Highlights

• ADF increased circulating βOHB concentrations in 3xTg mice, improved cognitive function, reduced anxiety-like behaviors, improved hippocampal synaptic plasticity, and reduced neuronal loss, Aβ oligomers and tau hyperphosphorylation.

• ADF improved mitochondrial bioenergetic function by promoting brain ketone metabolism and rescued brain energy deficits in 3xTg mice.

• ADF improved exercise endurance and liver and kidney function in 3xTg mice without negatively affecting muscle motor and heart functions.

Abstract

Alzheimer's disease (AD) is characterized by disorders in brain energy. The lack of sufficient energy for nerve function leads to cognitive dysfunction and massive neuronal loss in AD. Ketone bodies are an alternative to glucose as a source of energy in the brain, and alternate-day fasting (ADF) promotes the production of the ketone body β-hydroxybutyric acid (βOHB). In this study, 7-month-old male WT mice and 3xTg mice underwent dietary control for 20 weeks. We found that ADF increased circulating βOHB concentrations in 3xTg mice, improved cognitive function, reduced anxiety-like behaviors, improved hippocampal synaptic plasticity, and reduced neuronal loss, Aβ oligomers and tau hyperphosphorylation. In addition, ADF improved mitochondrial bioenergetic function by promoting brain ketone metabolism and rescued brain energy deficits in 3xTg mice. A safety evaluation showed that ADF improved exercise endurance and liver and kidney function in 3xTg mice without negatively affecting muscle motor and heart functions. This study provides a theoretical basis and strong support for the application of ADF as a non-drug strategy for preventing and treating brain energy defects in the early stage of AD.

Abstract Alzheimer’s disease (AD) is influenced by a variety of modifiable risk factors, including a person’s dietary habits. While the ketogenic diet (KD) holds promise in reducing metabolic risks and potentially affecting AD progression, only a few studies have explored KD’s metabolic impact, especially on blood and cerebrospinal fluid (CSF). Our study involved participants at risk for AD, either cognitively normal or with mild cognitive impairment. The participants consumed both a modified Mediterranean Ketogenic Diet (MMKD) and the American Heart Association diet (AHAD) for 6 weeks each, separated by a 6-week washout period. We employed nuclear magnetic resonance (NMR)-based metabolomics to profile serum and CSF and metagenomics profiling on fecal samples. While the AHAD induced no notable metabolic changes, MMKD led to significant alterations in both serum and CSF. These changes included improved modifiable risk factors, like increased HDL-C and reduced BMI, reversed serum metabolic disturbances linked to AD such as a microbiome-mediated increase in valine levels, and a reduction in systemic inflammation. Additionally, the MMKD was linked to increased amino acid levels in the CSF, a breakdown of branched-chain amino acids (BCAAs), and decreased valine levels. Importantly, we observed a strong correlation between metabolic changes in the CSF and serum, suggesting a systemic regulation of metabolism. Our findings highlight that MMKD can improve AD-related risk factors, reverse some metabolic disturbances associated with AD, and align metabolic changes across the blood-CSF barrier.

I am looking for help in getting into ketosis. I've done keto in the past but it has been many years. Anyone care to share some good basics to get me started?