History of Head Injury and Risk of Amyotrophic Lateral Sclerosis: An Updated Comprehensive Systematic Review with Meta-Analysis of 5,033,215 Participants

May combine two claims.

After exclusion of Anns et al. 2025, heterogeneity was resolved and the pooled estimate shifted to statistical significance (RR = 2.10; 95% CI: 1.28-3.47; I2 = 19.1%).

“Heterogeneity was resolved after exclusion of Anns et al. 2025 and the pooled estimate shifted to statistical significance (RR = 2.10; 95% CI: 1.28-3.47,I 2 =19.1%).”

• Also stated in: § 4. Discussion · plain

  “Upon excluding Anns et al. 2025, both heterogeneity resolved and statistical significance emerged.”

The quote only partly states this claim.

There was a statistically significant association between head injury and ALS across four studies reporting a time lag of less than one year (AOR = 3.59; 95% CI: 2.74-4.70).

“There was a statistically significant association across four studies reporting a time lag of less than one year and more than three years (AOR = 3.59; 95% CI: 2.74-4.70)and (AOR = 1.24; 95% CI: 1.03-1.49),with no significant heterogeneity.”

May combine two claims.

Although the pooled estimate was influenced by one large registry-based study (Levison et al., 2025), leave-one-out analysis showed that the association remained stable.

“Although the pooled estimate was influenced by one large registry-based study (Levison et al., 2025), leave-one-out analysis showed that the association remained stable.”

May combine two claims.

From 2016 onward, the cumulative estimate remained statistically significant and varied only between 1.34 and 1.55, converging on the final pooled estimate.

“From 2016 onward the cumulative estimate remained statistically significant and varied only between 1.34 and 1.55, converging on the final pooled estimate.”

• Also stated in: § 4. Discussion · hedged

  “From 2016 onward the cumulative estimate remained statistically significant and varied only between approximately 1.34 and 1.55, converging on the final pooled estimate.”

May combine two claims.

Savica et al. 2012 retrospectively followed high school American football players between 1946 and 1956 and did not cause any source of heterogeneity.

“Despite that Savica et al. 2012 retrospectively followed high school American football players in the period between 1946 and 1956, it did not cause any source of heterogeneity.”

May combine two claims.

Estimates from the 1980s were imprecise, with pooled ORs ranging from 1.00 to 3.03 and confidence limits between 0.14 and 15.55, reaching statistical significance only from 1987 onward.

“Estimates from the 1980s were imprecise, with pooled ORs ranging from 1.00 to 3.03 and confidence limits between 0.14 and 15.55, reaching statistical significance only from 1987 onward.”

May combine two claims.

The pooled adjusted HR did not reveal a statistically significant association between head injury and ALS (HR = 1.55; 95% CI: 0.89-2.71; I2 = 76.4%), with significant heterogeneity.

“It did not reveal a statistically significant association between head injury and ALS (HR = 1.55; 95% CI: 0.89-2.71,I 2 =76.4%), with significant heterogeneity.”

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

The included studies comprised 22 case-control studies and seven cohort studies.

“These comprised 22 case-control studies and seven cohort studies.”

May combine two claims.

Eight studies explicitly defined head injury as a mechanical injury that led to intracranial injury and showed a statistically significant association with ALS (AOR = 1.37; 95% CI: 1.25-1.51), with no heterogeneity between studies.

“Eight studies explicitly defined head injury as a mechanical injury that led to intracranial injury (Fracture, concussion, loss of consciousness, etc).They showed a statistically significant association (AOR = 1.37; 95% CI: 1.25-1.51),with no heterogeneity between studies.”

• Also stated in: § 4. Discussion · boosted

  “Eight studies clearly identified head injury as traumatic brain injury that lead to intracranial injury (Fracture, concussion, loss of consciousness, etc).and they showed a statistically significant association.”

May combine two claims.

Nine studies reported a single head injury; the pooled adjusted effect estimate showed a significant association between single head injury and risk of ALS (AOR = 1.22; 95% CI: 1.11-1.34), with homogeneity among included studies (I2 = 0%).

“Nine studies reported a single head injury were included in the meta-analysis.The pooled adjusted effect estimate showed significant association between single head injury and risk of ALS (AOR = 1.22; 95% CI: 1.11-1.34),with homogeneity among included studies (I 2 =0%).”

May combine two claims.

Anns et al. 2025 and Savica et al. 2012 had minimal impact on the adjusted model.

“while Anns et al. 2025 and Savica et al. 2012 had minimal impact on the adjusted model.”

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

There was a mild asymmetry observed by visual inspection of the funnel plot.

“Regarding publication bias, there was a mild asymmetry observed by visual inspection of the funnel plot.”

May combine two claims.

Estimates from studies published in the 1980s were imprecise, with pooled ORs ranging between 1.00 and 3.03 with wide CIs (range: 0.14-15.55).

“Estimates from studies published in 1980s were imprecise, with pooled ORs ranging between 1.00 and 3.03 with wide CIs (range: 0.14 -15.55).”

May combine two claims.

Omitting Zhu et al. 2025 solved the heterogeneity, but the overall direction remained insignificant (HR = 1.16; 95% CI: 0.85-1.59; I2 = 0%).

“Although omitting Zhu et al. 2025 solved the heterogeneity, the overall direction remained insignificant (HR = 1.16; 95% CI: 0.85-1.59,I 2 =0%).”

• Also stated in: § 4. Discussion · plain

  “After excluding this study, heterogeneity was resolved and the association remained non-significant (HR 1.16, 95% CI 0.85-1.59;I² = 0%)”

May combine two claims.

After imputation of two studies in trim-and-fill analysis, the pooled estimate changed from OR 1.49 (95% CI: 1.30-1.70) to OR 1.42 (95% CI: 1.22-1.65) and remained statistically significant.

“After imputation of two studies, the pooled estimate changed from OR 1.49 (95% CI: 1.30-1.70)to OR 1.42 (95% CI: 1.22-1.65)and remained statistically significant.”

May combine two claims.

Exposure to two or more head injuries showed a positive trend yet not statistically significant association with ALS (AOR = 1.30; 95% CI: 0.93-1.82), with no significant heterogeneity (I2 = 33.5%).

“Interestingly, exposure to two or more head injuries showed positive trend yet not statistically significant (AOR = 1.30; 95% CI: 0.93-1.82),with no significant heterogeneity (I 2 = 33.5%)”

May combine two claims.

For MND/ALS specifically in Russell et al. 2022, no events occurred in the comparison group, and the reported estimate (OR 15.17, 95% CI 2.10-178.96) was derived only after reassigning one comparison-group participant as an event; the estimate was too unstable to pool, and the study was retained in qualitative synthesis only.

“For MND/ALS specifically, no events occurred in the comparison group, and the reported estimate (OR 15.17, 95% CI 2.10-178.96)was derived only after reassigning one comparison-group participant as an event; the estimate was therefore too unstable to pool, and the study was retained in the qualitative synthesis only [17].”

• cites [17]Not matched

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

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

The protocol of this study is registered on PROSPERO (CRD420261331222).

“The protocol of this study is registered on PROSPERO (CRD420261331222).”

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

Publication bias was assessed visually using funnel plots and statistically using Egger's regression test.

“Publication biases were assessed visually using funnel plots and was confirmed statistically using Egger's regression test.”

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

The systematic review and meta-analysis were conducted according to PRISMA 2020 reporting guidelines and the Cochrane handbook.

“Our systematic review and meta-analysis were conducted according to the guidelines of metaanalysis and systematic review, including the utilization of PRISMA 2020 reporting guidelines and the Cochrane handbook [15].”

• cites [15]Not matched

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

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

Lifestyle factors may contribute to ALS pathogenesis through chronic inflammatory processes which cause damage to the motor units.

“Also, lifestyle factors may contribute to ALS pathogenesis through its chronic inflammatory processes which cause damage to the motor units [33].”

• cites [33]Not matched

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

May combine two claims.

Case-control studies showed a more consistent association between head injury and ALS risk, which may partly reflect their greater efficiency for studying rare outcomes such as ALS and their ability to include larger numbers of cases.

“Case-control studies showed a more consistent association between head injury and ALS risk, which may partly reflect their greater efficiency for studying rare outcomes such as ALS and their ability to include larger numbers of cases.”

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

The positive trend for two or more head injuries is due to the cumulative effects of repeated trauma and the insufficient time of brain and spinal cord to be completely repaired.

“This is due to the cumulative effects of repeated trauma and the insufficient time of brain and spinal cord to be completely repaired.”

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

All cohort studies were deemed of good quality.

“All cohort studies were deemed of good quality.”

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

Lifestyle factors can cause metabolic derangement which might be associated with increased ALS risk.

“Also, it can cause metabolic derangement which might be associated with increased ALS risk [34].”

• cites [34]Not matched

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

May combine two claims.

Cohort studies provide stronger temporal evidence by assessing head injury before ALS onset and minimizing recall bias, but they are challenged by the rarity of ALS events, limited statistical power, and the requirement for prolonged follow-up to capture potential latency periods.

“In contrast, cohort studies provide stronger temporal evidence by assessing head injury before ALS onset and minimizing recall bias, but they are challenged by the rarity of ALS events, limited statistical power, and the requirement for prolonged follow-up to capture potential latency periods.”

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

Influence diagnostics as Baujat plots and Viechtbauer-Cheung influence characteristics as well as potential outliers were assessed using a random-effects framework.

“In addition, influence diagnostics as Baujat plots and Viechtbauer-Cheung influence characteristics as well as potential outliers were assessed using random-effects”

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

Regarding case-control studies, 10 were at a low risk of bias, 11 were rated as fair with some limitations, and one was rated as poor quality.

“Regarding case-control studies, 10 were at a low risk of bias, 11 were rated as fair with some limitations, and one was rated as poor quality.”

Classified as probably not a substantial claim.

An evidence-based review by Armon and Nelson (2012), including 12 epidemiological studies, found no sufficient evidence to support a causal association between single-instance head trauma and ALS risk.

“An evidence-based review by Armon and Nelson (2012), including 12 epidemiological studies, found no sufficient evidence to support a causal association between single-instance head trauma and ALS risk [35].”

• cites [35]Not matched

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

May combine two claims.

The time lag subgrouping is considered a bimodal pattern of injury time lag association to ALS, as two periods (less than one year and more than three years) were significantly correlated.

“This is considered as a bimodal pattern of injury time lag association to ALS, as two periods (less than one year and more than three years) were significantly correlated [28].”

• cites [28]Not matched

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

May combine two claims.

Limited number of studies and lack of dose response hinders a definitive conclusion regarding numbers of repeated exposures.

“Though, limited number of studies and lack of dose response hinders a definitive conclusion regarding numbers of repeated exposures.”

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

Sensitivity analyses and cumulative meta-analyses were performed to evaluate robustness and temporal stability of the evidence.

“Moreover, sensitivity analyses and cumulative meta-analyses were performed to evaluate robustness and temporal stability of the evidence.”

May combine two claims.

The magnitude of the association became more stable and more precise as evidence accumulated.

“This indicates that the magnitude of the association became more stable and more precise as evidence accumulated, although these findings should still be interpreted alongside the limitations inherent to observational evidence [19].”

• cites [19]Not matched

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

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

These abnormal TDP-43 species may act as self-templating seeds capable of recruiting native TDP-43 and promoting prion-like propagation between cells, mechanisms that are strongly implicated in ALS pathogenesis.

“These abnormal TDP-43 species may act as self-templating seeds capable of recruiting native TDP-43 and promoting prion-like propagation between cells, mechanisms that are strongly implicated in ALS pathogenesis.”

• cites [21]Not matched

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

• cites [22]Not matched

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

• cites [23]Not matched

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

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

ALS is common in males due to higher exposure to toxins, environmental factors, occupational circumstances like trauma, hormonal effects (lack of protective estrogens) and genetic associations such as SOD-1 gene.

“ALS is common in males due to higher exposure to toxins, environmental factors, occupational circumstances like trauma, hormonal effects (lacks of protective estrogens) and genetic associations such as SOD-1 gene [32].”

• cites [32]Not matched

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

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

One possible biological explanation for an association between head trauma and ALS involves trauma-induced axonal injury and subsequent disruption of neuronal homeostasis.

“One possible biological explanation for an association between head trauma and ALS involves trauma-induced axonal injury and subsequent disruption of neuronal homeostasis.”

• cites [21]Not matched

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

• cites [22]Not matched

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

• cites [23]Not matched

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

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

Under pathological conditions, TDP-43 can translocate from the nucleus to the cytoplasm, where it undergoes misfolding, hyperphosphorylation, ubiquitination, and aggregation.

“Under pathological conditions, TDP-43 can translocate from the nucleus to the cytoplasm, where it undergoes misfolding, hyperphosphorylation, ubiquitination, and aggregation.”

• cites [21]Not matched

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

• cites [22]Not matched

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

• cites [23]Not matched

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

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

The finding that only one head injury was significantly associated with ALS could be attributed to the possibility of reverse causation.

“However, this could be attributed to the possibility of the reverse causation.”

May combine two claims.

This cumulative effect leads to chronic inflammation, activation of apoptotic mechanisms and disruption of cellular mechanisms which eventually cause toxic excitotoxicity via greater glutamate amounts release.

“This leads to chronic inflammation, activation of apoptotic mechanisms and disruption of cellular mechanisms which eventually causing toxic excitotoxicity via greater glutamate amounts release [25][26][27].”

• cites [25]Not matched

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

• cites [26]Not matched

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

• cites [27]Not matched

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

The quote only partly states this claim.

In a New Zealand retrospective cohort of high-level rugby players, high-level rugby participation was associated with an increased risk of neurodegenerative disease (HR 1.22).

“High-level rugby participation was associated with increased neurodegenerative disease risk (HR 1.22), including Alzheimer's disease (HR 1.61) and MND (HR 1.16).”

• cites Anns et al. 2025 sourceFetching the cited paper…

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

ALS was significantly associated with a history of surgical operations before service.

“ALS was significantly associated with a history of trauma and surgical operations before service.”

• cites Kurtzke-Beebe et al. 1980Not matched

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

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

ALS was significantly associated with a history of trauma before service.

“ALS was significantly associated with a history of trauma and surgical operations before service.”

• cites Kurtzke-Beebe et al. 1980Not matched

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

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

The systematic review used a PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only.

“PRISMA 2020 flow diagram for new systematic reviews which included searches of databases and registers only”

The quote only partly states this claim.

In that New Zealand cohort, high-level rugby participation was associated with an increased risk of motor neuron disease (HR 1.16).

“High-level rugby participation was associated with increased neurodegenerative disease risk (HR 1.22), including Alzheimer's disease (HR 1.61) and MND (HR 1.16).”

• cites Anns et al. 2025 sourceFetching the cited paper…

May combine two claims.

The initial odds ratio for ALS associated with hospital-diagnosed traumatic head injury was 1.3 but declined over time.

“The initial OR was 1.3 but declined over time.”

• cites Levison et al. 2025 sourceNot checked — no full text of the source

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

The quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS).

“Quality assessment of included studies using the Newcastle-Ottawa Scale (NOS)”

May combine two claims.

Despite pooling the risk ratio from four cohort studies and finding a positive association between head injury exposure and ALS, the evidence from cohort studies remains weak, heterogeneous and requires further investigation.

“Despite pooling the risk ratio from four cohort studies and found positive association between head injury exposure and ALS, the evidence from cohort studies remains weak, heterogenous and requires further investigation.”

May combine two claims.

This updated meta-analysis provides evidence that a history of head injury is associated with an increased risk of ALS, with consistent findings across multiple subgroup analyses and adjusted estimates.

“This updated meta-analysis provides evidence that a history of head injury is associated with an increased risk of ALS, with consistent findings across multiple subgroup analyses and adjusted estimates.”

Classified as probably not a substantial claim.

Head trauma was a significant risk factor for ALS (multivariable OR 4.045).

“Head trauma was a significant risk factor for ALS (multivariable OR 4.045).”

• cites Lian et al. 2019Not matched

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

May combine two claims.

Head trauma was associated with increased ALS risk (adjusted OR 1.60), particularly for injuries occurring ≥10 years before onset.

“Head trauma was associated with increased ALS risk (adjusted OR 1.60), particularly for injuries occurring ≥10 years before onset.”

May combine two claims.

Although we found a significant association between head injury and ALS, our study showed limitations in determining the direction of the association.

“Although we found a significant association between head injury and ALS, our study showed limitations in determining the direction of the association.”

Classified as probably not a substantial claim.

Results from cohort studies might be considered with caution because of the presence of heterogeneity among population, follow-up periods, ALS ascertainment methods, and head injury definition.

“And the results from cohort studies might be considered with caution because of the presence of heterogeneity among population, follow-up periods, ALS ascertainment methods, and Head injury definition.”

The quote only partly states this claim.

The standardized morbidity ratio for ALS following head trauma with presumed brain injury was 1.05 (95% CI 0.027-5.85).

“The standardized morbidity ratio for ALS was 1.05 (95% CI 0.027-5.85)”

• cites Williams et al. 1991Not matched

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

The quote only partly states this claim.

Veterans with head injuries during the 15 years before the reference date had an adjusted OR of 2.33 for ALS.

“Veterans with head injuries during the 15 years before the reference date had an adjusted OR of 2.33.”

• cites Schmidt et al. 2010Not matched

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

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

Given the observational nature of available evidence and the remaining possibility of reverse causation and residual confounding, these findings should be interpreted cautiously.

“However, given the observational nature of available evidence and the remaining possibility of reverse causation and residual confounding, these findings should be interpreted cautiously.”

May combine two claims.

History of head trauma was reported in 25% of ALS cases and 13% of controls.

“History of head trauma was reported in 25% of cases and 13% of controls.”

• cites Mitsi et al. 2023 sourceFetching the cited paper…

The quote only partly states this claim.

In that New Zealand cohort, high-level rugby participation was associated with an increased risk of Alzheimer's disease (HR 1.61).

“High-level rugby participation was associated with increased neurodegenerative disease risk (HR 1.22), including Alzheimer's disease (HR 1.61) and MND (HR 1.16).”

• cites Anns et al. 2025 sourceFetching the cited paper…