Higher ‘Good’ Cholesterol Linked to Worse ALS Survival Rate

Lower levels of 'bad' cholesterol found in people with advanced disease

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A dropper squirts blood alongside several vials half-filled with blood.

Elevated levels of high-density lipoprotein (HDL) — commonly called the “good” cholesterol — are significantly associated with a poorer survival rate among people with amyotrophic lateral sclerosis (ALS), according to a population-based study in the Netherlands.

In contrast, levels of total cholesterol and low-density lipoprotein — the “bad” cholesterol — were lower in people with more advanced disease stages.

The findings suggest that lipid, or fat molecules “may contain valuable information about disease severity and prognosis, because [blood] concentrations seem to be dependent on disease severity,” the researchers wrote.

The team noted, however, that their findings may be at odds with some previous research, which found that higher good cholesterol levels are linked with a lower risk of ALS.

“As our results are not in line with previous studies on a causal effect of the lipid profile on ALS disease progression, we believe this new information may contribute to ongoing efforts to disentangle ALS pathogenesis [disease development],” the researchers wrote.

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The new study, “Association Between Serum Lipids and Survival in Patients With Amyotrophic Lateral Sclerosis: A Meta-analysis and Population-Based Study,” was published in the journal Neurology.

Lipids are an essential component of the cellular membrane. They also work as molecular messengers and energy sources, and are required for the normal functioning of cells, including nerve cells.

A number of studies suggest a link between ALS and lipid metabolism, with high lipid levels being linked with a more aggressive disease course. However, other studies actually suggest that lipids can exert a protective effect.

To shed more light on this association, a team of researchers in the Netherlands initially conducted a systematic review and meta-analysis of studies published through June 2022. Their aim was to assess the prognostic value of biomarkers of lipid metabolism in ALS. This is a form of analysis that combines data from multiple studies and provides a stronger statistical confidence in the results.

The team then investigated the prognostic value of certain lipid molecules in a group of patients diagnosed with ALS at the University Medical Center Utrecht from 2012 to 2017.

From a total of 624 studies, nine were considered for the systematic review. Five of them showed a significant association between survival and circulating levels of triglycerides, total cholesterol, HDL, and the ratio of LDL/HDL.

In the meta-analysis, a total of four studies — involving 1,120 patients in all — were included. No statistically significant association was seen between lipid biomarkers (total cholesterol, HDL, LDL, triglycerides) and overall survival.

However, the researchers noted that there was “considerable heterogeneity between study results.”

The population-based study involved 1,324 patients with ALS, 1,185 of whom (89.5%) had died by July 2020. In this population, the median survival since diagnosis was 16.5 months.

Overall, 20.1% of patients had elevated levels of total cholesterol on the day of diagnosis. Of them, 42% had high levels of LDL and 19.2% had elevated triglycerides. Additionally, 4.9% of patients showed reduced levels of HDL at diagnosis.

After adjusting for potential confounding factors, such as age, disease progression, ALS mutations, and lung function, the researchers found that an increase of one millimole per liter (mmol/L) in HDL was associated with a 33% higher risk of death and shorter survival time after ALS diagnosis.

This effect was more pronounced among females, in whom a 1 mmol/L increase in HDL was linked with a 48% higher risk of death, but was not impacted by the age at diagnosis.

Among the 419 patients with available disease progression measurements, the rate of progression was a decline of 0.79 points per month on the ALS Functional Rating Scale Revised (ALSFRS-R).

However, analyses showed that each 1 mmol/L increase in HDL translated into a 0.10 point higher rate of progression in ALSFRS-R scores. No association was seen with any of the remaining lipid biomarkers.

Gaining further insight into lipid metabolism … could improve the monitoring of patients.

Finally, in an exploratory analysis, the team assessed how genetics affected the biomarkers of lipid metabolism, a parameter called polygenic profile scores (PPS).

The analysis, involving 688 ALS patients, showed that each PPS showed a significant correlation with the respective level of the lipid molecule — total cholesterol, HDL, LDL, and triglycerides. However, PPS showed no association with overall survival, suggesting that “lipid levels change as a consequence of the disease rather than vice versa,” the researchers wrote.

“Gaining further insight into lipid metabolism and longitudinal data [collected at different periods] on serum concentrations of the lipid profile could improve the monitoring of patients,” they wrote.