Decreased energy metabolism is an invariant feature of the brains of Alzheimer’s disease (AD) patients, yet
the specific use of pharmacologic strategies to manipulate energy metabolism in the brain remains relatively
untested. We have developed a new approach to treating AD that utilizes fundamental biochemical principles
such as the law of mass action, and additionally exploits redox ratios (in particular NAD+/NADH coupling) that
gate some bioenergetic fluxes. Our overarching hypothesis is that enhancing brain respiration flux, glycolysis
flux, or both will benefit AD patients. We have created new drugs that induce a near-ketogenic state, which we
propose will enhance brain metabolism and reduce amyloid pathology.
The purpose of this exploratory R21 proposal is test our hypothesis that our new “bioenergetic” drug
approach will increase brain energy utilization and reduce amyloid plaque formation in both aged wild-type and
transgenic mice. We recently completed a Phase 1B clinical trial of the bioenergetic compound oxaloacetate
(OAA) in AD patients with mild dementia (NCT02593318), which showed increased default mode network brain
glucose utilization by 18FDG-PET and increased parietal and frontoparietal reduced glutathione on magnetic
resonance spectroscopy (MRS) scans. However, enhancement was only seen at the highest doses of 2g/day.
We have developed new prodrugs that combine OAA with additional bioenergetic molecules that we propose
will enhance ketone bodies and pyruvate levels in the brain, synergistically increasing brain metabolism. Aim 1
will test our hypothesis that prodrugs of OAA and ß-hydroxybutyrate (BHB) or propylene glycol (PG) can increase
available ketone bodies and pyruvate levels, respectively, and affect brain metabolism. Aim 2 will further test this
hypothesis in transgenic mice that have rapid accumulation of amyloid plaques (5xFAD). We will further verify
activity in aged wild-type mice, which more accurately recapitulate the whole body (and thus brain) declines in
mitochondria function and imbalances in ketone bodies and glucose metabolism.
In summary, bioenergetic medicine, i.e. the correction of age-induced mitochondria dysfunction, is a
fundamentally different approach to AD therapy from current clinical approaches. The biological studies we
propose here could show that there is a firm rationale to develop new clinical drugs that take advantage of
multiple bioenergetic mechanisms to reduce brain amyloidosis and age-related brain metabolic decline –
spurring development of bioenergetic pharmaceutical approaches.