Effects of Acute Ketone Supplementation on the Brain

Alzheimer's disease and other age-related neurodegenerative conditions are associated with changes in brain energy metabolism that can occur years before symptoms develop. One of the earliest findings in these conditions is reduced utilization of glucose by certain brain regions. Ketones, including beta-hydroxybutyrate, can serve as an alternative fuel source for the brain and may help support brain metabolism when glucose utilization is impaired. Experimental evidence also suggests ketones may influence cerebral blood flow, neurotransmitter balance, and functional brain connectivity.

Despite growing interest in ketone supplementation, the acute effects of ketone esters on multiple aspects of human brain function have not been comprehensively evaluated. This study will investigate whether acute ketone ester ingestion alters cerebral blood flow, brain neurochemistry, resting-state brain connectivity, and cognitive performance in healthy adults.

This is a randomized, double-blind, placebo-controlled crossover study. Participants will complete two intervention periods, receiving a ketone ester supplement during one period and a calorie-matched placebo during the other. The order of interventions will be randomized and separated by a washout period of 3 to 7 days. Participants will consume study beverages for two days prior to each testing session and will undergo detailed testing following an overnight fast.

At each testing visit, participants will provide fingerstick blood samples to measure ketone and glucose concentrations, complete standardized cognitive testing, and undergo advanced magnetic resonance imaging (MRI). Brain imaging will include arterial spin labeling (ASL) to evaluate cerebral blood flow, proton magnetic resonance spectroscopy (1H-MRS) to assess brain metabolite and neurotransmitter concentrations, and functional MRI (fMRI) to assess resting-state brain network connectivity. Cardiac MRI measures will also be collected to explore relationships between cardiovascular and cerebrovascular responses.

The primary goal is to determine whether acute ketone supplementation changes cerebral blood flow, brain metabolite concentrations, and functional brain connectivity compared with placebo. Secondary analyses will evaluate relationships between blood ketone concentrations, imaging measures, and cognitive performance. Results from this pilot study will provide important mechanistic information regarding how ketones affect the healthy aging brain and will support the development of future clinical trials in populations at risk for cognitive impairment.

The study lasts about two weeks. There are two main test days with 3-7 days in between. Each testing session will last up to 3.5 hours at most.

Inclusion criteria

• Age ≥45 years and ≤65 years
• Able to comply with study requirements including presenting for each test session following an overnight fast and not following a ketogenic diet during the duration of the study.
• BMI between 18.5 and 30 kg/m2

Exclusion criteria

• Non-English Speaking
• Currently taking a ketone ester supplement, ketone salt supplement, or on a ketogenic diet
• Pregnancy, a urine pregnancy test will be given to all women before scanning to confirm nonpregnant status
• Currently breastfeeding
• Allergies to components in the test products, including milk protein, and not lactose intolerant
• History of high blood pressure
• History of alcoholism (previous 2 years)
• History of illicit drug use
• History of head trauma involving loss of consciousness or skull fracture
• Diagnosed neurological disease
• Taking psychiatric prescriptive medications (antipsychotics, antidepressants, or barbiturates) or over-the-counter (OTC) medications (other than those taken as nutritional supplements for non-therapeutic indications)
• Current smoker
• Currently consuming a habitual ketogenic diet, or was consuming a habitual ketogenic diet in the past three months
• Any condition or material in the body that is a contraindication for MRI procedures