HDL Functionality, Cholesterol-Related Biomarkers and Incidence of Dementia: A Case–Cohort Study in Older Adults at High Cardiovascular Risk

Associations of lipid profiles, including qualitative and functional high-density lipoprotein (HDL) traits, and cholesterol-related biomarkers with incident dementia and Alzheimer’s disease (AD), remain unclear. In this regard, older adults at high cardiovascular risk are at particularly high risk of developing dementia. The aim is to evaluate whether these biomarkers are associated with the incidence of dementia and AD in older adults at high cardiovascular (CV) risk. In a case–cohort study, we selected 106 incident dementia cases (82 AD) and a random subcohort of 201 non-cases. We quantified (baseline and at one-year), lipid profile; HDL-mediate cholesterol efflux capacity in a model of human neurons; HDL-mediated anti-inflammatory protection in a model of brain endothelial cells; 24S-hydroxycholesterol and apolipoprotein E. Multivariable-adjusted Cox models were addressed. HDL cholesterol was inversely associated, whereas triglycerides directly associated, with dementia and AD incidence. Higher HDL-mediated cholesterol efflux was inversely associated with dementia (HR 0.64, 95% confidence interval (CI) 0.45–0.91) and AD (HR 0.52, 0.35–0.76). Greater HDL-mediated endothelial protection was associated with lower dementia and AD incidence (HR 0.68, 95% CI 0.47 to 0.99 and HR 0.61, 95% CI 0.41 to 0.91, respectively). A one-year increase in 24S-hydroxycholesterol was associated with a higher incidence of any dementia (HR 2.38, 1.33–4.27) and AD (HR 2.24, 1.11–4.53). Enhanced HDL functional properties ex vivo, in preclinical models using human brain cells, together with lower levels of 24S-hydroxycholesterol, are inversely associated with the incidence of dementia and AD, highlighting these factors as promising prognostic targets in older adults at high CV risk.