Lipid Fluctuations Over Time May Portend Dementia: ASPREE

Substantial changes in annual lipid measurements for older adults could signal an increased risk for dementia and cognitive decline, according to an analysis of the ASPREE trial. The findings suggest the potential of a “novel biomarker,” the authors say.

“Patients with substantial cholesterol fluctuations over years unrelated to medication use may warrant closer monitoring of dementia risk and other health conditions linked to increased dementia risk,” Zhen Zhou, PhD (Monash University, Melbourne, Australia) told TCTMD in an email. Zhou will present the research as an abstract at the upcoming 2024 American Heart Association (AHA) Scientific Sessions.

“Our study offers valuable insights into the potential ability of cholesterol variability in predicting dementia risk in older adults,” she added. “However, future studies are needed to help all of us clearly understand the biological mechanisms behind what we have observed in this study. Until then, older people should continue to adhere to their healthcare provider's recommendations for lipid management.”

In commentary prepared for the media by the AHA, Fernando D. Testai, MD, PhD (University of Illinois Chicago), said the study is aligned with prior evidence showing “time-dependent fluctuation in different parameters, such as blood pressure and glucose levels, for example, are linked to different types of diseases and most of the evidence is in heart disease and stroke. However, the effect of these fluctuations in cognition and dementia has been more recently recognized.”

These findings “add a very nice piece to the puzzle of how we can prevent brain health decline,” he added.

More Variability, More Dementia

For the study, Zhou and colleagues included 9,846 adults (median age 73.9 years; 54.9% female; 96% white) from the ASPREE trial who were relatively healthy at baseline without dementia and underwent annual cholesterol screenings between 2010 and 2014. Over a median follow-up period of almost 6 years after the cholesterol assessments, 509 patients reported incident dementia and 1,760 reported cognitive impairment-no dementia (CIND) events.

Those with the highest versus lowest quartiles of variability for total cholesterol and LDL cholesterol were at an increased risk for dementia (HR 1.60; 95% CI 1.23-2.08 and HR 1.48; 95% CI 1.15-1.91) and CIND events (HR 1.23; 95% CI 1.08-1.41 and HR 1.27; 95% CI 1.11-1.46). Variations in HDL cholesterol and triglycerides were not associated with cognitive decline or dementia.

Fluctuations over time in both total cholesterol and LDL cholesterol also were linked to faster decline in global cognition, episodic memory, psychomotor speed, and the composite score (all P < 0.001).

Zhou said the findings “support our hypothesis that cholesterol variability, rather than absolute levels, may be more useful in predicting dementia risk, given that they may reflect distinct pathophysiological mechanisms underlying dementia development.”

Changes in cholesterol could be an indicator that the body is at a reduced capacity to maintain homeostasis, she suggested. “Cholesterol fluctuation may also contribute to the destabilization of atherosclerotic plaque, of which LDL cholesterol is the main component.”

As such, Zhou called for more studies exploring the mechanisms linking cholesterol variability and dementia risk “to determine whether it serves as a genuine risk factor, a precursor, or merely a biomarker of dementia.”

More work also should be done to standardize the calculation of lipid variability, she said. “The variability metric used in our study requires complex statistical modelling. A simple, unified, and user-friendly method, similar to body mass index, is necessary to facilitate its integration into clinical practice.”