Risk factors for amyotrophic lateral sclerosis. Lifestyle, environment and genetics

In this thesis the results of studies aiming to identify risk factors for amyotrophic lateral sclerosis (ALS) are described. A population-based case-control design was used to perform (1) epidemiological risk factor studies, examining lifestyle factors and environmental exposures, and (2) genetic studies determining genetic risk variants in ALS. Within these studies novel exposures have been established, which had not been implicated in ALS before, including exposure to traffic related air pollution and diesel motor exhaust. We were able to identify these exposures in two independent populations, in The Netherlands and Ireland, as well as through different study approaches (residential and occupational exposure assessment), presenting convincing evidence for the positive association with ALS risk. These and other ALS associated risk factors described in this thesis (e.g. physical activity, head trauma, high dietary fat intake, low BMI and cholesterol levels, and low alcohol consumption) have provided us with new clues for pathophysiological mechanisms, such as mitochondrial dysfunction, oxidative stress, neuroinflammation and glutamate excitotoxicity. Moreover, we have shown that ALS has a complex etiology in which multiple genetic (and most probably also lifestyle and environmental) factors co-occur to cause ALS. Specifically co-occurring repeat expansions in C9orf72 and NIPA1 were identified. Taking all studies together, we have generated new hypotheses for futurefunctional biologicalstudies to elucidatepathophysiological mechanisms leading to this complex and devastating disease.