Yashashwi Pokharel, Farah Mouhanna, Vijay Nambi, Salim S. Virani, Ron Hoogeveen, Alvaro Alonso, Gerardo Heiss, Josef Coresh, Thomas Mosley, Rebecca F. Gottesman, Christie M. Ballantyne, Melinda C. Power
Neurology May 2019, DOI: 10.1212/WNL.0000000000007574
To examine the association of specific lipoproteins/inflammatory enzyme with cognitive change.
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 e4 status, and statin use. We also addressed questions of informative missingness, the role of stroke, and the influence of fasting status.
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 (D DSST z score, −0.010; 95% confidence interval [CI] −0.017, −0.002 and D global z score, −0.011; −0.021, −0.001) and the highest vs the lowest ApoB quintiles (D DSST z score, −0.092; −0.0164, −0.019 and D global z score, −0.101; −0.200, −0.002). Association for the ApoB quintiles with D global z score (−0.10) was comparable with that of having 1 APOE e4 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.
Optimal control of atherogenic lipoproteins such as ApoB and sdLDL-C in midlife for cardiovascular health may also benefit late-life cognitive health. Evidence of cognitive decline is a requirement for dementia diagnosis,1 and it is well-established that cognitive decline accelerates in the years prior to a dementia diagnosis.2 Thus, this period, where cognitive change is occurring but cognition is not impaired, may represent a potential therapeutic window for interventions.3 Stroke,4 subclinical atherosclerosis,5 and traditional cardiovascular risk factors,6–9 including elevated total cholesterol and low-density lipoprotein cholesterol (LDL-C),6,10–13 are all associated with increased risk for cognitive decline, attesting to the importance of vascular health for late-life cognitive health. However, the mechanisms underlying the link between cardiovascular health and late-life cognition, as well as ideal treatment of vascular risk factors for the preservation of cognition, remain unclear.
Consideration of biomarkers linked to atherosclerosis and cardiovascular health may yield additional insight. Apolipoprotein B (ApoB) reflects total atherogenic lipoprotein particles including and beyond explained by LDL-C.14 Lipoprotein (a) (Lp[a]) has been implicated by Mendelian randomization studies to be in the causal pathway for atherosclerotic cardiovascular disease.15 Small dense LDL-C (sdLDL-C) is a measure of the cholesterol content in small dense low-density lipoproteins that likely have enhanced atherogenic potential.16,17 Lipoprotein-associated phospholipase A2 (LpPLA2) is an enzyme transported by lipoproteins and secreted by inflammatory cells in atherosclerotic plaques.18 These lipoproteins and enzymes may be involved in subclinical and overt brain injury leading to cognitive change through a variety of mechanisms, including enhancing atherosclerosis, thrombosis, inflammation, microvascular dysfunction, and hypoperfusion.14,19–22 However, the existing data on the association between these biomarkers and cognition show conflicting results and are constrained by smaller sample sizes and case-control or cross-sectional designs.23–31 Thus, the purpose of this study was to examine the associations of baseline levels of ApoB, sdLDL-C, Lp(a), and LpPLA2 activity with 15-year change in cognitive function in the Atherosclerosis Risk in Communities (RIC)
ApoB = apolipoprotein B; ARIC = Atherosclerosis Risk in Communities; CI = confidence interval; DSST = Digit-Symbol Substitution Test; DWRT = Delayed Word Recall Test; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); LpPLA2 = lipoprotein-associated phospholipase A2; sdLDL-C = small dense low-density lipoprotein cholesterol; WFT = Word Fluency Test.
Using a biracial, large, prospective cohort study, we showed that higher levels of ApoB as well as sdLDL-C were associated with greater cognitive decline, primarily in executive function, over 15 years. Analysis using quintile and linear terms to assess for nonlinear relationships indicated that the association between ApoB and cognitive change may be limited to those with high ApoB levels, whereas the association with sdLDL-C appears linear. Conversely, higher Lp(a) levels were associated with slower cognitive decline in semantic fluency.