More than simply leftovers: a new link between remnant cholesterol and dementia
Authors: Nil Saez-Calveras, Makoto Ishii
Journal: The Lancet Healthy Longevity (2024)

Traditional risk factors for cardiovascular disease, including hyperlipidaemia during midlife, are increasingly being recognised as risk factors for later-life dementia.1Wee J Sukudom S Bhat S et al.The relationship between midlife dyslipidemia and lifetime incidence of dementia: a systematic review and meta-analysis of cohort studies.Alzheimers Dement (Amst). 2023; 15: e12395Crossref PubMed Scopus (17) Google Scholar Although higher concentrations of circulating lipids such as total cholesterol, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C) are associated with an increased risk of dementia,1Wee J Sukudom S Bhat S et al.The relationship between midlife dyslipidemia and lifetime incidence of dementia: a systematic review and meta-analysis of cohort studies.Alzheimers Dement (Amst). 2023; 15: e12395Crossref PubMed Scopus (17) Google Scholar,2Ferguson EL Zimmerman SC Jiang C et al.Low- and high-density lipoprotein cholesterol and dementia risk over 17 years of follow-up among members of a large health care plan.Neurology. 2023; 101: e2172-e2184Crossref PubMed Scopus (4) Google Scholar randomised placebo-controlled trials of statin therapy have largely yielded negative results.3Shepherd J Blauw GJ Murphy MB et al.Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.Lancet. 2002; 360: 1623-1630Summary Full Text Full Text PDF PubMed Scopus (3133) Google Scholar,4Heart Protection Study Collaborative GroupMRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.Lancet. 2002; 360: 7-22Summary Full Text Full Text PDF PubMed Scopus (7845) Google Scholar This finding suggests that reducing the concentration of LDL-C, the primary target of statins, might not be sufficient to eliminate the risk of dementia associated with hyperlipidaemia. Cholesterol in triglyceride-rich lipoproteins, known as remnant cholesterol (remnant-C), accounts for approximately a third of the total circulating cholesterol in humans and has been associated with cardiovascular disease risk and outcomes independent of traditional risk factors and LDL-C and apolipoprotein B concentrations.5Navarese EP Vine D Proctor S et al.Independent causal effect of remnant cholesterol on atherosclerotic cardiovascular outcomes: a mendelian randomization study.Arterioscler Thromb Vasc Biol. 2023; 43: e373-e380Crossref PubMed Scopus (17) Google Scholar,6Quispe R Martin SS Michos ED et al.Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study.Eur Heart J. 2021; 42: 4324-4332Crossref PubMed Scopus (161) Google Scholar Despite increasing evidence linking remnant-C to cardiovascular disease, data on the relationship between remnant-C and dementia are scarce. In The Lancet Healthy Longevity, Ji Hye Heo and colleagues7Heo JH Jung HN Roh E et al.Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea.Lancet Healthy Longev. 2024; 5: e524-e533Summary Full Text Full Text PDF Scopus (1) Google Scholar evaluated the association between remnant-C concentrations and the risk of developing dementia using health insurance claims data and health examination outcomes from South Korea's National Health Insurance Service. Exclusion criteria included age younger than 40 years, triglyceride concentrations of 400 mg/dL or higher, and existing dementia at baseline or development of dementia within 1 year of baseline to avoid reverse causation. The final study cohort included 2 621 596 participants (1 316 040 women). Remnant-C concentrations were calculated using data from the baseline lipid profile as the total cholesterol concentration minus the LDL-C concentration minus the HDL-C concentration. During the median follow-up of 10·3 years (IQR 10·1–10·6), 5·6% of individuals developed all-cause dementia, 4·5% developed Alzheimer's disease, and 0·6% developed vascular dementia. When the population was stratified by remnant-C quartiles, higher remnant-C concentrations were incrementally associated with higher risks of developing all-cause dementia, Alzheimer's disease, and vascular dementia after adjusting for age, sex, and additional confounders such as income level, BMI, comorbidities, statin and fibrate use, and total cholesterol concentration. On comparing the highest with the lowest remnant-C quartile, the fully adjusted hazard ratios (HRs) were 1·11 (95% CI 1·09–1·13) for all-cause dementia, 1·11 (1·09–1·13) for Alzheimer's disease, and 1·15 (1·09–1·21) for vascular dementia. Subgroup analyses revealed that the increased risk of dementia for individuals in the higher remnant-C quartiles, compared with the lower quartiles, was greater in individuals aged 40–49 years than in individuals aged 60 years or older, with the risk being the highest in individuals aged 40–49 years (fully adjusted HR 1·52, 95% CI 1·36–1·69). Additionally, the risk of dementia was higher in individuals with type 2 diabetes than in those without type 2 diabetes, and this risk increased with an increase in the type 2 diabetes duration. Based on these observations, Heo and colleagues concluded that higher remnant-C concentrations are independently associated with increased risks of all-cause dementia, Alzheimer's disease, and vascular dementia, with the risks being highest in early midlife. These findings are consistent with those of previous studies that have linked midlife dyslipidaemia to increased risk of later-life dementia.1Wee J Sukudom S Bhat S et al.The relationship between midlife dyslipidemia and lifetime incidence of dementia: a systematic review and meta-analysis of cohort studies.Alzheimers Dement (Amst). 2023; 15: e12395Crossref PubMed Scopus (17) Google Scholar Heo and colleagues also showed that the increased risk of dementia associated with higher remnant-C concentrations was more pronounced in individuals with type 2 diabetes than in those without type 2 diabetes; additionally, the risk was heightened in individuals with a duration of diabetes of at least 5 years, which suggests an important interaction between diabetes and remnant-C that could enhance the risk of dementia. Supporting this possibility, diabetes alters remnant triglyceride-rich lipoprotein metabolism, which can increase circulating concentrations of remnant-C in these triglyceride-rich lipoproteins and mediate atherogenesis and cardiovascular disease independent of LDL-C.8Chait A Ginsberg HN Vaisar T Heinecke JW Goldberg IJ Bornfeldt KE Remnants of the triglyceride-rich lipoproteins, diabetes, and cardiovascular disease.Diabetes. 2020; 69: 508-516Crossref PubMed Scopus (132) Google Scholar A major strength of the study was the use of a large population cohort to examine the association between remnant-C and dementia over a 10-year period. Although the study was overall well designed, a key limitation was the absence of apolipoprotein E (APOE) genotyping in the study population as the APOE genotype can strongly affect lipid metabolism and the risk of dementia.9Dunk MM Li J Liu S et al.Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype.Alzheimers Dement. 2023; 19: 5742-5754Crossref PubMed Scopus (9) Google Scholar Other potential limitations include possible misclassification of dementia owing to the use of diagnostic codes, inability to completely exclude effects from related lipids and lipoproteins, indirectly measuring remnant-C concentrations, and missing potential confounders such as education level. Moreover, further research is needed to replicate and verify findings in other large cohorts, including those from different racial and ethnic groups. Despite these limitations, the study should be lauded as the largest ever to investigate the association between remnant-C and the risk of developing dementia in later life. As this study suggests an association but does not provide evidence for a causal relationship, there is a need for future studies to investigate any mechanistic role that remnant-C concentrations might have in the pathogenesis of later-life dementia and whether factors that have been linked to both lipid metabolism and dementia such as APOE and adipokines, including leptin and adiponectin, contribute to any of the pathological effects of remnant-C.9Dunk MM Li J Liu S et al.Associations of dietary cholesterol and fat, blood lipids, and risk for dementia in older women vary by APOE genotype.Alzheimers Dement. 2023; 19: 5742-5754Crossref PubMed Scopus (9) Google Scholar,10Ishii M Iadecola C Adipocyte-derived factors in age-related dementia and their contribution to vascular and Alzheimer pathology.Biochim Biophys Acta. 2016; 1862: 966-974Crossref PubMed Scopus (39) Google Scholar MI is supported by funding from the National Institutes of Health (R01AG070868). This work was supported by a grant from the National Institutes of Health (R01AG070868). NSC declares no competing interests. Association of remnant cholesterol with risk of dementia: a nationwide population-based cohort study in South Korea