Other potential risk factors remain unconfirmed, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock. There is a tentative association with exposure to various pesticides, including the organochlorine insecticides aldrin, dieldrin, DDT, and toxaphene. Head injury
A 2015 review found that moderate to severe traumatic brain injury is a risk factor for ALS, but whether mild traumatic brain injury increases rates was unclear. A 2017 meta-analysis found an association between head injuries and ALS; however, this association disappeared when the authors considered the possibility of reverse causation, which is the idea that head injuries are an early symptom of undiagnosed ALS, rather than the cause of ALS. Physical activity
A number of reviews prior to 2021 found no relationship between the amount of physical activity and the risk of developing ALS. A 2009 review found that the evidence for physical activity as a risk factor for ALS was limited, conflicting, and of insufficient quality to come to a firm conclusion. A 2014 review concluded that physical activity in general is not a risk factor for ALS, that soccer and American football are possibly associated with ALS, and that there was not enough evidence to say whether or not physically demanding occupations are associated with ALS. A 2016 review found the evidence inconclusive and noted that differences in study design make it difficult to compare studies, as they do not use the same measures of physical activity or the same diagnostic criteria for ALS.
Clinically, 50% of people with ALS have some cognitive or behavioral impairments and 5–15% have FTD, while 40% of people with FTD have some motor neuron symptoms and 12.5% have ALS. Pathologically, abnormal aggregations of TDP-43 protein are seen in up to 97% of ALS patients and up to 50% of FTD patients. In December 2021 a paper found the TDP-43 proteinopathy is in turn caused by defective cyclophilin A which regulates TARDBP gene expression. Other genes known to cause FTD-ALS include CHCHD10, SQSTM1, and TBK1. Environmental factors
Where no family history of the disease is present – around 90% of cases – no cause is known. Possible associations for which evidence is inconclusive include military service and smoking. Although studies on military history and ALS frequency are inconsistent, there is weak evidence for a positive correlation. Various proposed factors include exposure to environmental toxins (inferred from geographical deployment studies), as well as alcohol and tobacco use during military service.A 2016 review of 16 meta-analyses concluded that there was convincing evidence for an association with chronic occupational exposure to lead; suggestive evidence for farming, exposure to heavy metals other than lead, beta-carotene intake, and head injury; and weak evidence for omega-3 fatty acid intake, exposure to extremely low frequency electromagnetic fields, pesticides, and serum uric acid.In a 2017 study by the United States Centers for Disease Control and Prevention analyzing U.S. deaths from 1985 to 2011, occupations correlated with ALS deaths were white collar, such as in management, financial, architectural, computing, legal, and education jobs.