Short-term docosahexaenoic acid rich diet prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice

Rana Raffoul; Jessica Avila Lopez; Annick Vachon; Benoit Laurent; Mélanie Plourde

doi:10.1016/j.plefa.2026.102730

Short-term docosahexaenoic acid rich diet prevents cognitive deficits in human apolipoprotein E epsilon 4-targeted replacement mice

Prostaglandins Leukot Essent Fatty Acids. 2026 Mar 5:209:102730. doi: 10.1016/j.plefa.2026.102730. Online ahead of print.

Authors

Rana Raffoul¹, Jessica Avila Lopez¹, Annick Vachon², Benoit Laurent¹, Mélanie Plourde³

Affiliations

¹ Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 2500, boulevard de l'Université Sherbrooke, QC J1K 2R1 Canada; Centre de recherche sur le vieillissement, Centre intégré universitaire de santé et service sociaux de l'Estrie, 1036 Belvédère sud, Sherbrooke, QC J1H 4C4 Canada.
² Centre de recherche sur le vieillissement, Centre intégré universitaire de santé et service sociaux de l'Estrie, 1036 Belvédère sud, Sherbrooke, QC J1H 4C4 Canada.
³ Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, 2500, boulevard de l'Université Sherbrooke, QC J1K 2R1 Canada; Centre de recherche sur le vieillissement, Centre intégré universitaire de santé et service sociaux de l'Estrie, 1036 Belvédère sud, Sherbrooke, QC J1H 4C4 Canada. Electronic address: Melanie.Plourde2@USherbrooke.ca.

PMID: 41806661
DOI: 10.1016/j.plefa.2026.102730

Abstract

Background: Metabolism of docosahexaenoic acid (DHA), an omega-3 (Ω3) fatty acid (FA), differs between carriers of the epsilon 4 allele of the apolipoprotein E (APOE4)-the main genetic risk factor for late-onset Alzheimer's disease-and APOE3 carriers. Dietary DHA has been shown to prevent cognitive decline in APOE4 carriers. However, whether DHA must be consumed the whole life is unclear. We hypothesized that a DHA intake started later in life and for a shorter duration prevents cognitive decline in APOE4 mice.

Objective: To investigate three dietary durations of DHA on the prevention of cognitive decline in APOE4 mice.

Methods: Mice knock-in for the human APOE3 (control, n = 84; 34 males/50 females) or APOE4 (n = 84; 39 males/45 females) allele were fed either a DHA-free control diet for 8 months or a diet rich in calcium salt DHA (0.5 g DHA/100 g diet) for 2, 4 or 8 months. Recognition memory was assessed using the novel object recognition test. DHA was quantified using gas chromatography.

Results: APOE4 mice fed the control diet did not recognize the novel object as the APOE3 mice did suggesting cognitive decline in APOE4 mice. However, a DHA-Ca rich diet for 2 and 4 months prevented cognitive deficits in males (2M-P = 0.0414, 4M-P = 0.0073) and females (2M-P < 0.0001). 2-months DHA-Ca rich diet was associated with 18-25% higher cortical relative percentage of DHA in females and males compared to the control diet (Females-P = 0.0031; Males-P = 0.0010).

Conclusion: In APOE4 mice, it is not necessary to consume DHA-calcium salt throughout life to prevent cognitive decline.

Keywords: Apolipoprotein E; Cognitive decline; Diet duration; Docosahexaenoic acid.