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Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline

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Raúl González-Domínguez, Pol Castellano-Escuder, Sophie Lefèvre-Arbogast, Dorrain Y. Low, Andrea Du Preez, Silvie R. Ruigrok, Hyunah Lee, Catherine Helmer, Mercè Pallàs, Mireia Urpi-Sarda, Alex Sánchez-Pla, Aniko Korosi, Paul J. Lucassen, Ludwig Aigner, Claudine Manach, Sandrine Thuret, Cécilia Samieri, Cristina Andres-Lacueva

Original languageEnglish
Article number1
JournalAlzheimer's Research and Therapy
Issue number1
Early online date3 Jan 2022
E-pub ahead of print3 Jan 2022
PublishedDec 2022

Bibliographical note

Funding Information: This work was accomplished as a part of the D-CogPlast project (“Identification of dietary modulators of cognitive ageing and brain plasticity and proof of concept of efficacy for preventing/reversing cognitive decline”) supported within the European Joint Programming Initiative “A Healthy Diet for a Healthy Life” (JPI HDHL, ), granted by MINECO (Spain, PCIN-2015-229), ANR (France, ANR-15-HDHL-0002-05) and the Medical Research Council UK (UK, MR/N030087/1). This work also received funding from the JPI-HDHL ERA-Net Cofund on INtesTInal MICrobiomics (ERA-HDHL INTIMIC, AC19/00096), CIBERFES funded by Instituto de Salud Carlos III and co-funded by the European Regional Development Fund "A way to make Europe", and the Generalitat de Catalunya’s Agency AGAUR (2017SGR1546). RGD thanks the “Juan de la Cierva” program from MINECO (IJC2019-041867-I) and CAL the ICREA Academia award 2018. Aniko Korosi is supported by NWO and Alzheimer Nederland, Paul Lucassen by the UvA Urban Mental Health program and Alzheimer Nederland, Sophie Lefèvre-Arbogast was part of the University Research school (Ecole Universitaire de Recherche, EUR) Digital Public Health PhD program, supported within the framework of the French National Research Agency (ANR) “Programme d’Investissement d’Avenir” (Investment for the Future) PIA3 (17-EURE-0019). The Three-City Study is conducted under a partnership agreement between the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut de Santé Publique et Développement of the Victor Segalen Bordeaux University and Sanofi-Aventis. The Fondation pour la Recherche Médicale funded the preparation and initiation of the study. The 3C Study is also supported by the Caisse Nationale Maladie des Travailleurs Salariés, Direction Générale de la Santé, Mutuelle Générale de l’Education Nationale, Institut de la Longévité, Regional Governments of Aquitaine and Bourgogne, Fondation de France, Ministry of Research-INSERM Programme “Cohortes et collections de données biologiques”, French National Research Agency COGINUT ANR-06-PNRA-005, the Fondation Plan Alzheimer (FCS 2009–2012), and the Caisse Nationale pour la Solidarité et l’Autonomie (CNSA). Publisher Copyright: © 2021, The Author(s).

King's Authors


Background: Fatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive. Methods: In order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia. Results: When considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-ɛ4 non-carriers and women. Conclusions: Altogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches.

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