Increased Levels of Alpha-Linolenic Acid Linked With Disease Progression in ALS


Higher levels of the n-3 fatty acid eicosapentaenoic acid and the n-6 fatty acid linoleic acid were associated with a lower risk of death during follow-up.

Alberto Ascherio, MD, DrPH, professor of epidemiology and nutrition at Harvard University

Alberto Ascherio, MD, DrPH

Using participants from the EMPOWER clinical trial, recently published findings in Neurology showed that higher levels of alpha-linolenic acid (ALA) were associated with longer survival and slower functional decline in individuals with amyotrophic lateral sclerosis (ALS).1

Prior to the study, limited research had suggested that higher dietary intake and plasma levels of polyunsaturated fatty acids (PUFAs), in particular ALA, are associated with a lower risk of ALS. In the most recent analysis, after adjusting for age, sex, and baseline ALS Functional Rating Scale (ALSFRS-R) score, the HR for death comparing the highest and lowest quartile of ALA was 0.50 (95% CI, 0.29-0.86; P = 0.041).

"These results suggest that specific PUFAs, in particular AFA, may have a favortable effect on disease progression in patients with ALS,” senior investigator Alberto Ascherio, MD, DrPH, professor of epidemiology and nutrition at Harvard University, wrote.

The analysis featured 449 individuals with ALS, with characteristics that were similar distributed across the quartiles of ALA. The study end points included were death up to 18 months and a joint-rank test that considers both functional decline as change from baseline to month 12 in ALSFRS-R score and survival up to 12 months. Cox proportional hazards models and linear regression were used to evaluate the association of individual fatty acids with risk of death and joint-rank test score of functional decline and survival.

Of the cohort, 126 (28.1%) participants died during follow-up. Data showed that a lower number of participants in the top quartile of ALA (n = 21; 18.9%) died during follow-up compared with quartile 1 (n = 37; 32.7%), quartile 2 (n = 31; 27.4%), and quartile 3 (n = 37; 33.0%). HRs for death comparing the highest and lowest quartile of ALA remained similar in a multivariable analysis that additionally adjusted for body mass index, race/ethnicity, symptom duration, site of onset, riluzole (Rilutek) use, family history of ALS< predicted upright slow vital capacity, and treatment arm in the trial (HR, 0.55; 95% CI, 0.31-0.98; P-trend = 0.120).

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Among the other n-3 and n-6 PUFAs, higher plasma levels of eicosapentaenoic acid (multivariable adjusted HR, 0.45; 95% CI, 0.26-0.79; P-trend = 0.008) and linoleic acid (HR, 0.54; 95% CI, 0.31-0.93; P-trend = 0.048) were associated with a lower risk of death during follow-up. Multivariable adjusted analysis further revealed that higher levels of monounsaturated fatty acid palmitic acid were associated with a higher risk of death, while none of the other fatty acids demonstrated nominally statistically significant associations (P >.05).

In the joint-rank test analyses, after adjusting for age, sex, and baseline ALSFRS-R scores, higher ALA levels were associated with higher rank when ALA was modeled as a continuous variable (difference in joint-rank test score according to 1 SD increase, 10.7; 95% CI, 0.2-21.1; P = .045). The least-squared mean joint-rank test score for individuals in quartile 4 of ALA was 24.3 points (95% CI, –5.0 to 53.5) higher than in quartile 1, but the difference was not significant.

The study had several strengths, including the large number of patients with ALS with similar disease duration and progression. Investigators also had access to comprehensive data on demographic characteristics and clinical variables relevant for the diagnosis, prognosis, and progression of ALS. Lastly, the study included detailed data on time of death, study withdrawal, and discontinuation of participation for each participant, with time-at-risk accounted for in detail.

"The link our study found between diet and ALS is intriguing,” Ascherio said in a statement. “We are now reaching out to clinical investigators to promote a randomized trial to determine whether ALA is beneficial in people with ALS. Obtaining funding will be challenging, because ALA is not a patentable drug, but we hope to get it done."2

1. Bjornevik K, Cortese M, Furtado JD, et al. Association of polyunsaturated fatty acids and clinical progression in patients with ALS: post hoc analysis of the EMPOWER trial. Neurology. Published online June 21, 2023. doi:10.1212/WNL.00000000000207485
2. Omega-3 fatty acids linked with slower progression of ALS. News release. Harvard Medical School. June 21, 2023. Accessed July 7, 2023.
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