BACKGROUND: Nicotinamide, a form of B3 vitamin, is an NAD METHODS: In these post hoc, blinded analyses of plasma and CSF samples from the completed two-site placebo controlled randomized trial testing of 1500 mg PO BID oral nicotinamide, we used mass spectroscopy to measure nicotinamide and its inactive metabolite 1-methyl-nicotinamide in plasma at baseline, 6, and 12 months and in CSF at baseline and 12 months from 23 participants on drug and 24 on placebo. RESULTS: Pharmacokinetic analysis found mean 12 month plasma nicotinamide increased >
130-fold to 52 μM while mean methyl-nicotinamide increased >
600-fold to 91 μM in individuals receiving nicotinamide compared to those receiving placebo, whose levels were unchanged from baseline. However, CSF nicotinamide was only measurable in 6 of the 19 available participants (32%) (mean increase of at least 147-fold to 18 μM). These CSF nicotinamide concentrations were 66% of their plasma levels, indicating good CNS bioavailability in only some participants. In contrast to CSF nicotinamide, more treated participants had higher CSF methyl-nicotinamide (n = 9, 43 μM), suggesting high-dosage nicotinamide was sufficient to pass the blood-brain barrier, but 13 of 19 were metabolically inactivated. Treatment favorably decreased mean pTau CONCLUSIONS: Our findings suggest that oral administration markedly increased mean plasma nicotinamide levels, however CSF levels were below quantitation in a majority of participants and there was extensive metabolic inactivation to methyl-nicotinamide. Both the bioavailability and rapid metabolic methylation need to be addressed if nicotinamide is further developed as a potential intervention for AD. TRIAL REGISTRATION: NCT03061474, last updated 2023-10-17. https://clinicaltrials.gov/study/NCT03061474 .