Fluctuating Cholesterol Tied to Dementia, Cognitive Decline

Wide fluctuations in cholesterol levels over time were associated with significantly higher odds of developing dementia and cognitive decline in older adults compared with stable levels, new findings suggested.

After more than 5 years of follow-up, people with the largest variation in total cholesterol were 60% more likely to develop dementia and 23% more likely to develop cognitive decline than those with the least variability, investigators found.

An analysis by cholesterol type revealed a link between shifting levels of low-density lipoprotein (LDL) cholesterol and a higher risk for dementia and cognitive decline, while variations in triglycerides were associated only with an elevated risk for cognitive decline. Fluctuations in high-density lipoprotein (HDL) cholesterol were not associated with risk.

The yearly fluctuations were also significantly associated with faster cognitive decline, specifically global cognition, episodic memory, and psychomotor speed.

“Our data suggest that older adults with large cholesterol fluctuation unrelated to medication use may warrant closer monitoring of their dementia risk,” lead investigator Zhen Zhou, PhD, of Monash University in Melbourne, Australia, told Medscape Medical News.

The findings were published online on January 29 in Neurology.

Measuring Risk for Dementia

Research on the link between lipid changes later in life and dementia and cognitive decline is scarce. The few studies that exist are limited by short follow-up, younger study populations, or an absence of cognitive testing, investigators noted.

In addition, studying year-to-year fluctuations in cholesterol is a better way of identifying people at risk for dementia than measuring cholesterol levels at a single point in time, Zhou said.

To further investigate the topic, investigators used data from the ASPREE trial and a posttrial observational analysis, ASPREE XT.

ASPREE was a double-blind, randomized, placebo-controlled trial of low-dose aspirin in individuals aged 70 years or older who were free of dementia and cognitive problems at baseline. ASPREE-XT is the ongoing posttrial observational phase that is following ASPREE participants for an additional 5 years. For the current analyses, investigators used data from both studies, following some participants for up to 11 years.

The study’s main outcome was a diagnosis of all-cause dementia, which was made by an expert panel. Other outcomes were cognitive impairment with no dementia and changes in domain-specific cognition. Cognitive impairment was defined as a > 1.5 individual decline in the cognitive score of any domain in the absence of a dementia diagnosis.

Investigators measured levels of total cholesterol, LDL, HDL, and triglycerides at baseline and during each annual visit for the first 3 years of the study. A battery of cognitive tests was administered at baseline and years 1, 3, and 5, followed by a final visit and four subsequent ASPREE-XT visits.

Researchers collected information on participants’ medication use and potential confounders, such as body mass index, a history of family dementia, and apolipoprotein (APOE) ε4 carrier status.

Variability Tied to Dementia Risk

The study included 9846 individuals with an average age of 74 (55% women). Almost all (87%) were from Australia. During the study, 509 people developed incident dementia during a median follow-up of 5.8 years.

Participants were divided into four quartiles on the basis of the amount of variability between their first and fourth yearly cholesterol measurements. The difference between the measurements was 91 mg/dL on average in the group with the highest amount of change in total cholesterol and 22 mg/dL in the group with the lowest amount of change.

Dementia rates were 11.3 per 1000 person-years among those with the highest amount of fluctuation in total cholesterol vs 7.1 per 1000 person-years in those with the lowest variability.

After more than 5 years of follow-up, participants with the highest amount of variation in total cholesterol were 60% more likely to develop dementia (adjusted hazard ratio [aHR], 1.60; 95% CI, 1.23-2.08).

Dementia risk was 48% higher in those with the highest fluctuations in LDL than in those with the lowest variability (aHR, 1.48; 95% CI, 1.15-1.91).

Every 1-SD increase in total cholesterol and LDL variability was associated with a 13% and 12% increased risk for dementia, respectively (P = .002 and P = .004).

Additionally, a stronger association between total cholesterol variability and incident dementia was observed in APOE-ε4 carriers and those with a family history of dementia.

Risk for Cognitive Impairment

Cognitive impairment was 23% more likely in the group with the highest fluctuations in total cholesterol (aHR, 1.23; 95% CI, 1.08-1.41) and 27% more likely in those with the highest levels of LDL (aHR, 1.27; 95% CI, 1.11-1.46) than in the groups with the lowest levels of variability.

Triglycerides were linked to risk for cognitive impairment but not dementia. Individuals with the greatest fluctuations in triglyceride levels were 19% more likely to develop cognitive impairment (aHR, 1.19; 95% CI, 1.04-1.36) than those with the lowest variability.

Investigators also found that each 1-SD increase in the variability of total cholesterol, LDL, and triglycerides was associated with a respective 7%, 7%, and 8% higher risk for decline in cognitive scores.

Compared with the lowest quartile, the highest quartiles of total cholesterol and LDL variability were associated with a faster decline in global cognition, episodic memory, psychomotor speed, and composite cognition (P 

Those with the greatest shifts in total cholesterol and LDL had an increased risk for a decline in global cognition, episodic memory, and psychomotor speed as well as the composite cognition compared with those with the lowest levels of variation (P 

No associations were found between the outcomes studied and possible variations that may have been induced by lipid-lowering medications.

The findings may warrant closer monitoring of patients’ dementia risk, but since the study was observational in nature, “we are unclear whether reducing the fluctuations is beneficial for preventing dementia risk, and this warrants future research to investigate,” Zhou said.

While investigators could only speculate about the mechanisms underlying the association, Zhou posited that “variation in cholesterol levels may serve as an epiphenomenon of the body’s inability to maintain homeostasis with advancing age and increasing burden of morbidities, and hence, a higher risk of dementia.”

It is also possible that fluctuations in cholesterol levels can damage brain vasculature by destabilizing atherosclerotic plaques and increasing the likelihood of growth and rupture, she added.

Study limitations included the possibility that lipid variation was due to nonadherence to lipid-lowering medication or change in dosage, even though the study design excluded participants who initiated or discontinued statins during the study. The authors also noted clinical trials such as ASPREE are likely to enroll healthier participants than the general population.

Interpret With Caution

In an accompanying editorial, Erin Ferguson, University of California, San Francisco, and coauthors wrote that the findings “suggest an intriguing new dimension to the role of cholesterol and LDL in the development of dementia,” adding that “determining the causality of these relationships is the largest opportunity for future research.”

It is possible that early changes in neuropathology may cause the observed fluctuations in cholesterol, she wrote, and this could be investigated by further investigating genetic variants for dementia. In addition, more research is needed to identify possible genetic determinants of lipid variability.

Commenting on Medscape Medical News, Ozama Ismail, PhD, director of scientific programs at the Alzheimer’s Association, said while the findings are preliminary, “early detection is crucial for Alzheimer’s disease and related dementias to ensure individuals have more access to treatment options and time to plan their immediate and long-term future.”

Ismail emphasized the need for follow-up studies examining the relationship between chronic diseases and changes in cholesterol levels “in large-scale, diverse, representative study populations” to broaden understanding about why cholesterol changes may heighten dementia risk.”

He also noted that the findings should be interpreted with caution, as variability in lipid-lowering medication doses could have influenced the findings.

The study was funded by the National Heart Foundation of Australia. Zhou reported being supported by a 2022 postdoctoral fellowship from the National Heart Foundation of Australia. Ferguson reported no disclosures.