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ALS Risk Reduced in People With Higher Density Lipoprotein, Apolipoproteins

Even after excluding those who received ALS diagnosis in the 5 years prior, higher HDL and APOA1 levels were associated with a lower risk of ALS.

Data from a large, prospective, longitudinal cohort study showed that higher levels of high-density lipoprotein (HDL) and apolipoprotein A1 (APOA1), with corresponding lower total cholesterol, were associated with reduced risk of subsequent diagnosis of amyotrophic lateral sclerosis (ALS), independent of age and sex.1

Lead author Alexander G. Thompson, DPhil, BMBCh, BA, MRCP, clinician scientist and Lady Edith Wolfson Fellow, Oxford University Motor Neuron Disease Center, and colleagues examined the risk of subsequent ALS diagnosis in 502,409 individuals enrolled in the UK Biobank. Biochemical analysis of blood samples included measurement of blood total cholesterol, HDL, low density lipoprotein (LDL), APOA1, APOB, triglycerides, glycated hemoglobin A1c (HbA1c), and creatinine. Participants also self-reported exercise and body mass index (BMI).

A total of 343 participants obtained a diagnosis of ALS during follow-up, giving a crude incidence of 5.85 per 100,000 per year (95% CI, 5.25-6.51). Incorporating all incident ALS cases, higher HDL (HR, 0.84 [95% CI, 0.73-0.96]; P = .010; adjusted P = .035) and higher APOA1 (HR, 0.83 [95% CI, 0.72-0.94]; P = .005; adjusted P = .031) were associated with a reduced risk of subsequent diagnosis of ALS. Furthermore, increased risk of ALS was found in those with higher levels of total cholesterol (HR, 1.17 [95% CI, 1.05-1.31]; P = .006; adjusted P = .031).

"This study adds to the growing literature documenting differences in premorbid metabolic profile of those who eventually develop ALS," Thompson et al concluded. "In addition to providing novel insights into pathogenesis, this emphasizes the need to consider a broader set of potential presymptomatic ALS biomarkers. Such biomarkers might help to target population screening for ALS and also build confidence in future trials of preventive therapy."

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Even after excluding total cholesterol from the analysis due to a high degree of correlation with LDL, results remained similar, with higher HDL (HR, 0.78 [95% CI, 0.64-0.96]; P = .017; adjusted P = .054) and APOA1 (HR, 0.82 [95% CI, 0.68-0.97]; P = .024; adjusted P = .088) levels associated with reduced risk of ALS. Notably, smoking was not significant in combined models, whereas age, cerebrovascular disease, and coronary artery disease were associated with higher ALS risk in all models.

Higher HDL (HR, 0.66 [95% CI, 0.49-0.88]; P = .005; adjusted P = .020) or APOA1 (HR, 0.77 [95% CI, 0.61-0.98]; P = .034; adjusted P = .110) levels were still associated with this reduced risk after excluding those diagnosed within 5 years of their first visit. Furthermore, higher LDL (HR, 1.35 [95% CI, 1.09-.168]; P = .007; adjusted P = .021) and APOB (HR, 1.23 [95% CI, 1.00-1.25]; P = .050; adjusted P = .129) were associated with an increased risk of ALS.

The results of this study adds to the foundations laid out by Daniela Mariosa, MD, et al, which published longitudinal 20-year primary care trial data in 2017. . The Apoliprotein-related MOrtality RISk study (AMORIS) identified an association between 1-unit increase of LDL cholesterol (HR, 1.14 [95% CI, 1.02-1.27]), APOB (HR, 1.68 [95% CI, 1.17-2.42]), and APOB/APOA1 ratio (HR, 1.90 [95% CI, 1.29-2.78]) to be associated with a higher incidence of ALS. Additionally, high glucose level (≥6.11 mmol/L) was associated with a lower incidence (HR, 0.62 [95% CI, 0.42-0.93]), whereas high LDL/HDL (≥3.50 mmol/L; HR, 1.50 [95% CI, 1.15-1.96]) and high APOB/APOA1 (≥0.90 mmol/L for men, ≥0.8 for women; HR, 1.41 [95% CI, 1.04-1.90]) ratios were associated with a higher incidence.2

1. Thompson AG, Talbot K, Turner MR. Higher blood high density lipoprotein and apolipoprotein A1 levels are associated with reduced risk of developing amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. Published online September 13, 2021. doi:10.1136/jnnp-2021-327133
2. Mariosa D, Hammar N, Malmstrom H, et al. Blood biomarkers of carbohydrate, lipid, and apolipoprotein metabolisms and risk of amyotrophic lateral sclerosis: a more than 20-year follow-up of the Swedish AMORIS cohort. Ann Neurol. 2017;81(5):718-728. doi:10.1002/ana.24936