Effects of Exogenous β-Hydroxybutyrate on BDNF Signaling, Cognition, and Amyloid Precursor Protein Processing in Humans with Type 2 Diabetes and Insulin-Resistant Rodents

Academic Background

Patients with type 2 diabetes (T2D) have a significantly increased risk of developing neurodegenerative diseases, such as Alzheimer’s disease (AD), later in life. Studies suggest that exogenous ketone supplements, particularly those containing β-hydroxybutyrate (β-OHB), may protect the brain by supporting cerebral metabolism and promoting the expression of brain-derived neurotrophic factor (BDNF). BDNF is a crucial protein for neuroplasticity, neuronal survival, and cognitive function. Additionally, BDNF is believed to regulate the processing of amyloid precursor protein (APP), thereby influencing the pathological development of AD. However, the specific effects of exogenous ketone supplements on BDNF signaling, cognitive function, and APP processing remain unclear. Therefore, this study aims to investigate the impact of acute and short-term exogenous ketone supplementation on brain health-related indicators through parallel human and rodent trials.

Source of the Paper

This paper was authored by B. J. Baranowski, B. F. Oliveira, K. Falkenhain, and others, representing institutions such as Brock University and University of British Columbia. It was published in American Journal of Physiology-Cell Physiology and first appeared online on January 13, 2025.

Research Procedures and Key Methods

1. Human Trials

a) Acute Ketone Supplementation Trial

• Subjects: 18 participants aged 30–70 with type 2 diabetes, randomly assigned to either the ketone supplementation group or the placebo group.
• Experimental Design: A double-blind, randomized crossover design was used, where participants received either the ketone supplement or placebo on different experimental days.
• Procedure: Participants consumed the ketone supplement or placebo in a fasting state, followed by blood sampling at 0, 60, 120, and 180 minutes to assess plasma BDNF levels and cognitive function.
• Cognitive Function Tests: The Flanker task, Stroop task, and Digit Symbol Substitution Task (DSST) were used to evaluate executive function and information processing speed.
• Cerebral Blood Flow Assessment: Blood flow velocity and vessel diameter of the internal carotid artery, common carotid artery, and vertebral artery were measured using ultrasound.

b) 14-Day Ketone Supplementation Trial

• Subjects: 15 participants with type 2 diabetes, randomly assigned to either the ketone supplementation group or the placebo group.
• Experimental Design: Participants received the ketone supplement or placebo three times daily over 14 days while following a standardized diet.
• Procedure: Blood samples were collected before and after the intervention to assess serum and plasma BDNF levels, and cognitive function tests were conducted.

2. Rodent Trials

a) Acute Ketone Supplementation Trial

• Subjects: 40 male C57BL/6J mice divided into normal diet and high-fat diet groups, with each group further subdivided into ketone supplementation and saline control groups.
• Experimental Design: Mice received a single dose of ketone supplement or saline via gavage, followed by a Novel Object Recognition Test (NORT) 4 hours later, after which brain tissue samples were collected.
• Procedure: BDNF content, BACE1 (β-site amyloid precursor protein cleaving enzyme 1) activity, and APP-processing-related proteins were measured in the prefrontal cortex and hippocampus.

b) Chronic Ketone Supplementation Trial

• Subjects: 40 male C57BL/6J mice divided into normal diet and high-fat diet groups, with each group further subdivided into ketone supplementation and saline control groups.
• Experimental Design: Mice received daily doses of ketone supplement or saline via gavage over 4 weeks, during which body weight and food intake were recorded weekly. A glucose tolerance test and NORT were conducted at the end of the trial.
• Procedure: Prefrontal cortex and hippocampal samples were collected to analyze BDNF signaling pathways and APP-processing-related proteins.

Main Results

1. Human Trials

• BDNF Levels: Neither acute nor 14-day ketone supplementation significantly altered plasma or serum BDNF levels.
• Cognitive Function: Ketone supplementation had no significant effect on cognitive performance in the Flanker task, Stroop task, or DSST.
• Cerebral Blood Flow: Ketone supplementation did not significantly affect blood flow velocity or vessel diameter in the internal carotid artery, common carotid artery, or vertebral artery.

2. Rodent Trials

• BDNF Signaling: Neither acute nor chronic ketone supplementation significantly altered BDNF content or downstream signaling pathways in the prefrontal cortex or hippocampus.
• Cognitive Function: Ketone supplementation had no significant effect on performance in the NORT.
• APP Processing: Acute ketone supplementation reduced BACE1 activity in the prefrontal cortex but increased it in the hippocampus. Chronic ketone supplementation reduced BACE1 activity in the prefrontal cortex of high-fat diet-fed mice.

Conclusions and Implications

This study systematically investigated the effects of exogenous ketone supplementation on BDNF signaling, cognitive function, and APP processing in humans with type 2 diabetes and insulin-resistant rodents for the first time. The results indicate that neither acute nor short-term ketone supplementation significantly increased BDNF levels or improved cognitive function. However, the regulatory effect of ketone supplementation on BACE1 activity suggests its potential as a therapeutic strategy to prevent or delay the pathological progression of Alzheimer’s disease. Future research may require longer interventions or higher doses of ketone supplementation to further validate its clinical application potential.

Research Highlights

• Cross-Species Study: This study provides more comprehensive evidence through parallel human and rodent trials.
• Systematic Evaluation of BDNF Signaling Pathways: For the first time, BDNF content and downstream signaling pathways were comprehensively assessed in both acute and chronic interventions.
• New Findings on BACE1 Activity: This study is the first to discover the regulatory effect of ketone supplementation on BACE1 activity, offering new insights for Alzheimer’s disease treatment.

Other Valuable Information

A limitation of this study is that only specific cognitive domains were assessed; future studies could expand to include more cognitive function tests. Additionally, the study focused solely on male mice, and future research should explore gender differences in responses to ketone supplementation.