What are the risk factors for amyotrophic lateral sclerosis (ALS)?

Risk Factors for Amyotrophic Lateral Sclerosis (ALS)

The risk factors for ALS include both genetic and environmental exposures, with the most strongly established being C9orf72 repeat expansions (40% of familial cases), head trauma, electrical injuries, lead exposure, smoking, and lower body mass index. 1, 2, 3

Genetic Risk Factors

Established Genetic Mutations

• C9orf72 repeat expansions are the most common known genetic cause, accounting for approximately 40% of familial ALS cases and 10% of sporadic cases 3
• Intermediate CAG repeat expansion in ATXN2 is associated with increased ALS risk 1
• Over 30 monogenic mutations are associated with approximately 10% of all ALS cases 1
• APOE variants represent a major late-onset susceptibility gene for neurodegenerative diseases including ALS 4

Environmental and Occupational Risk Factors

Heavy Metal Exposures

• Lead exposure shows the strongest association among hobby-related exposures (adjusted OR 2.92,95% CI 1.45-5.91), with effects most pronounced when exposure occurred 20 or more years prior to diagnosis 2
• Mercury exposure has been identified as a putative risk factor in systematic reviews 1

Occupational Exposures

• Jobs in mechanics, painting, or construction are associated with increased ALS risk 2
• Occupations requiring repetitive or strenuous physical work increase risk 1
• Military service has been proposed as a risk factor, though causality is not definitively established 3
• Exposure to pesticides and organic solvents are associated with ALS onset 1, 5
• Electromagnetic field exposure has been examined as a potential risk factor 5

Physical Trauma

• Head trauma is associated with increased ALS risk (adjusted OR 1.60,95% CI 1.04-2.45), with significantly greater effects for injuries occurring 10 or more years prior to symptom onset (P = 0.037) 2
• History of physical trauma or injury in general has been identified as a risk factor 1
• Severe electrical burns show strong association with ALS (adjusted OR 2.86,95% CI 1.37-6.03), with highest odds ratios for burns after age 30 (OR 3.14) and burns 10 or more years prior to symptom onset (OR 3.09) 2

Lifestyle and Behavioral Risk Factors

Smoking

• Smoking is a weak risk factor for ALS, particularly in women 1
• Smoking is also associated with ALS progression rate 1

Body Composition and Nutrition

• Lower body mass index (BMI) is associated with increased ALS risk 1
• At diagnosis, weight loss >5% compared to usual weight doubles the risk of death (HR 1.92,95% CI 1.15-3.18) 4
• Each 5% weight loss during follow-up increases mortality risk by 34% (HR 1.34,95% CI 1.18-1.51) 4
• Vitamin D deficiency is associated with faster ALS progression 1

Physical Activity

• Participating in professional sports has been identified as a potential risk factor 1
• Physical exercise and physical fitness levels have been examined, though the relationship is complex 5

Educational and Socioeconomic Factors

• Lower educational attainment is associated with increased ALS risk 1

Other Potential Risk Factors

Biological Exposures

• Exposure to Beta-N-methylamino-L-alanine (BMAA) has been proposed as a risk factor 1, 5
• Viral infections have been examined as potential contributors 1, 5

Medical Comorbidities

• Metabolic diseases may be linked to ALS risk 5
• Cancer has been examined for potential associations 5
• Inflammatory diseases have been studied as potential risk factors 5

Factors Associated with Disease Progression

Nutritional Status

• Malnutrition during follow-up increases death risk by 2.2 to 7.4-fold (95% CI 1.09-4.25; p = 0.01) 4
• Each 1-point BMI loss increases mortality risk by 24% (HR 1.24,95% CI 1.13-1.36) 4
• Higher fat mass during disease improves survival, with each 2.5 kg increase reducing death risk by 10% (HR 0.90,95% CI 0.83-0.96) 4

Other Progression Factors

• Ethnicity and genetic factors influence progression rate 1
• Lack of supportive multidisciplinary care accelerates progression 1
• Comorbidities affect disease trajectory 1

Critical Temporal Considerations

A key pattern emerges across multiple risk factors: exposures occurring 10-20 years or more before symptom onset show stronger associations than recent exposures, suggesting a long latency period between environmental insult and disease manifestation 2. This is particularly evident for head trauma, electrical burns, and lead exposure, where the temporal relationship strengthens the case for causality rather than reverse causation.

Important Caveats

• Most ALS cases (85-90%) are sporadic with no identified genetic cause, emphasizing the likely importance of environmental factors 3
• The peak age of onset is 55-70 years with male predominance 6
• While many associations have been identified, establishing definitive causality requires further prospective studies and mechanistic research 1, 2
• The incidence of ALS appears to be increasing in recent decades, though this may partly reflect improved diagnosis 5