Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis

Abstract

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.

Keywords: cholesterol; epidemiology.

Figure 1

Temporal differences in LDL and HDL cholesterol, ApoB and apoA1 and diagnosis of ALS. Participants going on to develop ALS (red) were each matched by age of sampling in years, date of sampling ±60 days and sex to 20 participants not going on to develop ALS (blue). Lines indicate linear model fit for ALS (red) and non-ALS (blue) participants. P values indicate interaction between ALS status and time, indicating difference in temporal trajectory of biomarkers over time. ApoA1, apolipoprotein A1; ApoB, apolipoprotein B; ALS, amyotrophic lateral sclerosis; HDL-C, high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol.