UC Irvine

The NEAT trial of high-dose oral nicotinamide efficacy to treat Alzheimer’s Disease ended without reaching the primary endpoint of lowering CSF pTau181. However, knowledge of drug levels in the blood or whether the drug reached the CNS were not included in the primary study. In post hoc, blinded analysis of plasma and CSF samples by mass spectroscopy, we measured blood plasma and CSF levels of nicotinamide and its breakdown product 1-methyl-nicotinamide from 23 patients on drug and 24 patients on placebo for 12 months. We found that mean plasma nicotinamide from drug-treated patient’s increased >130-fold while mean methyl-nicotinamide increased >600-fold over pre-treatment and placebo. Plasma nicotinamide reached the CNS at measurable levels in only 29% of the patients (mean increase of 147-fold), and associated with elevated methyl-nicotinamide in the CSF for 45% of the drug treated patients. Importantly, treatment favorably decreased the concentration of r pTau231 by a mean of 33% in patients with elevated CSF levels of nicotinamide in the CNS compared to 3.7% in those without measurable CSF levels. Our findings suggest nicotinamide may be efficacious if it reaches measurable levels in CSF, but that there are CNS bioavailability problems that include methyl inactivation that need to be addressed in future formulations for treating AD.