Variability in LDL Cholesterol Linked to Impaired Cognitive Performance in the Elderly

Individuals whose LDL cholesterol levels fluctuate the most from visit to visit tend to have poorer performance on certain cognitive tests, lower cerebral blood flow, and a higher load of brain lesions associated with impaired cognition, an observational analysis shows. The findings are independent of average LDL cholesterol levels.

“To the best of our knowledge, this study is the first to examine the association between lipid variability and cognitive performance and provides further evidence that lipid variability could be of clinical significance,” researchers led by Roelof Smit, MD (Leiden University Medical Center, Leiden, the Netherlands), report in a study published online July 18, 2016, ahead of print in Circulation.

Though “the findings do not have immediate practical value for patient care” because of the study’s observational design, Smit told TCTMD in an email, “they add to the emerging picture that vascular factors are important to brain health and call for further research into the etiology and causality of lipid variability.”

Commenting on the study for TCTMD, Larry Goldstein, MD (University of Kentucky, Lexington), said that more and more data are accruing to suggest that, in addition to absolute levels of certain parameters, like blood pressure, “variability seems to have an additional impact on vascular risk and on cognition.”

What’s unclear is whether variability itself is having an impact or is reflective of other unmeasured factors, he said, pointing out that studies like the current one cannot provide a definitive answer because they are not prospective. The findings are consistent with a mechanism in which changes in lipid levels have adverse effects on the vascular endothelium, predisposing to vascular-related injury, Goldstein said. “So it all sort of fits together, but that doesn’t prove it.”

To prove that hypothesis, he said, a prospective study would be needed to show that choosing treatments that reduce variability—while achieving similar overall lipid levels—improves clinical outcomes.

Relationships Independent of Statin Treatment

Smit said there has been growing interest in the issue of variability because of recent evidence that fluctuations in measures such as blood pressure and heart rate are associated with clinical outcomes. Prior studies have shown that variability in lipid levels is tied to risks of cardiovascular events, progression of diabetic kidney disease, and mortality, Smit noted, adding that relationships with cognitive measures are less clear.

To explore that issue, the investigators looked at data on 4,428 patients participating in the PROSPER trial, a study of pravastatin in high-risk seniors. LDL cholesterol variability was defined based on the intraindividual standard deviation over four postbaseline measurements (at 3, 6, 12, and 24 months).

Cognitive function was measured at month 30. The domains evaluated for the current study were selective attention, information processing speed, and memory (immediate and delayed recall). Neuroimaging outcomes—via MRI—were also available in a subset of 535 patients.

After adjustment for mean LDL cholesterol levels and cardiovascular risk factors, higher visit-to-visit variability in LDL cholesterol levels was tied to poorer cognitive function in both the placebo and pravastatin arms of the trial. Deficits were seen in selective attention, processing speed, and memory, although not all relationships reached statistical significance.

Greater variability was also related to lower cerebral blood flow in both trial arms and with greater white matter hyperintensity load in the pravastatin arm.

There were no significant interactions between variability and pravastatin treatment for any cognitive or neuroimaging outcomes.

“This advocates against increased LDL cholesterol variability purely reflecting the known beneficial and harmful pleiotropic effects of statins or behavioral factors that may undermine response to lipid-lowering treatment, most notably nonadherence,” the authors say.

Mechanisms Unclear

Although the study cannot establish a causal relationship between LDL cholesterol variability and any of the outcomes, it is possible that there is a direct effect, according to the authors.

“Varying levels of LDL cholesterol could theoretically lead to fluctuations in the composition of atherosclerotic plaques, possibly inducing plaque instability and thereby increasing the risk of (sub)clinical cerebrovascular damage,” they write, adding that endothelial dysfunction could also be playing a role.

On the other hand, it is possible that variability is simply a marker of other unmeasured processes that are leading to cognitive dysfunction, they point out.

To date, the evidence in favor of the clinical significance of lipid variability results primarily from research with participants at high risk for vascular disease, which is also true for our study population,” Smit explained. “It is therefore tempting to suggest that our findings reflect either age- or disease-related disturbances to homeostatic mechanisms.

“However, it remains important to note that we cannot conclude what cause, and what effect, is due to our study design,” he continued. “For example, it is equally possible that poor brain health, which may be reflected by lower cognitive function, leads to increased fluctuations of lipid levels.”

Further studies, ideally with longitudinal measures of neuroimaging, are needed to replicate the findings, the authors say.

In addition, “it would be of great interest to examine whether these associations are also present in other (eg, younger, healthier) populations,” Smit said. “Moreover, it would be interesting to explore whether drug-class effects exist, which have been described for visit-to-visit variability of other physiological measures.

The findings could also have implications for the evaluation of the new class of lipid-lowering medications, PCSK9 inhibitors, the authors suggest.

“Although it should be noted that these events are uncommon and that adverse event reporting is not part of a systematic evaluation of neurocognitive function, currently available trial evidence suggests that neurocognitive adverse events may occur more frequently in individuals receiving [PCSK9] inhibitors independently of on-treatment LDL levels,” they write, noting that high-dose monthly regimens of the drugs leads to substantial fluctuations of LDL cholesterol between doses.

“On the basis of our results, this increased variability could possibly contribute to the observed higher rate of neurocognitive events and should be examined by currently ongoing . . . trials,” they say.

However, Smit stressed, “While our findings . . . add to this ongoing discussion, they should be interpreted with caution.



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Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • Smit RAJ, Trompet S, Sabayan B, et al. Higher visit-to-visit low-density lipoprotein cholesterol variability is associated with lower cognitive performance, lower cerebral blood flow, and greater white matter hyperintensity load in older subjects. Circulation. 2016;134:212-221.

  • The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb.
  • Smit reports no relevant conflicts of interest.
  • Goldstein reports serving as a speaker for Pfizer and as a member of the steering committee for the SPARCL trial.