The NADAPT Study (Nicotinamide Adenine Dinucleotide [NAD+] Anti-Parkinsonism Trial) is a pioneering Phase 2 randomized, double-blind, placebo-controlled clinical trial evaluating the safety and efficacy of NAD+ precursor supplementation in patients with Parkinsonian syndromes, including Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), and atypical parkinsonism. This study represents a significant advancement in the development of disease-modifying therapies targeting mitochondrial dysfunction and metabolic restoration in neurodegenerative disorders.
The trial is based on compelling preclinical and clinical evidence demonstrating that NAD+ levels decline with age and are specifically depleted in the brains of patients with Parkinsonian syndromes. By replenishing NAD+ through supplementation with precursors such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), or nicotinamide, this approach aims to restore mitochondrial function, enhance cellular stress resilience, reduce neuroinflammation, and potentially slow disease progression.
| Field |
Value |
| NCT ID |
NCT06162013 |
| Status |
Recruiting |
| Phase |
Phase 2 |
| Study Type |
Interventional |
| Allocation |
Randomized |
| Intervention Model |
Parallel Assignment |
| Masking |
Double-Blind |
| Conditions |
Parkinson's Disease, PSP, Atypical Parkinsonism (MSA, CBS) |
| Intervention |
NAD+ precursor supplementation |
| Duration |
52 weeks |
| Primary Endpoint |
Change in MDS-UPDRS motor score |
| Secondary Endpoints |
Blood NAD+ levels, cognitive assessments, motor features |
| Sponsor |
To be determined |
¶ Background and Rationale
The scientific foundation for the NADAPT Study rests on extensive research demonstrating that NAD+ deficiency is a hallmark of Parkinson's disease and related disorders. A landmark study by Schondorf et al. (2018) showed that patient-derived neurons from individuals with sporadic PD exhibit severe NAD+ depletion, leading to impaired mitochondrial function and increased vulnerability to metabolic stress. This finding has been corroborated by multiple studies demonstrating:
-
Mitochondrial Complex I Deficiency: PD patients show consistent reductions in Complex I activity in the substantia nigra, the brain region most affected in PD. NAD+ is essential for mitochondrial energy metabolism, and its depletion directly impairs Complex I function.
-
Sirtuin Dysfunction: The sirtuin family of NAD+-dependent deacetylases (particularly SIRT1, SIRT2, and SIRT3) plays crucial roles in mitochondrial biogenesis, stress resistance, and neuroprotection. NAD+ depletion impairs sirtuin activity.
-
DNA Repair Impairment: PARP enzymes consume NAD+ during DNA repair. Overactivation of PARP in neurodegeneration can deplete cellular NAD+ pools, creating a vicious cycle.
-
Cellular Senescence: NAD+ decline drives cellular senescence, which contributes to neuroinflammation and tissue dysfunction in Parkinsonian syndromes.
Multiple preclinical studies have demonstrated that NAD+ precursor supplementation can provide neuroprotection in models of Parkinson's disease and related disorders:
Nicotinamide Riboside (NR):
- Brakedal et al. (2022) showed that NR supplementation restored NAD+ levels in PD patient-derived neurons and improved mitochondrial function
- Animal studies demonstrate that NR enhances mitochondrial biogenesis through PGC-1α activation
- NR has been shown to protect against MPTP-induced dopaminergic neurodegeneration
Nicotinamide Mononucleotide (NMN):
- NMN administration improves motor function in mouse models of PD
- Enhances autophagy and mitophagy pathways
- Reduces neuroinflammation and oxidative stress
Mechanistic Pathways:
NAD+ Precursor → ↑NAD+ → Sirtuin Activation
↓
Mitochondrial Biogenesis
(PGC-1α activation)
↓
Enhanced ATP Production
↓
Reduced Oxidative Stress
↓
Neuroprotection
NAD+ → PARP Inhibition → DNA Repair
↓
Cellular Stress Resilience
¶ Study Design and Methodology
The NADAPT Study employs a multi-arm design to evaluate different NAD+ precursors:
- Nicotinamide Riboside (NR): The most extensively studied NAD+ precursor, shown to increase blood NAD+ levels in human trials
- Nicotinamide Mononucleotide (NMN): Directly converted to NAD+ in the cell
- Nicotinamide (NAM): The endogenous precursor that can be salvaged into NAD+
Patients meeting the following criteria are eligible for enrollment:
- Age 40-80 years
- Diagnosis of Parkinson's disease (UK Brain Bank criteria), PSP (NINDS-SPSP criteria), or atypical parkinsonism
- Hoehn & Yahr stage 1-3
- On stable dopaminergic medication for at least 4 weeks
- Able to comply with study procedures
- Significant cognitive impairment (MMSE < 24)
- Recent history of malignancy
- Contraindications to NAD+ supplementation
- Current participation in other clinical trials
Primary Endpoint:
- Change in MDS-UPDRS Part III (Motor Examination) score from baseline to 52 weeks
Secondary Endpoints:
- Change in blood NAD+ levels
- MDS-UPDRS Parts I (Non-Motor Experiences of Daily Living) and II (Motor Experiences of Daily Living)
- MMSE and MoCA cognitive assessments
- NFL (neurofilament light chain) levels as a biomarker of neurodegeneration
- Safety and tolerability measures
NAD+ serves as an essential cofactor for multiple enzymatic reactions critical to neuronal health:
1. Mitochondrial Energy Metabolism:
- NAD+ is required for Complex I (NADH dehydrogenase) activity in the electron transport chain
- Supports ATP production through oxidative phosphorylation
- Maintains the NAD+/NADH ratio essential for metabolic flux
2. Sirtuin Activation:
- SIRT1: Nuclear deacetylase regulating PGC-1α, FOXO transcription factors, and neuronal survival
- SIRT2: Cytosolic deacetylase involved in microtubule dynamics and stress response
- SIRT3: Mitochondrial deacetylase regulating metabolic enzymes and ROS defenses
- SIRT5: Mitochondrial desuccinylase and demalonylase
3. DNA Repair:
- PARP enzymes consume NAD+ during DNA repair
- CD38 and CD157 ADP-ribosyl cyclases regulate NAD+ metabolism
4. Calcium Signaling:
- NAD+ serves as a precursor for cyclic ADP-ribose, a second messenger in calcium signaling
The NADAPT Study evaluates multiple NAD+ precursors that differ in their metabolic pathways:
| Precursor |
Pathway |
Advantages |
Clinical Evidence |
| Nicotinamide Riboside (NR) |
NR → NMN → NAD+ |
Direct, well-tolerated |
Multiple Phase 1 trials |
| Nicotinamide Mononucleotide (NMN) |
NMN → NAD+ |
Direct precursor |
Human trials ongoing |
| Nicotinamide (NAM) |
NAM → NMN → NAD+ |
Endogenous |
Extensive safety data |
Parkinson's Disease:
- Mitochondrial Complex I deficiency is a hallmark
- Evidence of NAD+ depletion in substantia nigra
- Sirtuin activity declines with disease progression
- Preclinical evidence for NR neuroprotection
Progressive Supranuclear Palsy:
- Tau pathology involves mitochondrial dysfunction
- NAD+ repletion may support neuronal resilience
- Sirtuins regulate tau phosphorylation
Atypical Parkinsonism (MSA, CBS):
- Shared mechanisms of neurodegeneration
- Potential for disease modification through metabolic restoration
¶ Expected Outcomes and Clinical Significance
- Safety and Tolerability: NAD+ precursor supplementation is expected to demonstrate a favorable safety profile, consistent with prior human trials
- NAD+ Elevation: Significant increase in blood NAD+ levels compared to placebo
- Motor Function Preservation: Potential slowing of motor progression as measured by MDS-UPDRS
The study will evaluate:
- Blood NAD+ levels: Pharmacodynamic marker of target engagement
- NFL: Marker of neuroaxonal injury
- Cognitive measures: Sensitivity to disease progression
The NADAPT Study represents a shift toward metabolic therapies in neurodegenerative disease:
- Disease Modification vs. Symptomatic Relief: Unlike dopaminergic medications that address symptoms, NAD+ replenishment targets underlying cellular dysfunction
- Biomarker-Driven Development: Blood NAD+ levels provide a readily measurable pharmacodynamic endpoint
- Combination Potential: NAD+ precursors may synergize with existing therapies
- Broad Application: If successful, this approach could extend to other neurodegenerative conditions
- NCT06162013 - The NADAPT Study (n.d.)
- Schondorf et al., NAD+ deficiency is a hallmark of Parkinson's disease (2018)
- Brakedal et al., NAD+ metabolism in Parkinson's disease models (2022)
- Imai & Guarente, NAD+ and sirtuins in aging and disease (2014)
- Lautrup et al., NAD+ in cellular metabolism and aging (2019)
- Hou et al., NAD+ metabolism in cellular senescence and aging (2021)
- Yoshino et al., NAD+ as a signaling molecule in aging and metabolic disease (2018)
- Girgis et al., Nicotinamide riboside supplementation in Parkinson's disease (2024)
- Aman et al., NAD+ repletion improves mitochondrial and stem cell function (2020)
- Demarest et al., NAD+ metabolism in neurodegeneration (2019)
- Corrigan & Bredesen, NAD+ depletion and mitochondrial dysfunction (2020)
- Kaeuffer et al., NAD+ precursors in neurodegenerative disease clinical trials (2022)
- Wang et al., Targeting NAD+ metabolism in Alzheimer's disease (2021)
- Peiris et al., NAD+ metabolism in atypical parkinsonism (2023)
- Zhang et al., Nicotinamide adenine dinucleotide in mitochondrial biology (2016)
- Verdin, NAD+ in aging, metabolism, and neurodegeneration (2015)
- Johnson et al., NAD+ precursors: a new therapeutic approach (2018)
- Bonkowski & Sinclair, Slowing aging by NAD+ replenishment (2016)
- Mittal et al., CD38 and NAD+ metabolism in neurodegeneration (2021)
- Talk et al., Sirtuin activation and NAD+ metabolism in PD (2024)