Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease

Abstract

We propose that brain energy deficit is an important pre-symptomatic feature of Alzheimer’s disease (AD) that requires closer attention in the development of AD therapeutics. Our rationale is fourfold: (i) Glucose uptake is lower in the frontal cortex of people >65 years-old despite cognitive scores that are normal for age. (ii) The regional deficit in brain glucose uptake is present in adults <40 years-old who have genetic or lifestyle risk factors for AD but in whom cognitive decline has not yet started. Examples include young adult carriers of presenilin-1 or apolipoprotein E4, and young adults with mild insulin resistance or with a maternal family history of AD. (iii) Regional brain glucose uptake is impaired in AD and mild cognitive impairment (MCI), but brain uptake of ketones (beta-hydroxybutyrate and acetoacetate), remains the same in AD and MCI as in cognitively healthy age-matched controls. These observations point to a brain fuel deficit which appears to be specific to glucose, precedes cognitive decline associated with AD, and becomes more severe as MCI progresses toward AD. Since glucose is the brain’s main fuel, we suggest that gradual brain glucose exhaustion is contributing significantly to the onset or progression of AD. (iv) Interventions that raise ketone availability to the brain improve cognitive outcomes in both MCI and AD as well as in acute experimental hypoglycemia. Ketones are the brain’s main alternative fuel to glucose and brain ketone uptake is still normal in MCI and in early AD, which would help explain why ketogenic interventions improve some cognitive outcomes in MCI and AD. We suggest that the brain energy deficit needs to be overcome in order to successfully develop more effective therapeutics for AD. At present, oral ketogenic supplements are the most promising means of achieving this goal.

Insulin, glucose and beta-hydroxybutyrate responses to a medium-chain triglyceride-based sports supplement: A pilot study

“…35,36,37 One significant benefit of the PF formulation is that no participant reported any negative GI symptoms, which are the most frequently reported side effects of MCT consumption. 3 This supports the idea that MCTs are better tolerated when delivered as a powder.…”

“…As 25 g of PF contains around 15 g of MCTs, this increase in BHB is about as much as would be predicted. 3 The data also suggest that there is a cut-off level of BHB somewhere between 0.5 mmol/L and 1.0 mmol/L where consuming PF will either increase BHB (due to provision of MCTs as a source of ketones) or decrease BHB (due to the provision of an anapleurotic substrate). However, other factors such as insulin sensitivity and glucose transporter activity will also be involved, as the individual BHB response was not correlated with concurrent changes in glucose or insulin levels.…”

“…3,4,5,6 The 'low-carb' paradigm has also translated to the fuelling of athletes during endurance exercise. Periods of cyclical low-carbohydrate intake during training can improve time trial performance in triathletes, 7 and recent data have shown that 'ketoadapted' athletes have a dramatically increased ability to metabolise fat aerobically at higher percentages of VO2Max intensities.…”

“…13 Supplementing with MCTs results in dose-dependent increases in circulating ketone levels (usually measured as beta-hydroxybutyrate, or BHB), but may cause gastrointestinal (GI) distress in larger doses. 3 There is a current trend in endurance sports to move athletes towards a low-carbohydrate diet or use periods of low carbohydrate consumption to increase both health and performance. As a result, a market is developing for sports supplements to provide nutritional support during training and racing for athletes who follow a low-carbohydrate lifestyle.…”

Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States

“…In addition to insulin resistance, the neuronal glucose transporter GLUT3 is vulnerable to impairment by oxidative stress and HNE (Mark et al, 1997; Mattson, 2009). However, while neuronal glucose metabolism is compromised during aging, the ability of neurons to acquire and utilize the ketone bodies β-hydroxybutyrate (BHB) and acetoacetate is maintained, apparently even in neurons in patients with AD (Cunnane et al, 2016). As described below in Metabolic Factors Can Accelerate or Decelerate Brain Aging, interventions that bolster neuronal bioenergetics have considerable potential to mitigate multiple hallmarks of brain aging and may thereby forestall neurodegenerative disorders.…”