ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change

Abstract

Objective: To examine the association of specific lipoproteins/inflammatory enzyme with cognitive change.

Methods: We examined the association of apolipoprotein B (ApoB), small-dense low-density lipoprotein cholesterol (sdLDL-C), lipoprotein (a) (Lp[a]), and lipoprotein-associated phospholipase A₂ (LpPLA₂) activity with 15-year change in Delayed Word Recall Test, Digit Symbol Substitution Test (DSST), Word Fluency Test (WFT), and overall summary score in 9,350 participants in the Atherosclerosis Risk in Communities study. We assessed interaction by race, sex, education, APOE ε4 status, and statin use. We also addressed questions of informative missingness, the role of stroke, and the influence of fasting status.

Results: The mean (SD) age was 63.4 (5.7) years; 56.4% were women and 17.4% were black. We observed faster cognitive decline on DSST and global z scores with every 10-mg/dL higher sdLDL-C level (Δ DSST z score, -0.010; 95% confidence interval [CI] -0.017, -0.002 and Δ global z score, -0.011; -0.021, -0.001) and the highest vs the lowest ApoB quintiles (Δ DSST z score, -0.092; -0.0164, -0.019 and Δ global z score, -0.101; -0.200, -0.002). Association for the ApoB quintiles with Δ global z score (-0.10) was comparable with that of having 1 APOE ε4 allele (-0.11). Higher Lp(a) was associated with slower decline in DSST, WFT, and global z scores. LpPLA₂ activity was not associated with cognitive change. Results were similar in sensitivity analyses. The associations of sdLDL-C or Lp(a) on cognitive change were more pronounced in statin users.

Conclusions: Optimal control of atherogenic lipoproteins such as ApoB and sdLDL-C in midlife for cardiovascular health may also benefit late-life cognitive health.

Figure 1. Sample development

*Necessary for imputation. **Primary analyses additionally excluded people missing the exposure of interest, resulting in slightly different n by lipid biomarker. Lp(a) = lipoprotein (a); LpPLA2 = lipoprotein-associated phospholipase A2; sdLDL-C = small dense low-density lipoprotein cholesterol.

Figure 2. Effect modification

(A) Effect modification by visit 4 statin use for the association between small dense low-density lipoprotein cholesterol (sdLDL-C) and cognitive decline.Interaction p values are 0.03, 0.05, 0.01, and 0.05 for Digit-Symbol Substitution Test (DSST), Delayed Word Recall Test (DWRT), global, and Word Fluency Test (WFT) z scores, respectively. (B) Effect modification by visit 4 statin use for the association between lipoprotein (a) (Lp[a]) and cognitive decline. Interaction p values are 0.03 and 0.01 for DWRT and global z scores, respectively. (C) Effect modification of Lp(a) and cognitive decline by subsequent development of dementia. Interaction p values are 0.001, <0.001, and 0.051 for global z scores, DSST, and WFT, respectively. CI = confidence interval.