This study evaluated how well nicotinamide (NAM) reaches the brain and its effect on phosphorylated tau (pTau231), a key protein linked to Alzheimer’s disease (AD).

Key Points: 

• Some participants had no NAM increase after supplementation

• An AD biomarker decreased in participants with increased NAM levels

• Individual differences in metabolism influenced responses to NAM supplementation

NAM Supplementation Evaluated in Alzheimer’s Disease Patients

Researchers examined how NAM is processed in the body and brain by analyzing samples from a previous clinical trial - the Nicotinamide as an Early AD Treatment (NEAT) study. 

They measured how much NAM reached the blood and spinal fluid, how much was broken down into an inactive form, and whether changes in these levels were linked to changes in a key Alzheimer’s disease marker called pTau231.

Participants:

• 23 received nicotinamide (1500 mg taken orally twice a day)

• 24 received placebo

Samples analyzed: 

• Plasma: Collected at baseline, 6 months, and 12 months

• Cerebrospinal fluid: Collected at baseline and 12 months

39% of Participants were “Non-Responders”

After a year of NAM treatment, just over half (61%) of the participants showed elevated levels of NAM in their plasma.

However, the remaining 39% of participants did not have this increase.

"The reason for treatment resulting in unelevated plasma levels for these 9 participants of 23 (39%) is that the drug was entirely methylated or entirely adsorbed into tissue."

Similar results were seen in the cerebrospinal fluid, which was measured to assess brain penetration. 

"CSF [cerebrospinal fluid] nicotinamide was only measurable in 6 of the 19 available participants (32%)”

Biomarker for Alzheimer's Disease Reduced in “Responders” 

Participants who showed that NAM had reached their brains (indicated by increased NAM in their cerebrospinal fluid) also had reduced levels of pTau231, a protein associated with Alzheimer's disease.

This was not observed in the “Non-Responders.”

“Treatment favorably decreased mean pTau231 levels by 34% in those six participants with elevated CSF levels of nicotinamide, compared to 3% elevation in participants who did not have elevated CSF nicotinamide, and a 3% decrease for placebo.”

Metabolic Differences Between Responders and Non-Responders

One likely explanation for why some participants didn’t show elevated NAM levels is increased activity of an enzyme called nicotinamide N-methyltransferase (NNMT), which deactivates NAM by converting it into methylated byproducts.

A similar finding was seen in another study. Participants who didn't experience an increase in NAD+ after taking NMN supplements ("Non-Responders") were found to have higher amounts of enzymes that break down NAD+.

Conclusion

The study suggests that although high oral doses of NAM can significantly raise plasma levels, its potential as a treatment for Alzheimer’s disease may be limited by poor brain penetration and rapid metabolism.

"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."

One explanation for the lack of elevated plasma NAM in some participants is that it may have been rapidly methylated or absorbed into tissues.

"Both the bioavailability and rapid metabolic methylation need to be addressed if nicotinamide is further developed as a potential intervention for AD."

The authors propose potential strategies to overcome these limitations, such as:

• Identifying individuals with lower plasma NNMT activity who might be more likely to respond to NAM treatment

• Co-administering NAM with inhibitors of NNMT to reduce its metabolism and increase availability in the brain.

"Inhibiting methylation may improve the bioavailability of nicotinamide. At present, these problems remain unsolved and limit its use in AD."

Importantly, in a subset of participants who did reach elevated brain NAM levels (“Responders”), there was a 34% reduction in pTau231, a biomarker associated with Alzheimer’s pathology - suggesting a potential therapeutic effect if sufficient brain levels can be achieved.

"Treatment favorably decreased mean pTau231 levels by 34% in those six participants with elevated CSF levels of nicotinamide..."