Greater Total Cholesterol Variability Linked to 60% Greater Dementia Risk

A recent study showed greater total cholesterol and low-density lipoprotein cholesterol (LDL-c) were linked to a quicker decline in global cognition, episodic memory, and psychomotor speed.1 The results were published yesterday in Neurology, the medical journal of the American Academy of Neurology.

“These results suggest that fluctuating cholesterol, measured annually, may be a new biomarker for identifying people at risk of dementia, providing more information than the actual cholesterol levels measured at a single time point,” said lead investigator Zhen Zhou, PhD, of Monash University in Melbourne, Australia.2

Biological aging, functional decline, reduced ability to maintain homeostasis, and nutrient intake influence lipid metabolism in older adults.1 In turn, the dysregulation of lipid metabolism may negatively impact brain health. Investigators sought to evaluate the link between year-to-year lipid variability and the subsequent risk of cognitive decline and dementia in community-dwelling older adults.

The team conducted a post-hoc analysis of the randomized trial ASPirin in Reducing Events in the Elderly (ASPREE), which examined aspirin in 19,114 participants aged ≥ 65 years from the United States and Australia who did not have dementia or major cognitive impairment. The post-hoc analysis included participants with available data on lipid levels at baseline and years 1, 2, and 3; those who initiated or discontinued lipid-lowering therapy during this period were excluded. Investigators followed participantsfor up to 11 years and quantified year-to-year variability in total cholesterol, LDL-c, high-density lipoprotein cholesterol (HDL-c), and triglycerides over the first 3 years.

Multivariable Cox proportional hazards regression, adjusted for age, smoking status, and high blood pressure, was used to assess associations with incident dementia and cognitive impairment with no dementia. A linear mixed model was used to evaluate the association with changes in 4 cognitive function domains: global, memory, processing speed, verbal fluency, and composite score from baseline to end of follow-up.

The study included 9846 participants (mean age, 73.9 years; 54.9% female), with 509 who had incident dementia and 1760 who had cognitive impairment with no dementia after a follow-up of 5.8 and 5.4 years, respectively. The participants were divided into 4 groups based on the amount of change between their first and fourth cholesterol measurements.

Among the group who had the largest amount of change in total cholesterol, 147 of the 2408 people in the group developed dementia, a rate of 11.3 per 1000 person-years. As for the group with the lowest amount of change in total cholesterol, 98 of 2437 people developed dementia, a rate of 7.1 per 1000 person-years.

The adjusted analysis showed that individuals with greater variability in total cholesterol levels had a 60% greater risk of developing dementia compared to those with the lowest variability (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.23 – 2.08). Moreover, individuals with the highest variability in LDL-C had a 48% greater risk of developing dementia compared to those with the lowest variability (HR, 1.48; 95% CI, 1.15 – 1.91). Moreover, those with greater variability in total cholesterol levels and LDL-C had a 23% (HR, 1.23; 95% CI, 1.08 – 1.41) and 27% (HR, 1.27; 95% CI, 1.11 – 1.46) greater risk of developing cognitive impairment with no dementia, respectively, than those with lower variability.

The study also found that greater total cholesterol and LDL-c variability were associated with a faster decline in global cognition, episodic memory, psychomotor speed, and composite score (P < .001). Additionally, there was no strong evidence for an association of HDL-c and triglyceride variability with dementia and cognitive change.

Investigators wrote that the findings may be limited by not having data on changes in cholesterol medication dosage or not taking their medication as prescribed. Although they excluded people who started or stopped taking cholesterol drugs, changing doses could affect cholesterol levels.

“Older people’s cholesterol should be monitored for changes over time to help identify people who may be at risk of cognitive impairment or dementia and could benefit from interventions, which could include lifestyle changes or making sure they start or keep taking statin to prevent fluctuations in their cholesterol and potentially reduce the risk of dementia,” Zhou said.2

References

1. Zhou Z, Moran C, Murray AM, Zoungas S, Magnussen C, Chong TT, Shah RC, Sheets KM, Nelson M, Zhu C, Tonkin AM, Talic S, Ernst ME, Orchard SG, McNeil JJ, Wolfe R, Woods RL, Neumann JT, Qiu P, Ryan J. Association of Year-to-Year Lipid Variability With Risk of Cognitive Decline and Dementia in Community-Dwelling Older Adults. Neurology. 2025 Feb 25;104(4):e210247. doi: 10.1212/WNL.0000000000210247. Epub 2025 Jan 29. PMID: 39879572; PMCID: PMC11774555.
2. Changing cholesterol over time tied to risk of dementia. EurekAlert! January 29, 2025. https://www.eurekalert.org/news-releases/1071473. Accessed January 30, 2025.