Ketones and improved cognition in MCI: Links to ApoE and white matter energetics. (31st December 2021)

• Record Type: Journal Article
• Authors: Cunnane, Stephen; Roy, Maggie; Rheault, François; Fortier, Melanie; Descoteaux, Maxime; Castellano, Christian‐Alexandre; St. Pierre, Valerie; Bocti, Christian; Fulop, Tamas
• Is Part Of: Alzheimer's & dementia. Volume 17(2021)Supplement 10
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-12-31
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.055678
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: The capacity of ketones to improve cognition in mild cognitive impairment (MCI) may depend on ApoE4 status. In the BENEFIC RCT (NCT02551419), improvement in three cognitive domains was directly related to ketones from medium chain triglyceride (kMCT) improving global brain energy status. Post‐kMCT, ketone uptake increased 2.9‐fold in total white matter (WM) and was significantly positively correlated to improved processing speed composite score in 8/9 WM fascicles, especially the fornix (r = 0.47‐0.61; p = 0.014‐0.072; n=16‐17/group). Here we report from the same trial the relationship to both ApoE4(‐) and to WM structural properties post‐intervention. Methods: In MCI, cognitive outcomes were assessed before and after a 6‐month intervention involving an active arm (15 g kMCT twice/day; n=39) and placebo arm (non‐ketogenic vegetable oil; n=43), both emulsified into a lactose‐free skim milk drink. Brain imaging ( 18 F‐fluorodeoxyglucose [FDG] and 11 C‐acetoacetate PET, diffusion MRI at 3 Tesla) was done on a subset of the main cohort. Results: Participant demographics and imaging methods were previously reported (Fortier et al. Alz Dementia 2019). In ApoE4(‐) participants, two measures of executive function (verbal fluency [p≤0.016] and Stroop total errors [0.008]) improved more post‐kMCT (n=28) compared to placebo (n=32). Faster completion of the Trail‐making test (motor speed and visual scanning conditions that measure attention and processing speed), was also directly correlated to higher ketone uptake in most of these nine fascicles. Six months on kMCT did not significantly affect WM fascicle structural properties measured by diffusion imaging (apparent fiber density, free water). Diffusion‐tensor imaging metrics and FDG uptake were also unaffected in total WM and in most individual fascicles. Conclusions: In MCI, the beneficial effect of kMCT on executive function was greater in ApoE4(‐). Better processing speed and attention was directly linked to improved WM energetics, specifically higher ketone uptake in fascicles affected in AD, but did not alter WM structural properties measurable by diffusion imaging. Ketones improved outcomes in all five main cognitive domains in MCI so a ketone‐based prevention‐type trial to delay the onset of AD is warranted. Acknowledgements: Supported by the Alzheimer Association, Nestlé Health Science, MITACS, FRQS and USherbrooke.