NAD+ repletion through nicotinamide mononucleotide (NMN) supplementation will improve cognitive function and reduce disease progression in patients with early-stage Alzheimer's disease (AD) by restoring mitochondrial function, enhancing sirtuin activity, and reducing neuroinflammation.
NAD+ levels decline with age and are further reduced in neurodegenerative diseases [@cantó2012]. This decline affects:
NAD+ repletion through nicotinamide mononucleotide (NMN) supplementation will improve cognitive function and reduce disease progression in patients with early-stage Alzheimer's disease (AD) by restoring mitochondrial function, enhancing sirtuin activity, and reducing neuroinflammation.
NAD+ levels decline with age and are further reduced in neurodegenerative diseases [@cantó2012]. This decline affects:
| Study | Model | Key Finding |
|-------|-------|-------------|
| Liu et al. 2023 | APP/PS1 mice | NMN reduced amyloid plaques, improved cognition [@liu2023] |
| Zhou et al. 2024 | 3xTg-AD mice | NMN ameliorated mitochondrial dysfunction [@zhou2024] |
| Mills et al. 2016 | Aged mice | NMN improved mitochondrial function and cognitive behavior [@mills2016] |
NMN has demonstrated safety in Phase I trials (100-500mg single doses) and is currently in multiple Phase II trials for age-related conditions. No Phase II trial has specifically tested NMN in early AD patients with cognitive endpoints.
This experiment tests whether NAD+ augmentation is disease-modifying in early AD:
| Parameter | Value |
|-----------|-------|
| Design | Double-blind, placebo-controlled RCT |
| Population | Early AD (MCI due to AD or mild AD dementia) |
| Sample Size | 60 patients (30 per arm) |
| Duration | 12 months treatment |
| Dose | NMN 300mg/day oral |
| Control | Placebo (identical capsule) |
| Visit | Week | Assessments |
|-------|------|-------------|
| Screening | -4 to -2 | Medical history, MRI, PET, cognitive tests |
| Baseline | 0 | Blood draw, cognitive tests, safety labs |
| Month 3 | 12 | Blood draw, cognitive tests, safety labs |
| Month 6 | 24 | Blood draw, cognitive tests, MRI, safety labs |
| Month 12 | 48 | Blood draw, cognitive tests, MRI, PET, safety labs |
| Endpoint | Measure | Timepoint |
|----------|---------|-----------|
| Cognitive change | ADAS-Cog13 change from baseline | Month 12 |
Hypothesis: NMN group will show ≤2 points decline vs ≤5 points in placebo (minimum clinically important difference = 3 points)
| Endpoint | Sample | Method |
|----------|--------|--------|
| NAD+ levels | Blood (plasma RBC) | HPLC |
| Mitochondrial function | PBMCs | Seahorse bioenergetics |
| Neurofilament light (NfL) | Plasma | Simoa |
| p-tau181 | Plasma | Simoa |
| Aβ42/40 ratio | CSF (subset) | Lumipulse |
| Brain FDG-PET | Regional glucose metabolism | PET/CT |
| Endpoint | Measure | Timepoint |
|----------|---------|-----------|
| Global cognition | MMSE | Months 3, 6, 12 |
| Executive function | Trail Making Test A/B | Months 6, 12 |
| Memory | Logical Memory Delayed Recall | Months 6, 12 |
| Functional status | ADCS-MCI-ADL | Months 6, 12 |
| Clinical progression | CDR-SB | Months 6, 12 |
| Item | Cost (USD) |
|------|------------|
| NMN study drug (300mg/day × 365 days) | $3,650 |
| Placebo | $500 |
| Clinical assessment visits | $4,800 |
| MRI (baseline + 6mo + 12mo) | $2,400 |
| FDG-PET (baseline + 12mo) | $3,000 |
| Plasma biomarkers (NAD+, NfL, p-tau) | $1,800 |
| CSF collection (optional subgroup) | $800 |
| Safety labs | $600 |
| Total per patient | $17,550 |
| Category | Cost (USD) |
|----------|------------|
| Direct costs (60 patients) | $1,053,000 |
| Site management (10%) | $105,300 |
| Data management & biostatistics | $150,000 |
| Regulatory & IRB | $50,000 |
| Estimated total | $1,358,300 |
| Dimension | Score | Rationale |
|-----------|-------|-----------|
| Scientific Value (SV) | 9 | Addresses NAD+/mitochondria-AD link; potential to reveal novel mechanisms |
| Feasibility (F) | 8 | Established NMN formulation; standard AD trial infrastructure |
| Novelty (N) | 9 | First Phase II RCT testing NMN specifically in early AD with comprehensive biomarker panel |
| Disease Impact (DI) | 9 | Potential to slow cognitive decline in AD; addresses unmet need |
| Reach (R) | 6 | Initial focus on early AD; expandable to MCI, PD |
| Cost Efficiency (CE) | 8 | Reasonable cost for Phase II; comprehensive readouts justify investment |
| Time Efficiency (TE) | 8 | 12-month duration is standard for AD trials; results meaningful at 6 months |
| Evidence Base (EB) | 8 | Strong preclinical data; established safety in Phase I |
| Addresses Uncertainty (AU) | 8 | Tests whether NAD+ restoration translates to clinical benefit in AD |
| Translation Potential (TP) | 9 | If positive, immediately scalable; NAD+ augmentation is novel therapeutic approach |
| Risk | Severity | Mitigation |
|------|----------|------------|
| GI discomfort | Mild | Start with 150mg BID, titrate to 300mg by week 2 |
| Flushing | Mild | Rare at oral doses; monitor and reduce if occurs |
| Interaction with supplements | Low | Restrict NAD+ precursors during study |
| Worsening cognition | Moderate | Stopping rules with independent DSMB review |
| Milestone | Time |
|-----------|------|
| Protocol finalization | Month 0 |
| IRB approval | Month 2 |
| First patient enrolled | Month 3 |
| Last patient enrolled | Month 9 |
| Database lock | Month 15 |
| Results publication | Month 18 |