Dietary Neuroketotherapeutics for Alzheimer's Disease: An Evidence Update and the Potential Role for Diet Quality

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disease with growing prevalence as the global population ages. Currently available treatments for AD have minimal efficacy and there are no proven treatments for its prodrome, mild cognitive impairment (MCI). AD etiology is not well understood and various hypotheses of disease pathogenesis are currently under investigation. A consistent hallmark in patients with AD is reduced brain glucose utilization; however, evidence suggests that brain ketone metabolism remains unimpaired, thus, there is a great deal of increased interest in the potential value of ketone-inducing therapies for the treatment of AD (neuroketotherapeutics; NKT). The goal of this review was to discuss dietary NKT approaches and mechanisms by which they exert a possible therapeutic benefit, update the evidence available on NKTs in AD and consider a potential role of diet quality in the clinical use of dietary NKTs. Whether NKTs affect AD symptoms through the restoration of bioenergetics, the direct and indirect modulation of antioxidant and inflammation pathways, or both, preliminary positive evidence suggests that further study of dietary NKTs as a disease-modifying treatment in AD is warranted.

Keywords: Alzheimer’s disease; bioenergetics; cognition; diet quality; fasting; ketogenic diet; medium-chain triglyceride; neuroketotherapeutics; β-hydroxybutyrate.

Figure 1

The major mechanisms to induce ketosis. (1) After glycogen stores are exhausted during prolonged fasting, lower levels of circulating insulin signals lipolysis of endogenous adipose, resulting in a rise in circulating free fatty acids, and ketogenesis. Fatty acids are transported into liver mitochondria for synthesis of the ketone bodies acetoacetate, β-hydroxybutyrate, and acetone to a lesser degree. Ketone bodies are transported out of the mitochondria via monocarboxylate transporters (MCT) 1 and 2, enter circulation, and enter extra-hepatic mitochondria via the same MCT 1 and 2 for ketolysis. Ketone bodies are retroconverted to acetyl CoA, enter the citric acid (TCA) cycle for ATP production, and the resulting NADH and FADH2 facilitate energy production via the electron transport chain (ETC). (2) The KD’s exogenous fat substrate and restricted carbohydrate initiates an action similar to fasting by increasing circulating fatty acids and reduced insulin. During a KD, both exogenous and endogenous fatty acids are destined for ketogenesis. (3) Medium chain triglycerides are gastrointestinally digested to medium chain fatty acids, absorb across the intestinal lumen, and rapidly enter the liver via the portal vein, bypassing the lymphatic system and peripheral circulation. Medium chain fatty acids enter the ketogenesis pathway at the level of acetyl CoA. (4) Exogenous β-hydroxybutyrate esters are cleaved into β-hydroxybutyrate and 1,3 butanediol by local gut esterases. Both products enter the liver via the portal vein, enter mitochondria at the β-hydroxybutyrate or acetoacetate level of ketogenesis, and enter circulation as β-hydroxybutyrate or acetoacetate.