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

Abstract

Introduction: Brain bioenergetics are defective in Alzheimer's disease (AD). Preclinical studies find oxaloacetate (OAA) enhances bioenergetics, but human safety and target engagement data are lacking.

Methods: We orally administered 500 or 1000 mg OAA, twice daily for 1 month, to AD participants (n = 15 each group) and monitored safety and tolerability. To assess brain metabolism engagement, we performed fluorodeoxyglucose positron emission tomography (FDG PET) and magnetic resonance spectroscopy before and after the intervention. We also assessed pharmacokinetics and cognitive performance.

Results: Both doses were safe and tolerated. Compared to the lower dose, the higher dose benefited FDG PET glucose uptake across multiple brain regions (P < .05), and the higher dose increased parietal and frontoparietal glutathione (P < .05). We did not demonstrate consistent blood level changes and cognitive scores did not improve.

Conclusions: 1000 mg OAA, taken twice daily for 1 month, is safe in AD patients and engages brain energy metabolism.

Keywords: Alzheimer's disease; bioenergetics; metabolism; oxaloacetate; safety.

Conflict of interest statement

CONFLICT OF INTEREST: The authors report no conflicts of interest.

© 2020 the Alzheimer's Association.

Figures

Figure 1.. Dose by timepoint FDG PET SUVR by region of interest.

The box and whiskers plots illustrate pre- and post-treatment SUVR values across 12 regions. The lower dose is shown in red, and the higher dose in blue. P values were determined using a linear mixed-model approach and reflect the significance of the primary effect of interest, the dose by time interaction. They were obtained by likelihood ratio tests of a full linear mixed model of OAA dose and study timepoint. This was tested against a reduced model without the interaction. P values between 0.045 and 0.049 are designated as

Figure 2.. Brain GSH.

(A) GSH MRSI slice placement (left), GSH maps (middle), and representative MR spectra of GSH and simultaneously measured creatine and choline signals (right). (B) Frontal region percent changes between pre- and post-treatment GSH levels. (C) Parietal region percent changes between pre- and post-treatment GSH levels. (D) Frontoparietal (F-P) region percent changes between pre- and post-treatment GSH levels. (E) Mean regional GSH levels pre and post the 1 g/day dose. Levels mostly decreased over the 1-month treatment period. (F) Mean regional GSH levels pre and post the 2 g/day dose. Levels mostly increased over the 1-month treatment period. Error bars in B-D are SEM.