The NAD+ Breakthrough Every APOE4 Carrier Must Know (And a Warning about Your Supplements)
APOE4: Beat the OddsSummary
A recent study published on December 22, 2025, challenges the long-held belief that Alzheimer's disease is irreversible, suggesting that cognitive deficits in advanced Alzheimer's models can be fully reversed. The research, conducted by teams at Case Western Reserve University and University Hospitals, highlights the role of NAD+ (nicotinamide adenine dinucleotide) in maintaining cognitive function, particularly for individuals with the ApoE4 gene variant, which significantly increases the risk of developing Alzheimer's.
The study found that a compound called P7C3A20, which activates an enzyme involved in NAD+ production, successfully reversed cognitive deficits in mice with advanced Alzheimer's. The researchers noted that preserving NAD+ levels may be crucial for cognitive resilience, as individuals who remain cognitively intact despite Alzheimer's pathology often have maintained NAD+ levels. However, the study also issued a stark warning regarding over-the-counter NAD+ precursors, such as NMN and NR, which can raise NAD+ levels to potentially dangerous heights that may promote cancer.
In light of these findings, the podcast emphasizes the importance of natural methods to support NAD+ levels, including regular exercise, fasting, and dietary adjustments, particularly for ApoE4 carriers. The discussion encourages proactive approaches to brain health while awaiting further developments in treatment options like P7C3A20.
Show Notes
Originally published on YouTube on 1 March 2026. Original video: https://www.youtube.com/watch?v=-uu0L2Y-PlI Free guide: The APOE4 Supplement Guide https://thephoenix.community/guides/supplement-guide A December 2025 Cell Reports Medicine study reported cognitive recovery in mouse models of advanced Alzheimer's after restoring NAD+ homeostasis. I explain the study, the researchers' warning about over-the-counter NAD+ precursors, and the exercise, diet and inflammation strategies discussed in the episode. RESOURCES Apply to join Phoenix: https://apoe4.link/NAD Essential APOE4 Guide: https://apoe4.link/NADG Weekly Newsletter: https://apoe4.link/NADN CHAPTERS 00:00 Introduction 01:45 What is NAD+ and why it matters 02:40 The Alzheimer's Paradox: NDAN Individuals 03:43 The breakthrough study explained 04:47 Safety warning about supplements 07:13 Natural ways to support NAD+ 09:46 Reducing NAD+ consumption 10:50 Key takeaways 14:42 Conclusion ORIGINAL LINKS AND REFERENCES Ketosis and APOE4: Why Generic Keto Fails (And What Actually Works) https://youtu.be/ayi3qDYeYvo Zone 2 Training for APOE4: Your Exact Heart Rate Targets For Maximum Brain Health - https://youtu.be/XnRBrxA0Z_U https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1 Harrington Discovery Institute / Case Western Reserve University Press Release: 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 Wu et al. (2025). NR supplementation clinical trial: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70023 Nick Norwitz NAD+ analysis: https://staycuriousmetabolism.substack.com/p/never-get-alzheimers-disease-the Norwitz NG, et al. (2021). Precision Nutrition for Alzheimer's Prevention in ApoE4 Carriers: https://www.mdpi.com/2072-6643/13/4/1362
More from APOE4: Beat the Odds
Originally published on YouTube on 17 February 2026. Original video: https://www.youtube.com/watch?v=ayi3qDYeYvo Free guide: The APOE4 Metabolic Guide https://thephoenix.community/guides/metabolic-guide As an APOE4/4 carrier, I have spent years researching and experimenting with ketogenic approaches. I compare the clinical trials, explain the differences between MCTs, and walk through my cycling approach and a framework for adapting ketosis to APOE4. RESOURCES Apply to join Phoenix: https://apoe4.link/Keto Essential APOE4 Guide: https://apoe4.link/KetoG Weekly Newsletter: https://apoe4.link/KetoN CHAPTERS 00:00 Introduction 00:39 The Brain Energy Crisis 02:20 Why Generic Keto Fails APOE4 Carriers 05:57 APOE4-Specific Modifications 07:52 The Cycling Approach - When to Use Ketosis 11:34 Practical Application 13:53 Key Takeaways 15:44 Conclusion ORIGINAL LINKS AND REFERENCES AC-1202 Trial (Henderson et al., 2009): https://pmc.ncbi.nlm.nih.gov/articles/PMC2731764/ BENEFIC Trial (Fortier et al., 2021): https://pmc.ncbi.nlm.nih.gov/articles/PMC8048678/ MCT Ketogenic Effects (Lin et al., 2021): https://pmc.ncbi.nlm.nih.gov/articles/PMC8650700/ Brain Ketone Review (Cunnane et al., 2016): https://pmc.ncbi.nlm.nih.gov/articles/PMC4937039/ APOE4 Neuroimaging (Brandon et al., 2018): https://www.frontiersin.org/journals/aging-neuroscience/articles/10.3389/fnagi.2018.00180/full APOE4+ Case Study (Morrill & Gibas, 2019): https://pubmed.ncbi.nlm.nih.gov/31336463/ Ketones & Neurodegeneration (Jensen et al., 2020): https://pmc.ncbi.nlm.nih.gov/articles/PMC7699472/ Exogenous Ketones (Stubbs et al., 2017): https://pmc.ncbi.nlm.nih.gov/articles/PMC5670148/ Keto & Athletes (McSwiney et al., 2019): https://pmc.ncbi.nlm.nih.gov/articles/PMC6863116/ Keto & Performance 2023 (Borszcz et al., 2023): https://pubmed.ncbi.nlm.nih.gov/37144460/ APOE4 & Saturated Fat (Griffin et al., 2018): https://pmc.ncbi.nlm.nih.gov/articles/PMC6213759/ Ketosis & Cognition Review (Altayyar et al., 2022): https://pmc.ncbi.nlm.nih.gov/articles/PMC8840718/
Two copies of APOE4. Does every memory lapse mean something, and would more testing help? Dr. Gayatri Devi explains why she starts with a cognitive baseline, not constant self-checking. Dr. Devi directs Park Avenue Neurology in New York and is Clinical Professor of Neurology and Psychiatry at the Zucker School of Medicine at Hofstra/Northwell. I went in with concerns Phoenix members had raised about memory lapses and testing before symptoms. I did not ask the submitted questions on camera. Several of those concerns still came up. WANT YOUR QUESTION IN THE NEXT INTERVIEW? Members can submit questions before future interviews. Not every question fits. Phoenix also helps you build your personal protocol, review your own blood tests and find support from other carriers. Apply to join Phoenix: https://apoe4.link/GayatriQnA1 RESOURCES → Brain Biomarker Guide: https://apoe4.link/GayatriQnA1G → Free newsletter: https://apoe4.link/GayatriQnA1N → Free Clinical Trial Engine: https://apoe4.link/GayatriQnA1C A NOTE ON WHAT THIS IS Educational, not medical advice or a product endorsement. Take this to your own clinician. APOE4 is a risk factor, not a diagnosis. KEY TAKEAWAYS 1. A useful baseline measures more than memory. Language, visual-spatial skills and switching tasks also matter. An age-average score may not reflect your own earlier ability. 2. Repeating tests can improve test familiarity. Dr. Devi tells her patients to leave at least a year between routine assessments. This is not a rule to delay care for new symptoms. 3. A positive p-tau217 result needs context. She discusses whether amyloid is present, not a person's odds of developing dementia. 4. She notes that most people in their 80s with amyloid are cognitively intact. That does not mean someone will never develop symptoms. Her amyloid case series is unpublished. 5. Her priorities include aerobic exercise, blood vessel health, sleep and stress. Her more proactive views on scans and treatment before symptoms go beyond the guidance and trial evidence she describes. QUESTIONS FOR YOUR CLINICIAN What would this test measure? How would you interpret it for someone like me? What would change after a positive, negative or unclear result? These are discussion prompts, not a testing or treatment protocol. Full sources and limits are in the original YouTube description. WHAT WE COVER 00:00 Teaser 01:10 Why a second APOE4 copy matters 02:34 What two copies of APOE4 means, and why age at discovery matters 05:22 What a proper baseline test includes 07:42 Practice effect: how often to retest 08:54 Biomarkers vs. real risk: why plaques don't always mean dementia 14:41 How reliable is the P-tau217 blood test? 16:01 Handling the anxiety: sleep and other no-brainer interventions 17:58 Amyloid scans for people without symptoms 20:08 The amyloid hypothesis and anti-amyloid drugs 24:17 ARIA brain bleed risk and slow dosing 26:48 Final advice from Dr. Devi 28:30 Outro: Kevin's three takeaways
Originally published on YouTube on 25 February 2026. Original video: https://www.youtube.com/watch?v=XnRBrxA0Z_U Free guide: The APOE4 Exercise Protocol https://thephoenix.community/guides/exercise-protocol I explain Zone 2 training for APOE4 carriers: how the MAF formula estimates a heart-rate range, how to use the talk test, what to track and how to combine aerobic training with higher-intensity exercise. The episode includes a sample training week and the research behind the approach. RESOURCES Apply to join Phoenix: https://apoe4.link/Zone2 Essential APOE4 Guide: https://apoe4.link/Zone2G Weekly Newsletter: https://apoe4.link/Zone2N CHAPTERS 00:00 Introduction 02:06 Why Zone 2 Matters for APOE4 Brains 05:07 Calculating Your Zone 2 Heart Rate 05:40 MAF Formula Calculation 10:04 Tracking Methods and Weekly Protocol 11:56 Why You Need HIIT Too 13:47 Key Takeaways 15:22 Conclusion ORIGINAL LINKS AND REFERENCES - Erickson et al. 2011 - Aerobic exercise increases hippocampal volume by 2% https://pubmed.ncbi.nlm.nih.gov/21282661/ - Kaufman et al. 2021 - APOE4 carriers show greater blood flow improvement from exercise https://pmc.ncbi.nlm.nih.gov/articles/PMC8327103/ - De la Rosa et al. 2020 - Meta-analysis: 45% AD risk reduction from regular exercise https://pmc.ncbi.nlm.nih.gov/articles/PMC7498620/ - Tokgoz & Claassen 2021 - Exercise as treatment for APOE4 carriers (systematic review) https://pmc.ncbi.nlm.nih.gov/articles/PMC8126521/ - FINGER Trial - Lifestyle interventions benefit APOE4 carriers MORE https://www.alzdiscovery.org/cognitive-vitality/blog/healthy-lifestyle-changes-may-benefit-cognition-in-older-people-with-apoe4 - Hu et al. 2021 - HIIT stimulates BDNF expression in hippocampus https://pmc.ncbi.nlm.nih.gov/articles/PMC7946986/ - Park et al. 2021 - High-intensity exercise and hippocampal mitochondrial biogenesis https://pmc.ncbi.nlm.nih.gov/articles/PMC8481603/
Originally published on YouTube on 15 April 2026. Original video: https://www.youtube.com/watch?v=Xoq4DTX_YtM Free guide: The APOE4 Diet Playbook https://thephoenix.community/guides/diet-playbook What did the 2026 JAMA Network Open study actually find about meat and APOE4? I walk through the study, processed versus unprocessed meat, its limitations and what I am doing with the findings, alongside the broader research on lifestyle and cognition. RESOURCES Apply to join Phoenix: https://apoe4.link/Meat Essential APOE4 Guide: https://apoe4.link/MeatG Weekly Newsletter: https://apoe4.link/MeatN CHAPTERS 00:00 Introduction 01:16 What the Study Found 03:16 Processed vs Unprocessed Meat 04:55 Why This Doesn’t Prove Cause 05:20 Limits of this study 07:42 What Should APOE4 Carriers Eat? 11:06 Lifestyle Matters More 13:49 Conclusion ORIGINAL LINKS AND REFERENCES 1. Norgren J et al. "Meat Consumption and Cognitive Health by APOE Genotype." JAMA Network Open. 2026 https://doi.org/10.1001/jamanetworkopen.2026.6489 2. Jin X et al. "APOE e4 genotype and lifestyle with cognitive function." PLoS Med. 2021 https://doi.org/10.1371/journal.pmed.1003597 3. Zhong WF et al. "Combined effects on cognitive impairment with APOE consideration." Alzheimers Res Ther. 2025 https://doi.org/10.1186/s13195-025-01806-7 4. Moon SY et al. "SUPERBRAIN-MEET RCT." Alzheimers Dement. 2025 https://doi.org/10.1002/alz.14517 5. Sun Y et al. "Cognitive Activities, Lifestyle, and APOE4." Gerontology. 2023 https://doi.org/10.1159/000531109 6. Clinical Trial: ALA Nutrition for APOE4 MCI (NCT07392723) https://clinicaltrials.gov/study/NCT07392723
Originally published on YouTube on 27 April 2026. Original video: https://www.youtube.com/watch?v=oY_R_VOiwys Free guide: The APOE4 Woman's Guide https://thephoenix.community/guides/womens-guide Should APOE4 carriers consider hormone replacement therapy? I review research on HRT, menopause, testosterone and Alzheimer's risk, including the Women's Health Initiative, timing, formulation, APOE4-specific findings and the clinical trials discussed in this April 2026 recording. RESOURCES Apply to join Phoenix: https://apoe4.link/HRT Essential APOE4 Guide: https://apoe4.link/HRT-G Weekly Newsletter: https://apoe4.link/HRT-N CHAPTERS 00:00 Introduction 02:23 WHI Study What Was Studied vs What Wasn't 06:31 The Critical Window : Timing Is Everything 09:38 Why ApoE4 Changes Everything 14:19 Formulation Matters: Patches, Pills & Progesterone 19:09 Men, APOE4 & Testosterone 22:44 Clinical Trials Being Studied Right Now 23:10 Active Clinical Trials 26:19 5 Steps To Take This Week ORIGINAL LINKS AND REFERENCES Saleh et al. 2023 (EPAD): https://doi.org/10.1186/s13195-022-01121-5 Melville et al. 2025 (Lancet): https://doi.org/10.1016/j.lanhl.2025.100803 Nerattini et al. 2023: https://doi.org/10.3389/fnagi.2023.1260427 Whitmer et al. 2011: https://doi.org/10.1002/ana.22239 Kantarci et al. 2016 (KEEPS): https://doi.org/10.3233/JAD-160258 Wang/Brinton 2025: https://doi.org/10.3389/fnagi.2025.1632877 Blanchard et al. 2022 (Nature): https://doi.org/10.1038/s41586-022-05439-w Yeap & Flicker 2022: https://doi.org/10.1007/s11154-022-09728-7 Burkhardt et al. 2006: https://doi.org/10.1210/jc.2005-1072