Lipid Levels Tied to ALS Risk

Pauline Anderson

September 14, 2021

Elevated levels of high-density lipoprotein (HDL) and apolipoprotein A1 (apoA1) are associated with a reduced risk for amyotrophic lateral sclerosis (ALS), new research shows.

The study also linked a higher ratio of total cholesterol to HDL with an increased risk for ALS. These findings, investigators note, point to potential future biomarkers in screening for ALS and perhaps an approach to reduce risk or delay onset of ALS in the longer term.

Dr Alexander Thompson

"They may help build a biochemical picture of what's going on and who might be at risk of developing ALS in the near future, particularly in people with a genetic predisposition to ALS," study investigator Alexander G. Thompson, DPhil, Medical Research Council clinician scientist, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom, told Medscape Medical News.

He emphasized that although the current observational study cannot show cause and effect, such a relationship may exist.

The study was published online September 13 in the Journal of Neurology, Neurosurgery and Psychiatry.

Registry Data

ALS is a disorder of progressive degeneration of upper and lower motor neurons. Genetic variants account for fewer than 15% of cases. The factors that are associated with the greatest risk are unclear.

To investigate, the researchers used data from the UK Biobank, a prospective cohort study of persons aged 39–72 years. Participants underwent an initial assessment between March 2006 and October 2010 and were followed for a median of 11.9 years.

In addition to providing demographic and health information, participants provided blood samples for biochemical analysis. This included measurements of total cholesterol, HDL, low-density lipoprotein (LDL) cholesterol, triglycerides, apoA1, apolipoprotein B (apoB), A1c, and creatinine.

Researchers used diagnostic codes in inpatient health records and death certificate information to verify ALS diagnoses.

The analysis included data from 502,409 participants. The mean age of trhe participants was 58 years, and 54.4% were women. During follow-up, 343 participants were diagnosed with ALS, yielding a crude incidence of 5.85 per 100,000 per year (95% CI, 5.25 – 6.51).

After controlling for sex and age, results showed that higher HDL (hazard ratio [HR], 0.84; 95% CI, 0.73 – 0.96; P = .010) and higher apoA1 (HR, 0.83; 95% CI, 0.72 – 0.94, P = .005) were associated with a reduced risk for subsequent ALS.

A higher ratio of total cholesterol to HDL was associated with increased ALS risk.

A rise in neurofilaments and other markers of neuronal loss typically occur within about a year of ALS symptom onset. To ensure that they were capturing participants whose blood samples taken before the onset of neurodegeneration, the researchers performed a secondary analysis that excluded ALS diagnoses within 5 years of the baseline study visit.

Results of the analysis were largely consistent with models incorporating all participants with regard to magnitude and direction of associations. In addition, the findings persisted in models that controlled for statin use, smoking, and vascular disease.

Mechanism Unclear

To examine more closely lipid status prior to ALS diagnosis, the researchers performed a nested case-control analysis that involved matching each participant who developed ALS with 20 participants of similar age, sex, and time of enrollment who did not develop the disease.

Linear models showed that levels of LDL and apoB, which are closely correlated, decrease over time in those who developed ALS. This was not the case for HDL and apoA1.

"This suggests LDL levels are going down, and we think it's happening quite some time before symptoms start, even before neurodegeneration starts," said Thompson.

How blood lipid levels correlate with ALS risk is unclear. Thompson noted that LDL is an oxidative stressor and can provoke inflammation, whereas HDL is an antioxidant that is involved in healing.

However, given that LDL and HDL don't cross into the brain in great amounts, "the lipid changes may be a reflection of something else going on that contributes to the risk of ALS," he said.

More evidence of a causal relationship is needed before any clinical implications can be drawn, including the potential manipulation of lipid levels to prevent ALS, said Thompson.

In addition, even were such a relationship to be established, altering lipid levels in a healthy individual who has no family history of ALS would be unlikely to alter risk.

Thompson added among those with a genetic predisposition, lipid changes "may be a marker or clue that something's going wrong in the nervous system and that ALS might be about to start. That would be the ideal time to treat people at risk of ALS with gene therapy."

Metabolism Gone Awry

Commenting on the findings for Medscape Medical News, Stephen Goutman, MD, director, Pranger ALS Clinic, associate professor of neurology, Neuromuscular Program, University of Michigan, Ann Arbor, Michigan, called the study "very interesting."

Of particular note was a trend of decreasing LDL and apoB levels prior to an ALS diagnosis, said Goutman.

The results are in agreement with several studies that show an alteration in metabolism in individuals with ALS, he said. "These altered metabolic pathways may provide some signal that something has gone awry," he comments.

He agreed that an "ultimate goal" is to identify factors or biomarkers that can be used to predict whether individuals will develop ALS and to enable intervention to decrease the risk.

This new research highlights the value of population-based registries and large prospective cohorts, said Goutman. "These help to better define the genetic, environmental, and metabolic factors that increase and predict ALS risk," he said.

But more work is needed, said Goutman. He noted that in the study, only 192 participants were diagnosed with ALS more than 5 years after enrollment.

"This means additional large cohort studies are needed, especially those that reflect the diversity of the population, for us to solve the mystery of ALS and to prevent it," he said.

Thompson and Goutman have disclosed no relevant financial relationships.

J Neurol Neurosurg Psychiatry. Published online September 13, 2021. Full text

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