BACKGROUND: Premorbid body mass index, physical activity, diabetes and 
cardiovascular disease have been associated with an altered risk of developing 
amyotrophic lateral sclerosis (ALS). There is evidence of shared genetic risk 
between ALS and lipid metabolism. A very large prospective longitudinal 
population cohort permits the study of a range of metabolic parameters and the 
risk of subsequent diagnosis of ALS.
METHODS: The risk of subsequent ALS diagnosis in those enrolled prospectively to 
the UK Biobank (n=502 409) was examined in relation to baseline levels of blood 
high and low density lipoprotein (HDL, LDL), total cholesterol, total 
cholesterol:HDL ratio, apolipoproteins A1 and B (apoA1, apoB), triglycerides, 
glycated haemoglobin A1c (HbA1c) and creatinine, plus self-reported exercise and 
body mass index.
RESULTS: 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.
CONCLUSIONS: The association of HDL, apoA1 and LDL levels with risk of ALS 
contributes to an increasing body of evidence that the premorbid metabolic 
landscape may play a role in pathogenesis. Understanding the molecular basis for 
these changes will inform presymptomatic biomarker development and therapeutic 
targeting.