Rethinking Neurodegeneration: The Case for NAD+

For over a century, neurodegenerative diseases like Alzheimer’s and Parkinson’s disease have been considered protein disorders, characterised by the accumulation of amyloid-beta plaques, tau tangles, and Lewy bodies. Research and drug development followed the same logic: target the proteins, slow the disease. The results, after decades of trials and considerable investment, have been largely disappointing.

A growing body of research now suggests this framing may be incomplete. Neurodegeneration is increasingly being proposed to have a significant metabolic component, linked to declining levels of a molecule called Nicotinamide Adenine Dinucleotide (NAD+). Interestingly, individuals with significant amyloid and tau accumulation showing no signs of cognitive impairment appear to have relatively preserved NAD+ metabolism in the brain. 

This raises an interesting question: could restoring NAD+ offer a new therapeutic avenue for diseases that have, so far, been deemed incurable?

What Does NAD+ Actually Do?

NAD+ is present in each of our cells, participating in over 500 different enzymatic reactions. It exists in two forms: oxidised NAD+, which accepts electrons to drive the production of ATP (the cell’s primary energy currency), and reduced NADH, which is recycled to keep that cycle going. Beyond energy metabolism, NAD+ is consumed by enzymes involved in cellular stress responses and gene regulation, DNA repair, and calcium signalling in immune and neural cells. Each of these processes plays an important role, but together they create a high demand for NAD+. When supply falls, these systems compete for what NAD+ remains, and cellular homeostasis suffers. 

NAD+ levels decline with age across most tissues, including the brain. A 2024 study demonstrated that as NAD+ levels decline, mitochondria initially act as a buffer by compensating for the depletion. However, when mitochondrial NAD+ itself begins to fall, the entire system loses its safety net and begins to fail.

Why Neurons Are Particularly Vulnerable

Neurons are post-mitotic, meaning that they cannot undergo mitosis or regenerate, and any damage must be repaired rather than replaced. They also have extremely long axons (the projections that carry signals between neurons), which carry a significant energy cost and require a continuous local supply of NAD+ to function.

"Individuals with significant amyloid and tau accumulation showing no signs of cognitive impairment appear to have relatively preserved NAD+ metabolism in the brain."

When NAD+ falls short, the downstream consequences are wide-ranging: mitochondrial dysfunction, unrepaired DNA damage, chronic inflammation, and the structural breakdown of axons. Research published in 2025 confirmed that in human CNS neurons, loss of the NAD+ synthesis enzyme NMNAT2 occurs within two hours of injury, with NAD+ depletion following within four to six hours, preceding and driving neuronal degeneration.

Compounding this, an enzyme called SARM1 becomes activated when NAD+ levels drop and its precursor NMN accumulates. Once triggered, SARM1 rapidly consumes whatever NAD+ remains, creating a self-reinforcing cycle of depletion and damage. Loss of SARM1 function is protective across multiple neurodegeneration models, including ALS, suggesting it plays a significant role in driving neuronal loss.

Together, these findings suggest that NAD+ depletion may not simply accompany neurodegeneration, but actively contribute to its progression.

A Pattern Across Diseases

NAD+ depletion is now recognised as a feature of Alzheimer’s, Parkinson’s, ALS, and Huntington’s disease. In Alzheimer’s, reduced NAD+ levels in the hippocampus and cortex are detectable before symptom onset, suggesting that metabolic dysfunction may be a driver of disease rather than a consequence.

A study published by Chaubey et al. demonstrated substantial reversal of cognitive and pathological deficits in advanced Alzheimer’s mouse models using a compound called P7C3-A20, which restores normal NAD+ homeostasis without elevating it beyond physiological levels. The results showed significant improvement in cognitive deficits, tau pathology, blood-brain-barrier deterioration, and neuroinflammation across both amyloid- and tau-driven mouse models. Importantly, while notable, these findings are in animal models, with human data from postmortem tissue only.

"Oral supplementation does raise blood NAD+ levels, but translating this into measurable cognitive improvements in people without existing disease has not been demonstrated."

Similar findings have also been observed in Parkinson’s disease, where mutations in LRRK2 (the most common genetic risk factor for PD) are linked to reduced NAD+ levels and impaired sirtuin activity compared to healthy controls. Phase 1 and 2 clinical trials of nicotinamide riboside (NR, a NAD+ precursor) in Parkinson’s patients have shown encouraging early results, with NR recipients demonstrating increased cerebral NAD+ levels and mild clinical improvements.  

Should We All Be Taking NAD+ Supplements?

Naturally, these findings have raised an important question: if NAD+ depletion contributes to neurodegeneration, could supplementing with NAD+ precursors help prevent it? 

The supplement industry has been quick to capitalise on this research, with precursors such as NR and NMN (nicotinamide mononucleotide) now widely marketed as longevity supplements. However, the evidence does not currently support their use in cognitively healthy individuals. Oral supplementation does raise blood NAD+ levels, but translating this into measurable cognitive improvements in people without existing disease has not been demonstrated. A 2025 randomised crossover trial of NR in older adults with mild cognitive impairment showed no significant cognitive benefit or improvement in AD biomarkers.

There are also safety concerns. Over-the-counter precursors raise NAD+ levels beyond physiological levels, and because tumour cells are heavy NAD+ consumers, artificially high levels carry a theoretical cancer risk that has been observed in some animal studies. In people with established neurodegeneration, where NAD+ depletion is present, this risk-benefit calculation may be different. However, for healthy individuals, the evidence is not yet there.

Where does this leave us?

The NAD+ story does not replace the protein aggregation framework: it adds to it. Amyloid and tau pathology is real, and recent approvals of anti-amyloid therapies confirm that targeting them holds clinical value. However, if NAD+ depletion precedes and exacerbates this pathology, the relationship between the two needs to be better understood before either can be effectively targeted.

There is also the question of what drives the initial depletion. Ageing itself likely plays a role: DNA damage accumulates, PARP activity rises, and NAD+ is steadily consumed over time³. Chronic neuroinflammation, increasingly recognised as a significant feature of most neurodegenerative diseases, further accelerates this depletion via CD38 upregulation. Whether there are more disease-specific triggers, and whether they can be intercepted, is where much of the current research is heading.

What is clear is that viewing neurodegeneration through a protein-centric lens may have been limiting our therapeutic options. The metabolic aspect to neurodegeneration is real, and if the ongoing clinical trials prove effective, potentially actionable. We may find that restoring the brain’s energy balance is one of the more important interventions we can make.

References

1. Chaubey, K., Vázquez-Rosa, E., Tripathi, S.J., Shin, M.K., Yu, Y., Dhar, M., Chakraborty, S., Yamakawa, M., Wang, X., Sridharan, P.S., Miller, E., Bud, Z., Corella, S.G., Barker, S., Caradonna, S.G., Koh, Y., Franke, K., Cintrón-Pérez, C.J., Rose, S., Fang, H., Cintrón-Pérez, A.A., Tomco, T., Zhu, X., Fujioka, H., Gefen, T., Flanagan, M.E., Williams, N.S., Wilson, B.M., Chen, L., Dou, L., Cheng, F., Rexach, J.E., Woo, J.A., Kang, D.E., Paul, B.D. and Pieper, A.A. (2026) 'Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain', Cell Reports Medicine, 7(1), p.102535. 

2. Manjula, R., Anuja, K. and Alcain, F.J. (2021) 'SIRT1 and SIRT2 activity control in neurodegenerative diseases', Frontiers in Pharmacology, 11, p.585821. 

3. Martire, S., Mosca, L. and d'Erme, M. (2015) 'PARP-1 involvement in neurodegeneration: a focus on Alzheimer's and Parkinson's diseases', Mechanisms of Ageing and Development, 146–148, pp.53–64. 

4. Guerreiro, S., Privat, A.L., Bressac, L. and Toulorge, D. (2020) 'CD38 in neurodegeneration and neuroinflammation', Cells, 9(2), p.471. 

5. Høyland, L.E., Niere, M., Pereira, J., Ziegler, M. et al. (2024) 'Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD+', Nature Metabolism. 

6. Kustermann, M., Boeckmans, J., Genth, H., Leist, M. and Neri, M. (2025) 'Programmed neurite degeneration in human central nervous system neurons driven by changes in NAD+ metabolism', Cell Death and Disease, 16, p.32. 

7. Gerdts, J., Brace, E.J., Sasaki, Y., DiAntonio, A. and Milbrandt, J. (2015) 'SARM1 activation triggers axon degeneration locally via NAD+ destruction', Science, 348(6233), pp.453–457. 

8. Schwab, A.J., Sison, S.L., Meade, M.R., Broniowska, K.A., Corbett, J.A. and Ebert, A.D. (2017) 'Decreased sirtuin deacetylase activity in LRRK2 G2019S iPSC-derived dopaminergic neurons', Stem Cell Reports, 9(6), pp.1839–1852. 

9. Brakedal, B., Dölle, C., Riemer, F., Ma, Y., Nido, G.S., Skeie, G.O., Craven, A.R., Schwarzlmüller, T., Brekke, N., Diab, J., Sverkeli, L., Skjeie, V., Varhaug, K., Tysnes, O.B., Peng, S., Haugarvoll, K., Ziegler, M., Grüner, R., Eidelberg, D. and Tzoulis, C. (2022) 'The NADPARK study: a randomized phase I trial of nicotinamide riboside supplementation in Parkinson's disease', Cell Metabolism, 34(3), pp.396–407. 

10. Wu, C.Y., Kupferschmid, A.C., Chen, L. et al. (2025) 'Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment', Alzheimer's and Dementia: Translational Research and Clinical Interventions, 11(1), p.e70023.

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This article was written by Susannah Leese and edited by Julia Dabrowska, with graphics produced by Lilly Green. If you enjoyed this article, be the first to be notified about new posts by signing up to become a WiNUK member (top right of this page)! Interested in writing for WiNUK yourself? Contact us through the blog page and the editors will be in touch.