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.

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Publication Details

Journal
International Journal of Molecular Sciences
Published
2026-10-16
DOI
https://doi.org/10.3390/ijms27209197
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Mireia Malcampo, Antoni Riera‐Mestre, Jordi Salas‐Salvadó, Olha Khymenets et al.
International Journal of Molecular Sciences
Dementia and Cognitive Impairment Research
article

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

Mireia Malcampo, Antoni Riera‐Mestre, Jordi Salas‐Salvadó, Olha Khymenets, Juan Timiraos, Dolores Corella, Miguel Ruiz‐Canela, Xavier Pintó, José Lapetra, Rosa Maria Lamuela-Raventós, Enrique Gómez‐Gracia, Aleix Sala‐Vila, José Vicente Sorlí, Miguel Ángel Martínez‐González, Álvaro Hernáez, Emilio Ros, Javier Hernando‐Redondo, Nancy Babió, Lluís Serra‐Majem, Olga Castañer, Albert Puig‐Pijoan, Fitó Montserrat, Ramón Estruch, Miquel Fiol
article en

Abstract

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.

International Journal of Molecular SciencesVol. 27(20)
Harvard University (US), Universitat de València (ES), Hospital Universitario Insular de Gran Canaria (ES), Instituto de Salud Carlos III (ES), Bellvitge University Hospital (ES), Institut d'Investigació Biomédica de Bellvitge (ES), Centro de Investigación en Red en Enfermedades Cardiovasculares (ES), Institut de Recerca Biomèdica Catalunya Sud (ES), Hospital Universitario Araba (ES), Navarre Institute of Health Research (ES), Centro de Investigación Biomédica en Red (ES), Hospital Clínic de Barcelona (ES), Health Research Institute of the Balearic Islands (ES), Institut Universitari d'Investigació en Atenció Primària Jordi Gol (ES), Hospital Del Mar (ES), Municipal Institute for Medical Research (ES), Institut Català de la Salut (ES), Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (ES), Hospital del Mar Research Institute (ES), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), Universitat Ramon Llull (ES), Universitat Rovira i Virgili (ES), Universitat de Barcelona (ES), Universidad de Málaga (ES), Universidad de Navarra (ES)
European Commission, Institució Catalana de Recerca i Estudis Avançats, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III
Good health and well-being
Openalex Percentile: Top 13%
Dementia and Cognitive Impairment Research
DOIOpen Access PDFOpenAlex
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