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A Modified Mediterranean Ketogenic Diet mitigates modifiable risk factors of Alzheimer's Disease: a serum and CSF-based metabolic analysis.

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.

SUBMITTER: Schweickart A

PROVIDER: S-EPMC10705656 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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A Modified Mediterranean Ketogenic Diet mitigates modifiable risk factors of Alzheimer's Disease: a serum and CSF-based metabolic analysis.

Schweickart Annalise A Batra Richa R Neth Bryan J BJ Martino Cameron C Shenhav Liat L Zhang Anru R AR Shi Pixu P Karu Naama N Huynh Kevin K Meikle Peter J PJ Schimmel Leyla L Dilmore Amanda Hazel AH Blennow Kaj K Zetterberg Henrik H Blach Colette C Dorrestein Pieter C PC Knight Rob R Craft Suzanne S Kaddurah-Daouk Rima R Krumsiek Jan J

medRxiv : the preprint server for health sciences 20231127

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 Mediterrane ...[more]

PMID: 38076824

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Project description:BackgroundBrain energy metabolism is impaired in Alzheimer's disease (AD), which may be mitigated by a ketogenic diet. We conducted a randomized crossover trial to determine whether a 12-week modified ketogenic diet improved cognition, daily function, or quality of life in a hospital clinic of AD patients.MethodsWe randomly assigned patients with clinically confirmed diagnoses of AD to a modified ketogenic diet or usual diet supplemented with low-fat healthy-eating guidelines and enrolled them in a single-phase, assessor-blinded, two-period crossover trial (two 12-week treatment periods, separated by a 10-week washout period). Primary outcomes were mean within-individual changes in the Addenbrookes Cognitive Examination - III (ACE-III) scale, AD Cooperative Study - Activities of Daily Living (ADCS-ADL) inventory, and Quality of Life in AD (QOL-AD) questionnaire over 12 weeks. Secondary outcomes considered changes in cardiovascular risk factors and adverse effects.ResultsWe randomized 26 patients, of whom 21 (81%) completed the ketogenic diet; only one withdrawal was attributed to the ketogenic diet. While on the ketogenic diet, patients achieved sustained physiological ketosis (12-week mean beta-hydroxybutyrate level: 0.95 ± 0.34 mmol/L). Compared with usual diet, patients on the ketogenic diet increased their mean within-individual ADCS-ADL (+ 3.13 ± 5.01 points, P = 0.0067) and QOL-AD (+ 3.37 ± 6.86 points, P = 0.023) scores; the ACE-III also increased, but not significantly (+ 2.12 ± 8.70 points, P = 0.24). Changes in cardiovascular risk factors were mostly favourable, and adverse effects were mild.ConclusionsThis is the first randomized trial to investigate the impact of a ketogenic diet in patients with uniform diagnoses of AD. High rates of retention, adherence, and safety appear to be achievable in applying a 12-week modified ketogenic diet to AD patients. Compared with a usual diet supplemented with low-fat healthy-eating guidelines, patients on the ketogenic diet improved in daily function and quality of life, two factors of great importance to people living with dementia.Trial registrationThis trial is registered on the Australia New Zealand Clinical Trials Registry, number ACTRN12618001450202 . The trial was registered on August 28, 2018.

Project description:BackgroundKetogenic diets have been used to treat both obesity and neurological disorders, including epilepsy and more recently Alzheimer's disease (AD), likely due to favorable effects on both central and peripheral metabolism. Improvements in body composition have also been reported; however, it is unclear if diet-induced changes in adiposity are related to improvements in AD and related neuropathology.PurposeWe examined the effects of a Modified Mediterranean Ketogenic (MMK) diet vs. an American Heart Association (AHA) diet on body weight, body composition, and body fat distribution and their association with cerebrospinal fluid (CSF) biomarkers in older adults at risk for AD.MethodsTwenty adults (mean age: 64.3 ± 6.3 years, 35% Black, 75% female) were randomly assigned to a crossover trial starting with either the MMK or AHA diet for 6 weeks, followed by a 6-week washout and then the opposite diet for 6 weeks. At baseline and after each diet adiposity was assessed by dual-energy x-ray absorptiometry and CSF biomarkers were measured. Linear mixed effect models were used to examine the effect of diet on adiposity. Spearman correlations were examined to assess associations between adiposity and CSF biomarkers.ResultsAt baseline there was a high prevalence of overweight/obesity and central adiposity, and higher visceral fat and lower peripheral fat were associated with an adverse CSF biomarker profile. The MMK and AHA diets led to similar improvements in body composition and body fat distribution. Significant correlations were found between changes in adiposity and changes in CSF biomarkers (r's = 0.63-0.92, p's < 0.05), with notable differences by diet. Decreases in body fat on the MMK diet were related to changes in Aβ biomarkers, whereas decreases in body fat on the AHA diet were related to changes in tau biomarkers and cholinesterase activity. Interestingly, increases in CSF Aβ on the MMK diet occurred in those with less fat loss.ConclusionAn MMK diet leads to favorable changes in body composition, body fat distribution, and CSF biomarkers. Our data suggest that modest weight loss that maximizes visceral fat loss and preserves peripheral fat, may have the greatest impact on brain health.Clinical trial registration[www.ClinicalTrials.gov], identifier [NCT02984540].

Project description:BackgroundAlzheimer's disease (AD) prevalence is increasing, but its etiology remains elusive. Gut microbes can contribute to AD pathology and may help identifying novel markers and therapies against AD. Herein, we examine how the gut microbiome differs in older adults with mild cognitive impairment compared to cognitively normal counterparts, and whether and how a modified Mediterranean-ketogenic diet (MMKD) alters the gut microbiome signature in association with cerebrospinal fluid (CSF) AD biomarkers.MethodsA randomized, double-blind, cross-over, single-center pilot study of MMKD versus American Heart Association Diet (AHAD) intervention is performed on 17 subjects (age: 64.6 ± 6.4 yr), of which 11 have mild cognitive impairment, while 6 are cognitively normal. Subjects undergo MMKD and AHAD intervention for 6-weeks separated by 6-weeks washout periods. Gut microbiome, fecal short-chain fatty acids (SCFAs), and markers of AD in CSF including amyloid β (Aβ)-40 and Aß-42, total tau, and phosphorylated tau-181 (tau-p181) are measured at before and after diet interventions.FindingsAt baseline, subjects with normal vs. impaired cognition show no notable difference in microbiome diversity but several unique microbial signatures are detected in subjects with mild cognitive impairment. Proteobacteria correlate positively with Aβ-42: Aβ-40 while fecal propionate and butyrate correlates negatively with Aβ-42 in subjects with mild cognitive impairment. Several bacteria are differently affected by the two diets with distinct patterns between cognitively normal and impaired subjects. Notably, the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae and Erysipelotriaceae increases while that of Bifidobacterium and Lachnobacterium reduces on MMKD, while AHAD increases Mollicutes. MMKD slightly reduces fecal lactate and acetate while increasing propionate and butyrate. Conversely, AHAD increases acetate and propionate while reducing butyrate.InterpretationThe data suggest that specific gut microbial signatures may depict the mild cognitive impairment and that the MMKD can modulate the gut microbiome and metabolites in association with improved AD biomarkers in CSF.

Project description:Extracellular vesicles have emerged as a less-invasive nano-tool for discovering biomarkers of Alzheimer's disease and related dementia. Here, we analysed different neuron-enriched extracellular vesicles from plasma to predict response and molecular mechanisms of ketogenic diet's efficacy in mild cognitive impairment participants. The study was a randomized crossover design in which cognitively normal and mild cognitive impairment participants consumed a modified Mediterranean-ketogenic diet or American Heart Association diet for 6 weeks, followed by other diet after washout. L1 cell adhesion molecule, synaptophysin and neural cell adhesion molecule surface markers were used to enrich for neuron-secreted small extracellular vesicles (sEVL1CAM, sEVSYP and sEVNCAM). For the first time, we have presented multiple evidences, including immunogold labelling/transmission electron microscopy, clusters of differentiation 63-ELISA-based assay, confocal microscopy fluorescent images and flow cytometry data confirming the presence of L1 cell adhesion molecule on the surface of sEVL1CAM, validating purity and relative abundance of sEVL1CAM in the plasma. Cargo analysis of sEVL1CAM showed that modified Mediterranean-ketogenic diet intervention reduces amyloid beta 1-42 (50.3%, P = 0.011), p181-tau (34.9%, P = 0.033) and neurofilament light (54.2%, P = 0.020) in mild cognitive impairment participants. Moreover, sEVL1CAMshowed better sensitivity compared with CSF in analysing increased glutamate (6-folds, P < 0.0001) from mild cognitive impairment participants following modified Mediterranean-ketogenic diet intervention. sEVL1CAM characterization also suggested that modified Mediterranean-ketogenic diet differentially targets the expression of various glutamate receptors-glutamate receptor ionotropic NMDA1, glutamate receptor ionotropic NMDA2A, glutamate receptor ionotropic NMDA2B and glutamate receptor ionotropic AMPA type subunit 1. Importantly, these sEVL1CAM measures strongly correlated with corresponding clinical CSF biomarkers (neurogranin, amyloid beta 1-42, neurofilament light and tau). Furthermore, sEVL1CAM were loaded with less advanced glycation endproducts and exhibited anti-inflammatory activity following modified Mediterranean-ketogenic diet intervention. Most importantly, the expression of monocarboxylate transporter 2 on the surface of sEVL1CAM predicted the amyloid beta 1-42 response to modified Mediterranean-ketogenic diet intervention (area under the curve = 0.87, P = 0.0044) and offered a novel screening tool to identify participants responsive to this dietary intervention. Finally, sEVL1CAM, sEVSYP and sEVNCAM showed significantly high concordance in analysing amyloid beta 1-42 (Pearson correlation coefficient ≥ 0.63, P < 0.01) and neurofilament light (Pearson correlation coefficient ≥ 0.49, P < 0.05). Together, small extracellular vesicles in plasma offers promise in assessing the efficacy of dietary/therapeutic intervention against mild cognitive impairment/Alzheimer's disease.

Project description:The ketogenic diet (KD) is an established treatment for patients with medically intractable epilepsy and is chiefly characterized by the production of ketone bodies (KB) such as β-hydroxybutyrate (BHB). However, after more than a century of clinical use, the mechanisms underlying its efficacy remain unclear. While prior investigations have examined the effects of the KD and its metabolic substrates on synaptic transmission, few studies have explored a potential connection between astrocytic ion channels and seizure genesis. One essential function of astrocytes is spatial potassium buffering which influences passive potassium conductance (PPC), and when impaired, can result in neuronal hyperexcitability. In the present study, we demonstrate that the KD can mitigate hippocampal astrogliosis in the Kcna1-null (KO) mouse model of developmental epilepsy. Specifically, we observed a significant increase in GFAP expression in KO mice fed a control diet compared to wild-type (WT) animals, and that the KD prevented this change. Furthermore, we noted a reduction in hippocampal astrocytic PPC in epileptic mice, whereas KD-treated KO animals exhibited nearly normal passive conductance levels. In this regard, we also provide evidence for the role of Kir4.1 channels in mediating astrocytic PPC, and the activation of these inwardly rectifying potassium channels by BHB. To further explore these findings at a molecular level, we conducted bulk RNA-seq analysis which revealed down-regulation of factors linked to hippocampal astrogliosis, notably those involved with neuroinflammation, consistent with earlier reports highlighting the anti-inflammatory effects of the KD and its metabolic substrates such as BHB. Our findings indicate that the KD protects against epilepsy-associated astrogliosis and astrocytic PPC changes, underscoring a novel mechanism of KD action, and the potential functional role of extracellular potassium in neuronal-glial interactions in the epileptic brain.

Dataset Information

A Modified Mediterranean Ketogenic Diet mitigates modifiable risk factors of Alzheimer's Disease: a serum and CSF-based metabolic analysis.

Publications

A Modified Mediterranean Ketogenic Diet mitigates modifiable risk factors of Alzheimer's Disease: a serum and CSF-based metabolic analysis.

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