Document Type

Article

Publication Date

12-23-2025

Comments

This article is the author’s final published version in Alzheimer's and Dementia: The Journal of the Alzheimer's Association, Volume 21, Issue S7, 2025, Article number e108851.

 

The published version is available at https://doi.org/10.1002/alz70856-106860. Copyright © 2025 The Alzheimer’s Association.

 

Abstract

 

Abstract

Background

The decline of nicotinamide adenine dinucleotide (NAD+) with aging may elevate risk of Alzheimer’s disease and related neurocognitive disorders (ADRD) by impairing cellular energy metabolism and reducing cerebral blood flow.

Method

We conducted a 12-week double-blind, randomized, placebo-controlled pilot study to evaluate the safety, tolerability, and preliminary efficacy of the NAD+ precursor, nicotinamide riboside (NR; 500 mg b.i.d.), for enhancing cognitive function and cerebral perfusion in older adults with mild cognitive impairment (MCI).

Result

52 participants (33 females, 19 males) were randomized and 42 completed the trial (NR = 22, placebo = 20). Adherence was similar between groups (NR = 85 ± 20% vs. placebo = 91 ± 5%), with no serious adverse effects and comparable side effects. Blood NAD+ increased with NR (pre: 23.36 ± 1.94; post: 48.52 ± 4.12 µM) compared with placebo (pre: 24.12 ± 1.70; post: 25.14 ± 1.58 µM) with a significant treatment by time interaction (p < 0.001). Cognitive function did not significantly improve, however, there was a modest increase in delayed recall memory from the WMS-IV in the NR group (interaction p = 0.062). Perfusion of the left hippocampus increased with NR (pre: 51.7 ± 3.3; post: 58.0 ± 3.8 ml/min/100g) compared with placebo (pre: 55.6 ± 2.8; post: 51.7 ± 2.3 ml/min/100g; interaction p = 0.033); however, this was not associated with the change in memory performance. These outcomes were not strongly influenced by baseline plasma pTau-217.

Conclusion

 

NR is well-tolerated in older adults with MCI and may enhance perfusion of the hippocampus regardless of underlying AD pathology. However, this was not associated with improved memory performance in this short-duration trial. A larger phase-III trial over a longer treatment duration is warranted to determine the efficacy of NR for delaying cognitive impairment due to ADRD.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English

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