Metabolic Cofactor Supplementation in Alzheimer's Disease (AD) and Parkinson's Disease (PD) Patients

In this study, investigators aim to activate mitochondria of brain cell-types in AD and PD patients by increasing the hepatic, plasma and brain levels of pivotal metabolic cofactors via simultaneous dietary supplementation of serine, L-carnitine, N-acetylcysteine (NAC) and nicotinamide riboside (NR). The study is based on a three-step strategy to activate the mitochondria in human brain cells: (1) The investigators will use L-carnitine tartrate to enhance the transport of fatty acids across the mitochondrial membrane (by forming a long chain acetylcarnitine ester and being transported by carnitine palmitoyltransferase \[CPT\] I and CPT II) and to stabilize acetyl-CoA and coenzyme A levels. (2) Nicotinamide riboside, precursor of NAD+ will be included to boost the level of hepatic β-oxidation of fatty acids in mitochondria. Decreased electron transport chain function combined with impaired rates of fatty acid β-oxidation leads to the accumulation of incomplete products of β-oxidation, which combined with increased levels of reactive oxygen species (ROS), contribute to insulin resistance. Nicotinamide riboside stimulates the transfer of fatty acids from cytosol to mitochondria, similar to L-carnitine tartrate. (3) Two glutathione precursors, serine and N-acetylcysteine, will be included to increase glutathione levels in the hepatocytes. Increased glutathione levels will also protect against free radical-mediated oxidative stress generated by the increased β-oxidation of fatty acids in mitochondria. Previous studies showed that each agent is able to activate mitochondria separately and a proof-of-concept study using serine supplementation, and a phase I study using this three-step approach resulted in a significant decrease in plasma metabolites associated with mitochondrial dysfunction without significant side effect. The novel design with this study is to give the L-carnitine, NR, serine and NAC as a cocktail. Based on investigators' earlier results, that this will improve the efficacy of the intervention. The study population will consist of 60 Alzheimer's and 60 Parkinson's disease patients. Eligible subjects must have signed an informed consent, meet all inclusion criteria and have none of the exclusion criteria listed below. Patients will be randomized on a 2:1 basis to the cofactor mixture or placebo in two different centres. The subjects will take a mixture of cofactors or matching placebo as powder dissolved in water by mouth. Subjects in active treatment will receive dietary supplementation with N-acetylcysteine, L-carnitine tartrate, nicotinamide riboside, and serine, administered as a mixture. Half dosage of the co-factors will be given for two weeks (one dose taken just after dinner), and full dosage for 8 weeks (two equal doses taken just after breakfast and dinner). Patients who cannot tolerate taking full dose may continue the study with half dose (i.e. one dose taken just after dinner). Patients who cannot tolerate the study agents will be withdrawn from the study. Active treatment duration will be 12 weeks for each subject and the total study duration is estimated as 6 months. Study comprises four clinical visits; (1) a screening visit, (2) randomization visit, (3) treatment visit and (4) end of treatment visit. At visit 1 and visit 4, all procedures including clinical and physical examination, adverse events recording, MRI volumetric and rest-state fMRI, determination of the motor, cognitive and behavioral functions using clinical scales, biochemical, omic and oral/gut microbiota analysis will be done. At visit 2, eligible study subjects will be randomized to active therapy or placebo groups and study agents will be dispensed. At visit 3, clinical and physical examination, determination of the motor, cognitive and behavioural functions using clinical scales, laboratory safety parameters, omic and oral/gut microbiota analysis will be repeated as in Visit 1. After the visit 4, participants will stop taking study agents. A subject will be considered as having completed the study if he/she has completed all assessments at the End of Treatment Visit (Visit 4) and has been followed up until 12 weeks after initiation of the study drugs. Statistics for the primary outcome parameter will be analysed by Mann-Whitney U test or t-test depending on the results of the normality test. For the secondary outcome parameters, one-way repeated measures ANOVA will be performed.