Scientists Found a Way to Help the Brain Bounce Back From Alzheimer’s

Alzheimer’s has long been seen as irreversible, but new findings suggest that assumption may be wrong.

• For more than a century, Alzheimer’s disease has been widely viewed as a condition that cannot be reversed. Because of this, most research has focused on preventing the disease or slowing its progression rather than attempting to restore lost brain function.
• By studying several mouse models of Alzheimer’s alongside human Alzheimer’s brain tissue, researchers identified a critical biological weakness at the heart of the disease. They found that the brain’s inability to maintain healthy levels of a vital cellular energy molecule called NAD⁺ plays a major role in driving Alzheimer’s.
• In animal studies, keeping brain NAD⁺ levels in balance prevented Alzheimer’s from developing. Even more striking, restoring NAD⁺ balance after the disease was already advanced allowed the brain to repair damage and fully recover cognitive function.
• These results suggest that treatments designed to restore the brain’s energy balance could move Alzheimer’s care beyond slowing decline and toward the possibility of recovery.
• The findings also open the door to further research, including complementary treatment strategies and carefully designed clinical trials to determine whether these results can translate to patients.

Alzheimer’s Has Long Been Viewed as Irreversible

For more than a hundred years, Alzheimer’s disease (AD) has been regarded as a condition that cannot be undone. Because of this assumption, most scientific efforts have focused on stopping the disease before it starts or slowing its progression, rather than attempting to restore lost brain function. Despite decades of research and billions of dollars invested, no drug trial for Alzheimer’s has ever been designed with the explicit goal of reversing the disease and restoring normal brain performance.

That long-standing belief is now being directly tested by researchers from University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center. Their work asked a fundamental question that had rarely been explored: Can brains already damaged by advanced Alzheimer’s recover?

A New Study Examines Brain Energy Loss

The study was led by Kalyani Chaubey, PhD, of the Pieper Laboratory and was published on December 22 in Cell Reports Medicine. By analyzing multiple preclinical mouse models alongside brain tissue from people with Alzheimer’s, the researchers identified a critical biological problem underlying the disease. They found that Alzheimer’s is strongly driven by the brain’s failure to maintain normal levels of a key cellular energy molecule called NAD⁺. Just as important, they showed that keeping NAD⁺ levels in balance can both prevent the disease and, under certain conditions, reverse it.

NAD⁺ naturally declines throughout the body as people age, including in the brain. When this balance is disrupted, cells gradually lose the ability to carry out essential processes needed for normal function and survival. The team found that this loss of NAD⁺ is far more pronounced in the brains of people with Alzheimer’s. The same severe decline was also observed in mouse models of the disease.

How Alzheimer’s Was Modeled in Mice

Although Alzheimer’s occurs only in humans, scientists can study its mechanisms using mice that carry genetic mutations known to cause the disease in people. In this research, two such mouse models were used. One group carried multiple human mutations affecting amyloid processing, while the second group carried a human mutation in the tau protein.

Amyloid buildup and tau abnormalities are among the earliest and most important features of Alzheimer’s. In both mouse models, these mutations led to extensive brain damage that closely resembles the human condition. This included breakdown of the blood-brain barrier, damage to nerve fibers, chronic inflammation, reduced formation of new neurons in the hippocampus, weakened communication between brain cells, and widespread oxidative damage. The mice also developed severe memory and thinking problems similar to those experienced by people with Alzheimer’s.

Testing Prevention and Reversal of Alzheimer’s Damage

After confirming that NAD⁺ levels drop sharply in both human and mouse Alzheimer’s brains, the researchers explored two different strategies. They tested whether preserving NAD⁺ balance before symptoms appear could prevent Alzheimer’s, and whether restoring NAD⁺ balance after the disease was already well established could reverse it.

This work built on earlier findings from the same group, published in Proceeding of the National Academy of Sciences USA, which showed that restoring NAD⁺ balance led to both structural and functional recovery after severe, long-lasting traumatic brain injury. In the current study, NAD⁺ balance was restored using a well-characterized pharmacological compound, P7C3-A20, developed in the Pieper laboratory.

Cognitive Function Fully Restored in Animal Models

The results exceeded expectations. Maintaining healthy NAD⁺ levels prevented mice from developing Alzheimer’s, but even more striking outcomes were seen when treatment began later. In mice with advanced disease, restoring NAD⁺ balance allowed the brain to repair major pathological damage caused by the genetic mutations.

Both mouse models showed complete recovery of cognitive function. This recovery was supported by blood tests showing normalized levels of phosphorylated tau 217, a recently approved clinical biomarker of Alzheimer’s in people. These findings provided strong evidence that the disease process had been reversed and highlighted a potential biomarker for future clinical trials.

Researchers React to the Findings

“We were very excited and encouraged by our results,” said Andrew A. Pieper, MD, PhD, senior author of the study and Director of the Brain Health Medicines Center, Harrington Discovery Institute at UH. “Restoring the brain’s energy balance achieved pathological and functional recovery in both lines of mice with advanced Alzheimer’s. Seeing this effect in two very different animal models, each driven by different genetic causes, strengthens the idea that restoring the brain’s NAD⁺ balance might help patients recover from Alzheimer’s.”

Dr. Pieper also holds the Morley-Mather Chair in Neuropsychiatry at UH and the CWRU Rebecca E. Barchas, MD, DLFAPA, University Professorship in Translational Psychiatry. He serves as Psychiatrist and Investigator in the Louis Stokes VA Geriatric Research Education and Clinical Center (GRECC).

A Potential Shift in Alzheimer’s Treatment Thinking

The findings suggest a major change in how Alzheimer’s could be approached in the future. “The key takeaway is a message of hope – the effects of Alzheimer’s disease may not be inevitably permanent,” said Dr. Pieper. “The damaged brain can, under some conditions, repair itself and regain function.”

Dr. Chaubey added, “Through our study, we demonstrated one drug-based way to accomplish this in animal models, and also identified candidate proteins in the human AD brain that may relate to the ability to reverse AD.”

Why This Approach Differs From Supplements

Dr. Pieper cautioned that this strategy should not be confused with over-the-counter NAD⁺-precursors. Studies in animals have shown that such supplements can raise NAD⁺ to dangerously high levels that promote cancer. The approach used in this research relies instead on P7C3-A20, which helps cells maintain a healthy NAD⁺ balance during extreme stress without pushing levels beyond their normal range.

“This is important when considering patient care, and clinicians should consider the possibility that therapeutic strategies aimed at restoring brain energy balance might offer a path to disease recovery,” said Dr. Pieper.

Next Steps Toward Human Studies

The findings also encourage further research into related strategies and eventual testing in people. The technology is currently being commercialized by Glengary Brain Health, a Cleveland-based company co-founded by Dr. Pieper.

“This new therapeutic approach to recovery needs to be moved into carefully designed human clinical trials to determine whether the efficacy seen in animal models translates to human patients,” Dr. Pieper explained. “Additional next steps for the laboratory research include pinpointing which aspects of brain energy balance are most important for recovery, identifying and evaluating complementary approaches to Alzheimer’s reversal, and investigating whether this recovery approach is also effective in other forms of chronic, age-related neurodegenerative disease.”

Reference: “Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain” by Kalyani Chaubey, Edwin Vázquez-Rosa, Sunil Jamuna Tripathi, Min-Kyoo Shin, Youngmin Yu, Matasha Dhar, Suwarna Chakraborty, Mai Yamakawa, Xinming Wang, Preethy S. Sridharan, Emiko Miller, Zea Bud, Sofia G. Corella, Sarah Barker, Salvatore G. Caradonna, Yeojung Koh, Kathryn Franke, Coral J. Cintrón-Pérez, Sophia Rose, Hua Fang, Adrian A. Cintrón-Pérez, Taylor Tomco, Xiongwei Zhu, Hisashi Fujioka, Tamar Gefen, Margaret E. Flanagan, Noelle S. Williams, Brigid M. Wilson, Lawrence Chen, Lijun Dou, Feixiong Cheng, Jessica E. Rexach, Jung-A Woo, David E. Kang, Bindu D. Paul and Andrew A. Pieper, 22 December 2025, Cell Reports Medicine.
DOI: 10.1016/j.xcrm.2025.102535

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