Restoring Brain Energy Molecule NAD+ Reverses Alzheimer’s in Mice

Scientists just accomplished something Alzheimer’s researchers have chased for more than a century. For decades, medical experts believed brain damage from Alzheimer’s disease moved in only one direction: worse. Once neurons died and toxic proteins accumulated, nothing could undo the destruction. Patients and families watched helplessly as memories disappeared and personalities changed, knowing medicine offered no way back. A team at University Hospitals Cleveland Medical Center tested a different approach in mice with advanced Alzheimer’s disease. What happened next challenges everything we thought we knew about whether dementia can be reversed. Brain tissue that looked hopeless transformed back toward normal. Cognitive abilities that vanished came flooding back. Results suggest some forms of memory loss might not be permanent after all.

What Scientists Discovered About Brain Energy

Researchers at University Hospitals Cleveland Medical Center, working with Case Western Reserve University and Louis Stokes Cleveland VA Medical Center, analyzed two different Alzheimer’s mouse models plus human Alzheimer’s brain tissue. Every sample showed the same problem: severe declines in a molecule called NAD+.

NAD+ serves as a central cellular energy molecule that cells need for basic survival functions. Dr. Andrew A. Pieper, senior study author and director of the Brain Health Medicines Center at Harrington Discovery Institute, explained that this enzyme proves essential for energy production, cell maintenance, and long-term cell health.

Levels naturally decline as people age, but Alzheimer’s brains showed drastically lower amounts than normal aging alone could explain. When NAD+ falls below necessary thresholds, cells cannot perform essential maintenance and survival functions. Brain cells become unable to repair damage, clear out toxic proteins, or generate enough energy to function properly.

Human brains consume around 20 percent of total body energy despite representing only about 2 percent of body weight. Neurons demand enormous amounts of fuel to fire electrical signals, maintain connections, and perform constant repair work. Without adequate NAD+ to power these energy-intensive processes, brain cells struggle and eventually die.

Dr. Charles Brenner, chief scientific advisor for Niagen and an expert on NAD+ biology who was not involved in the study, noted that brain tissue has particularly high demands for NAD+ because of cellular energy production needs and DNA repair requirements. Neurons must adapt to various physiological stresses and support processes associated with brain health, all of which depend on sufficient NAD+ availability.

Previous research from the same laboratory demonstrated that restoring NAD+ balance helped speed recovery after severe traumatic brain injury. Evidence suggested this molecule played a crucial role in brain resilience and repair capacity. Those findings led researchers to wonder whether NAD+ restoration might help with Alzheimer’s disease as well.

How a Medication Changed Everything

Scientists tested a medication called P7C3-A20 in mouse models with Alzheimer’s disease. P7C3-A20 works by restoring normal levels of NAD+ throughout the brain. Rather than directly attacking amyloid plaques or tau tangles like most experimental Alzheimer’s treatments, this approach targeted the underlying energy crisis.

Researchers gave the medication to mice at different stages of disease progression. Some received treatment before significant brain changes occurred, while others already showed advanced Alzheimer’s pathology with extensive protein buildup and cognitive decline.

Results varied by disease stage but proved remarkable across the board. In mice treated before major brain changes developed, P7C3-A20 blocked the onset of Alzheimer’s disease. Brain tissue remained health,y and cognitive function stayed normal despite genetic predispositions toward developing the disease.

Even more striking outcomes appeared in mice with advanced Alzheimer’s disease. Animals already showing severe brain pathology and profound memory loss received the NAD+-restoring medication. Brain tissue analysis after treatment revealed something researchers had never seen before in Alzheimer’s models.

Amyloid plaques and tau tangles, the hallmark protein buildups that define Alzheimer’s disease, reversed dramatically. Protein deposits that had accumulated over time began clearing from the brain tissue. Tau tangles that had twisted into destructive formations started unraveling. Brain tissue architecture began returning toward normal patterns.

Cognitive function in these animals improved just as dramatically. Memory tests that mice had failed before treatment now showed normal performance. Behavioral assessments demonstrated restored brain function across multiple domains. Animals that had lost the ability to navigate mazes, recognize objects, or remember previous experiences regained these capacities.

Blood analysis showed another promising finding. Treated mice demonstrated normalized levels of phosphorylated tau 217, an important biomarker that doctors use in human Alzheimer’s research. Elevated phosphorylated tau 217 in blood signals ongoing brain degeneration in people. Seeing this marker return to normal suggested deep biological changes rather than superficial improvements.

Why This Discovery Matters So Much

Dr. Pieper emphasized that for more than a century, Alzheimer’s has been considered irreversible. Medical textbooks taught students that once dementia began, nothing could stop or reverse the process. Experimental treatments aimed at slowing decline or preventing disease onset, not undoing damage already done.

Experiments now provide proof of principle that some forms of dementia may not be inevitably permanent. If brain energy metabolism can be restored, even severely damaged neural networks might recover function. Neurons that appeared dead or dying might retain capacity for repair and regeneration, given proper metabolic support.

Researchers felt struck by how robustly advanced Alzheimer’s reversed in mouse brains when NAD+ homeostasis was restored. Treatment did not directly target amyloid plaques, yet those toxic deposits cleared anyway. The approach focused on restoring normal cellular metabolism rather than attacking specific disease proteins.

Results suggest that energy failure might drive Alzheimer’s progression more than previously recognized. Amyloid and tau accumulation could be consequences of failing cellular energy rather than primary causes. Restoring proper energy metabolism might allow cells to clear protein buildups through their natural quality control systems.

Brain cells possess sophisticated machinery for identifying and removing damaged proteins. Under normal conditions, these quality control systems prevent toxic accumulation. When energy runs low, cleanup systems fail, and proteins pile up. Restoring energy availability could restart these protective mechanisms.

Research demonstrates potential benefits of NAD+ supplementation in brain health conditions beyond Alzheimer’s disease. Parkinson’s disease and ataxia telangiectasia also show links to NAD+ deficiency. Multiple neurodegenerative conditions might share underlying metabolic problems despite different symptoms and protein accumulations.

What Works in Mice Might Not Work in People

Study authors acknowledge significant limitations that temper enthusiasm about immediate human applications. Research was conducted only in mouse models and may not directly translate to human disease. Mice and humans share many biological similarities but differ in crucial ways.

Dr. Pieper stressed that Alzheimer’s is a complex, multifactorial, uniquely human disease. Mouse models capture some aspects of pathology but cannot replicate the full disease experience. Genetic, environmental, lifestyle, and aging factors interact differently in humans than in laboratory mice.

Efficacy in animal models does not guarantee the same results in human patients. Many treatments that worked beautifully in mice failed miserably in human clinical trials. Dozens of experimental Alzheimer’s drugs showed promise in animals but proved ineffective or harmful in people.

Mouse lifespans measure months while human lifespans measure decades. Alzheimer’s develops over 20 or 30 years in people, with protein accumulation beginning long before symptoms appear. Mouse models accelerate disease progression into weeks or months through genetic modifications. Whether treatments effective in rapid-onset mouse disease will work in slow-developing human disease remains unknown.

Human brains are vastly more complex than mouse brains. Humans possess larger prefrontal cortices, more elaborate neural networks, and different patterns of protein processing. Medications that restore function in relatively simple mouse brains might not navigate the complexity of human neural architecture as successfully.

Safety concerns also require careful evaluation. Treatments that mice tolerate well sometimes cause serious side effects in humans. Dose levels, administration routes, and treatment duration all need optimization for human physiology. Years of clinical trials lie ahead before any NAD+-restoring medication could become available for Alzheimer’s patients.

Still, findings provide reason for cautious optimism that similar strategies may one day benefit people. Understanding that energy metabolism plays such a crucial role in disease progression opens new avenues for treatment development. Rather than focusing exclusively on protein removal, researchers can now explore metabolic restoration approaches.

My Personal RX on Supporting Brain Energy and Cognitive Function

Brain energy metabolism declines with age in everyone, not just people developing Alzheimer’s disease. Supporting your brain’s ability to generate and use energy becomes increasingly important as you get older. While we wait for medications like P7C3-A20 to go through human trials, you can take steps now to optimize NAD+ levels and brain energy production through lifestyle choices, nutrition, and targeted supplements. Protecting cognitive function requires a multi-pronged approach that addresses energy metabolism, reduces inflammation, supports mitochondrial health, and provides brain cells with the nutrients they need for repair and maintenance.

1. Eat Foods That Support NAD+ Production: Milk, fish, mushrooms, green vegetables, and whole grains contain NAD+ precursors that your body converts into active forms. Include these foods daily to provide the raw materials your cells need for energy production. Vitamin B3 (niacin) serves as a direct NAD+ precursor.
   
2. Exercise to Boost Brain Energy Metabolism: Physical activity increases NAD+ levels, improves mitochondrial function, and promotes brain-derived neurotrophic factor production. Aim for at least 30 minutes of moderate exercise most days, combining aerobic activity with strength training for maximum cognitive benefits.
   
3. Prioritize Deep Sleep for Brain Cleanup: Your brain clears toxic proteins and restores energy reserves during deep sleep stages. Sleep Max contains magnesium, GABA, 5-HTP, and taurine that promote restorative REM sleep, giving your brain optimal conditions for maintenance, repair, and energy restoration that protects against cognitive decline.
   
4. Consider NAD+ Precursor Supplements: Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ precursors available as supplements. While human trials continue, preliminary evidence suggests these compounds may safely boost NAD+ levels. Discuss appropriate doses with your healthcare provider before starting.
   
5. Fill Nutritional Gaps After 40: Your body’s ability to produce and use NAD+ declines with age, partly due to nutrient deficiencies. The 7 Supplements You Can’t Live Without is a free guide explaining which nutrients support brain energy metabolism, the key supplements that restore optimal levels, and how to identify quality products that deliver real results.
   
6. Limit Alcohol and Avoid Smoking: Both alcohol and tobacco accelerate NAD+ depletion and impair mitochondrial function. If you drink, keep consumption light and occasional. Quit smoking entirely to protect brain energy systems and reduce oxidative stress that damages neurons.
   
7. Manage Chronic Stress Actively: Stress hormones deplete NAD+ reserves and impair energy production throughout your body, especially in the brain. Practice daily stress reduction through meditation, deep breathing, yoga, or other relaxation techniques that calm your nervous system and preserve cellular energy stores.
   
8. Stay Mentally Active to Maintain Neural Networks: Cognitive stimulation keeps brain cells active and energy-demanding, which signals your body to maintain robust energy production systems. Challenge your mind with learning, puzzles, reading, creative hobbies, and social interactions that keep neural networks firing and energy metabolism high.

Source: Chaubey, K., Vázquez-Rosa, E., Tripathi, S. J., Shin, M., Yu, Y., Dhar, M., Chakraborty, S., Yamakawa, M., Wang, X., Sridharan, P. S., Miller, E., Bud, Z., Corella, S. G., Barker, S., Caradonna, S. G., Koh, Y., Franke, K., Cintrón-Pérez, C. J., Rose, S., . . . Pieper, A. A. (2025). Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain. Cell Reports Medicine, 7(1), 102535. https://doi.org/10.1016/j.xcrm.2025.102535