NCT06582706: Nicotinic Acid for Alzheimer's Disease

NCT06582706: Nicotinic Acid for Alzheimer's Disease

Overview

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

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

• 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

• 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

• 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

• 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

• 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

• 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

The Metabolic Crisis

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+ 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

Connection to Other Trials

This trial connects to the broader NAD+ replenishment research landscape:

Related NeuroWiki Trials

• [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

Related Mechanisms

• [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

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