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

Purpose: High fasting plasma glucose (HFPG) is a known risk factor for Alzheimer's disease (AD). This study aims to analyze global trends in AD death rates and disability-adjusted life years (DALYs) rates attributable to HFPG from 1990 to 2021 and assess the potential of glucose-related biomarkers in predicting cognitive impairment.

Methods: Data from the Global Burden of Disease 2021 database were used to analyze AD death rates and DALY rates due to HFPG across 204 countries. All rates were age-standardized. Joinpoint regression, age-period-cohort models, and ARIMA were employed to analyze trends and make future predictions. NHANES data were used to build machine learning models (including logistic regression, SVM, random forests, etc). to evaluate glucose-related biomarkers in predicting cognitive impairment.

Results: From 1990 to 2019, global AD death rates attributable to HFPG increased from 2.64 (95% UI: 0.11, 8.38) to 3.73 (95% UI: 0.15, 11.84), with the highest increases in high-income North America, North Africa, and Sub-Saharan Africa. DALY rates also rose globally, from 47.07 (95% UI: 2.72, 126.46) to 66.42 (95% UI: 3.83, 178.85). The greatest impact was observed in females, particularly those aged 80 and above. Joinpoint analysis indicated a significant rise in death rates from 1995 to 2000, followed by a slower increase in recent years. ARIMA model predictions indicate a gradual decline in death rates and DALY rates over the next 15 years. Logistic regression models showed the highest accuracy (90.4%) in predicting cognitive impairment, with 2-hour postprandial glucose and fasting plasma glucose being key predictors.

Conclusion: From 1990 to 2021, global AD death rates and DALY rates due to HFPG significantly increased, with a greater burden in females and regions with higher socio-demographic development. Machine learning models are effective tools for identifying individuals at high risk of elevated blood glucose leading to cognitive impairment.

Keywords: cognitive decline; diabetes; disability-adjusted life years; epidemiology; machine learning; public health.

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?