Variable Levels of Lipoprotein Cholesterol Linked to Dementia

Fluctuating levels of low-density lipoprotein (LDL) cholesterol and total cholesterol in older adults living in communities could be a biomarker for dementia and cognitive decline, according to a new study published in Neurology.1

Older adults are more often afflicted by dementia2 and general cognitive decline with the ability to slow progression if it is caught early on. The relationship between lipid levels and neurocognitive decline has not been as defined and understudied. This study aimed to use data from other large-scale randomized trials to assess the association between variability in lipid measurements and the risk of cognitive decline and dementia in older adults.

Data from the ASPirin in Reducing Events in the Elderly (ASPREE) and its posttrial observational phase, ASPREE-extension, were included in this study. The study recruited those aged 70 years and older in both Australia and the United States; US ethnic minorities could be aged 65 years and older. All included participants had no physical disability that limited their independence, had diagnosed dementia, significant cognitive decline, or any previous cardiovascular disease events. Although ASPREE concluded in June 2017 with a data cutoff date of 2021, the posttrial observation is still in progress.

Older adults had a higher risk of dementia if their levels of total cholesterol and lipoprotein varied year to year | Image credit: comzeal - stock.adobe.com

Blood samples were collected from each participant after fasting. All blood samples were collected at a local clinic or a pathology center. LDL cholesterol was calculated in all patients based on their blood sample. All participants included in the analysis had 4 blood samples collected: 1 at baseline and yearly collections for the next 3 years. Participants who initiated or discontinued lipid-lowering treatment were excluded from the study, as the researchers aimed to assess the variability outside of changes to treatment.

The primary outcome was change in total cholesterol from year to year, with LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides also assessed. The main endpoint was all-cause dementia. Cognitive impairment without dementia and changes in domain-specific cognition acted as other end points for the study. Tests that measured global cognitive function, episode memory, language and executive function, and psychomotor speed were used to measure these end points.

There were 9846 participants included in this study, of which 54.9% were women, and the median (IQR) age was 73.9 (71.7-77.3) years. The total absolute change in total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides was 2.36, 2.07, 0.81, and 1.46 mmol/L, respectively, in the highest quartile; the absolute change was 1.02, 0.92, 0.35, and 0.57 mmol/L, respectively.

A total of 5% of participants developed dementia during a median of 5.8 (4.5-7.1) years of follow-up. A higher incidence rate of dementia was found in the higher quartile of total cholesterol variability compared with the lowest quartile (11.3 vs 7.1 cases per 1000 person-years). The risk of dementia was 37%, 44%, and 60% in the second-lowest, second-highest, and highest quartiles compared with the lowest. A 13% and 12% increased risk of dementia was found with every 1 SD increase in total cholesterol and LDL cholesterol variability.

A total of 25% of participants experienced cognitive decline after a median follow-up of 5.4 (4.1-6.5) years. Those in the highest quartile of total cholesterol and LDL cholesterol had the greatest risk of cognitive decline (total cholesterol: HR, 1.23; 95% CI, 1.08-1.41 and LDL cholesterol: HR, 1.27; 95% CI, 1.11-1.46) when compared with the lowest quartile. A more rapid decline in global cognition, psychomotor speed, and episodic memory were found in those with higher quartiles of total cholesterol and LDL cholesterol variability.

There were some limitations to this study. A change in dosage or nonadherence to lipid-lowering agents could have accounted for variability in total cholesterol and LDL cholesterol levels. The data for this study came from a clinical trial, which is more likely to enroll healthy participants and could limit generalizability. Dietary patterns were not accounted for in this study. Reverse causation is possible.

The researchers concluded that a higher risk of dementia, cognitive decline, and cognitive impairment were associated with greater variability in total cholesterol and LDL cholesterol in older adults. Future studies should focus on whether those with lipid variability qualify as a high-risk group.

References

1. Zhou Z, Moran C, Murray AM, et al. Association of year-to-year lipid variability with risk of cognitive decline and dementia in community-dwelling older adults. Neurology. 2025;104(4):e210247. doi:10.1212/WNL.0000000000210247
2. Fact sheet: U.S. dementia trends. Population Reference Bureau. Accessed January 30, 2025. https://www.prb.org/resources/fact-sheet-u-s-dementia-trends/