki of the World Medical Association, and was approved by the Institutional Review Boards of the Durham VA and Duke University Medical Centers. All study participants provided informed consent.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    APOE genotypes were in Hardy-Weinberg equilibrium in both cases and controls, and their frequencies were similar to previous reports for the relevant age groups.

    “APOE genotypes were in Hardy-Weinberg equilibrium in both cases and controls; their frequencies (Table 4) were similar to previous reports for the relevant age groups (44;47;48).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [44] Bennet, 2007, Association of apolipoprotein E genotypes with lipid levels and coronary risk, JAMA source
    • cites [47] Farrer, 1997, Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium, JAMA source
    • cites [48] Song, 2004, Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease, Ann Intern Med source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    ALS diagnoses in the Registry were based on medical record reviews by six neurologists with expertise in ALS using the El Escorial criteria for definite, probable or possible ALS.

    “the patient’s diagnosis recorded by the Registry was based on medical record reviews conducted by six neurologists with particular expertise in ALS, who used the El Escorial criteria for definite, probable or possible ALS.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Head injuries have previously been associated with ALS risk.

    “and head injuries (14;20–22).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [14] Deapen, 1986, A case–control study of amyotrophic lateral sclerosis, Am J Epidemiol source
    • cites [20] Kondo, 1981, Case–control studies of motor neuron disease: association with mechanical injuries, Arch Neurol source
    • cites [21] Chen, 2007, Head injury and amyotrophic lateral sclerosis, Am J Epidemiol source

      Not checked in the free run.

    • cites [22] Binazzi, 2008, An exploratory case–control study on spinal and bulbar forms of amyotrophic lateral sclerosis in the province of Rome, Amyotroph Lateral Scler source

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

    Study design and conductown data

    All frequency distributions were very similar when the sample was restricted to non-Hispanic Caucasian cases and controls.

    “All frequency distributions were very similar when the sample was restricted to non-Hispanic Caucasian cases and controls.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Carriers of the APOE-4 allele may have an earlier age at onset of Parkinson's disease.

    “Carriers of the APOE-4 allele may have an earlier age at onset of Parkinson’s disease (33)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Li, 2004, Apolipoprotein E controls the risk and age at onset of Parkinson disease, Neurology source

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

    Study design and conductreasoning

    The analysis was restricted to ALS patients who agreed to participate in the Registry within 12 months of diagnosis and did not report a first-degree family history of ALS.

    “we restricted the analysis to ALS patients who agreed to participate in the Registry within 12 months of diagnosis and did not report a first-degree family history of ALS”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Cigarette smoking has previously been associated with ALS risk.

    “Environmental factors that have previously been associated with ALS risk include cigarette smoking (3–5)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] Kamel, 1999, Association of cigarette smoking with amyotrophic lateral sclerosis, Neuroepidemiology source
    • cites [4] Nelson, 2000, Population-based case–control study of amyotrophic lateral sclerosis in western Washington State. I. Cigarette smoking and alcohol consumption, Am J Epidemiol source
    • cites [5] Weisskopf, 2004, Prospective study of cigarette smoking and amyotrophic lateral sclerosis, Am J Epidemiol source

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

    Study design and conductreasoning

    To reduce recall bias and account for injuries due to early signs of muscle weakness, head injuries reported within two years of the reference date were excluded.

    “To reduce recall bias, and to account for the fact that injuries reported by ALS cases may be due to early signs of muscle weakness, any head injuries reported within two years of the reference date were excluded.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Excluding head injuries reported within two years of the reference date is sufficient to remove injuries caused by early ALS symptoms.

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

    Premisecitation

    Carriers of the APOE-4 allele may have a worse prognosis following an ALS diagnosis.

    “and possibly a worse prognosis following an ALS diagnosis (34–37).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [34] Al-Chalabi, 1996, Association of apolipoprotein E ε4 allele with bulbar-onset motor neuron disease, Lancet source
    • cites [35] Moulard, 1996, Apolipoprotein E genotyping in sporadic amyotrophic lateral sclerosis: evidence for a major influence on the clinical presentation and prognosis, J Neurol Sci source
    • cites [36] Smith, 1996, Apolipoprotein E epsilon 4 in bulbar-onset motor neuron disease, Lancet source
    • cites [37] Li, 2004, Apolipoprotein E is associated with age at onset of amyotrophic lateral sclerosis, Neurogenetics source

  • May combine two claims.

    Study design and conductcitation

    The analysis dataset included PMA patients but excluded PLS patients.

    “our analysis dataset included PMA patients, who typically experience a similarly progressive disease course (n=37 with interviews; n=66 with DNA samples), while PLS patients, who typically progress much more slowly (41), were excluded.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Tartaglia, 2007, Differentiation between primary lateral sclerosis and amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during follow-up, Arch Neurol source

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

    Study design and conductnone given

    Genotyping required 95% efficiency and matching quality control sample genotypes within and across all plates for inclusion in statistical analysis.

    “We required 95% genotyping efficiency and matching genotypes of quality control samples within and across all plates in order to include samples in the statistical analysis.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The APOE-4 (ε4) allele is a strong risk factor for Alzheimer's disease.

    “It is well known that the APOE-4 (ε4) allele is a strong risk factor for AD (29).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Corder, 1993, Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families, Science source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Head injuries experienced in later adulthood may more likely be experienced by individuals with a lifetime history of vigorous physical activity.

    “they may more likely be experienced by individuals with a lifetime history of vigorous physical activity.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The median survival time is well within the range reported by several population-based studies, which extends from 16 months to 28 months, with most studies reporting values between 19 and 23 months.

    “it is well within the range reported by several population-based studies, which extends from 16 months (65;66) to 28 months (67), with most studies reporting values between 19 and 23 months (68–70).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [65] O'Toole, 2008, Epidemiology and clinical features of amyotrophic lateral sclerosis in Ireland between 1995 and 2004, J Neurol Neurosurg Psychiatry source
    • cites [66] Zoccolella, 2008, Analysis of survival and prognostic factors in amyotrophic lateral sclerosis: a population based study, J Neurol Neurosurg Psychiatry source
    • cites [67] Kamel, 2008, Association of lead exposure with survival in amyotrophic lateral sclerosis, Environ Health Perspect source
    • cites [68] Sorenson, 2002, Amyotrophic lateral sclerosis in Olmsted County, Minnesota, 1925 to 1998, Neurology source
    • cites [69] Chio, 2002, Early symptom progression rate is related to ALS outcome: a prospective population-based study, Neurology source
    • cites [70] del Aguila, 2003, Prognosis in amyotrophic lateral sclerosis: a population-based study, Neurology source

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

    Premisecitation

    A study of 93 twin pairs discordant for PD replicated the association between head injury and PD with an OR of 3.8 (95% CI 1.3-11.0).

    “A study of 93 twin pairs who were discordant for PD replicated this association with a similarly large effect size (OR 3.8, 95% CI 1.3–11.0) (56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Goldman, 2006, Head injury and Parkinson's disease risk in twins, Ann Neurol source

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationown data

    The observed statistical association supports continued evaluation of apoe as a potential injury-response protein in experimental studies of motor neuron degeneration.

    “Our observed statistical association supports a continued evaluation of apoe as a potential “injury-response” protein in experimental studies of motor neuron degeneration (62).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Haasdijk, 2002, Increased apolipoprotein E expression correlates with the onset of neuronal degeneration in the spinal cord of G93A-SOD1 mice, Neurosci Lett source

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

    Premisecitation

    The meta-analysis supported an earlier hypothesis that the effect of head injury on AD may be restricted to males.

    “and supported an earlier hypothesis that this effect may be restricted to males (52).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Mortimer, 1985, Head injury as a risk factor for Alzheimer's disease, Neurology source

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

    Premisecitation

    Professional or intense recreational soccer playing has been associated with ALS in some reports.

    “The latter category includes professional or intense recreational soccer playing, which has been associated with ALS in some reports (17;50).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Chio, 2005, Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players, Brain source

      Not checked in the free run.

    • cites [50] Chio, 2008, Amyotrophic lateral sclerosis and soccer: a different epidemiological approach strengthen the previous findings, J Neurol Sci source

  • May combine two claims.

    Study design and conductown data

    The study did not query participants about the context of the reported head injuries and does not have access to more detailed medical or military records about the nature and severity of these injuries.

    “An additional study limitation is that we did not query participants about the context of the reported head injuries and do not have access to more detailed medical or military records about the nature and severity of these injuries.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    The study results are consistent with a recently reported trend for an increasing ALS association with a decreasing number of years between the last head injury and ALS diagnosis, and with an increasing age at the last injury.

    “Our results are consistent with a recently reported trend for an increasing ALS association with a decreasing number of years between the last head injury and ALS diagnosis, and with an increasing age at the last injury (21).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Chen, 2007, Head injury and amyotrophic lateral sclerosis, Am J Epidemiol source

      Not checked in the free run.

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

    Premisecitation

    In a population-based study of PD, an OR of 4.3 (95% CI 1.2-15.2) was reported for head injuries leading to loss of consciousness or hospitalization.

    “In a population-based study of PD, an OR of 4.3 (95% CI 1.2–15.2) was reported for head injuries leading to loss of consciousness or hospitalization, as documented in medical records (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Bower, 2003, Head trauma preceding PD: a case–control study, Neurology source

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

    Study design and conductnone given

    The study had a relatively large sample size.

    “Strengths of our study include its relatively large sample size”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    ALS patients were approximately twice as likely as controls to have always been slim or to have been varsity athletes.

    “a previous study reported that ALS patients were approximately twice as likely as controls to have always been slim or to have been varsity athletes (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Scarmeas, 2002, Premorbid weight, body mass, and varsity athletics in ALS, Neurology source

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

    Study design and conductnone given

    The case enrollment methods may have increased the proportion of more slowly progressing individuals in the analysis sample.

    “that the case enrollment methods may have increased the proportion of more slowly progressing individuals in the analysis sample.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    There are multiple biological mechanisms by which head injuries may trigger the molecular pathways leading to neuronal degeneration.

    “As previously discussed (56), there are multiple biological mechanisms by which head injuries may trigger the molecular pathways leading to neuronal degeneration.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Goldman, 2006, Head injury and Parkinson's disease risk in twins, Ann Neurol source

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

    Premisecitation

    In the prior study, the strongest association was observed for the interval <=10 years between last injury and diagnosis (OR 3.2, 95% CI 1.0-10.2), with a slightly elevated risk for the interval 11-30 years.

    “In that study, the strongest association was observed for the interval “<=10 years between last injury and diagnosis” (OR 3.2, 95% CI 1.0–10.2), with a slightly elevated risk for the interval 11–30 years.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Chen, 2007, Head injury and amyotrophic lateral sclerosis, Am J Epidemiol source

      Not checked in the free run.

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

    Premisecitation

    A meta-analysis of 15 studies yielded an estimated OR for AD of 1.6 (95% CI 1.2-2.1) due to ever having sustained a head injury with loss of consciousness.

    “A meta-analysis of 15 studies yielded an estimated OR for AD of 1.6 (95% CI 1.2–2.1) due to ever having sustained a head injury with loss of consciousness (51)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Fleminger, 2003, Head injury as a risk factor for Alzheimer's disease: the evidence 10years on; a partial replication, J Neurol Neurosurg Psychiatry source

  • May combine two claims.

    Premisecitation

    Modifying effects of the different apoe protein isoforms on these pathways are biologically plausible and have been evaluated in experimental model systems.

    “modifying effects of the different apoe protein isoforms on these pathways are biologically plausible and have been evaluated in experimental model systems (61).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Crawford, 2009, Apolipoprotein E-genotype dependent hippocampal and cortical responses to traumatic brain injury, Neuroscience source

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

    Premisecitation

    Synergistic effects of head injury and APOE genotypes in AD were reported by some studies but not all.

    “Synergistic effects of head injury and APOE genotypes in AD were reported by some (30–32), but not all studies (53;54).”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [30] Mayeux, 1995, Synergistic effects of traumatic head injury and apolipoprotein-epsilon 4 in patients with Alzheimer's disease, Neurology source
    • cites [31] Katzman, 1996, Apolipoprotein-epsilon4 and head trauma: synergistic or additive risks?, Neurology
    • cites [32] Plassman, 2000, Documented head injury in early adulthood and risk of Alzheimer's disease and other dementias, Neurology source
    • cites [53] O'Meara, 1997, Head injury and risk of Alzheimer's disease by apolipoprotein E genotype, Am J Epidemiol source
    • cites [54] Mehta, 1999, Head trauma and risk of dementia and Alzheimer's disease: the Rotterdam Study, Neurology source

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

    Premisecitation

    These mechanisms range from inflammatory and glutamate excitotoxicity pathways, which increase metabolic demands of neurons and microglia, to oxidative stress pathways that may impact mitochondrial function.

    “They range from inflammatory and glutamate excitotoxicity pathways (57;58), which increase the metabolic demands of neurons and microglia, to oxidative stress pathways that may impact mitochondrial function (59).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [57] Lenzlinger, 2001, The duality of the inflammatory response to traumatic brain injury, Mol Neurobiol source
    • cites [58] Arundine, 2004, Molecular mechanisms of glutamate-dependent neurodegeneration in ischemia and traumatic brain injury, Cell Mol Life Sci source
    • cites [59] Frantseva, 2002, Neurotrauma/neurodegeneration and mitochondrial dysfunction, Prog Brain Res source

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

    Study design and conductnone given

    The control participation rate was 41%.

    “Although the control participation rate of 41% is less than ideal”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The risk of head injuries is generally twice as high in men as in women.

    “While the risk of head injuries is generally twice as high in men as in women (49)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Langlois, 2003, Traumatic brain injury-related hospital discharges. Results from a 14-state surveillance system, 1997, MMWR Surveill Summ

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

    Interpretationreasoning

    Several specific attributes of the GENEVA study population, beyond its high proportion of men, may contribute to the higher prevalence of head injuries.

    “several specific attributes of the GENEVA study population, beyond its high proportion of men, may contribute to the higher prevalence of head injuries.”
    Quote in the paperNot a substantial claim
54 of 54

  • The paper relies on this without support.

    Excluding head injuries reported within two years of the reference date is sufficient to remove injuries caused by early ALS symptoms.

    “To reduce recall bias, and to account for the fact that injuries reported by ALS cases may be due to early signs of muscle weakness, any head injuries reported within two years of the reference date were excluded.”

  • The paper relies on this without support.

    The association between head injury and ALS is not due to unmeasured confounding.

    “All results were adjusted for age, sex, race/ethnicity and education.”

  • The paper relies on this without support.

    Excluding smoking data reported within the last two years before the reference date is sufficient to remove smoking changes caused by early ALS symptoms.

    “to account for the fact that ALS cases may stop smoking due to early signs of the disease, smoking data (duration, dose) reported within the last two years before the reference date were excluded”

  • The paper relies on this without support.

    Most previous studies of ALS and head injury did not include a more detailed analysis of the injury-to-onset interval or the age at which head injuries occurred.

    “Most previous studies of ALS and head injury did not include a more detailed analysis of the injury-to-onset interval or the age at which head injuries occurred.”

  • The paper relies on this without support.

    None of the studies conducted to date examined APOE genotypes jointly with head injuries.

    “None of the studies conducted to date examined APOE genotypes jointly with head injuries.”

  • The paper relies on this without support.

    The success of GWAS in ALS has been much more limited than for other complex human diseases.

    “the success of GWAS in ALS has been much more limited than for other complex human diseases.”

  • The paper relies on this without support.

    Environmental risk factors have been completely ignored in all of the ALS GWAS studies published to date.

    “environmental risk factors, which have been completely ignored in all of the ALS GWAS studies published to date.”

  • The paper relies on this without support.

    Recall bias would lead to under-reporting of milder injuries by controls.

    “which would be expected to lead to under-reporting of milder injuries by controls.”
8 of 8

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In a veteran cohort, those with head injury, especially head injuries within 15 years prior to diagnosis, were significantly more likely to have developed ALS.

    “Moreover, in a veteran cohort, those with head injury, especially head injuries within 15 years prior to diagnosis, were found to be significantly more likely to have developed ALS (16).”

    From Chronic Traumatic Encephalopathy Within an Amyotrophic Lateral Sclerosis Brain Bank Cohort (2018) · cites this paper as [16]

    The Results (Association of ALS with Head Injury; page not supplied) report significantly higher ALS odds for veterans whose last head injury occurred within 15 years before the reference date (OR 2.33, 95% CI 1.18–4.61). They also state that the absolute number of head injuries was not associated with ALS, so the claim is too broad if it says head injury generally was significantly associated. The paper uses the reference date, rather than diagnosis, for the 15-year interval. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Some data suggests that trauma and athletic exposure are risk factors for developing ALS, although there are conflicting reports regarding single versus repetitive head injury.

    “Some data suggests that trauma and athletic exposure are risk factors for developing ALS [30, 31, 166], although there are conflicting reports regarding single versus repetitive head injury [24].”

    From The neuropathology of sport (2014) · cites this paper as [166]

  • Some studies have reported that multiple head injuries and age at first head injury were associated with ALS, which is consistent with the findings we observed in our study.

    “Some studies have reported that multiple head injuries and age at first head injury were associated with ALS, which is also consistent with the findings we observed in our study [18,20,61,62].”

    From Head Injury and Amyotrophic Lateral Sclerosis: Population-Based Study from the National ALS Registry (2025) · cites this paper as [18]

Cites

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Related

Authors
Schmidt, S., Kwee, L. C., Allen, K. D., & Oddone, E. Z.
Affiliations
Duke Medical Center (US)
Corresponding author
Schmidt, Silke
ORCID
Venue
Journal of the Neurological Sciences
Publisher
Elsevier BV
Published
2010-04
Volume
291
Issue
1-2
Pages
22-29
ISSN
0022-510X (ISSN-L)
DOI
10.1016/j.jns.2010.01.011
PMC
PMC2840700
OpenAlex
W1988832005
Semantic Scholar
e9ed91a7ef1637a4dac73b42f33a0a92f4b69671
Cited by
117
References
76
Citations by year
2026: 2 · 2025: 4 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 6 · 2012: 15
FWCI
6.67
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Journal of the Neurological Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Environmental Health Sciences (R01ES013244)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
amyotrophic lateral sclerosis, traumatic brain injury, cigarette smoking, APOE genotype, APOE ε4, veterans, environmental risk factors, gene-environment interaction, neurodegenerative diseases
MeSH terms
Amyotrophic Lateral Sclerosis, Apolipoproteins E, Environmental Exposure, Female, Genotype, Craniocerebral Trauma, Heterozygote, Humans, Male, Middle Aged, Risk Factors, Smoking, United States, Veterans, Logistic Models, Odds Ratio, Genetic Predisposition to Disease, White People, Apolipoprotein E4

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-11-07.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-11-07.

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