Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients

Vidoni, Eric D.; Choi, In‐Young; Lee, Phil; Reed, Gregory A.; Zhang, Na; Pleen, Joseph; Mahnken, Jonathan D.; Clutton, Jonathan; Becker, Annette M.; Sherry, Erica; Bothwell, Rebecca; Anderson, Heidi; Harris, Robert A.; Brooks, William M.; Wilkins, Heather; Mosconi, Lisa; Burns, Jeffrey M.; Swerdlow, Russell H.

doi:10.1002/alz.12156

Cited by 15 publications

(7 citation statements)

References 48 publications

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“…The recent trial of oxaloacetate doses in AD (TOAD) study showed that oxaloacetate is safe and well tolerated in AD patients, and engages brain energy metabolism. 50…”

Section: Therapeutic Interventions For Mitochondrial Dysfunction and ...mentioning

confidence: 99%

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The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis

Ashleigh

Swerdlow

Beal

2022

Alzheimer's & Dementia

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173

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To promote new thinking of the pathogenesis of Alzheimer's disease (AD), we examine the central role of mitochondrial dysfunction in AD. Pathologically, AD is characterized by progressive neuronal loss and biochemical abnormalities including mitochondrial dysfunction. Conventional thinking has dictated that AD is driven by amyloid beta pathology, per the Amyloid Cascade Hypothesis. However, the underlying mechanism of how amyloid beta leads to cognitive decline remains unclear. A model correctly identifying the pathogenesis of AD is critical and needed for the development of effective therapeutics. Mitochondrial dysfunction is closely linked to the core pathological feature of AD: neuronal dysfunction. Targeting mitochondria and associated proteins may hold promise for new strategies for the development of disease-modifying therapies.According to the Mitochondrial Cascade Hypothesis, mitochondrial dysfunction drives the pathogenesis of AD, as baseline mitochondrial function and mitochondrial change rates influence the progression of cognitive decline.

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“…The recent trial of oxaloacetate doses in AD (TOAD) study showed that oxaloacetate is safe and well tolerated in AD patients, and engages brain energy metabolism. 50…”

Section: Therapeutic Interventions For Mitochondrial Dysfunction and ...mentioning

confidence: 99%

“…Oxaloacetate, an intermediate in the Krebs cycle, has also been shown to enhance bioenergetics. The recent trial of oxaloacetate doses in AD (TOAD) study showed that oxaloacetate is safe and well tolerated in AD patients, and engages brain energy metabolism 50 …”

Section: Therapeutic Interventions For Mitochondrial Dysfunction and ...mentioning

confidence: 99%

The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis

Ashleigh

Swerdlow

Beal

2022

Alzheimer's & Dementia

Self Cite

173

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“…The reduced fuel available to the cell can be a direct source of fatigue. Oxaloacetate has been shown to increase glucose uptake in trials with diabetic patients and Alzheimer’s patients [ 38 , 39 ] providing a mechanism to increase the amount of fuel available for cellular functions.…”

Section: Discussionmentioning

confidence: 99%

Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial

Cash

Kaufman

2022

J Transl Med

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Background There is no approved pharmaceutical intervention for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS). Fatigue in these patients can last for decades. Long COVID may continue to ME/CFS, and currently, it is estimated that up to 20 million Americans have significant symptoms after COVID, and the most common symptom is fatigue. Anhydrous Enol-Oxaloacetate, (AEO) a nutritional supplement, has been anecdotally reported to relieve physical and mental fatigue and is dimished in ME/CFS patients. Here, we examine the use of higher dosage AEO as a medical food to relieve pathological fatigue. Methods ME/CFS and Long-COVID patients were enrolled in an open label dose escalating “Proof of Concept” non-randomized controlled clinical trial with 500 mg AEO capsules. Control was provided by a historical ME/CFS fatigue trial and supporting meta-analysis study, which showed average improvement with oral placebo using the Chalder Scale of 5.9% improvement from baseline. At baseline, 73.7% of the ME/CFS patients were women, average age was 47 and length of ME/CFS from diagnosis was 8.9 years. The Long-COVID patients were a random group that responded to social media advertising (Face Book) with symptoms for at least 6 months. ME/CFS patients were given separate doses of 500 mg BID (N = 23), 1,000 mg BID (N = 29) and 1000 mg TID (N = 24) AEO for six weeks. Long COVID patients were given 500 mg AEO BID (N = 22) and 1000 mg AEO (N = 21), again over a six-week period. The main outcome measure was to compare baseline scoring with results at 6 weeks with the Chalder Fatigue Score (Likert Scoring) versus historical placebo. The hypothesis being tested was formulated prior to data collection. Results 76 ME/CFS patients (73.7% women, median age of 47) showed an average reduction in fatigue at 6 weeks as measured by the “Chalder Fatigue Questionnaire” of 22.5% to 27.9% from baseline (P < 0.005) (Likert scoring). Both physical and mental fatigue were significantly improved over baseline and historical placebo. Fatigue amelioration in ME/CFS patients increased in a dose dependent manner from 21.7% for 500 mg BID to 27.6% for 1000 mg Oxaloacetate BID to 33.3% for 1000 mg TID. Long COVID patients’ fatigue was significantly reduced by up to 46.8% in 6-weeks. Conclusions Significant reductions in physical and metal fatigue for ME/CFS and Long-COVID patients were seen after 6 weeks of treatment. As there has been little progress in providing fatigue relief for the millions of ME/CFS and Long COVID patients, anhydrous enol oxaloacetate may bridge this important medical need. Further study of oxaloacetate supplementation for the treatment of ME/CFS and Long COVID is warranted. Trial Registrationhttps://clinicaltrials.gov/ct2/show/NCT04592354 Registered October 19, 2020. Graphical Abstract

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“…The pattern of hypometabolism that is typically detected by 18 FDG‐PET in patients with Alzheimer’s disease (AD) involves the temporo‐parietal association cortex, the precuneus, and the posterior cingulate cortex 5 . 18 FDG‐PET has demonstrated high sensitivity and specificity in identifying patients with AD from healthy elderly individuals and has demonstrated an ability measure target engagement with investigational agents dosed for limited duration in small numbers of AD patients 6 . While few AD clinical trials have included 18 FDG PET as an outcome measure, methodologies have evolved that suggest that it may be reliably embraced as part of multisite trials in the future, with an ability to detect treatment effects with smaller sample sizes 7,8 …”

Section: Detecting Changes In Cellular Metabolismmentioning

confidence: 99%

“…5 18 FDG-PET has demonstrated high sensitivity and specificity in identifying patients with AD from healthy elderly individuals and has demonstrated an ability measure target engagement with investigational agents dosed for limited duration in small numbers of AD patients. 6 While few AD clinical trials have included 18 FDG PET as an outcome measure, methodologies have evolved that suggest that it may be reliably embraced as part of multisite trials in the future, with an ability to detect treatment effects with smaller sample sizes. 7,8 IDENTIFYING PROGRESSION OF MOLECULAR PATHOLOGY Detection of changes in some molecular species either in the intracellular or extracellular milieu can predict progression of neurodegeneration.…”

Section: Detecting Changes In Cellular Metabolismmentioning

confidence: 99%

Neurodegenerative Diseases: The Value of Early Predictive End Points

Hsieh

Alexopoulou

Mehrotra

et al. 2022

Clin Pharma and Therapeutics

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Use of early predictive biomarkers of neurodegenerative disease in phase I clinical trials may improve the translation of novel drug therapies from preclinical development through late-stage studies. This article provides a categorical summary of promising biomarker approaches or clinical end points in molecular, cellular, metabolic, electrophysiological, or clinical function that can be used to predict or quantify the progression of neurodegenerative disorders and guide program support.

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Safety and target engagement profile of two oxaloacetate doses in Alzheimer's patients

Cited by 15 publications

References 48 publications

The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis

The role of mitochondrial dysfunction in Alzheimer's disease pathogenesis

Oxaloacetate Treatment For Mental And Physical Fatigue In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Long-COVID fatigue patients: a non-randomized controlled clinical trial

Neurodegenerative Diseases: The Value of Early Predictive End Points

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