Variability in LDL cholesterol levels may contribute to cognitive decline

An observational analysis of a randomized trial found that adults who had higher variability in their low-density lipoprotein (LDL) cholesterol had lower cognitive test performances regardless of their mean LDL cholesterol levels.

Lead researcher Roelof A.J. Smit, MD, of Leiden University Medical Center in the Netherlands, and colleagues published their results online in Circulation on July 18.

“Our findings suggest for the first time that it’s not just the average level of your LDL-cholesterol that is related to brain health, but also how much your levels vary from one measurement to another,” Smit said in a news release.

The researchers evaluated 4,428 adults who participated in PROSPER (Prospective Study of Pravastatin in the Elderly at Risk), a trial that randomized patients to receive pravastatin or placebo.

The study enrolled patients who were 70 to 82 years old and had preexisting vascular disease or had a history of hypertension, cigarette smoking or diabetes. The participants were recruited in Scotland, Ireland and the Netherlands and were required to have a total cholesterol of 4.0 to 9.0 mmol/L and triglyceride concentrations less than 6.0 mmol/L.

The researchers measured LDL cholesterol levels measured at baseline and at 3, 6, 12 and 24 months. They also used the following cognitive measures: the Stroop Color and Word Test; the Letter-Digit Coding Test; and the Picture-Word Learning Test. They assessed cognitive measures at 30 months.

They also conducted an MRI substudy of 646 participants from the Netherlands and examined results from imaging performed after a mean follow-up period of 33 months.

Participants in the placebo and pravastatin groups who had higher visit-to-visit LDL cholesterol variability had higher systolic blood pressure variability and higher mean LDL cholesterol levels. They were also more likely to be female and less likely to be Dutch rather than Scottish or Irish.

In both groups, a higher LDL cholesterol variability was associated with lower cognitive function, including selective attention, processing speed and memory. Higher LDL cholesterol variability was also associated with lower cerebral blood flow in both groups, while higher LDL cholesterol variability was associated with greater white matter hyperintensity load in the pravastatin group.

“These results add an important puzzle piece to the emerging evidence that vascular risk factors are closely related to brain health,” Smit said.  “Our study is just the first exciting step. Further studies are needed to examine whether these findings could truly influence clinical practice.”

The researchers mentioned a few potential limitations of the study, including its observational design, which prevents them from making causal relationships. They also only could measure cognitive performance at a few time periods and only used a few neurocognitive tests, which did not include information on visual constructive function or language.

“Our findings underscore the potential of [LDL cholesterol] variability as a useful prognostic marker for different clinical outcomes,” the researchers wrote. “Future replication studies are needed to corroborate these findings and should ideally also use longitudinal assessments of neuroimaging to further elucidate the possible relationship between [LDL cholesterol] variability and cerebral blood flow and white matter hyperintensities.”