Fluctuating Cholesterol Over Time Associated With Dementia Risk in Older Adults

According to new study results published in the American Academy of Neurology, variability in cholesterol levels over time in older adults could be associated with a heightened risk of developing dementia compared with those whose cholesterol remains stable. Though the results do not indicate a causation, they demonstrate the potential feasibility of using cholesterol as a biomarker for dementia risk.^1,2

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The onset of dementia can be undetected and come as a major surprise to older adults who suddenly are dealing with cognitive complications. Detecting dementia and starting treatment early can slow the progression of the disease, making it critical for researchers to find novel, effective ways of determining dementia risk.^1,2

Measuring variability in cholesterol levels, including total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), could provide valuable information as to the risk of cognitive decline and dementia in older people. Fluctuations of LDL-C levels in older adults over time have been shown to have prognostic importance in measuring cardiovascular risk. Still, there have been few thorough clinical investigators of this relationship, and those that exist are burdened by small sample sizes and short follow-up.^1,3

Investigators in this current study leveraged data from the ASPirin in Reducing Events in the Elderly (ASPREE) randomized clinical trial and it’s post-trial observational phase, ASPREE-eXTension, to examine the potential association between the change in lipid metrics and the subsequent risk of incident dementia or related cognitive impairment in older adults. The primary end point of the analysis was incident all-cause dementia, with patient diagnosis confirmed by an expert panel blinded to the study protocol.^1,2

A total of 9846 participants were included in the analysis after excluding patients who started or ceased lipid-lowering medications, stopped follow-up before year 3, and those who had missing data. The study investigators measured the cumulative annual absolute change in each lipid metric and determined the change between the first and last measurements. For patients in the highest quartile, the total absolute change in TC, LDL-C, HDL-C, and triglycerides was 2.36, 2.07, 0.81, and 1.46 mmol/L, respectively, while the absolute change between the first and last measurements was 1.02, 0.92, 0.35, and 0.57 mmol/L, respectively, the study authors found.¹

Next, the risk of incident dementia was elucidated. Observations indicated that patients in the higher quartile of TC variability had a higher incidence rate (Q4 vs Q1: 11.3 vs 7.1 cases per 1000 person-years). The risk of dementia in Q2, Q3, and Q4 of TC quartiles was increased by 37%, 44%, and 60%, respectively, compared with the lowest quartile of TC variability. Furthermore, there was a similarly steep increase in dementia risk with higher quartiles of LDL-C variability. In a critical observation, every 1-standard deviation (SD) increase in TC and LDL-C variability was associated with a 13% (P = .002) and 12% (P = .004) increased risk of dementia, respectively.¹

Cognitive change over time was also examined in the context of fluctuating lipid levels. Investigators found that, compared with the lowest quartile, higher quartiles of LDL-C and TC variability were associated with more significant and rapid decline in episodic memory, global cognition, and psychomotor speed, in addition to composite cognition. No associations were found in language and executive function.¹

“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,” Zhen Zhou, PhD, study author at Monash University in Melbourne, Australia, said in the news release. “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.”²

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). doi:10.1212/WNL.0000000000210247

2. American Academy of Neurology. Changing cholesterol over time tied to the risk of dementia. EurekAlert! News Release. Released January 29, 2025. Accessed February 20, 2025. https://www.eurekalert.org/news-releases/1071473

3. Baber U, Halperin JL. Variability in low-density lipoprotein cholesterol and cardiovascular risk: Should consistency be a new target? JACC. 2015;65(15):1549-1551. doi:10.1016/j.jacc.2015.02.048