The NAD+ study every APOE4 carrier needs to see (and the warning they buried)

Hi Phoenix friend,

A December 2025 study just challenged what we thought we knew about Alzheimer's disease. For APOE4 carriers, this could change everything about how we approach brain health.

I've been an APOE4/4 carrier my entire life. I've read hundreds of Alzheimer's studies. When researchers claim to "challenge the century-old dogma that Alzheimer's disease is intrinsically irreversible," I pay attention.

But here's what you need to understand: this breakthrough comes with a critical safety warning about NAD+ supplements that most headlines completely ignored. Before you order another bottle of NMN or NR, you need to know what the study authors themselves are saying about over-the-counter precursors.

In this post, I'll break down exactly what this research found, why it matters specifically for APOE4 carriers, and most importantly, what you can actually do about it right now — without exposing yourself to unnecessary risks.

What This December 2025 NAD+ Study Actually Found

The research, published in Cell Reports Medicine on December 22, 2025, represents something we rarely see in Alzheimer's research: full reversal of cognitive deficits in advanced disease models.

The research team at Case Western Reserve University and University Hospitals used a compound called P7C3-A20, which activates an enzyme called NAMPT — the rate-limiting enzyme in your body's NAD+ recycling pathway.

Here's what they discovered:

In mice with advanced Alzheimer's disease, treatment with P7C3-A20 fully reversed cognitive deficits. Not slowed. Not stabilized. Reversed. According to the researchers, "both lines of mice fully recovered cognitive function."

The treatment addressed multiple disease processes simultaneously — reversing tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation.

Perhaps most significantly for translation to humans, the researchers identified 46 proteins that were abnormally expressed in the Alzheimer's mouse brain and normalized by treatment — and these same proteins show similar alterations in human Alzheimer's brains.

This suggests the mechanism might actually work in human brains.

The NDAN Paradox: Why Some People With Alzheimer's Pathology Never Show Symptoms

Here's where this research becomes especially relevant for APOE4 carriers thinking about long-term brain health.

Scientists have long studied a fascinating population called NDAN — Non-Demented with Alzheimer's Neuropathology. These are individuals whose brains, examined after death, show all the hallmarks of Alzheimer's disease: amyloid plaques, tau tangles, the full pathology.

But during their lives? They remained cognitively sharp. No symptoms. No decline.

How is this possible?

This December 2025 study suggests one key answer: preserved NAD+ levels.

The researchers found that people who maintain cognitive function despite having Alzheimer's pathology tend to have preserved NAD+ homeostasis. NAD+ appears to function as a "resilience factor" — protecting cognitive function even when disease pathology is present.

This aligns with what we know about APOE4: carriers have accelerated metabolic dysfunction and may experience faster NAD+ decline. The good news? We can actively support NAD+ through multiple pathways.

CRITICAL: The OTC Supplement Safety Warning Researchers Issued

This is the part that most people reporting on this study completely missed. And it's perhaps the most important section of this entire post.

The study authors issued a direct warning. Here's Dr. Pieper, one of the lead researchers:

Let that sink in. Dangerously high levels that promote cancer.

The researchers emphasized that their approach with P7C3-A20 is fundamentally different. It enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress — without elevating NAD+ to supraphysiologic levels.

Here's the critical distinction:

• P7C3-A20 activates NAMPT, allowing cells to produce NAD+ as needed while maintaining homeostatic balance

• OTC precursors like NMN and NR bypass this regulation entirely, potentially flooding cells with more NAD+ than they can safely handle

What Should You Do If You're Currently Taking NMN or NR?

1. Don't panic and stop immediately — that's not what the research suggests

2. Have a conversation with your doctor about these findings

3. Consider whether the potential risks align with your personal health situation (especially important if you have cancer risk factors)

4. Explore the natural NAD+ support strategies below as complementary or alternative approaches

Natural Strategies to Support NAD+ Levels (Without Supplement Risks)

While P7C3-A20 isn't available for human use yet, evidence-based lifestyle interventions can support your NAD+ levels through the same NAMPT pathway — without the theoretical risks of megadosing precursors.

Exercise: The Most Powerful NAD+ Intervention We Have

Both aerobic training and resistance training increase NAMPT expression — the same enzyme P7C3-A20 targets. Research shows that NAMPT levels remain positively associated with lean body mass and VO2 max.

This is why exercise consistently shows the strongest benefits for brain health across studies. It's directly hitting the NAD+ production pathway.

Fasting and Time-Restricted Eating

Caloric restriction and intermittent fasting activate AMPK and upregulate NAMPT. This metabolic stress signal tells your cells to ramp up their NAD+ recycling machinery.

Even a 16:8 eating window — eating within an 8-hour window and fasting for 16 hours — can activate these pathways without extreme interventions.

Ketogenic Diet: Especially Relevant for APOE4 Carriers

This deserves special attention for APOE4 carriers. Nick Norwitz, a Harvard-trained researcher who is himself an APOE4 carrier (along with both his parents), has published peer-reviewed research on precision nutrition for Alzheimer's prevention in APOE4 carriers. His work suggests ketogenic diets may be among the most powerful dietary interventions for those with this genetic variant.

Why it's particularly powerful for APOE4:

1. Ketones boost NAD+ through the AMPK/NAMPT pathway

2. Ketones bypass glucose hypometabolism — the reduced ability to use glucose for brain fuel that characterizes APOE4 brains

It's hitting the problem from two directions simultaneously.

Reducing NAD+ Consumption (Often Overlooked)

It's not just about making more NAD+ — it's also about consuming less of it.

Your body uses NAD+ to fight inflammation, repair oxidative damage, and fix DNA. If you're chronically inflamed, your NAD+ gets consumed faster than you can replenish it.

Priority interventions:

• Reduce chronic inflammation: Eliminate processed foods and seed oils, prioritize sleep, manage stress

• Natural CD38 inhibitors: CD38 is an enzyme that breaks down NAD+. Quercetin (found in capers, red onions, kale, broccoli) and apigenin (found in chamomile tea, parsley, thyme, oregano) have been shown to inhibit CD38 activity

Your Action Steps for This Week

Key Takeaways

• December 2025 breakthrough: Researchers demonstrated full reversal of cognitive deficits in advanced Alzheimer's mouse models by restoring NAD+ homeostasis — challenging the dogma that AD is irreversible

• NAD+ as resilience factor: People who remain cognitively intact despite Alzheimer's pathology (NDAN individuals) have preserved NAD+ levels — suggesting NAD+ protects cognition independent of pathology

• Critical supplement warning: Study authors explicitly warn that OTC NAD+ precursors may raise levels to "dangerously high levels that promote cancer" — the P7C3-A20 compound works differently by maintaining homeostasis

• Natural support available now: Exercise, fasting, ketogenic diet, and CD38 inhibitors (quercetin, apigenin) can support NAD+ through the same NAMPT pathway without theoretical overdose risks

• APOE4 relevance: Carriers may experience faster NAD+ decline and benefit especially from ketogenic approaches that both boost NAD+ and bypass glucose hypometabolism

Track Your Progress With Phoenix

If you're an APOE4 carrier implementing these strategies, tracking matters. Inside Phoenix, our bloodwork module helps you monitor inflammatory markers (hs-CRP, IL-6), metabolic health (fasting glucose, insulin, HbA1c), and lipid panels optimized for APOE4 ranges.

Our supplement tracking module lets you log NMN, NR, or natural CD38 inhibitors alongside your biomarker data — so you can see what's actually moving the needle for your biology.

At the time of writing, over 400+ APOE4 carriers are already running n-of-1 experiments and sharing what works. If you've been looking for a community that takes this as seriously as you do, we'd love to have you.

If you are not a member yet, and have read until here, you definitely will fit with us.
Join Phoenix here!

Sources

1. Chaubey K, et al. (2025). Pharmacologic reversal of advanced Alzheimer's disease in mice and identification of potential therapeutic nodes in human brain. Cell Reports Medicine. December 22, 2025. DOI: 10.1016/j.xcrm.2025.102535.^[DOI] https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1

2. Harrington Discovery Institute / Case Western Reserve University Press Release. (2025). New study shows Alzheimer's disease can be reversed to achieve full neurological recovery. December 22, 2025. https://www.harringtondiscovery.org/news-media/2025/12/22/new-study-shows-alzheimers-disease-can-be-reversed-in-animal-models-to-achieve-full-neurological-rec

3. Wu et al. (2025). Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment. Alzheimer's & Dementia: Translational Research & Clinical Interventions. https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70023

4. Wang G, et al. (2014). P7C3 Neuroprotective Chemicals Function by Activating the Rate-limiting Enzyme in NAD Salvage. Cell. https://pmc.ncbi.nlm.nih.gov/articles/PMC4163014/

5. NAD+ reverses Alzheimer's neurological deficits via regulating differential alternative RNA splicing of EVA1C. (2025). Science Advances. November 2025. https://www.science.org/doi/10.1126/sciadv.ady9811

6. Zhao et al. (2023). P7C3-A20 Attenuates Microglial Inflammation and Brain Injury after ICH through Activating the NAD+/Sirt3 Pathway. Oxidative Medicine and Cellular Longevity. https://pmc.ncbi.nlm.nih.gov/articles/PMC9936507/

7. Norwitz N. (2026). Never get Alzheimer's Disease: The NAD+ Breakthrough. Stay Curious Metabolism. January 2, 2026. https://staycuriousmetabolism.substack.com/p/never-get-alzheimers-disease-the

8. Norwitz NG, et al. (2021). Precision Nutrition for Alzheimer's Prevention in ApoE4 Carriers. Nutrients. 13(4):1362. https://www.mdpi.com/2072-6643/13/4/1362

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