Never get Alzheimer’s Disease: The NAD Breakthrough
In a Nutshell
Alzheimer's disease stems from NAD depletion disrupting brain energy metabolism, not just amyloid plaques, as evidenced by cognitively normal people with plaques who maintain high NAD levels, and mouse models where boosting NAD via NAMPT activators like P7C3A20 prevents/reverses cognitive deficits, amyloid/tau buildup, neuroinflammation, and blood-brain barrier dysfunction. Human data confirms NAD imbalances in Alzheimer's, with parallels to animal findings. Boost NAD naturally through exercise, fasting/ketogenic diets (via AMPK-NAMPT activation), precursors like NMN/NR (600-900mg daily), and reducers of consumption like quercetin/apigenin, plus personalized options like Lyso-DHA and low-dose lithium orotate.
These notes were generated by AI and may contain inaccuracies.
This new paper changed the way I think about Alzheimer's disease and gave hope for preventing it in myself, my family, and the field of Alzheimer's research. For decades, Alzheimer's has been treated as a problem of amyloid plaques in the brain, with attempts to scrape them away failing. 99.6% of Alzheimer's drugs have failed, flushing tens of billions of dollars down the toilet because we've been barking up the wrong tree. Alzheimer's is a problem of energy metabolism and energy trafficking in the brain. Fixing the energy problem could prevent or even reverse Alzheimer's.
Our results, our data challenge the long-held view that Alzheimer's disease is intrinsically irreversible. The amyloid plaques are not sufficient to cause dementia. We open up a radically different new therapeutic window.
For more details, full references, and related content, check the bestselling Science Stay Curious Metabolism newsletter linked below.
Five main chapters:
- NAD, the brain's metabolic lynchpin, and why it matters in Alzheimer's.
- The amyloid Alzheimer's paradox: some people stay sharp despite Alzheimer's pathology.
- Lab breakthrough: boosting NAD prevents or reverses Alzheimer's in animal models.
- Human data: evidence these mechanisms apply to us.
- Action steps: natural ways to support NAD for brain health.
NAD (nicotinamide adenine dinucleotide) is a vital compound in every cell, playing foundational roles in energy metabolism. It functions as an electron carrier, shuttling electrons through glycolysis (carb burning), beta oxidation (fat burning), TCA cycle, oxidative phosphorylation in mitochondria. Energy production relies on NAD; without it, cells don't function, mitochondria fail, energy collapses.
NAD levels decline with age and especially in metabolic diseases like Alzheimer's. Faster, more severe decline leads to pathological states: mitochondrial dysfunction, disrupted cellular signaling, Alzheimer's.
Classical hallmark of Alzheimer's: amyloid plaques. But they are not sufficient to cause dementia. 20-50% of human brains with high amyloid plaque burden are cognitively normal, no dementia (nondemented with Alzheimer's neuropathology).
Key distinction: higher NAD levels in cognitively normal brains with amyloid act as a resilience factor, buffering neuronal function despite Alzheimer's hallmarks. Alzheimer's brains are depleted in NAD/NADH ratio.
If NAD depletion drives Alzheimer's, restoring or preserving NAD levels could defend against or reverse it.
Researchers used 5xFAD mouse model of Alzheimer's. NAD levels declined 30% at 6 months, 45% by 1 year.
Treated with P7C3A20 (NAD booster), an NAMPT activator that creates NAD.
- Prevented NAD depletion.
- Prevented/reversed deficits in spatial learning/memory (Morris Water Maze, novel object recognition).
- Prevented/reversed impairments in motor learning/coordination, anxiety-like behaviors.
Long-term potentiation (LTP, cellular basis of learning/memory): decayed in untreated mice; preserved/restored with NAD boost, recovering neuronal learning capacity.
Neuropathology:
- Reversed amyloid accumulation.
- Obliterated phosphorylated tau (p-tau, creates neurofibrillary tangles, biomarker in blood).
- Rescued blood-brain barrier dysfunction (prevents/reverses leakiness, improves toxin clearance, cerebral blood flow).
- Reversed neuroinflammation (astrocytes, microglia shift to pro-inflammatory state; NAD calms them).
Findings replicated in PS19 mouse model; boosting NAD even at terminal stages recovered cognitive deficits.
Our results challenge the long-held view that Alzheimer's disease is intrinsically irreversible and position the restoration of brain NAD homeostasis as a potentially transformative therapeutic approach.
In human Alzheimer's, NAD disruption is dominant, correlates with tau pathology. Cognitively normal with amyloid have higher NAD.
Enzymes: increased NAD breakdown (consumption), decreased NAD production in Alzheimer's, tipping balance toward depletion.
Parallels between mouse/human: NAD depletion/replenishment affected gene expression/proteins conserved, supporting relevance to humans.
Three NAD pathways:
- Preiss-Handler (niacin).
- De novo (tryptophan).
- Salvage pathway (main for NAD recycling/production; NAMPT rate-limiting enzyme).
Activate NAMPT:
- AMPK (energy sensor) via exercise, fasting, ketogenic diets activates NAMPT.
- Ketogenic diets: increase NAD; neuroprotective (clear misfolded proteins, reduce neuroinflammation, provide ketone fuel).
- Exercise: aerobic/resistance training increase NAMPT; associated with lean mass, V2 max. Improves aerobic fitness/muscle mass boosts NAD > supplements. Exercise is brain medicine.
Reduce NAD consumption (by PARPs, CD38 activated by oxidative stress/inflammation):
- Improve metabolic health: sleep, physical activity, nutrient-dense whole food diet.
- Over age 60: antioxidants like astaxanthin (endogenous defenses decline).
- CD38 inhibitors: quercetin (capers, red onions), apigenin (chamomile tea). Cumulative nudges, not silver bullets.
NAD precursors: nicotinamide riboside (NR), nicotinamide mononucleotide (NMN) increase NAD (e.g., 600-900mg NMN daily in RCT increased blood NAD, improved performance/health).
Checklist:
- Support production (salvage): exercise (V2 max, muscle), fasting/ketogenic (AMPK->NAMPT), NMN/NR.
- Reduce consumption: lower inflammation/oxidative stress, antioxidants (>60), quercetin/apigenin.
Personal supplements:
- Lyso-DHA (lysophosphatidylcholine DHA, 2 capsules daily; crosses BBB better; for APOE4 carrier).
- Microdose lithium orotate (5mg/day; emerging data for prevention).
Alzheimer's not a one-way street. Focus on restoring brain's energetic foundation (NAD) opens new therapeutic window. NAD as gatekeeper of brain resilience. Not a cure-all, but progress with actionable strategies. Offers hope grounded in biology.
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