Plasma high-density lipoprotein cholesterol and risk of dementia: observational and genetic studies

Abstract

Aims The association of plasma high-density lipoprotein (HDL) cholesterol with risk of dementia is unclear. We therefore tested the hypothesis that high levels of plasma HDL cholesterol are associated with increased risk of dementia and whether a potential association is of a causal nature. Methods and results In two prospective population-based studies, the Copenhagen General Population Study and the Copenhagen City Heart Study (N = 111,984 individuals), we first tested whether high plasma HDL cholesterol is associated with increased risk of any dementia and its subtypes. These analyses in men and women separately were adjusted multifactorially for other risk factors including apolipoprotein E (APOE) genotype. Second, taking advantage of two-sample Mendelian randomization, we tested whether genetically elevated HDL cholesterol was causally associated with Alzheimer’s disease using publicly available consortia data on 643,836 individuals. Observationally, multifactorially adjusted Cox regression restricted cubic spline models showed that both men and women with extreme high HDL cholesterol concentrations had increased risk of any dementia and of Alzheimer’s disease. Men in the 96th-99th and 100th versus the 41st-60th percentiles of HDL cholesterol had multifactorially including APOE genotype adjusted hazard ratios of 1.66 (95% confidence interval 1.30-2.11) and 2.00 (1.35-2.98) for any dementia and 1.59 (1.16-2.20) and 1.87 (1.11-3.16) for Alzheimer’s disease. Corresponding estimates for women were 0.94 (0.74-1.18) and 1.45 (1.03-2.05) for any dementia and 0.94 (0.70-1.26) and 1.69 (1.13-2.53) for Alzheimer’s disease. Genetically, the two-sample Mendelian randomization odds ratio for Alzheimer’s disease per 1 standard deviation increase in HDL cholesterol was 0.92 (0.74-1.10) in the IGAP2019 consortium and 0.98 (0.95-1.00) in the ADSP/IGAP/PGC-ALZ/UKB consortium. Similar estimates were observed in sex stratified analyses. Conclusion High plasma HDL cholesterol was observationally associated with increased risk of any dementia and Alzheimer’s disease, suggesting that HDL cholesterol can be used as an easily accessible plasma biomarker for individual risk assessment. Translational Perspective The present study identifies very high plasma HDL cholesterol levels as an independent risk factor for any dementia and Alzheimer’s disease in both men and women of the general population. Two-sample Mendelian randomization studies do not support that this association is of a causal nature, indicating HDL cholesterol as a non-causal risk factor for Alzheimer’s disease. Our findings suggest that very high HDL cholesterol can be used as an easily accessible plasma biomarker to evaluate increased risk of dementia and potential identification of high-risk individuals for early targeted prevention – an area highly recommended to direct attention towards.

Blood-Based Biomarkers for Alzheimer’s Disease Diagnosis and Progression: An Overview

“…For example, evidence from a cross-sectional study conducted on 1889 Chinese participants reported an inverse U-shaped association between total cholesterol levels and cognitive score only in the subgroup of patients characterized by normal levels of homocysteine [ 325 ], while Huang et al could reach statistical significance only in late-life obese APOE-ε 4 non-carriers [ 326 ]. Furthermore, similar to the U-shaped relationship observed for total cholesterol, higher plasma HDL levels have been found in AD patients versus controls in two prospective population-based investigations [ 327 ], while very low circulating HDL content was reported to be associated with cognitive decline [ 328 ]. Given the central role of apolipoprotein E in the pathogenesis of AD [ 329 ], biomarkers based on its alteration should be investigated.…”

Pharmacists’ Knowledge of Factors Associated with Dementia: The A-to-Z Dementia Knowledge List

“…Evidence suggests that high total cholesterol levels in mid-life increased the risk of AD in later life [6]. Moreover, high plasma HDL cholesterol has been observationally associated with an increased risk of dementia and AD [8]. However, a study with 19 years of follow-up found that HDL cholesterol levels in mid-life are inversely associated with MCI and dementia in late life [7].…”

“…Regarding midlife, hearing loss appears to be the most influential factor, accounting for 8% of the dementia modifiable risk, followed by traumatic brain injury (3%), hypertension (2%), alcohol (1%) and obesity (1%) [3,4]. Not included among those factors, but probably important as well, may be the presence of hypercholesterolemia [5][6][7][8][9] and the exposure to heavy metals or to certain mycotoxins, produced by molds or cyanobacteria [10,11]. Finally, smoking (5% of the total modifiable dementia risk), depression (4%), social isolation (4%), physical inactivity (2%), air pollution (2%) and diabetes (1%) may contribute to an increased risk of dementia at later life.…”

Assessing the role of vascular risk factors in dementia: Mendelian randomization meta-analysis and comparison with observational estimates

“…There were three primary MR studies each for type 2 diabetes [16][17][18] and LDL cholesterol [19][20][21] ; two studies each for HDL cholesterol 19,22 , total cholesterol 19,23 , triglycerides 19,21 , and systolic blood pressure 20,24 ; and one study each for diastolic blood pressure 25 , BMI 26 and circulating glucose 27 (Figure 1). The MR studies for diastolic blood pressure, BMI, and circulating glucose reported an overall estimate produced through the meta-analysis of two or more outcome cohorts.…”