Preventive factors for ALS

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Protective factors found to prevent ALS.

Nutrition[edit]

Fruits and vegetables[edit]

"A higher consumption of all fruits and vegetables and fruit alone in the highest quartiles was associated with a statistically significantly reduced risk of ALS. Although not statistically significant, a beneficial association between intake of all vegetables, green and yellow vegetables and other vegetables and ALS was found. No statistically significant dose-response relationship was observed between intake of beta-carotene, vitamin C and vitamin E and the risk of ALS. ... Our findings suggest that higher intake of food rich in antioxidants such as fruit and vegetables confer protection against the development of ALS."[1]

"Vigorous physical activity, self reported stress, a type A behavior pattern, and less frequent intakes of green-yellow vegetables were significantly associated with increased risk of ALS, whereas smoking and drinking habits were not. The greatest effect on risk for ALS was posed by the combination of a type A behavior pattern and less frequent intakes of green-yellow vegetables (adjusted OR, 11.2; 95% CI, 3.8 to 33.0). ... These data suggested that imbalances between excessive productions of oxidants as patient-specific factors and a diminished or missing antioxidant defense system in motor neurons may increase the risk of ALS."[2]

Carotenoids[edit]

"A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61-0.91, p for trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for β-carotene and lutein were 0.85 (95% CI = 0.64-1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64-0.96, p for trend = 0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS. ... Consumption of foods high in carotenoids may help prevent or delay onset of ALS." [3]

Vitamin E[edit]

"Among 1,055,546 participants, 805 developed ALS. Overall, using vitamin E supplements was not associated with ALS. However, within cohorts with information on duration of vitamin E supplement use (231 cases), ALS rates declined with increasing years of use (P-trend=0.01). Compared with nonusers, the multivariable-adjusted relative risk was 1.05 (95% confidence interval (CI): 0.60, 1.84) among users for ≤1 year (12 cases), 0.77 (95% CI: 0.33, 1.77) among users for 2-4 years (7 cases), and 0.64 (95% CI: 0.39, 1.04) among users for ≥5 years (18 cases). For dietary vitamin E intake, the multivariable-adjusted relative risk comparing the highest quartile with the lowest was 0.79 (95% CI: 0.61, 1.03); an inverse dose-response was evident in women (P-trend=0.002) but not in men (P-trend=0.71). In this large, pooled prospective study, long-term vitamin E supplement use was associated with lower ALS rates. A possible protective effect of vitamin E deserves further consideration."[4]

"A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). ... A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically."[5]

PUFAs (polyunsaturated fatty acids)[edit]

"A total of 995 ALS cases were documented during the follow-up. A greater ω-3 PUFA intake was associated with a reduced risk for ALS. The pooled, multivariable-adjusted RR for the highest to the lowest quintile was 0.66 (95% CI, 0.53-0.81; P < .001 for trend). Consumption of both α-linolenic acid (RR, 0.73; 95% CI, 0.59-0.89; P = .003 for trend) and marine ω-3 PUFAs (RR, 0.84; 95% CI, 0.65-1.08; P = .03 for trend) contributed to this inverse association. Intakes of ω-6 PUFA were not associated with ALS risk. ... Consumption of foods high in ω-3 PUFAs may help prevent or delay the onset of ALS."[6]

"A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). ... A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically."[7]

Higher HDL and apolipoprotein A1 levels[edit]

"Controlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS."Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis

Dietary fiber[edit]

"...dietary fiber intake was associated with a decreased risk of ALS (highest vs. lowest quartile, fat-adjusted OR = 0.3, 95% CI: 0.1, 0.7; p for trend = 0.02)."[8]

Alcohol (ethyl alcohol)[edit]

"Five articles, including one cohort study and seven case-control studies, and a total of 431,943 participants, were identified. The odds ratio for the association between alcohol consumption and amyotrophic lateral sclerosis was 0.57 (95 % confidence interval 0.51-0.64). Subgroup and sensitivity analyses confirmed the result. Evidence for publication bias was detected. Alcohol consumption reduced the risk of developing amyotrophic lateral sclerosis compared with non-drinking. Alcohol, therefore, has a potentially neuroprotective effect on the development of amyotrophic lateral sclerosis."[9]

"... Current alcohol consumption was associated with a reduced risk of ALS (incident patient group: odds ratio = 0.52, 95% CI: 0.40, 0.75)" [10]

Pharmaceuticals[edit]

Aspirin[edit]

"The inverse association between aspirin and ALS was present predominately in patients older than 55 years. ... The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people."[11]

Angiotensin-converting enzyme inhibitors[edit]

"There was a dose-dependent inverse association between ACEI use and the risk for developing ALS. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 (95% CI, 0.65-1.07; P = .15) for the group prescribed ACEIs lower than 449.5 of the cDDD and 0.43 cDDD (95% CI, 0.26-0.72; P = .001) for the group with a cumulative ACEI use of greater than 449.5 cDDD. The association was most predominant in men older than 55 years. ... Use of ACEIs exhibited a dose-dependent inverse association with ALS. This study demonstrated a 57% risk reduction in the chance for developing ALS in people who used ACEIs greater than 449.5 cDDD in 4 years."[12]


Risk factors[edit]

Lifestyle, psychology, behavioural patterns[edit]

Vigorous physical activity, stress, type A behavior[edit]

"Vigorous physical activity, self reported stress, a type A behavior pattern, and less frequent intakes of green-yellow vegetables were significantly associated with increased risk of ALS, whereas smoking and drinking habits were not. The greatest effect on risk for ALS was posed by the combination of a type A behavior pattern and less frequent intakes of green-yellow vegetables (adjusted OR, 11.2; 95% CI, 3.8 to 33.0). ... These data suggested that imbalances between excessive productions of oxidants as patient-specific factors and a diminished or missing antioxidant defense system in motor neurons may increase the risk of ALS."

"...suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS. "[13]

Dietary factors[edit]

Glutamate[edit]

"Glutamate intake was associated with an increased risk of ALS (adjusted OR for highest vs. lowest quartile = 3.2, 95% CI: 1.2, 8.0; p for trend < 0.02). ... The positive association with glutamate intake is consistent with the etiologic theory that implicates glutamate excitotoxicity in the pathogenesis of ALS..."[14]

Dietary fats in general[edit]

"dietary fat intake was associated with an increased risk of ALS (highest vs. lowest quartile, fiber-adjusted odds ratio (OR) = 2.7, 95% confidence interval (CI): 0.9, 8.0; p for trend = 0.06) ... the associations with fat and fiber intake warrant further study and biologic explanation."[15]

"...higher premorbid intake of total fat (1.14; 1.07-1.23; P < .001), saturated fat (1.43; 1.25-1.64; P < .001), trans-fatty acids (1.03; 1.01-1.05; P < .001), and cholesterol (1.08; 1.05-1.12; P < .001) was associated with an increased risk of ALS"[16]

High LDL and apolipoprotein B levels, high total cholesterol:HDL ratio, coronary artery disease, cerebrovascular disease[edit]

"Controlling for age and sex, higher HDL (HR 0.84, 95% CI 0.73 to 0.96, p=0.010) and apoA1 (HR 0.83, 95% CI 0.72 to 0.94, p=0.005) were associated with a reduced risk of ALS. Higher total cholesterol:HDL was associated with an increased risk of ALS (HR 1.17, 95% CI 1.05 to 1.31, p=0.006). In models incorporating multiple metabolic markers, higher LDL or apoB was associated with an increased risk of ALS, in addition to a lower risk with higher HDL or apoA. Coronary artery disease, cerebrovascular disease and increasing age were also associated with an increased risk of ALS."Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis

High intake of carbohydrate and low intakes of fat[edit]

"A high intake of carbohydrate was significantly associated with an increased risk of ALS (adjusted OR = 2.14, 95% CI 1.05-4.36; the highest versus the lowest tertile). ORs for the second and third tertile of total fat were 0.57 and 0.41 (95% CI 0.21-0.80), respectively. ORs for the highest tertile of intake versus the lowest were 0.41 (95% CI 0.21-0.80) for total fat, 0.30 (95% CI 0.16-0.5) for saturated fatty acids (SFAs), 0.35 (95% CI 0.18-0.69) for monounsaturated fatty acids (MUFAs) and 0.58 (95%CI 0.40-0.96) for polyunsaturated fatty acids (PUFAs). Our findings suggest that high intakes of carbohydrate and low intakes of fat and some kinds of fatty acids may, when combined, increased the risk of ALS."[17]

Less frequent intakes of green-yellow vegetables[edit]

"Vigorous physical activity, self reported stress, a type A behavior pattern, and less frequent intakes of green-yellow vegetables were significantly associated with increased risk of ALS, whereas smoking and drinking habits were not. The greatest effect on risk for ALS was posed by the combination of a type A behavior pattern and less frequent intakes of green-yellow vegetables (adjusted OR, 11.2; 95% CI, 3.8 to 33.0). ... These data suggested that imbalances between excessive productions of oxidants as patient-specific factors and a diminished or missing antioxidant defense system in motor neurons may increase the risk of ALS."

References[edit]

  1. ↑ Okamoto et al.: Fruit and vegetable intake and risk of amyotrophic lateral sclerosis in Japan. Neuroepidemiology 2009;32:251-6. PMID: 19209004. DOI. BACKGROUND: There has been little interest in the role of nutrition in the prevention of amyotrophic lateral sclerosis (ALS). We investigated the relationship between dietary intake of vegetables, fruit, and antioxidants and the risk of ALS in Japan. METHODS: Between 2000 and 2004, we recruited 153 ALS patients aged 18-81 years with disease duration of 3 years within the study period in accordance with El Escorial World Federation of Neurology criteria. Three hundred and six gender- and age-matched controls were randomly selected from the general population. Information on dietary factors was collected using a validated self-administered diet history questionnaire. RESULTS: A higher consumption of all fruits and vegetables and fruit alone in the highest quartiles was associated with a statistically significantly reduced risk of ALS. Although not statistically significant, a beneficial association between intake of all vegetables, green and yellow vegetables and other vegetables and ALS was found. No statistically significant dose-response relationship was observed between intake of beta-carotene, vitamin C and vitamin E and the risk of ALS. CONCLUSION: Our findings suggest that higher intake of food rich in antioxidants such as fruit and vegetables confer protection against the development of ALS.
  2. ↑ Okamoto et al.: Lifestyle factors and risk of amyotrophic lateral sclerosis: a case-control study in Japan. Ann Epidemiol 2009;19:359-64. PMID: 19342254. DOI. PURPOSE: We examined the associations between lifestyle factors and the risk of amyotrophic lateral sclerosis (ALS) using a case-control study in Aichi Prefecture, Japan. METHODS: The study comprised 183 ALS patients diagnosed by the El Escorial World Federation of Neurology criteria as well as 366 gender- and age-matched controls randomly selected from the general population with the use of the basic register of residents. Detailed information on lifestyle factors was obtained through a mailed self-administered questionnaire. The strength of association between ALS and a potential risk factor was assessed by calculating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Vigorous physical activity, self reported stress, a type A behavior pattern, and less frequent intakes of green-yellow vegetables were significantly associated with increased risk of ALS, whereas smoking and drinking habits were not. The greatest effect on risk for ALS was posed by the combination of a type A behavior pattern and less frequent intakes of green-yellow vegetables (adjusted OR, 11.2; 95% CI, 3.8 to 33.0). CONCLUSION: These data suggested that imbalances between excessive productions of oxidants as patient-specific factors and a diminished or missing antioxidant defense system in motor neurons may increase the risk of ALS.
  3. ↑ Fitzgerald et al.: Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: pooled results from 5 cohort studies. Ann. Neurol. 2013;73:236-45. PMID: 23362045. DOI. OBJECTIVE: Prior research has suggested the possible role of oxidative stress in the pathogenesis of amyotrophic lateral sclerosis (ALS). Prospective data examining dietary antioxidants such carotenoids and vitamin C are limited. METHODS: Risk of ALS associated with carotenoid and vitamin C intake was investigated in 5 prospective cohorts: the National Institutes of Health-Association of American Retired Persons Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort, the Health Professionals Follow-up Study (HPFS), and the Nurses Health Study (NHS). ALS deaths were documented using the National Death Index, and confirmed nonfatal ALS cases were included from HPFS and NHS. A total of 1,153 ALS deaths occurred among 1,100,910 participants (562,942 men; 537,968 women). Participants were categorized into cohort-specific quintiles of intake for dietary variables. We applied Cox proportional hazards regression to calculate cohort-specific risk ratios (RRs), and pooled results using random-effects methods. RESULTS: A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61-0.91, p for trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for β-carotene and lutein were 0.85 (95% CI = 0.64-1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64-0.96, p for trend = 0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS. INTERPRETATION: Consumption of foods high in carotenoids may help prevent or delay onset of ALS.
  4. ↑ Wang et al.: Vitamin E intake and risk of amyotrophic lateral sclerosis: a pooled analysis of data from 5 prospective cohort studies. Am. J. Epidemiol. 2011;173:595-602. PMID: 21335424. DOI. The authors investigated whether vitamin E intake was associated with amyotrophic lateral sclerosis (ALS) in the Nurses' Health Study (1976-2004), the Health Professionals Follow-up Study (1986-2004), the Cancer Prevention Study II Nutrition Cohort (1992-2004), the Multiethnic Cohort Study (1993-2005), and the National Institutes of Health-AARP Diet and Health Study (1995-2005). ALS deaths were identified through the National Death Index. In the Nurses' Health Study and the Health Professionals Follow-up Study, confirmed nonfatal ALS cases were also included. Cohort-specific results were estimated using Cox proportional hazards models and pooled using random-effects models. Among 1,055,546 participants, 805 developed ALS. Overall, using vitamin E supplements was not associated with ALS. However, within cohorts with information on duration of vitamin E supplement use (231 cases), ALS rates declined with increasing years of use (P-trend=0.01). Compared with nonusers, the multivariable-adjusted relative risk was 1.05 (95% confidence interval (CI): 0.60, 1.84) among users for ≤1 year (12 cases), 0.77 (95% CI: 0.33, 1.77) among users for 2-4 years (7 cases), and 0.64 (95% CI: 0.39, 1.04) among users for ≥5 years (18 cases). For dietary vitamin E intake, the multivariable-adjusted relative risk comparing the highest quartile with the lowest was 0.79 (95% CI: 0.61, 1.03); an inverse dose-response was evident in women (P-trend=0.002) but not in men (P-trend=0.71). In this large, pooled prospective study, long-term vitamin E supplement use was associated with lower ALS rates. A possible protective effect of vitamin E deserves further consideration.
  5. ↑ Veldink et al.: Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatr. 2007;78:367-71. PMID: 16648143. DOI. BACKGROUND: To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS). METHODS: Patients referred to our clinic during 2001-2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case-control study (132 patients and 220 healthy controls). A food-frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking). RESULTS: A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B2, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS. CONCLUSION: A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically.
  6. ↑ Fitzgerald et al.: Dietary ω-3 polyunsaturated fatty acid intake and risk for amyotrophic lateral sclerosis. JAMA Neurol 2014;71:1102-10. PMID: 25023276. DOI. IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a severe progressive disease that cannot be prevented or cured. Diet-derived long-chain polyunsaturated fatty acids (PUFAs) are incorporated in brain lipids and modulate oxidative and inflammatory processes and could thus affect ALS risk and progression. OBJECTIVE: To examine the association between ω-6 and ω-3 PUFA consumption and ALS risk. DESIGN, SETTING, AND PARTICIPANTS: Longitudinal analyses based on 1,002,082 participants (479,114 women and 522,968 men) in 5 prospective cohorts: the National Institutes of Health-AARP Diet and Health Study, the Cancer Prevention Study II Nutrition Cohort, the Health Professionals Follow-up Study, the Multiethnic Cohort Study, and the Nurses' Health Study. Diet was assessed via food frequency questionnaire developed or modified for each cohort. Participants were categorized into cohort-specific quintiles of intake of energy-adjusted dietary variables. MAIN OUTCOMES AND MEASURES: Cohort-specific multivariable-adjusted risk ratios (RRs) of ALS incidence or death estimated by Cox proportional hazards regression and pooled using random-effects methods. RESULTS: A total of 995 ALS cases were documented during the follow-up. A greater ω-3 PUFA intake was associated with a reduced risk for ALS. The pooled, multivariable-adjusted RR for the highest to the lowest quintile was 0.66 (95% CI, 0.53-0.81; P < .001 for trend). Consumption of both α-linolenic acid (RR, 0.73; 95% CI, 0.59-0.89; P = .003 for trend) and marine ω-3 PUFAs (RR, 0.84; 95% CI, 0.65-1.08; P = .03 for trend) contributed to this inverse association. Intakes of ω-6 PUFA were not associated with ALS risk. CONCLUSIONS AND RELEVANCE: Consumption of foods high in ω-3 PUFAs may help prevent or delay the onset of ALS.
  7. ↑ Veldink et al.: Intake of polyunsaturated fatty acids and vitamin E reduces the risk of developing amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatr. 2007;78:367-71. PMID: 16648143. DOI. BACKGROUND: To assess whether the premorbid dietary intake of fatty acids, cholesterol, glutamate or antioxidants was associated with the risk of developing amyotrophic lateral sclerosis (ALS). METHODS: Patients referred to our clinic during 2001-2002, who had definite, probable or possible ALS according to El Escorial criteria, without a familial history of ALS, were asked to participate in a case-control study (132 patients and 220 healthy controls). A food-frequency questionnaire was used to assess dietary intake for the nutrients of interest. Multivariate logistic regression analysis was performed with adjustment for confounding factors (sex, age, level of education, energy intake, body mass index and smoking). RESULTS: A high intake of polyunsaturated fatty acid (PUFA) and vitamin E was significantly associated with a reduced risk of developing ALS (PUFA: odds ratio (OR) = 0.4, 95% confidence interval (CI) = 0.2 to 0.7, p = 0.001; vitamin E: OR = 0.4, 95% CI = 0.2 to 0.7, p = 0.001). PUFA and vitamin E appeared to act synergistically, because in a combined analysis the trend OR for vitamin E was further reduced from 0.67 to 0.37 (p = 0.02), and that for PUFA from 0.60 to 0.26 (p = 0.005), with a significant interaction term (p = 0.03). The intake of flavonols, lycopene, vitamin C, vitamin B2, glutamate, calcium or phytoestrogens was not associated with the risk of developing ALS. CONCLUSION: A high intake of PUFAs and vitamin E is associated with a 50-60% decreased risk of developing ALS, and these nutrients appear to act synergistically.
  8. ↑ Nelson et al.: Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am. J. Epidemiol. 2000;151:164-73. PMID: 10645819. The association of nutrient intake with the risk of amyotrophic lateral sclerosis (ALS) was investigated in a population-based case-control study conducted in three counties of western Washington State from 1990 to 1994. Incident ALS cases (n = 161) were identified and individually matched on age and gender to population controls (n = 321). A self-administered food frequency questionnaire was used to assess nutrient intake. Conditional logistic regression analysis was used to compute odds ratios adjusted for education, smoking, and total energy intake. The authors found that dietary fat intake was associated with an increased risk of ALS (highest vs. lowest quartile, fiber-adjusted odds ratio (OR) = 2.7, 95% confidence interval (CI): 0.9, 8.0; p for trend = 0.06), while dietary fiber intake was associated with a decreased risk of ALS (highest vs. lowest quartile, fat-adjusted OR = 0.3, 95% CI: 0.1, 0.7; p for trend = 0.02). Glutamate intake was associated with an increased risk of ALS (adjusted OR for highest vs. lowest quartile = 3.2, 95% CI: 1.2, 8.0; p for trend < 0.02). Consumption of antioxidant vitamins from diet or supplement sources did not alter the risk. The positive association with glutamate intake is consistent with the etiologic theory that implicates glutamate excitotoxicity in the pathogenesis of ALS, whereas the associations with fat and fiber intake warrant further study and biologic explanation.
  9. ↑ E et al.: Association between alcohol consumption and amyotrophic lateral sclerosis: a meta-analysis of five observational studies. Neurol. Sci. 2016;37:1203-8. PMID: 27103621. DOI. The purpose of this study is to examine the association between alcohol consumption and amyotrophic lateral sclerosis. Published literature on the association between alcohol consumption and amyotrophic lateral sclerosis was retrieved from the PubMed and Embase databases. Two authors independently extracted the data. The quality of the identified studies was evaluated according to the Newcastle-Ottawa scale. Subgroup and sensitivity analyses were performed and publication bias was assessed. Five articles, including one cohort study and seven case-control studies, and a total of 431,943 participants, were identified. The odds ratio for the association between alcohol consumption and amyotrophic lateral sclerosis was 0.57 (95 % confidence interval 0.51-0.64). Subgroup and sensitivity analyses confirmed the result. Evidence for publication bias was detected. Alcohol consumption reduced the risk of developing amyotrophic lateral sclerosis compared with non-drinking. Alcohol, therefore, has a potentially neuroprotective effect on the development of amyotrophic lateral sclerosis.
  10. ↑ de Jong et al.: Smoking, alcohol consumption, and the risk of amyotrophic lateral sclerosis: a population-based study. Am. J. Epidemiol. 2012;176:233-9. PMID: 22791740. DOI. Smoking has been posited as a possible risk factor for amyotrophic lateral sclerosis (ALS), but large population-based studies of patients with incident disease are still needed. The authors performed a population-based case-control study in the Netherlands between 2006 and 2009, including 494 patients with incident ALS and 1,599 controls. To prove the relevance of population-based incidence cohorts in case-control studies, the authors compared results with those from cohorts including patients with prevalent ALS and referral patients. Subjects were sent a questionnaire. Multivariate analyses showed an increased risk of ALS among current smokers (odds ratio = 1.38, 95% confidence interval (CI): 1.02, 1.88) in the incident patient group only. Cox regression models showed that current smoking was also independently associated with shorter survival (hazard ratio = 1.51, 95% CI: 1.07, 2.15), explaining the lack of association in the prevalent and referral patient groups. Current alcohol consumption was associated with a reduced risk of ALS (incident patient group: odds ratio = 0.52, 95% CI: 0.40, 0.75). These findings indicate that current smoking is associated with an increased risk of ALS, as well as a worse prognosis, and alcohol consumption is associated with a reduced risk of ALS, further corroborating the role of lifestyle factors in the pathogenesis of ALS. The importance of population-based incident patient cohorts in identifying risk factors is highlighted by this study.
  11. ↑ Tsai et al.: Aspirin use associated with amyotrophic lateral sclerosis: a total population-based case-control study. J Epidemiol 2015;25:172-7. PMID: 25721071. DOI. BACKGROUND: The association of aspirin use and nonsteroid anti-inflammatory drug (NSAID) use with amyotrophic lateral sclerosis (ALS) risk is unclear. This study determined whether use of any individual compound is associated with ALS risk by conducting a total population-based case-control study in Taiwan. METHODS: A total of 729 patients with newly diagnosed ALS who had a severely disabling disease certificate between January 1, 2002, and December 1, 2008, comprised the case group. These cases were compared with 7290 sex-, age-, residence-, and insurance premium-matched controls. Drug use by each Anatomical Therapeutic Chemical code was analyzed using conditional logistic regression models. False discovery rate (FDR)-adjusted P values were reported in order to avoid inflating false positives. RESULTS: Of the 1336 compounds, only the 266 with use cases exceeding 30 in our database were included in the screening analysis. Without controlling for steroid use, the analysis failed to reveal any compound that was inversely associated with ALS risk according to FDR criteria. After controlling for steroid use, we found use of the following compounds to be associated with ALS risk: aspirin, diphenhydramine (one of the antihistamines), and mefenamic acid (one of the NSAIDs). A multivariate analysis revealed that aspirin was independently inversely associated with ALS risk after controlling for diphenhydramine, mefenamic acid, and steroid use. The inverse association between aspirin and ALS was present predominately in patients older than 55 years. CONCLUSIONS: The results of this study suggested that aspirin use might reduce the risk of ALS, and the benefit might be more prominent for older people.
  12. ↑ Lin et al.: Angiotensin-converting enzyme inhibitors and amyotrophic lateral sclerosis risk: a total population-based case-control study. JAMA Neurol 2015;72:40-8. PMID: 25383557. DOI. IMPORTANCE: Although several studies have shown that use of angiotensin-converting enzyme inhibitors (ACEIs) potentially decreased amyotrophic lateral sclerosis (ALS) risk in animal models, to our knowledge, there has been no human study in the literature discussing this issue. OBJECTIVE: To investigate the association between the use of ACEIs and the risk for developing ALS. DESIGN, SETTING, AND PARTICIPANTS: This case-control study was conducted using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The case group comprised 729 patients with newly diagnosed ALS and a severely disabling disease certificate between January 1, 2002, and December 31, 2008. These cases were compared with 14,580 sex-, age-, residence-, and insurance premium-matched control individuals. EXPOSURES: Use of ACEIs was analyzed using a conditional logistic regression model that controlled for other antihypertensives, aspirin, steroids, nonsteroidal anti-inflammatory drugs, Charlson Comorbidity Index score, length of hospital stay, and number of outpatient visits. The cumulative defined daily dose (cDDD), which indicates the exposed duration of drug use, was estimated as the sum of dispensed DDD of drug and compared with the risk for ALS. MAIN OUTCOMES AND MEASURES: All patients with ALS fulfilled El Escorial criteria in this study. Medical claim data past 1 to 5 years of ALS first diagnosis date for patients and claim data from their matched control individuals were included in the analysis. RESULTS: There was a dose-dependent inverse association between ACEI use and the risk for developing ALS. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 (95% CI, 0.65-1.07; P = .15) for the group prescribed ACEIs lower than 449.5 of the cDDD and 0.43 cDDD (95% CI, 0.26-0.72; P = .001) for the group with a cumulative ACEI use of greater than 449.5 cDDD. The association was most predominant in men older than 55 years. CONCLUSIONS AND RELEVANCE: Use of ACEIs exhibited a dose-dependent inverse association with ALS. This study demonstrated a 57% risk reduction in the chance for developing ALS in people who used ACEIs greater than 449.5 cDDD in 4 years.
  13. ↑ Julian et al.: Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes. EBioMedicine 2021;68:103397. PMID: 34051439. DOI. BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a universally fatal neurodegenerative disease. ALS is determined by gene-environment interactions and improved understanding of these interactions may lead to effective personalised medicine. The role of physical exercise in the development of ALS is currently controversial. METHODS: First, we dissected the exercise-ALS relationship in a series of two-sample Mendelian randomisation (MR) experiments. Next we tested for enrichment of ALS genetic risk within exercise-associated transcriptome changes. Finally, we applied a validated physical activity questionnaire in a small cohort of genetically selected ALS patients. FINDINGS: We present MR evidence supporting a causal relationship between genetic liability to frequent and strenuous leisure-time exercise and ALS using a liberal instrument (multiplicative random effects IVW, p=0.01). Transcriptomic analysis revealed that genes with altered expression in response to acute exercise are enriched with known ALS risk genes (permutation test, p=0.013) including C9ORF72, and with ALS-associated rare variants of uncertain significance. Questionnaire evidence revealed that age of onset is inversely proportional to historical physical activity for C9ORF72-ALS (Cox proportional hazards model, Wald test p=0.007, likelihood ratio test p=0.01, concordance=74%) but not for non-C9ORF72-ALS. Variability in average physical activity was lower in C9ORF72-ALS compared to both non-C9ORF72-ALS (F-test, p=0.002) and neurologically normal controls (F-test, p=0.049) which is consistent with a homogeneous effect of physical activity in all C9ORF72-ALS patients. INTERPRETATION: Our MR approach suggests a positive causal relationship between ALS and physical exercise. Exercise is likely to cause motor neuron injury only in patients with a risk-genotype. Consistent with this we have shown that ALS risk genes are activated in response to exercise. In particular, we propose that G4C2-repeat expansion of C9ORF72 predisposes to exercise-induced ALS. FUNDING: We acknowledge support from the Wellcome Trust (JCK, 216596/Z/19/Z), NIHR (PJS, NF-SI-0617-10077; IS-BRC-1215-20017) and NIH (MPS, CEGS 5P50HG00773504, 1P50HL083800, 1R01HL101388, 1R01-HL122939, S10OD025212, P30DK116074, and UM1HG009442).
  14. ↑ Nelson et al.: Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am. J. Epidemiol. 2000;151:164-73. PMID: 10645819. The association of nutrient intake with the risk of amyotrophic lateral sclerosis (ALS) was investigated in a population-based case-control study conducted in three counties of western Washington State from 1990 to 1994. Incident ALS cases (n = 161) were identified and individually matched on age and gender to population controls (n = 321). A self-administered food frequency questionnaire was used to assess nutrient intake. Conditional logistic regression analysis was used to compute odds ratios adjusted for education, smoking, and total energy intake. The authors found that dietary fat intake was associated with an increased risk of ALS (highest vs. lowest quartile, fiber-adjusted odds ratio (OR) = 2.7, 95% confidence interval (CI): 0.9, 8.0; p for trend = 0.06), while dietary fiber intake was associated with a decreased risk of ALS (highest vs. lowest quartile, fat-adjusted OR = 0.3, 95% CI: 0.1, 0.7; p for trend = 0.02). Glutamate intake was associated with an increased risk of ALS (adjusted OR for highest vs. lowest quartile = 3.2, 95% CI: 1.2, 8.0; p for trend < 0.02). Consumption of antioxidant vitamins from diet or supplement sources did not alter the risk. The positive association with glutamate intake is consistent with the etiologic theory that implicates glutamate excitotoxicity in the pathogenesis of ALS, whereas the associations with fat and fiber intake warrant further study and biologic explanation.
  15. ↑ Nelson et al.: Population-based case-control study of amyotrophic lateral sclerosis in western Washington State. II. Diet. Am. J. Epidemiol. 2000;151:164-73. PMID: 10645819. The association of nutrient intake with the risk of amyotrophic lateral sclerosis (ALS) was investigated in a population-based case-control study conducted in three counties of western Washington State from 1990 to 1994. Incident ALS cases (n = 161) were identified and individually matched on age and gender to population controls (n = 321). A self-administered food frequency questionnaire was used to assess nutrient intake. Conditional logistic regression analysis was used to compute odds ratios adjusted for education, smoking, and total energy intake. The authors found that dietary fat intake was associated with an increased risk of ALS (highest vs. lowest quartile, fiber-adjusted odds ratio (OR) = 2.7, 95% confidence interval (CI): 0.9, 8.0; p for trend = 0.06), while dietary fiber intake was associated with a decreased risk of ALS (highest vs. lowest quartile, fat-adjusted OR = 0.3, 95% CI: 0.1, 0.7; p for trend = 0.02). Glutamate intake was associated with an increased risk of ALS (adjusted OR for highest vs. lowest quartile = 3.2, 95% CI: 1.2, 8.0; p for trend < 0.02). Consumption of antioxidant vitamins from diet or supplement sources did not alter the risk. The positive association with glutamate intake is consistent with the etiologic theory that implicates glutamate excitotoxicity in the pathogenesis of ALS, whereas the associations with fat and fiber intake warrant further study and biologic explanation.
  16. ↑ Huisman et al.: Effect of Presymptomatic Body Mass Index and Consumption of Fat and Alcohol on Amyotrophic Lateral Sclerosis. JAMA Neurol 2015;72:1155-62. PMID: 26280944. DOI. IMPORTANCE: Because dietary intake may influence pathophysiologic mechanisms in sporadic amyotrophic lateral sclerosis (ALS), the association between premorbid dietary intake and the risk of sporadic ALS will provide insight into which mechanisms are possibly involved in ALS pathophogenesis. OBJECTIVE: To systematically determine the association between premorbid dietary intake and the risk of sporadic ALS. DESIGN, SETTING, AND PARTICIPANTS: A population-based case-control study was conducted in a general community setting in the Netherlands from January 1, 2006, to September 30, 2011. Analysis was conducted April 1, 2013, to November 15, 2014. All patients with a new diagnosis of possible, probable (laboratory supported), or definite ALS according to the revised El Escorial criteria were included and multiple sources were used to ensure complete case ascertainment. Of 986 eligible patients, 674 gave informed consent and returned a complete questionnaire; 2093 controls randomly selected from the general practitioners' registers and frequency matched to the patients for sex and age were included. MAIN OUTCOMES AND MEASURES: We studied the premorbid intake of nutrients in association with the risk of ALS by using a 199-item food frequency questionnaire adjusted for confounding factors and corrected for multiple comparisons while minimizing recall bias. RESULTS: Presymptomatic total daily energy intake in patients, reported as mean (SD), was significantly higher compared with controls (2258 [730] vs 2119 [619] kcal/day; P < .01), and presymptomatic body mass index (calculated as weight in kilograms divided by height in meters squared) was significantly lower in patients (25.7 [4.0] vs 26.0 [3.7]; P = .02). With values reported as odds ratio (95% CI), higher premorbid intake of total fat (1.14; 1.07-1.23; P < .001), saturated fat (1.43; 1.25-1.64; P < .001), trans-fatty acids (1.03; 1.01-1.05; P < .001), and cholesterol (1.08; 1.05-1.12; P < .001) was associated with an increased risk of ALS; higher intake of alcohol (0.91; 0.84-0.99; P = .03) was associated with a decreased risk of ALS. These associations were independent of total energy intake, age, sex, body mass index, educational level, smoking, and lifetime physical activity. No significant associations between dietary intake and survival were found. CONCLUSIONS AND RELEVANCE: The combination of independent positive associations of a low premorbid body mass index and a high fat intake together with prior evidence from ALS mouse models transgenic for SOD1 and earlier reports on premorbid body mass index support a role for increased resting energy expenditure before clinical onset of ALS.
  17. ↑ Okamoto et al.: Nutritional status and risk of amyotrophic lateral sclerosis in Japan. Amyotroph Lateral Scler 2007;8:300-4. PMID: 17852010. DOI. Only a few human studies have reported the relationship between dietary factors and the risk of amyotrophic lateral sclerosis (ALS). We therefore analyzed the relationship between macronutrients (carbohydrate, protein and fat) and the risk of ALS using a case-control study in Japan. The study comprised 153 ALS patients diagnosed by the El Escorial World Federation of Neurology criteria, and 306 gender- and age- matched controls randomly selected from the general population. A self-administered food frequency questionnaire was used to estimate pre-illness intakes of food groups and nutrients. The strength of association between ALS and a potential risk factor was assessed by calculating odds ratios (ORs) and 95% confidence intervals (CIs). A high intake of carbohydrate was significantly associated with an increased risk of ALS (adjusted OR = 2.14, 95% CI 1.05-4.36; the highest versus the lowest tertile). ORs for the second and third tertile of total fat were 0.57 and 0.41 (95% CI 0.21-0.80), respectively. ORs for the highest tertile of intake versus the lowest were 0.41 (95% CI 0.21-0.80) for total fat, 0.30 (95% CI 0.16-0.5) for saturated fatty acids (SFAs), 0.35 (95% CI 0.18-0.69) for monounsaturated fatty acids (MUFAs) and 0.58 (95%CI 0.40-0.96) for polyunsaturated fatty acids (PUFAs). Our findings suggest that high intakes of carbohydrate and low intakes of fat and some kinds of fatty acids may, when combined, increased the risk of ALS.
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