NCT06582706: Nicotinic Acid for Alzheimer's Disease
Overview
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This Phase 1/2 clinical trial (NCT06582706) evaluates extended-release niacin (vitamin B3) as a potential treatment for Alzheimer's disease (AD)[@nct06582706]. Niacin (nicotinic acid) is a precursor to NAD+ (nicotinamide adenine dinucleotide), a critical coenzyme that becomes depleted in the aging brain and is particularly deficient in neurodegenerative conditions.
This trial represents a metabolic approach to AD treatment, targeting the fundamental cellular energy crisis that accompanies neurodegeneration. By replenishing NAD+ through niacin supplementation, the study aims to support mitochondrial function, enhance cellular repair mechanisms, and potentially slow disease progression.
...NCT06582706: Nicotinic Acid for Alzheimer's Disease
Overview
Mermaid diagram (expand to render)
This Phase 1/2 clinical trial (NCT06582706) evaluates extended-release niacin (vitamin B3) as a potential treatment for Alzheimer's disease (AD)[@nct06582706]. Niacin (nicotinic acid) is a precursor to NAD+ (nicotinamide adenine dinucleotide), a critical coenzyme that becomes depleted in the aging brain and is particularly deficient in neurodegenerative conditions.
This trial represents a metabolic approach to AD treatment, targeting the fundamental cellular energy crisis that accompanies neurodegeneration. By replenishing NAD+ through niacin supplementation, the study aims to support mitochondrial function, enhance cellular repair mechanisms, and potentially slow disease progression.
Trial Details
| Attribute | Value |
|-----------|-------|
| NCT ID | NCT06582706 |
| Phase | Phase 1/2 |
| Status | Recruiting (verified March 2026) |
| Intervention | Extended-Release Niacin (500 mg daily) |
| Control | Placebo (microcrystalline cellulose) |
| Condition | Alzheimer's Disease (mild-moderate) |
| Participants | 30 (estimated) |
| Sponsor | Indiana University |
| Principal Investigator | Jared R. Brosch, MD |
| Collaborator | Alzheimer's Association |
| Location | IU Health Neuroscience Center, Indianapolis, Indiana |
| Design | Randomized, Triple-Blinded, Placebo-Controlled |
| Duration | 60 days |
Scientific Rationale
The NAD+ Depletion Hypothesis
NAD+ is essential for multiple cellular processes that become impaired in Alzheimer's disease:
- Mitochondrial function: NAD+ is required for oxidative phosphorylation and ATP production
- Sirtuin activity: NAD+-dependent deacetylases regulate stress response, DNA repair, and mitochondrial biogenesis
- DNA repair: PARP enzymes use NAD+ to repair DNA damage, which accumulates in aging neurons
- Calcium homeostasis: NAD+ regulates calcium signaling crucial for synaptic function
Multiple studies have documented NAD+ depletion in AD brain tissue[@chen2024]. The decline in cellular NAD+ levels correlates with:
- Impaired mitochondrial function and energy production
- Reduced sirtuin activity and cellular stress resilience
- Increased neuroinflammation
- Accelerated neuronal death
Niacin as NAD+ Precursor
Niacin (nicotinic acid) is one of several NAD+ precursors, along with nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). Unlike NR and NMN, niacin has been used clinically for decades at high doses for lipid management, establishing a well-characterized safety profile.
Advantages of niacin for AD:
- Proven safety at doses up to 2,000+ mg daily
-readily crosses the blood-brain barrier
- Directly converts to NAD+ through the Preiss-Handler pathway
- Low cost compared to novel NAD+ precursors
- Long clinical history in cardiovascular applications[@liu2022]
Preclinical Evidence
Niacin and NAD+ replenishment have shown promise in multiple preclinical models:
In AD models:
- Niacin supplementation improved cognitive function in APP/PS1 transgenic mice
- NAD+ restoration reduced amyloid-beta toxicity in neuronal cultures
- Sirtuin activation (via NAD+) decreased tau hyperphosphorylation
- Mitochondrial function improved with NAD+ precursor administration
In aging models:
- Niacin improved memory performance in aged rodents
- NAD+ restoration enhanced mitochondrial biogenesis
- Reduced oxidative stress markers in brain tissue
- Improved synaptic plasticity and LTP
Trial Design
Study Population
Inclusion criteria:
- Age 60-85 years
- Alzheimer's disease diagnosis (mild-moderate dementia)
- MMSE score: 14-24 (mild to moderate cognitive impairment)
- Stable cholinesterase inhibitor and/or memantine for 30+ days
- Required reliable co-participant (study partner)
- Neuroimaging (MRI/CT) within 1 year
Exclusion criteria:
- Contraindications to lumbar puncture
- Severe cerebrovascular disease
- Liver disease or elevated liver function tests
- Current vitamin B3 supplementation
- Renal impairment Stage 2+ (eGFR <60 mL/min/1.73m²)
Treatment Arms
| Arm | Intervention | Dose | Duration |
|-----|--------------|------|----------|
| Treatment | Extended-Release Niacin | 500 mg daily | 60 days |
| Control | Placebo | Microcrystalline cellulose | 60 days |
Outcome Measures
Primary Endpoint:
- Change in nicotinic acid levels in blood and cerebrospinal fluid (CSF)
- Assessment: Baseline vs. 60-day visit
Secondary Endpoint:
- Number of participants with treatment-related adverse events
- Safety and tolerability assessment
Eligibility Details
Cognitive Assessment
The MMSE (Mini-Mental State Examination) score range of 14-24 indicates mild to moderate dementia:
| MMSE Score | Cognitive Status |
|------------|------------------|
| 24-30 | Normal |
| 18-23 | Mild cognitive impairment |
| 12-17 | Moderate cognitive impairment |
| 0-11 | Severe cognitive impairment |
This trial specifically enrolls patients in the mild-to-moderate range, where potential cognitive benefits are most likely to be observed.
Stable Medication Requirement
Requiring stable cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and/or memantine for 30+ days ensures:
- Baseline cognitive status is not confounded by medication changes
- Any observed effects can be attributed to niacin rather than AD medication adjustments
- Reduced variability in study outcomes
Biomarker Collection
The inclusion of CSF sampling (lumbar puncture) is notable:
- Allows direct measurement of nicotinic acid in the central nervous system
- Provides evidence of blood-brain barrier penetration
- Enables correlation with potential biomarkers of treatment response
Safety Considerations
Niacin Safety Profile
Niacin has a well-established safety profile from decades of cardiovascular use:
Common adverse effects:
- Flushing (most common, diminishes with time)
- Pruritus (itching)
- Headache
- Gastrointestinal upset
Less common effects:
- Hepatotoxicity (usually with sustained-release formulations at high doses)
- Hyperglycemia
- Hyperuricemia
Trial-Specific Safety Measures
The trial includes specific safety exclusions:
- No contraindications to lumbar puncture (for CSF collection)
- No liver disease (niacin is hepatotoxic in susceptible individuals)
- No renal impairment Stage 2+ (metabolite clearance concerns)
Monitoring
Participants will be monitored for:
- Treatment-emergent adverse events
- Changes in liver function
- Cognitive status changes
- Flushing and other niacin-associated symptoms
NAD+ and Alzheimer's Disease
AD is increasingly recognized as a metabolic disease with fundamental deficits in cellular energy production:
Mitochondrial dysfunction:
- Impaired glucose metabolism in AD brain
- Reduced cytochrome oxidase activity
- Increased oxidative stress
- Accumulated mitochondrial DNA mutations
NAD+ decline:
- NAD+ levels decline with normal aging
- This decline is accelerated in AD
- Sirtuins require NAD+ for activity
- PARP activation consumes NAD+ during DNA repair
Therapeutic Implications
Restoring NAD+ levels through niacin supplementation may:
- Support mitochondrial function
- Activate sirtuins (particularly SIRT1)
- Enhance DNA repair capacity
- Reduce neuroinflammation
- Improve synaptic plasticity
This metabolic approach complements other AD therapeutic strategies that target amyloid, tau, or neuroinflammation directly.
Connection to Other Trials
This trial connects to the broader NAD+ replenishment research landscape:
- [NADAPT Study (NCT06162013)](/clinical-trials/nadapt-psp) — NAD therapy for atypical parkinsonism
- [NCT05980949](/clinical-trials/nct05980949) — Another NAD+ precursor study
- [Nicotinamide Riboside](/therapeutics/nicotinamide-riboside) — Alternative NAD+ precursor
- [NAD Metabolism in Neurodegeneration](/mechanisms/nad-metabolism-neurodegeneration)
- [Sirtuin Pathway](/mechanisms/sirtuin-mitochondrial-biogenesis-axis)
- [Mitochondrial Dynamics in AD](/mechanisms/mitochondrial-dysfunction-alzheimers)
Future Directions
If Successful
Positive results from this trial could:
- Establish niacin as an AD therapeutic option
- Justify larger Phase 2/3 trials
- Encourage combination approaches (niacin + other agents)
- Support NAD+ metabolic therapy as an AD treatment paradigm
Biomarker Development
Future studies may explore:
- CSF tau and amyloid markers as secondary outcomes
- FDG-PET imaging for metabolic changes
- Blood-based NAD+ levels as predictive biomarkers
Combination Approaches
NAD+ replenishment may synergize with:
- Amyloid-targeting immunotherapies
- Tau-directed agents
- Anti-inflammatory treatments
- Existing symptomatic treatments
Conclusion
The NCT06582706 trial represents an innovative metabolic approach to Alzheimer's disease treatment. By addressing the fundamental NAD+ depletion that accompanies neurodegeneration, niacin supplementation offers a mechanistically distinct therapeutic strategy.
The trial's strengths include:
- Clear metabolic rationale with strong preclinical support
- Expert leadership from Indiana University
- Collaboration with the Alzheimer's Association
- Rigorous design with CSF biomarker collection
- Established safety profile of the intervention
Given the limited treatment options for AD and the metabolic basis of neurodegeneration, this trial contributes important evidence for whether NAD+ replenishment can meaningfully impact disease progression.
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [NAD Precursors in Neurodegeneration](/therapeutics/nad-precursors-neurodegeneration)
- [NAD Metabolism Pathway](/mechanisms/nad-metabolism-pathway-neurodegeneration)
- [Niacin (Vitamin B3) in Neurodegeneration](/therapeutics/vitamin-b-complex-neurodegeneration)
- [Clinical Trials Dashboard](/clinical-trials/dashboard)
External Links
- [ClinicalTrials.gov - NCT06582706](https://clinicaltrials.gov/study/NCT06582706)
- [Indiana University Alzheimer's Research](https://medicine.iu.edu/)
- [Alzheimer's Association](https://www.alz.org/)
References
[Nicotinic Acid for the Treatment of Alzheimer's Disease - ClinicalTrials.gov (2024)](https://clinicaltrials.gov/study/NCT06582706)
[Girard BE, et al. Niacin supplementation and cognitive function in aging. Journal of Alzheimer's Disease (2023)]
[Chen X, et al. NAD+ metabolism in Alzheimer's disease brain. Nature Reviews Neurology (2024)]
[Liu Y, et al. Vitamin B3 and neurodegeneration. Progress in Lipid Research (2022)]