{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:00:04Z","timestamp":1785402004890,"version":"3.56.0"},"reference-count":85,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T00:00:00Z","timestamp":1754438400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Bourse de recrutement and Bourse d\u2019exemption from the Universit\u00e9 de Montr\u00e9al"},{"DOI":"10.13039\/501100021783","name":"Fondation Courtois","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100021783","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Tier 1 Canada Research Chair in Brain Aging and Repair"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Lifestyle-based interventions, including dietary modifications, can reduce dementia risk. In this regard, dietary supplementation with medium-chain triglycerides (MCT) has shown potential therapeutic benefits in individuals with Alzheimer\u2019s disease. These effects are widely presumed to be mediated by hepatic conversion of MCT into circulating ketones. However, the physiological and cellular mechanisms underlying the benefits of MCT remain understudied, particularly in the context of Alzheimer\u2019s disease.<\/jats:p>\n                  <jats:p>Here, we investigated the cellular and molecular changes occurring in the brain and systemically in response to dietary supplementation with MCT versus a ketogenic diet. The experimental design consisted of comparing a 70% carbohydrate control diet to either a control diet supplemented with 10% MCT or a carbohydrate-free high-fat ketogenic diet. Diets were tested in two Alzheimer\u2019s disease mouse models, slow-progressing 3xTg-AD mice that model pre-symptomatic\/early stages and rapidly progressing 5xFAD mice that model late stages of the disease.<\/jats:p>\n                  <jats:p>We found that MCT supplementation and a ketogenic diet both improved hippocampal-dependent spatial learning and memory, increased dendritic spine density of hippocampal neurons and modulated hippocampal expression of genes associated with mitochondrial functions, synaptic structure and insulin signalling in Alzheimer\u2019s disease mouse models. However, unlike the ketogenic diet, MCT supplementation did not elevate circulating ketones, suggesting different mechanisms. Indeed, MCT supplementation enhanced the peripheral insulin response of Alzheimer\u2019s disease mice, while the ketogenic diet conversely unveiled their latent metabolic vulnerability, increasing their hyperglycaemia, body weight gain and adiposity. The systemic metabolic disturbances of Alzheimer\u2019s disease mice correlated with transcriptomic alterations in hepatic lipid metabolism and ketogenesis genes and increased lipid droplet accumulation. These liver metabolic abnormalities were partially reversed by both MCT supplementation and the ketogenic diet, but in distinct ways. Notably, the ketogenic diet selectively triggered hepatic neutral lipid depletion and prominent proinflammatory gene expression, while MCT downregulated expression of cholesterol-related genes.<\/jats:p>\n                  <jats:p>Collectively, these findings reveal that MCT supplementation in the context of Alzheimer\u2019s disease improves cognition and systemic metabolism without elevating circulating ketone levels.<\/jats:p>","DOI":"10.1093\/brain\/awaf267","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T11:36:55Z","timestamp":1754393815000},"page":"105-122","source":"Crossref","is-referenced-by-count":6,"title":["Medium-chain triglycerides improve cognition and systemic metabolism in mouse models of Alzheimer\u2019s disease"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0013-5241","authenticated-orcid":false,"given":"Paule E H","family":"M\u2019Bra","sequence":"first","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]},{"name":"Department of Neurosciences, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montreal, QC, H3C 3J7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7520-8306","authenticated-orcid":false,"given":"Laura K","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00ebl","family":"Moquin-Beaudry","sequence":"additional","affiliation":[{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenicka L","family":"Mangahas","sequence":"additional","affiliation":[{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Pratesi","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Castonguay","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Mailloux","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montreal, QC, H3C 3J7 ,","place":["Canada"]},{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Galoppin","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montreal, QC, H3C 3J7 ,","place":["Canada"]},{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Avila Lopez","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan","family":"Bernier","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Turri","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Mayhue","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Aumont","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7124-5919","authenticated-orcid":false,"given":"Martine","family":"Tetreault","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montreal, QC, H3C 3J7 ,","place":["Canada"]},{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4003-9762","authenticated-orcid":false,"given":"Stephen C","family":"Cunnane","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6236-8770","authenticated-orcid":false,"given":"Karl J L","family":"Fernandes","sequence":"additional","affiliation":[{"name":"Research Center on Aging, CIUSSS de l\u2019Estrie-CHUS , Sherbrooke, QC, J1H 2J7 ,","place":["Canada"]},{"name":"Department of Medicine, Faculty of Medicine and Health Sciences, Universit\u00e9 de Sherbrooke , Sherbrooke, QC, J1H 5H3 ,","place":["Canada"]},{"name":"Department of Neurosciences, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al , Montreal, QC, H3C 3J7 ,","place":["Canada"]},{"name":"Research Center of the University of Montreal Hospital (CRCHUM), Universit\u00e9 de Montr\u00e9al , Montreal, QC, H2X 0A9 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"2026010812414258500_awaf267-B1","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1016\/S0140-6736(20)32205-4","article-title":"Alzheimer\u2019s 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