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Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain.

See https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1

(Chaubey et al., Cell Reports Medicine, 2025)

Your body has a built-in "NAD+ thermostat." In your youth, this system keeps NAD+ levels perfectly tuned. As we age (and especially in Alzheimer’s), the machinery doesn't just run out of fuel; it breaks down and begins to "leak" or "over-consume," leading to an energy crisis.

Here is the breakdown of the problem and the "machine-fixing" solutions.

1. The Problem: The "Drain" vs. The "Refill"

The paper highlights that in Alzheimer's and aging, NAD+ levels decline because the homeostatic balance is lost.

• The "Leak" (Consumption): Enzymes like CD38 and PARPs act like open drains. As inflammation increases (inflammaging), CD38 becomes hyperactive and starts "eating" NAD+ faster than your body can make it.
• The "Broken Pump" (Recycling): Your body is designed to recycle 99% of its NAD+ through the Salvage Pathway. The key engine here is an enzyme called NAMPT. In aging, this pump slows down.
• The "Waste Management" (NNMT): When the system is stressed, an enzyme called NNMT starts tagging the broken-down NAD+ (nicotinamide) to be thrown out in your urine rather than recycled.

The Study’s Insight: Simply dumping more NMN/NR (precursors) into the system is like trying to fill a bathtub without plugging the drain. The study used a compound (P7C3-A20) that helps the cell maintain its own balance.

2. Fixing the Machinery: Supplement Solutions

If you want to fix the "thermostat" rather than just "crank the heat" with NMN/NR, you look at supplements that target the enzymes responsible for the drain and the pump.

A. Plug the Drain: CD38 Inhibitors

CD38 is the primary "sink" that wastes NAD+ as we age.

• Supplement: Apigenin (found in chamomile and parsley) or Luteolin.
• The Fix: These are potent natural inhibitors of CD38. By slowing down CD38, you "plug the drain," allowing your body's natural NAD+ levels to rise and stabilize without external precursors.

B. Repair the Recycling Pump: NAMPT Activators

NAMPT is the rate-limiting "recycling engine." If this isn't working, no amount of NMN will help long-term.

• Solution: Aerobic & Resistance Exercise.
• The Fix: Exercise is the most powerful known activator of NAMPT. It literally upgrades the machinery so your cells become better at recycling the NAD+ they already have.

C. Stop the Waste: NNMT Inhibition

If your body is throwing away too much of the "spent" NAD+ (nicotinamide), you lose your raw materials.

• Supplement: Methyl Donors (TMG / Betaine).
• The Fix: While not a direct inhibitor, TMG helps manage the methylation process. High-dose NAD+ boosting can "drain" your methyl groups as the body tries to excrete excess nicotinamide. Taking TMG ensures that the "garbage disposal" (methylation) doesn't steal resources from other vital processes like DNA repair.

The "Paper" Conclusion

The Cell Reports Medicine study suggests that P7C3-A20 (a small molecule) could reverse Alzheimer’s because it didn't just "boost" NAD+; it stabilized the energy balance. For someone looking to follow this "machinery" philosophy today, the strategy would be:

• Inhibit the Drain: Apigenin (to stop CD38 from wasting NAD+).
• Activate the Pump: Exercise (to upregulate the NAMPT recycling enzyme).
• Protect the System: Quercetin or Fisetin (to clear out "senescent cells" which are the main source of the inflammation that triggers the NAD+ drain).