HDL Functionality, Cholesterol-Related Biomarkers and Incidence of Dementia: A Case–Cohort Study in Older Adults at High Cardiovascular Risk
Year: 2026
Type: article
Study design: Observational Study
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.
DOI: 10.3390/ijms27209197
Authors: Mireia Malcampo, Álvaro Hernáez, Javier Hernando-Redondo, Emilio Ros, Dolores Corella, Miguel Ángel Martínez-González, Jordi Salas-Salvadó, Ramon Estruch, Juan Timiraos, Enrique Gómez-Gracia, Miquel Fiol, José Lapetra, Lluis Serra-Majem, Antoni Riera-Mestre, Xavier Pintó, Albert Puig-Pijoan, Miguel Ruiz-Canela, José V. Sorlí, Nancy Babio, Rosa Maria Lamuela-Raventós, Olha Khymenets, Aleix Sala-Vila, Olga Castañer, Montserrat Fitó
Institutions: Municipal Institute for Medical Research, Hospital del Mar Research Institute, Instituto de Salud Carlos III, Centro de Investigación en Red en Enfermedades Cardiovasculares, Centro de Investigación Biomédica en Red, Universitat Ramon Llull, Consorci Institut D'Investigacions Biomediques August Pi I Sunyer, Universitat de València, Harvard University, Navarre Institute of Health Research, Universidad de Navarra, Institut de Recerca Biomèdica Catalunya Sud, Universitat Rovira i Virgili, Hospital Clínic de Barcelona, Hospital Universitario Araba, Universidad de Málaga, Health Research Institute of the Balearic Islands, Hospital Universitario Insular de Gran Canaria, Bellvitge University Hospital, Institut d'Investigació Biomédica de Bellvitge, Universitat de Barcelona, Hospital Del Mar, Institut Universitari d'Investigació en Atenció Primària Jordi Gol, Institut Català de la Salut, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7222675964