Review of Strategies to Overcome Brain Insulin Resistance Through Mild Nutritional Ketosis for Alzheimer’s and Mild Cognitive Impairment

Abstract

Objectives Insulin resistance with abnormal glucose uptake in the brain and inflammation are key pathologies in Alzheimer’s disease (AD), related dementias, and in some people with mild cognitive impairment (MCI). Mild nutritional ketosis could provide therapeutic benefit since ketones are an alternative fuel to glucose through production of adenosine triphosphate via the Kreb’s cycle and have anti-inflammatory effects. Methods Ketone uptake is normal in brain regions affected by abnormal glucose uptake in AD (Castellano, et al. J Alzheim Dis 2015). Ketones are anti-inflammatory and lessen beta amyloid plaques and tau tangles in animal models (Kashiwaya et al. PNAS 2000; Wu et al. FASEB 2020). Strategies to achieve mild nutritional ketosis (blood betahydroxybutyrate levels 0.5–2 mmol/L) include: (1) Intermittent fasting ≥ 10–14 hours. (2) MCT oil ≥ 18 gm/day. (3) Ketogenic diet (KD) (carbohydrates ≤ 50 grams per day and fat ≥ 50% of calories.) (4) Exogenous ketone salts and esters. Results Clinical trials and case studies have reported positive results using medium-chain triglyceride (MCT) oil, coconut oil (source of MCT oil), KD, or ketone ester in people with mild cognitive impairment and AD. KD improves biomarkers of insulin resistance in people with type 2 diabetes (Feinman et al. Nutrition 2015). Two people with mild AD had improved insulin-resistance biomarkers and normalization of MoCA cognitive test after 10 weeks of KD (Stoykovich and Gibas Alzheimers Dement 2019; Morrill and Gibas Diabetes Metab Syndr 2019). A study of 65 people with MCI taking MCT oil 30 gm/day for 6 months vs. placebo documented increased brain energy from ketones and cognitive improvement, without change in lipid profile or serious adverse effects (Fortier et al. Alzheimers Dement 2020). A study of 53 people with mild to moderate AD taking MCT oil 6 gm 3 x daily for 30 days reported improved cognition and lipid metabolomics (Xu et al. Clin Nutr 2020). Conclusions Given the lack any new FDA-approved drug for more than 15 years to treat or improve cognition in people with Alzheimer’s, accumulating evidence suggests that adopting strategies to achieve mild nutritional ketosis could provide a safe and reasonable therapeutic approach to improve symptoms and a strategy for prevention. Funding Sources None.