Abstract
It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults. Lipids were measured at baseline (1985-1986; age: 18-30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes. There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C <100 mg/dL, 101-129 mg/dL, 130-159 mg/dL, and ≥160 mg/dL, respectively. Standardized differences in all cognitive function test scores ranged from 0.16 SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV. Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.
Highlights
The prevalence of low-density cholesterol (LDL-C) ≥ 3.4 mmol/L declined from 42.9% in 1999–2000 to 29.4% in 2015–2016 among US adults, paralleling observed increases in the use of lipid-lowering medications (Ford & Capewell, 2013; Virani et al, 2020)
As cognitive decline often develops over an extended period of time (Jack et al, 2010) and low-density lipoprotein-cholesterol (LDL-C) levels attained may vary over time, we investigated the association of time-averaged low-density lipoprotein-cholesterol (LDL)-C over 25 years with cognitive function and with brain tissue and perfusion measures in the Coronary Artery Risk Development in Young Adults (CARDIA) study
Participants with higher versus lower time-averaged LDL-C were more likely to have a history of illicit drug use, diabetes, coronary heart disease (CHD), stroke/transient ischemic attack (TIA), higher mean Systolic blood pressure (SBP) and diastolic blood pressure (DBP), and to be taking antihypertensive medication, a statin, and other lipid-lowering medications at the Year 25 exam
Summary
The prevalence of low-density cholesterol (LDL-C) ≥ 3.4 mmol/L declined from 42.9% in 1999–2000 to 29.4% in 2015–2016 among US adults, paralleling observed increases in the use of lipid-lowering medications (Ford & Capewell, 2013; Virani et al, 2020). In the Cholesterol Treatment Trialists’ Collaboration, the risk of a major vascular event was 21% lower per 1 mmol/L reduction in LDL-C with statin use (Cholesterol Treatment Trialists et al, 2012). Findings from animal models suggested that statins altered the composition of brain lipids (Vecka et al, 2004) and there were early reports of adverse events related to memory and cognition in postmarket surveillance (“FDA Drug Safety Communication: important safety label changes to cholesterol-lowering statin drugs,” 2012). With findings from randomized clinical trials showing no difference in cognitive decline for those who received a statin to lower LDL-C compared with those who received a placebo, the current evidence suggests that statin use is not associated with cognition
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