NADAPT Study: NAD Replenishment Therapy for Atypical Parkinsonism

The NADAPT Study: NAD Replenishment Therapy for Atypical Parkinsonism

Overview

The NADAPT Study (NCT06162013) is an active Phase 2/3 clinical trial investigating NAD replenishment therapy for patients with atypical parkinsonian syndromes, including Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Syndrome (CBS)[@nadapt]. This trial represents a novel approach to neurodegenerative disease treatment by targeting fundamental cellular metabolism rather than directly targeting pathological proteins.

The NADAPT Study: NAD Replenishment Therapy for Atypical Parkinsonism

Overview

The NADAPT Study (NCT06162013) is an active Phase 2/3 clinical trial investigating NAD replenishment therapy for patients with atypical parkinsonian syndromes, including Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), and Corticobasal Syndrome (CBS)[@nadapt]. This trial represents a novel approach to neurodegenerative disease treatment by targeting fundamental cellular metabolism rather than directly targeting pathological proteins.

Atypical parkinsonian syndromes are severe neurodegenerative diseases with rapid progression and limited treatment options. Patients typically survive only 3-10 years following diagnosis, with no disease-modifying therapies currently approved. The NADAPT study explores whether replenishing cellular NAD+ levels may provide neuroprotective benefits in these conditions.

Trial Information

| Field | Value |
|-------|-------|
| NCT ID | NCT06162013 |
| Status | Recruiting |
| Start Date | March 5, 2024 |
| Phase | Phase 2/3 |
| Sponsor | To be determined |
| Clinicaltrials.gov | [NCT06162013](https://clinicaltrials.gov/study/NCT06162013) |
| Enrollment | Approximately 200 participants (estimated) |
| Study Duration | Approximately 78 weeks (18 months) |
| Study Design | Randomized, double-blind, placebo-controlled |

Scientific Rationale

Why NAD+ Replenishment

NAD+ (nicotinamide adenine dinucleotide) is a critical coenzyme involved in multiple cellular processes that become impaired in neurodegenerative diseases[@lautrup2023]:

• Mitochondrial function: NAD+ is essential for oxidative phosphorylation and ATP production
• Sirtuin activity: NAD+-dependent deacetylases regulate mitochondrial biogenesis, stress response, and aging
• DNA repair: PARP enzymes require NAD+ for DNA damage repair
• Cellular signaling: NAD+ serves as a substrate for various signaling pathways

• Mitochondrial dysfunction and energy deficiency
• Impaired cellular stress responses
• Increased neuroinflammation
• Accelerated neuronal death

Preclinical Evidence

NAD replenishment has shown promise in multiple preclinical models:

Parkinson's Disease Models

• Nicotinamide riboside (NR) protected dopaminergic neurons in MPTP models
• NMN administration improved mitochondrial function in PINK1 knockout models
• NAD+ precursors restored mitochondrial biogenesis

Tauopathy Models

• NAD+ depletion accelerated tau pathology in mouse models
• Sirtuin activation reduced tau acetylation and aggregation
• NAD+ replenishment improved cognitive function in tau transgenic mice

Aging and Neurodegeneration

• Age-related NAD+ decline correlates with mitochondrial dysfunction
• NAD+ precursors extend lifespan in animal models
• Improvement in multiple age-related biomarkers

Mechanism of Action

The neuroprotective effects of NAD+ replenishment operate through multiple pathways:

Study Design

Overview

The NADAPT study employs a rigorous randomized, double-blind, placebo-controlled design:

• Randomization: 1:1 ratio of active treatment to placebo
• Blinding: Double-blind (participants and investigators blinded)
• Duration: 78 weeks of treatment plus follow-up

Cohorts

The study enrolls patients with three distinct diagnoses:

Treatment Arms

• Active Treatment: NAD precursor (exact compound to be confirmed)
• Placebo: Matching inactive formulation

Primary Objective

To evaluate the safety and efficacy of NAD replenishment therapy in patients with atypical parkinsonian syndromes.

Primary Outcome Measure

• PSP Cohort: Between-group difference in PSP Rating Scale (PSPRS) total score from baseline to week 78

• Motor symptoms (gait, balance, facial expression)
• Oculomotor function
• Bulbar function
• Cognitive/behavioral features
• Disability

Secondary Outcome Measures

• MSA Cohort: Change in Unified Multiple System Atrophy Rating Scale (UMSARS)
• CBS Cohort: Change in Corticobasal Syndrome Rating Scale (CBS-RS)
• Motor assessments: MDS-UPDRS parts I-III
• Cognitive assessments: MMSE, MoCA
• Quality of life: PDQ-39, EQ-5D
• Biomarkers: NAD+ levels, mitochondrial function markers, neuroinflammation markers
• Safety: Adverse events, laboratory values, vital signs

Inclusion Criteria

Exclusion Criteria

• Significant medical conditions that may interfere with study participation
• Current treatment with NAD+ precursors or supplements
• Contraindications to the study drug
• Pregnant or breastfeeding
• Participation in other clinical trials within 30 days

Clinical Significance

Unmet Need in Atypical Parkinsonism

Atypical parkinsonian syndromes represent a significant unmet medical need:

• No approved disease-modifying therapies: All treatments are symptomatic
• Rapid progression: Median survival 6-9 years
• Severe disability: Patients require extensive care
• Limited response to dopaminergic therapy: Unlike PD

Paradigm Shift

The NADAPT trial represents an important shift in neurodegenerative disease treatment:

• Targeting cellular metabolism: Rather than specific pathological proteins
• Disease-modifying potential: Aiming to slow or halt progression
• Broad applicability: May benefit multiple neurodegenerative conditions
• Repurposing potential: NAD precursors are already available as supplements

Comparison with Other Approaches

| Approach | Target | Current Status |
|----------|--------|----------------|
| NADAPT | Cellular metabolism | Phase 2/3 |
| Anti-tau immunotherapies | Tau protein | Phase 2/3 |
| Anti-α-syn immunotherapies | α-synuclein | Phase 2/3 |
| Gene therapy | Specific genes | Phase 1/2 |

NAD+ Precursors in Development

Nicotinamide Riboside (NR)

• Form: Vitamin B3 derivative
• Mechanism: Converted to NAD+ via the NR kinase pathway
• Clinical trials: Ongoing in PD, AD, and aging
• Safety: Well-tolerated in human trials

Nicotinamide Mononucleotide (NMN)

• Form: Nucleotide precursor
• Mechanism: Directly converted to NAD+
• Clinical trials: Multiple trials in aging and metabolic disease
• Safety: Generally well-tolerated

Nicotinamide (NAM)

• Form: Vitamin B3
• Mechanism: Preceding step in NAD+ biosynthesis
• Considerations: May inhibit sirtuins at high doses

Comparison of NAD+ Precursors

| Precursor | Bioavailability | Conversion | Clinical Evidence |
|-----------|-----------------|------------|-------------------|
| NR | Good | Multi-step | Moderate |
| NMN | Good | Single step | Growing |
| NAM | Variable | Feedback inhibition | Extensive |
| NRPT | Good | Optimized | Early |

Biomarker Considerations

NAD+ Level Monitoring

• Blood NAD+ levels: Can be measured to confirm target engagement
• Response variability: Individual differences in NAD+ metabolism
• Dose optimization: May guide individual dosing

Disease Progression Markers

• Neurofilament light chain (NfL): Marker of neuronal injury
• Tau and α-synuclein: Disease-specific pathology markers
• Mitochondrial biomarkers: Markers of energy metabolism

Response Prediction

Potential biomarkers to predict treatment response:

• Baseline NAD+ levels
• Mitochondrial function assessments
• Genetic variants in NAD+ metabolism genes

Safety Profile

Expected Safety

NAD+ precursors have generally favorable safety profiles:

• NR: Well-tolerated up to 1000mg/day in clinical trials
• NMN: Safe in human studies up to 500mg/day
• Common adverse events: Generally mild GI symptoms

Potential Concerns

• Flushing: Common with niacin, less so with NR/NMN
• Liver enzymes: Monitor for elevated transaminases
• Drug interactions: Potential interactions with certain medications

Monitoring Plan

The trial includes comprehensive safety monitoring:

• Regular vital sign measurements
• Laboratory assessments (hematology, chemistry)
• Adverse event monitoring
• Physical examinations

Related Therapeutic Approaches

Mitochondrial Support

NAD+ replenishment is part of a broader approach to mitochondrial support:

• [Coenzyme Q10](/therapeutics/coq10-neurodegeneration)
• [Alpha-lipoic acid](/therapeutics/alpha-lipoic-acid-neurodegeneration)
• [Urolithin A](/therapeutics/urolithin-a-neurodegeneration)

Neuroprotective Strategies

Related approaches include:

• [Exercise and physical activity](/therapeutics/exercise-physical-activity-neuroprotection)
• [BDNF therapy](/therapeutics/bdnf-therapy)
• [Antioxidant therapy](/therapeutics/antioxidant-therapy-neurodegeneration)

Related Pages

Diseases

• [Progressive Supranuclear Palsy](/diseases/psp)
• [Multiple System Atrophy](/diseases/multiple-system-atrophy)
• [Corticobasal Syndrome](/diseases/corticobasal-syndrome)
• [Atypical Parkinsonism](/diseases/atypical-parkinsonism)

Mechanisms

• [Mitochondrial Dysfunction in Neurodegeneration](/mechanisms/mitochondrial-dysfunction)
• [Neuroinflammation in PSP](/mechanisms/neuroinflammation-psp)
• [NAD+ Metabolism in Brain](/mechanisms/nad-metabolism)

Therapeutics

• [NACET](/therapeutics/nacet) (glutathione precursor)
• [NMN](/therapeutics/nmn-nicotinamide-mononucleotide)
• [Nicotinamide Riboside](/therapeutics/nicotinamide-riboside)

Clinical Trial Enrollment

Finding the Trial

Patients interested in participating should:

Eligibility Assessment

Key factors for consideration:

• Confirmed diagnosis of PSP, MSA, or CBS
• Age 30-85 years
• Ability to attend regular study visits
• Willingness to undergo randomization

Patient Benefits

• Access to potential active treatment
• Comprehensive medical evaluation
• Contribution to advancing science
• Close monitoring by clinical team

Current Status and Timeline

Trial Progress (2025-2026)

• Recruitment status: Actively recruiting
• Primary completion: Expected 2026
• Results publication: Expected 2027-2028

Future Directions

If successful, NAD+ replenishment could:

• Become first disease-modifying therapy for atypical parkinsonism
• Be combined with other approaches (immunotherapy, gene therapy)
• Be applied to other neurodegenerative conditions
• Lead to biomarker-driven personalized treatment

Cross-Links

External Resources

• [ClinicalTrials.gov - NCT06162013](https://clinicaltrials.gov/study/NCT06162013)
• [CurePSP](https://www.curepsp.org/) - Foundation for PSP & CBS
• [Michael J. Fox Foundation](https://www.michaeljfox.org/)

See Also

• [Progressive Supranuclear Palsy](/gaps/progressive-supranuclear-palsy)
• [Multiple System Atrophy](/diseases/multiple-system-atrophy)
• [Corticobasal Syndrome
• [Atypical Parkinsonism](/diseases/atypical-parkinsonism)
• [Mitochondrial Dysfunction](/mechanisms/mitochondrial-dysfunction) CoQ10
• NACET](/diseases/parkinsons-disease)
• Personalized Treatment Plan — Atypical Parkinsonism

References

Related Hypotheses

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

• [Aquaporin-4 Polarization Rescue](/hypothesis/h-c8ccbee8) — <span style="color:#81c784;font-weight:600">0.67</span> · Target: AQP4
• [Microglial Purinergic Reprogramming](/hypothesis/h-5daecb6e) — <span style="color:#81c784;font-weight:600">0.66</span> · Target: P2RY12
• [Sphingolipid Metabolism Reprogramming](/hypothesis/h-6657f7cd) — <span style="color:#81c784;font-weight:600">0.61</span> · Target: CERS2
• [Complement C1q Subtype Switching](/hypothesis/h-5a55aabc) — <span style="color:#ffd54f;font-weight:600">0.59</span> · Target: C1QA
• [Glial Glycocalyx Remodeling Therapy](/hypothesis/h-c35493aa) — <span style="color:#ffd54f;font-weight:600">0.58</span> · Target: HSPG2
• [Ephrin-B2/EphB4 Axis Manipulation](/hypothesis/h-e6437136) — <span style="color:#ffd54f;font-weight:600">0.56</span> · Target: EPHB4
• [Netrin-1 Gradient Restoration](/hypothesis/h-05b8894a) — <span style="color:#ffd54f;font-weight:600">0.44</span> · Target: NTN1

Related Analyses:

• [4R-tau strain-specific spreading patterns in PSP vs CBD](/analysis/SDA-2026-04-01-gap-005) &#x1f504;

Pathway Diagram

The following diagram shows the key molecular relationships involving NADAPT Study: NAD Replenishment Therapy for Atypical Parkinsonism discovered through SciDEX knowledge graph analysis: