In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer’s mouse model

 

 Hopefully your competent? doctor is fully aware of what this can do. No knowledge is grounds for firing! I take no prisoners in trying to get stroke solved. Incompetent persons need to be outed and fired! YOUR RESPONSIBILITY, since your stroke hospital is completely failing at getting stroke solved to 100% recovery, they are incompetent to the core!

In vivo imaging of glutamate uncovers the neuroprotective effects of nicotinamide riboside on excitotoxicity in an Alzheimer’s mouse model

• Anshuman Swain, 
• Narayan Datt Soni, 
• Ryan B. Gaspar, 
• James G. Davis, 
• Fang Liu, 
• Halvor Juul, 
• Ravi Prakash Reddy Nanga, 
• Joseph A. Baur & 
• Ravinder Reddy 

• 3 Accesses

• Explore all metrics 

 We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Abstract

Background

Nicotinamide adenine dinucleotide (NAD⁺) precursors, such as nicotinamide riboside (NR), have gained interest as potential therapeutics for alleviating Alzheimer’s disease (AD) pathology. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) can provide insights into the effects of NR on AD by virtue of its sensitivity to monitoring the metabolic status of tissue in vivo.

Methods

This study used glutamate-weighted CEST (GluCEST) MRI to monitor glutamate-associated metabolic changes following NR treatment in the 5xFAD mouse model of AD. Drinking water was supplemented with NR or provided as is to animals over the course of expected disease progression prior to imaging experiments. Following imaging, an immunohistochemical assay to monitor the expression of glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (Iba1) was performed to assess the extent of neuroinflammatory glial responses. A two-way ANCOVA with interaction was performed for statistical analysis of both CEST and IHC data.

Results

Results from GluCEST revealed significantly higher glutamate levels in the hippocampal dentate gyrus of AD mice compared to WT, with a significant reduction following treatment. GFAP staining mirrored this trend, implicating reactive astrogliosis as a mechanism for elevated glutamate. Similar patterns were observed in the cerebral peduncles, a white matter bundle, in which GFAP and Iba1 supported GluCEST findings and suggested neuroinflammation in axonal tracts. Our findings are in concordance with studies reporting elevated glutamate associated with reactive gliosis and morphological changes disrupting glutamate imbalance. Interestingly, NR restores glutamate homeostasis and alleviates neuroinflammatory processes, thus rescuing tissue from excitotoxic insults.

Conclusion

Overall, this study demonstrates the potential of NR to mitigate glutamate-driven excitotoxicity in AD pathology, and highlights GluCEST as a sensitive in vivo, clinically translatable biomarker for neuroinflammation and excitotoxicity.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

AD:

Alzheimer’s disease

NR:

Nicotinamide riboside

NAM:

Nicotinamide

NAD⁺ :

Nicotinamide adenine dinucleotide

CEST:

Chemical exchange saturation transfer

MRI:

Magnetic resonance imaging

GFAP:

Glial fibrillary acidic protein

WT:

Wild–type

MT:

Magnetization transfer

APT:

Amide proton transfer

rNOE:

Relayed nueclar Overhauser effect

ANOVA:

Analysis of variance

ANTs:

Advanced Normalization tools

Aβ:

Amyloid beta

IHC:

Immunohistochemistry

GluCEST:

Glutamate–weighted chemical exchange saturation transfer

Natural Compound Combo Restores Aging Brain Cells

 Don't do anything with this until your doctor can guarantee the right prescription. Green tea extract can be dangerous.

 Be very careful with green tea extract:

Herbal supplements linked to at least six Australian organ transplants since 2011, data shows  March 2016

nicotinamide (5 posts to July 2013) You can tell from this date how incompetent your doctor is in not having protocols for this already!

 

How Green Tea Blocks Alzheimer's

The latest here:

Natural Compound Combo Restores Aging Brain Cells

Summary: Scientists have identified a natural compound combination that reverses aging-related brain cell decline and removes harmful Alzheimer’s-linked proteins. The treatment, combining nicotinamide (vitamin B3) and the green tea antioxidant epigallocatechin gallate, restores guanosine triphosphate (GTP) levels—critical for neuronal energy and protein cleanup.

In aged neurons, the restored energy boosted protein clearance, reduced oxidative stress, and reactivated key cell trafficking pathways. The findings suggest a potential non-drug strategy for combating Alzheimer’s, though more work is needed to optimize delivery.

Key Facts

• Energy Restoration: Nicotinamide and green tea antioxidant revived GTP levels in aged neurons to youthful levels.
• Protein Clearance Boost: Treatment improved the brain’s ability to remove toxic amyloid beta aggregates.
• Non-Pharmaceutical Potential: Findings point to a supplement-based approach for Alzheimer’s prevention or therapy.

Source: UC Irvine

Researchers at the University of California, Irvine have identified a promising nonpharmaceutical treatment that rejuvenates aging brain cells and clears away the buildup of harmful proteins associated with Alzheimer’s disease.

In a paper published recently in the journal GeroScience, the UC Irvine team reports that a combination of naturally occurring compounds – nicotinamide (a form of vitamin B3) and epigallocatechin gallate (a green tea antioxidant) – can reinstate levels of guanosine triphosphate, an essential energy molecule in brain cells.

“We found that restoring energy levels helps neurons regain this critical cleanup function.” Credit: Neuroscience News

In tests on neurons in a dish, the treatment reversed age-related cellular deficits and improved the brain cells’ ability to clear damaging amyloid protein aggregates, an Alzheimer’s hallmark.

“As people age, their brains show a decline in neuronal energy levels, which limits the ability to remove unwanted proteins and damaged components,” said lead author Gregory Brewer, adjunct professor of biomedical engineering at UC Irvine. “We found that restoring energy levels helps neurons regain this critical cleanup function.”

The researchers used a genetically encoded fluorescent sensor called GEVAL to track live guanosine triphosphate levels in neurons from aged Alzheimer’s model mice. They discovered that free GTP levels declined with age – particularly in mitochondria, the cells’ energy hubs – leading to impaired autophagy, the process by which cells eliminate damaged components.

But when aged neurons were treated for just 24 hours with nicotinamide and epigallocatechin gallate, GTP levels were restored to those typically seen in younger cells.

This revival triggered a cascade of benefits: improved energy metabolism; activation of key GTPases involved in cellular trafficking, Rab7 and Arl8b; and efficient clearance of amyloid beta aggregates. Oxidative stress, another contributor to neurodegeneration, was also reduced.

“This study highlights GTP as a previously underappreciated energy source driving vital brain functions,” Brewer said.

“By supplementing the brain’s energy systems with compounds that are already available as dietary supplements, we may have a new path toward treating age-related cognitive decline and Alzheimer’s disease.”

He cautioned, “More work is going to be required to find the best way to administer this treatment, since a recent clinical trial involving UC Irvine researchers showed that oral nicotinamide was not very effective because of inactivation in the bloodstream.”

Brewer’s collaborators were Ricardo Santana, a UC Irvine associate specialist in biomedical engineering, and Joshua McWhirt, a UC Irvine junior specialist who’s now a Ph.D. candidate at the Medical University of South Carolina.

Funding: Funding was provided by the National Institutes of Health and the UC Irvine Foundation.

About this supplements and brain aging research news

Author: Brian Bell
Source: UC Irvine
Contact: Brian Bell – UC Irvine
Image: The image is credited to Neuroscience News

Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline

 

Your competent? doctor distilled this into understandable dementia prevention protocols, right! Oh no, NOTHING HAPPENED, LIKE USUAL!

Do you prefer your doctor and hospital incompetence NOT KNOWING? OR NOT DOING?

The reason you need dementia prevention: 

1. A documented 33% dementia chance post-stroke from an Australian study?   May 2012.

2. Then this study came out and seems to have a range from 17-66%. December 2013.

3. A 20% chance in this research.   July 2013. 

Harnessing Metabolism to Combat Neurodegeneration: Strategies for Reversing Age-Related Cognitive Decline

Abstract

Age-related cognitive decline, a hallmark of neurodegenerative disorders such as Alzheimer’s disease, has been increasingly associated with metabolic dysregulation. Targeting metabolic pathways to enhance brain function and slow neurodegeneration presents a novel therapeutic approach. This review discusses key metabolic interventions that may reverse or delay cognitive decline. Mitochondrial dysfunction, oxidative stress, and impaired energy metabolism are central to neurodegenerative progression. Therapies aimed at boosting mitochondrial biogenesis, such as nicotinamide adenine dinucleotide (NAD+) precursors, adenosine monophosphate-activated protein kinase (AMPK) activators, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) modulators, have shown promise in improving neuronal energy balance and reducing oxidative damage. Metabolic interventions like caloric restriction, intermittent fasting, and ketogenic diets have demonstrated neuroprotective effects by enhancing insulin sensitivity, promoting autophagy, and shifting the brain’s energy reliance toward ketone bodies, which improves cognitive function. These strategies also mitigate neuroinflammation, a key driver of neuronal damage, by modulating immune responses and reducing the accumulation of toxic protein aggregates. Lipid metabolism also plays a crucial role in maintaining neuronal integrity. Enhancing lipid turnover, optimizing fatty acid profiles, and regulating cholesterol homeostasis may improve synaptic plasticity and reduce neuroinflammation, offering additional therapeutic avenues. By integrating current insights into metabolic regulation, this review underscores the potential of metabolic therapies to reverse or mitigate the cognitive decline associated with aging. Advancing our understanding of the intricate relationship between metabolism and neurodegeneration may pave the way for novel treatments targeting age-related cognitive impairment.

This publication is licensed for personal use by The American Chemical Society.

© 2025 American Chemical Society

NAD augmentation as a disease-modifying strategy for neurodegeneration

 

 Did your competent? doctor start doing something with this way back in 2003? NO? So, you DON'T have a functioning stroke doctor, do you?

Nicotinamide: necessary nutrient emerges as a novel cytoprotectant for the brain May 2003 

Maybe this would help prevent your chances of dementia post stroke.

The latest here: 

NAD augmentation as a disease-modifying strategy for neurodegeneration

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Tables (1)

1. Table 1

Available online 25 April 2025

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Open access

Highlights

• Nicotinamide adenine dinucleotide (NAD) augmentation is a multi-target therapeutic approach that impacts on multiple disease pathways across neurodegenerative diseases (NDDs).
• NAD augmentation shows strong preclinical evidence of benefit in several NDDs.
• Early-phase clinical trials show encouraging results regarding target engagement and preliminary efficacy in several NDDs.
• Current data indicate that NAD augmentation therapy is safe, but long-term data in appropriately sized cohorts are not yet available.
• The number of clinical trials testing NAD augmentation in NDDs is rising rapidly, but long-term, well-planned, and adequately powered efficacy trials are urgently needed.

Abstract

Neurodegenerative diseases (NDDs) pose a significant and rapidly growing global health challenge, but there are no effective therapies to delay or halt progression. In recent years augmentation of nicotinamide adenine dinucleotide (NAD) has emerged as a promising disease-modifying strategy that targets multiple key disease pathways across multiple NDDs, such as mitochondrial dysfunction, energy deficits, proteostasis, and neuroinflammation. Several early clinical trials of NAD augmentation have been completed, and many more are currently underway, reflecting the growing optimism and urgency within the field. We discuss the rationale and evolving therapeutic landscape of NAD augmentation. We argue that, to fully realize its therapeutic potential, it is essential to determine the specific contexts in which NAD supplementation is most effective and to address crucial knowledge gaps.

Keywords

neurodegenerative disease

Parkinson's disease

therapeutic

The challenge of neurodegenerative diseases

Over 80 million people are currently living with a neurodegenerative disease (NDD; see Glossary) such as Parkinson's disease (PD) or Alzheimer's disease (AD), and this number is expected to double within the next 20–30 years [1., 2., 3.]. No disease-modifying therapies (DMTs) are available to halt or prevent disease progression, and affected individuals face functional decline, early institutionalization, and significantly shortened life expectancy [4,5]. Consequently, NDDs impose a staggering socioeconomic burden, which has already surpassed the costs of cancer and cardiovascular disease combined, and is increasing exponentially [6., 7., 8.].

Although the etiopathogeneses of NDDs are unknown, they share several pathological and pathophysiological hallmarks. Neuronal dysfunction and degeneration occur across multiple regions of the nervous system in a partly disease-specific but overlapping distribution [9., 10., 11.]. Some form of protein misfolding and aggregation, commonly referred to as neurodegenerative proteinopathy, occurs across NDDs. This primarily includes α-synuclein in PD, dementia with Lewy bodies (DLB), and multiple system atrophy (MSA); amyloid-β and tau in AD; tau in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD); and TDP-43 in frontotemporal dementia (FTD) and amyloid lateral sclerosis (ALS) [11., 12., 13.]. However, mixed-type proteinopathy involving a combination of these pathologies is an increasingly recognized phenomenon across NDDs [11., 12., 13.]. Although these abnormalities are often attributed to aberrant proteostasis caused by proteasomal and lysosomal dysfunction, the precise mechanisms underlying the origin and propagation of the proteinopathy remain unknown.

Mitochondrial dysfunction is another well-established pathological hallmark observed across the spectrum of NDDs, and commonly manifests as quantitative and/or functional deficiencies in mitochondrial respiratory chain (MRC) complexes, particularly affecting complex I and, to a lesser degree, complex IV [14., 15., 16., 17.]. In addition, impaired mitochondrial DNA (mtDNA) maintenance, reactive oxygen species (ROS)-mediated cellular stress, and altered mitochondrial dynamics and quality control have been reported [18., 19., 20.]. Furthermore, neuroinflammation, particularly involving microglial and astrocyte activation, as well as secretion of proinflammatory cytokines, is believed to be involved in the pathogenesis of NDDs [21., 22., 23.].

Most past and present disease-modifying strategies for NDDs target one or more of the aforementioned processes [24,25]. However, no therapeutic intervention has yet achieved significant disease modification in clinical trials, with the notable exception of mild but encouraging effects of some immunotherapies against amyloid-β in AD [26,27]. One emerging therapeutic candidate in aging and neurodegeneration research is NAD, a vital molecule that is essential for all life. As a crucial redox cofactor in nutrient and energy metabolism pathways, NAD constantly shuttles between its oxidized (NAD⁺) and reduced (NADH) forms. Furthermore, NAD can be phosphorylated to NADP, which participates in anabolic redox reactions, the immune response, and oxidative stress defense [28]. In addition, oxidized NAD⁺ is a substrate for a multitude of signaling reactions, including protein, DNA, and RNA modifications and the generation of second-messenger molecules, all of which require hydrolysis of the molecule, removal of the nicotinamide (Nam) moiety, and transfer of the remaining ADP-ribose moiety onto an acceptor molecule [29]. These reactions regulate processes vital to cell survival, including DNA repair via the activity of poly(ADP-ribose) polymerases (PARPs), epigenetic regulation of gene expression (e.g., via histone deacetylation by NAD⁺-dependent sirtuins), and calcium signaling. NAD⁺-dependent signaling leads to the degradation of the molecule, and constant NAD biosynthesis is therefore necessary to replenish NAD levels.

However, NAD levels have been shown to decline with age, a phenomenon observed in multiple tissues including the brain in model organisms [30], supported by cross-sectional evidence in humans [31., 32., 33.], although true longitudinal studies over the human age spectrum are still lacking [34]. Although the precise mechanisms underlying age-related NAD decline remain unknown, it is primarily attributed to the increased activity and expression of NAD-degrading enzymes such as CD38 – an NAD glycohydrolase that hydrolyzes NAD and generates second-messenger molecules [35]. This age-dependent decline of NAD is hypothesized to contribute to the onset and progression of age-related diseases including neurodegeneration [36,37]. Conversely, augmenting NAD metabolism via supplementation of precursors has been shown to confer rejuvenating effects, including lifespan and healthspan extension in multiple animal models, neuroprotection in preclinical models of neurodegeneration, as well as promising early-phase clinical findings [30]. Building on these results, treatment with biosynthetic NAD precursors has moved into focus as a potential multi-target intervention for NDDs. In this review we discuss the rationale of NAD supplementation as therapeutic approach for NDDs and highlight crucial knowledge gaps in the field.

Clinical NAD augmentation approaches

NAD biosynthesis is multifaceted and can be initiated from several precursors or biosynthetic intermediates (Box 1). Enhancing NAD biosynthesis via precursor supplementation is currently the most widely used strategy for augmenting NAD levels in clinical applications. The most commonly utilized precursors are NR and NMN, although nicotinic acid (NA) is also being investigated. Unlike NR and NMN, NA binds to the GPR109A receptor – also referred to as HCAR2 and now commonly known as niacin receptor 1 (NIACR1). NA exerts a lipid-modifying effect and was applied in the clinic for decades as a cholesterol-lowering agent before the introduction of statins [38]. However, NIACR1 activation also triggers skin flushing, an unpleasant side effect that may limit tolerability. This can be mitigated or prevented through the use of extended release formulations and/or gradual dose escalation at the start of treatment [39,40].

Box 1

NAD biosynthesis

NAD biosynthesis generally takes place in two stages in which nucleosides or bases are first converted to the mononucleotide, followed by condensation to a dinucleotide by the addition of AMP from ATP [97,98]. The major pathway in mammals – the salvage pathway – uses nicotinamide (Nam), which is also a degradation product of NAD⁺-dependent signaling reactions, to generate nicotinamide mononucleotide (NMN) via nicotinamide phosphoribosyltransferase (NAMPT, Figure I). The acid form of Nam, niacin or nicotinic acid (NA), is also the major entry point to NAD synthesis in bacteria and plants and is converted to nicotinic acid mononucleotide (NAMN) by nicotinic acid phosphoribosyltransferase (NAPRT) via the Preiss–Handler pathway. Recently, trigonelline (Trg), a methylated form of NA, was shown to support NAD biosynthesis by generating NA via a so far unidentified process. Quinolinic acid (QA), which is generated by de novo synthesis from tryptophan (Trp) via the kynurenine pathway, also yields NAMN through conversion by quinolinic acid phosphoribosyl transferase (QPRT). All three enzymes require phosphoribosyl pyrophosphate (PRPP) as a cosubstrate. Nicotinamide riboside (NR) and its acid form nicotinic acid riboside (NAR) also yield the mononucleotides NMN and NAMN, respectively, by conversion via nicotinamide riboside kinases (NRKs). The reduced form of NR, NRH, is a substrate for adenosine kinase (ADK) and yields the reduced form of NMN, NMNH. The generation of the dinucleotides is catalyzed by the family of nicotinamide/nicotinic acid mononucleotide adenylyl transferases, N(A)MNATs, three of which are present in humans [98,99]. This yields either NAD⁺ from NMN, NADH from NMNH, or nicotinic acid adenine dinucleotide (NAAD) from NAMN. Conversion of NAAD to NAD⁺ is carried out by NAD synthetase (NADS or NADSYN1).

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Figure I. NAD biosynthesis pathways are diverse.

The major NAD precursors used in clinical trials (NR, NMN, and NA) are highlighted in green. This figure was created with BioRender.

Beyond precursor supplementation, alternative strategies for NAD augmentation focus on reducing NAD consumption by inhibiting the activities of NAD-degrading enzymes such as PARPs and NAD glycohydrolases including CD38 and SARM1. PARP inhibitors are primarily investigated as cytotoxic agents in cancer therapy [41], but are also being explored for their potential to preserve NAD levels. NAD glycohydrolase inhibition, for example by small-molecule inhibitors of CD38, has been shown to increase NAD levels and reverse aging-related NAD decline in mice [42,43], as well as to increase lifespan and healthspan in a mouse model of chronological aging [44]. In addition, targeting the enzymes that regulate the availability of NAD biosynthetic precursors or intermediates presents another avenue for intervention. One such enzyme, purine nucleoside phosphorylase (PNP), has been identified as a major factor for NR degradation in human cell and mouse experiments [45]. Conversely, activating key NAD biosynthetic enzymes, such as NAMPT, has been shown to elevate cellular NAD levels [46] and has shown promise in a mouse model of diabetes [47].

NAD supplementation as a disease-modifying strategy for NDDs

NAD augmentation treatment for NDDs is not an entirely new concept. In the 1980s and 90s, intravenous and oral NADH administration was tested in open-label studies for PD, with reportedly positive effects on disability and function, and it was hypothesized that this effect may be mediated by stimulation of dopamine synthesis [48., 49., 50.]. However, the lack of blinded, placebo-controlled trials at the time made it impossible to determine whether the observed effects were attributable to NADH or were placebo effects. This concern is particularly relevant in PD where placebo effects are well-documented and can significantly influence outcomes [51]. In recent years this field was revitalized with the introduction of precursors, and the first randomized blinded trials with NR in PD were reported in 2022 and 2023, marking a significant milestone in the area of NAD augmentation therapy [52,53]. Alongside these developments, there has been a surge of clinical trials investigating NAD augmentation strategies in various NDDs, primarily using NR and NMN, although NA is also being evaluated (Table 1).

Table 1

NAD precursor	Disease/condition	Phase	Dosage (mg/day)	Duration	Outcome(s)	NAD measurements	Clinical trial ID
NR	MCI/AD	1	1000	12 weeks	Brain energy metabolism and mitochondrial function Cognitive function	Brain NAD+ and NAD+/NADH ratio	NCT04430517
	AD	2	1000, 2000, 3000	12 weeks	Cerebral and CSF NAD FDG-PET Safety Clinical assessment	Brain NAD (31P-MRS)	NCT05617508
	PD	2	1000, 2000, 3000	3 months	Cerebral NAD FDG-PET Clinical assessment	Brain NAD (31P-MRS) Blood and CSF NAD metabolome	NCT05589766
	PD	3	1000	1 year	Clinical assessment	Brain NAD (31P-MRS) Blood NAD metabolome	NCT03568968
	PD	N/a	1000	Up to 3 years	Safety Clinical assessment	N.d.	NCT05546567
	Atypical Parkinsonism	2	3000	78 weeks	Clinical assessment Safety Nigrostriatal degeneration (DaTSCAN) CSF/serum biomarkers	Brain NAD (31P-MRS) CSF NAD	NCT06162013
	Multiple sclerosis		1000	30 months	Clinical assessment	N.d.	NCT05740722
	Ataxia telangiectasia	N/a	Maximum 900 (25 mg/kg)	12 months	Clinical assessment Serum NfL and IFN	N.d.	NCT06324877
	Friedreich's ataxia	N/a	300 (24–48 kg) 600 (49–72 kg) 900 (>72 kg)	12 weeks	Aerobic capacity (VO2max) Insulin sensitivity	N.d.	NCT04192136
NR (+ PT)	ALS	2	1000 NR + 200 PT 1500 NR + 300 PT	1 year	Clinical assessment Serum NfL	N.d.	NCT04562831
NMN	AD	1/2		90 days	CSF levels of NMN and key metabolites	Brain NAD (7T MRS) PBMC NAD	NCT05040321
NA	AD	1/2	500 mg	60 days	Blood and CSF NA levels Target engagement of HCAR2 in the CNS	N.d.	NCT06582706

a

Abbreviations: AD, Alzheimer's disease; ALS, amyloid lateral sclerosis; FDG-PET, fluorodeoxyglucose positron emission tomography; HCAR2, hydroxycarboxylic acid receptor 2, also known as GPR109A/NIACR1; MCI, mild cognitive impairment; MRS, magnetic resonance spectroscopy; N/a, not applicable; NA, nicotinic acid; N.d., not described; NfL, neurofilament light chain; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; PBMC, peripheral blood mononuclear cells; PD, Parkinson's disease; PT, pterostilbene; VO2Max, maximal oxygen uptake.

Rationale of NAD augmentation as a disease-modifying strategy in NDDs

A rapidly growing body of preclinical results and emerging clinical evidence suggests that increasing cellular NAD levels may exert neuroprotective, disease-modifying effects in NDDs. This premise is supported by multiple NAD-regulated pathways and mechanisms that influence key pathophysiological processes implicated in NDDs (Figure 1). One of the most compelling arguments lies in the observation that NAD levels decline with age, which remains the strongest known risk factor for neurodegenerative diseases such as AD and PD. Restoring brain NAD levels may therefore counteract age-related cellular stress and vulnerabilities and mitigate neurodegeneration. Moreover, NAD is essential for mitochondrial function because NADH is the substrate for MRC complex I. Mitochondrial dysfunction, particularly complex I deficiency, is a hallmark of many NDDs including AD and PD [20]. Given that mitochondrial metabolism is heavily dependent on NAD availability, NAD augmentation has the potential to enhance mitochondrial function and improve cellular bioenergetics. This is supported by evidence from multiple preclinical models [54], as well as by a recent clinical trial on mitochondrial myopathy where NAD supplementation led to improved clinical outcomes [40]. NAD augmentation also supports increased synthesis of NADP, a central factor in cellular antioxidant defense [28]. Although direct clinical evidence of antioxidant effects by NAD augmentation is lacking, a recent clinical study demonstrated significantly elevated NADP levels in blood upon high-dose NR supplementation [53]. In addition, NAD supplementation reduces neuroinflammation, a key component of NDDs [55] in preclinical models [56], and also reduces inflammation biomarkers in humans [52].

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Figure 1. Nicotinamide adenine dinucleotide (NAD) augmentation in neurodegenerative disease (NDD) is a multi-target approach.

NAD supplementation has the potential to affect several disease-relevant pathways that overlap in NDDs. These include pathways of protein homeostasis and turnover such as lysosomal degradation and autophagy, mitochondrial function and quality control, genetic and epigenetic transcription regulation and DNA repair mechanisms, oxidative stress defense, and neuroinflammatory mechanisms. Abbreviations: MRC, mitochondrial respiratory chain; PARP, poly(ADP-ribose) polymerase. This figure was created with BioRender.

Furthermore, NAD is central in DNA repair pathways, for example via the activity of PARP1. Enhancing NAD levels could therefore confer resilience to the DNA damage which accumulates in aging and NDDs [57].

Likewise, epigenetic dysregulation has been implicated in NDDs. For instance, changes in histone acetylation have been observed in postmortem brain samples from individuals with PD [58]. Sirtuins, a family of NAD⁺-dependent deacylases, play a key role in maintaining epigenetic balance. Reduced NAD levels may impair sirtuin activity and thus contribute to disease progression. Finally, NAD augmentation in humans has been shown to upregulate the expression of genes encoding lysosomal and proteasomal components, structures that are crucial for maintaining proteostasis and organellar quality control [52]. Thus, NAD augmentation may act as a multitarget strategy that exerts synergistic effects across several crucial pathways for NDDs, thereby enhancing cellular resilience to disease.

Parkinson's disease and related disorders

In preclinical research, NR was shown to alleviate mitochondrial function in induced pluripotent stem cell (iPSC)-derived neurons from an individual with glucocerebrosidase (GBA)-related PD, and to rescue the phenotype in Drosophila models of the same disorder [54]. In Caenorhabditis elegans, NAD⁺ treatment protected against methylmercury-induced dopaminergic neurodegeneration and ensuing behavioral deficits [59]. More recently, NR alleviated disease-related phenotypes in a C. elegans model of α-synuclein overexpression, possibly by activation of the mitochondrial unfolded protein response, and partially rescued behavioral dysfunction in a proteasome inhibition model of parkinsonism in mice [60]. Similarly, NR reduced motor dysfunction, increased survival time, and attenuated neurodegeneration in a toxic model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration in zebrafish [61]. Interestingly, NAD biosynthetic enzymes have also been found to exhibit moonlighting activity as molecular chaperones that can improve proteostasis and positively influence α-synuclein misfolding in a yeast model of PD [62].

Early-phase clinical trials exploring NAD replenishment in PD have yielded promising results while raising no significant safety concerns. The NADPARK study, a Phase 1 randomized double-blind trial, assessed target penetration and engagement of oral NR (1000 mg/day) in newly diagnosed, treatment-naïve PD patients. The study showed that oral administration of NR augments NAD metabolism both systemically and in the central nervous system (CNS), and this is associated with altered brain metabolism and mild clinical improvement. Furthermore, NR led to reduced inflammatory cytokines in cerebrospinal fluid (CSF) and changes in gene expression linked to mitochondrial function, antioxidant activity, and protein degradation pathways in peripheral tissues [52]. Another small trial using ¹H magnetic resonance spectroscopy (MRS) provided further support that NR supplementation increases cerebral NAD levels [63].

Building on this foundation, the NR-SAFE trial evaluated the safety and tolerability of a higher NR dose (3000 mg/day); it was well tolerated for a period of 30 days and led to robust NAD metabolome augmentation in blood, including increases in NAD⁺, the NAD⁺/NADH ratio, and NADP⁺. Interestingly, a potential symptomatic benefit was also observed. Although a transient rise in serum homocysteine was noted, it remained within the normal range and did not raise safety concerns [53].

Several larger-scale and ongoing studies are now expanding on these findings. The N-DOSE study is a Phase 2 dose-escalation trial designed to identify the optimal biological dose of NR for PD, with completion anticipated in early 2025 (NCT05589766). The NOPARK study is a randomized, double-blind, Phase 3 trial which aims to evaluate whether NR can slow clinical disease progression in early-stage PD. With 400 participants enrolled, the trial is expected to conclude by mid-2025 (NCT03568968). An open-label extension study, NOPARK-extension, will further assess the long-term safety and tolerability of NR (1000 mg/day) for a period of up to 4 years (NCT05546567). The NADAPT study is a Phase 2 randomized, double-blind trial with the primary objective to evaluate whether high-dose NR (3000/day) can delay the progression of atypical parkinsonism syndromes, including progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal syndrome (CBS; NCT06162013).

Evidence in Alzheimer's disease

In a C. elegans model of AD, NMN supplementation restored defective mitophagy, a phenotype also observed in human brains with AD, and attenuated cognitive decline [64]. NR has shown multiple beneficial effects in C. elegans and mouse models of AD, including increased mitochondrial proteostasis and mitochondrial gene expression, as well as reduced amyloid-β proteotoxicity, β-secretase levels, neuroinflammation, and cellular senescence, and also restored cognition [65., 66., 67.]. In a DNA repair-deficient AD model, NR reduced tau pathology and neuroinflammation, and improved synaptic transmission and cognition [68]. Similarly, supplementation with Nam was shown to reduce phosphorylated tau levels and to increase the acetylation levels of sirtuin substrates [69].

Early clinical trials with NAD precursors in AD or related conditions have provided mixed results so far. A study in healthy adults supplemented with NR (1000 mg/day for 6 weeks) reported augmented NAD levels in plasma extracellular vesicles enriched for neuronal origin (NEVs), and this was accompanied by reduced levels of amyloid-β42 (Aβ42) and neuroinflammatory markers [70]. However, a study in older adults with mild cognitive impairment (MCI) receiving NR 1000 mg/day or placebo for 10 weeks showed no change in cognition or other disease-related outcome measures [71]. Furthermore, a recent Phase 2 study of high-dose Nam (3000 mg/day) in persons with AD reported no significant changes in CSF levels of total tau, phosphorylated tau, or amyloid-β. Although a nominally significant effect was observed on cognitive decline, this did not survive multiple testing correction [72]. Several studies with NAD precursors in AD or MCI are currently ongoing (Table 1). Our N-DOSE_AD trial is exploring the optimal dose of NR in AD and monitors brain metabolism and cognitive function over a course of 3 months (NCT05617508). Another Phase 1 trial in MCI and mild Alzheimer's dementia is exploring the effect of 12 weeks NR on brain NAD levels and cerebral metabolism, as well as clinical and cognitive outcomes (NCT04430517). Moreover, a proof-of-concept trial is testing NMN treatment for 90 days with the aim of increasing sirtuin activity in the brain of individuals with AD and is monitoring among others circulating biomarkers of aging (NCT05040321). Treatment with NA is also being explored, although this focuses less on NAD augmentation and more on the ability of NA to bind to the receptor HCAR2 (i.e., NIACR1) and a potential related microglia response (NCT06582706).

Evidence in ALS and other NDDs

NAD augmentation has shown promising preclinical evidence for ALS, including reduced astrocyte-mediated neurotoxicity via SIRT6 activation in cells isolated from mice overexpressing mutant human SOD1 [73], attenuated mitochondrial dysfunction and improved function in motor neurons of a TDP-43-overexpressing mouse model [74], and delayed progression of motor impairment in mice carrying Sod1 mutations [75,76]. Moreover, the expression of several NAD biosynthesis enzymes and SIRT6 was decreased in postmortem spinal cord samples of persons with ALS, indicating that these pathways may be impaired [76]. An early, small-scale randomized double-blind clinical trial assessing the safety and efficacy of NR in combination with pterostilbene in ALS reported a significant clinical improvement in the treatment group [77]. The efficacy of this treatment is currently being assessed in the ongoing Phase 2 NO-ALS trial (NCT04562831, Table 1).

NAD augmentation has shown promising preclinical and/or clinical effects in several other neurodegenerative diseases. A few selected examples are mentioned in the following text. Encouraging preclinical effects have been reported in models of Huntington's disease [78], possibly mediated via the sirtuin1–PGC-1α–PPAR pathway [79]. A first clinical trial of NAD supplementation in Huntington's disease (NAD-HD) is planned to start in 2025 [80]. Furthermore, NAD treatment has shown beneficial preclinical effects in worm and mouse models of ataxia telangiectasia (AT), including enhanced lifespan and healthspan, likely via supporting mitophagy and DNA repair [81]. Two recently completed open-label trials of NR treatment in AT have reported highly encouraging results, including clinical attenuation of ataxia and amelioration of eye movements [82,83]. Another trial in AT is ongoing (NCT06324877, Table 1). In multiple sclerosis the importance of NAD has long been recognized [84], and preclinical studies have indicate beneficial effects of restoring NAD levels on demyelination and axonal damage, for instance via inhibiting the NLRP3 inflammasome [85]. A first clinical trial of NR supplementation in multiple sclerosis is ongoing (NCT05740722, Table 1).

Safety and risks of high-dose NAD supplementation and alternative strategies for NAD augmentation

According to the National Institutes of Health (NIH) Office of Dietary Supplements, the recommended daily vitamin B3 intake is 14 mg niacin equivalents (NE) for women and 16 mg NE for men. Thus, the doses currently tested in clinical trials – typically 1000–3000 mg/day – by far exceed the daily requirements for healthy, middle-aged persons. Nevertheless, no major adverse events have been reported so far. NA has been used in doses up to 2000 mg/day as an antilipidemic and, although transient skin flushing and gastrointestinal side effects were common, severe adverse events were rarely seen [86]. Moreover, skin flushing and gastrointestinal symptoms can be effectively mitigated by slow dose titration.

NR and NMN have so far demonstrated an excellent safety profile at up to 3000 mg and 1250 mg, respectively [53,87]. However, most trials to date have been very short, generally <6 months, and data from larger and longer studies are lacking. For NR, this will hopefully be addressed by the NOPARK and NOPARK-extension trials which will assess safety for up to 4 years.

NAD augmentation leads to elevated levels of excretion products such as methyl-Nam and methylated pyridones N-methyl-6-pyridone-3-carboxamide and N-methyl-4-pyridone-5-carboxamide (N-Me-6-PY and N-Me-4-PY, also known as 2PY and 4PY, respectively). The synthesis of these compounds requires methylation of Nam using S-adenosyl methionine (SAM) as the methyl donor. It has been speculated that increased utilization of SAM could lead to reduced methyl group availability, thus affecting other important pathways such as DNA methylation and leading to a harmful increase in homocysteine, a downstream intermediate of SAM utilization. However, thus far, all indications point to only a mild effect on homocysteine levels and no clinically relevant impact on systemic methylation metabolism [53,88]. Data from longer interventions will be necessary to provide conclusive evidence on this matter.

A theoretical risk of prolonged NAD augmentation is growth facilitation for existing cancers. This is supported by a recent study in mice that showed both increased tumor growth and metastasis formation on an NR-rich diet [89]. In fact, inhibition of NAD biosynthesis (e.g., using NAMPT inhibitors) and interference with NAD-dependent pathways (e.g., DNA repair by PARP1) are emerging strategies for cancer treatment. In contrast to facilitating the growth of existing tumors, no convincing data have been reported to date supporting a carcinogenic or genotoxic effect of NAD supplementation. Moreover, the safety profile of NAD precursor supplementation (in this case, NR) revealed no carcinogenic effect at 3000 mg/kg/day in rats [90], corresponding to ~33.9 g/day for a 70 kg human [91]. Although long-term exposure data from the ongoing NOPARK and NOPARK-extension trials is expected by the end 2025, it is likely wise to avoid administering high-dose NAD-augmentation treatment in people with active cancer disease.

Finally, a recent epidemiological study indicated that the downstream NAD metabolites Me-6-PY and Me-4PY may be associated with an increased risk for major cardiovascular events in high-risk populations [92]. However, because this study was based on epidemiological association, data from long-term, prospective interventions will be necessary to assess whether there is a causal relationship between these metabolites and increased cardiovascular risk. Notably, trials investigating NAD supplementation as a treatment of heart disease have not reported such adverse events [93]. Nevertheless, other pathways of NAD augmentation that may avoid the generation of methylated pyridones, including inhibition or downregulation of NADase CD38, or of purine nucleoside phosphorylase (PNP) which affects NR degradation to Nam, are now being explored as potential alternatives to increase NAD levels.

Concluding remarks and future perspectives

Although the field of clinical NAD research in NDDs is advancing rapidly, it remains in its infancy, and significant knowledge gaps and challenges must be addressed to sustain and build on current momentum (see Outstanding questions). Achieving sufficiently high doses in the brain is vital to properly evaluate the therapeutic effect of NAD augmentation in neurological diseases. It is not yet fully understood which pathways are involved in increasing brain NAD levels, especially in humans, or which intermediates (nucleosides, mononucleotides, or the dinucleotide itself) penetrate the brain. Furthermore, although oral precursor supplementation is a convenient delivery route, it would be beneficial to establish CNS-specific NAD augmentation approaches, for example via vehicle platforms, and some promising efforts have already been made [94].

A recurring observation in human trials is a substantial interindividual heterogeneity in both physiological NAD levels and the response to NAD augmentation treatment. This includes some participants who appear to be non-responsive in terms of cerebral NAD elevation based on ³¹P-MRS data. Several factors may contribute to this heterogeneity, including genetic predisposition and the gut microbiome composition, both of which may influence precursor uptake and utilization. Understanding these underlying mechanisms will be crucial for implementing personalized treatment strategies.

A key challenge in the field is the heavy reliance on animal models to study the effects of NAD supplementation. Although these models can be useful for hypothesis generation and for uncovering downstream mechanistic insights into treatment effects, they do not accurately reflect NDDs and have very limited, if any, translation potential to human treatments. Therefore, current models cannot predict treatment responses in humans. An important cautionary lesson in that regard is offered by PD, where all (>60) trials of potential DMTs to date have produced negative results, despite the fact that most had highly encouraging findings in preclinical studies [95,96]. Thus, only clinical trials can provide reliable evidence of potential disease-modifying properties of NAD augmentation therapy in NDDs. In that regard, the currently completed trials are mostly encouraging. Most importantly, larger and longer clinical trials are ongoing which are designed to provide definite answers to the question that matters the most – is NAD augmentation a successful disease-modifying strategy for NDDs?Outstanding questions

Acknowledgments

This work is supported by grants from the Norwegian Research Council (288164), Stiftelsen Kristian Gerhard Jebsen (SKGJ-MED-023), and the Western Norway Regional Health Authorities.

Declaration of interests

C.T. and C.D. are listed as inventors on international patent applications relating to the use of Nam riboside as a treatment for PD and related disorders. These patents have been filed by the Technology Transfer Office 'Vestlandets Innovasjonsselskap AS (VIS)' on behalf of Haukeland University Hospital, Bergen, Norway (PCT/EP2022/067412, PCT/EP2023/060962, EP4284387).

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Glossary

Disease-modifying therapy (DMT)

targets the underlying pathology and pathophysiology of a disease to alter its trajectory. A successful DMT should slow disease progression, arrest it entirely, or even reverse the disease process. In the context of NDDs, DMTs are often associated with neuroprotection with the aim of preserving neuronal structure and function. DMTs differ fundamentally from symptomatic treatments, which provide temporary relief of symptoms without affecting the long-term progression or underlying mechanisms of the disease.

Mitochondrial respiratory chain (MRC)

an electron transport chain located in the inner mitochondrial membrane, consisting of four protein complexes that accept and transfer electrons from reduced NADH (at complex I) and FADH₂ (at complex II) to the final electron acceptor oxygen. Complexes I, III, and IV of the MRC pump protons from the mitochondrial matrix into the intermembrane space, thus converting energy that is released during electron transfer into an electrochemical gradient over the inner mitochondrial membrane. The gradient is degraded by ATP synthase (complex V) and the released energy stored as newly formed ATP.

Neurodegenerative disease (NDD)

a disorder characterized by progressive degeneration and death of neurons in the central and/or peripheral nervous systems, resulting in progressive loss of function, structure, and connectivity of neuronal networks. This process typically leads to progressive neurological impairments that may include cognitive, motor, autonomic, sensory, and other functions, depending on the specific neural networks and brain regions affected.

Neurodegenerative proteinopathy

NDDs that are characterized by pathological aggregation of specific misfolded proteins such as α-synuclein, tau, amyloid-β, and TDP43 in the nervous system. These proteins often maintain an unstructured monomeric form in healthy conditions but in the disease state undergo a conformational, structural change leading to oligomerization and subsequent aggregate formation. These aggregates can be intracellular (e.g., Lewy bodies and neurofibrillary tangles) or extracellular (e.g., amyloid-β), and are generally assumed to be directly damaging to neurons and to contribute to the pathogenesis of neurodegeneration, although this is not fully proven.

Proteostasis

also known as protein homeostasis, proteostasis is the maintenance of physiological balance in the proteome, and includes protein synthesis, folding, trafficking, and degradation.

© 2025 The Authors. Published by Elsevier Ltd.

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