Research has found that restoring the brain’s energy balance can not only slow the progression of Alzheimer’s disease, but may actually reverse it.
- For more than a century, Alzheimer’s disease was widely thought to be permanent and untreatable once it developed. As a result, most research has focused on preventing the disease or slowing its progression, rather than reversing the disease.
- Researchers have identified a critical biological problem at the heart of Alzheimer’s disease by studying multiple mouse models of Alzheimer’s disease in parallel with human Alzheimer’s brain tissue. They discovered that the brain’s inability to maintain healthy levels of a key cellular energy molecule called NAD+ plays a major role in the development of Alzheimer’s disease.
- In animal models, maintaining normal brain NAD+ levels prevented the development of Alzheimer’s disease. Even more surprising, restoring NAD+ balance after the disease had already progressed repaired the brain damage and allowed cognitive function to fully recover.
- These results suggest that treatments aimed at restoring the brain’s energy balance may take the treatment of Alzheimer’s disease beyond slowing decline and toward meaningful recovery.
- This finding also opens the door to further research, including exploring complementary strategies and carefully designed clinical trials to determine whether these results can be translated to patients.
Long-held views on Alzheimer’s disease are called into question
For more than 100 years, Alzheimer’s disease (AD) has been widely viewed as an irreversible condition. Because of this belief, most scientific efforts have focused on preventing disease or slowing its progression, rather than restoring lost brain function. Even after decades of research and billions of dollars of investment, no Alzheimer’s disease drug trials have ever been planned with the goal of reversing the disease and restoring cognitive abilities.
This long-held assumption is now being challenged by researchers at University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center. Their study aimed to answer a bold question: Can the brain, already damaged by advanced Alzheimer’s disease, recover?
New research targets energy failure in the brain
The study was led by Dr. Kalyani Chaubey of the Pieper Laboratory and was published in the journal Dec. 22. cell report medicine. By examining both human Alzheimer’s brain tissue and multiple preclinical mouse models, the research team identified a key biological defect at the heart of Alzheimer’s disease. They discovered that the brain’s inability to maintain normal levels of a key cellular energy molecule called NAD+ plays a key role in the development of Alzheimer’s disease. Importantly, maintaining a proper NAD+ balance has been shown not only to prevent disease, but also to reverse it in experimental models.
NAD+ levels naturally decline throughout the body, including the brain, as we age. When NAD+ drops too low, cells lose their ability to carry out important processes necessary for normal function and survival. Researchers found that this functional decline was much more severe in the brains of Alzheimer’s patients. The same pattern was seen in mouse models of the disease.
How Alzheimer’s disease was modeled in the lab
Although Alzheimer’s disease only occurs in humans, scientists are studying Alzheimer’s disease using specially engineered mice that carry genetic mutations known to cause Alzheimer’s disease in humans. In this study, the researchers used two such models. One group of mice carried multiple human mutations that affect amyloid processing, and the other group carried human mutations in the tau protein.
Amyloid and tau abnormalities are one of the earliest and most important hallmarks of Alzheimer’s disease. In both mouse models, these mutations caused widespread brain damage that closely resembled the human disease. This includes disruption 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 extensive oxidative damage. The mice also developed severe memory and cognitive problems similar to those seen in people with Alzheimer’s disease.
Testing whether Alzheimer’s damage can be reversed
After confirming that NAD+ levels were sharply reduced in both human and mouse Alzheimer’s disease brains, the research team considered two possibilities. They tested whether maintaining NAD+ balance before symptoms appear could prevent Alzheimer’s disease, and whether restoring that balance after the disease had already progressed could reverse Alzheimer’s disease.
This approach builds on the group’s previous research published in the Proceedings of the National Academy of Sciences, which showed that restoring NAD+ balance leads to structural and functional recovery after severe and long-term traumatic brain injury. In the current study, the researchers used a well-characterized pharmacological compound called P7C3-A20, developed in the Pieper lab, to restore NAD+ balance.
Complete cognitive recovery observed in advanced disease
The results were amazing. Balancing NAD+ protected the mice from developing Alzheimer’s disease, but what was even more surprising was what happened when treatment was started after Alzheimer’s disease had already progressed. In these cases, by restoring NAD+ balance, the brain was able to repair the major pathological damage caused by the genetic mutation.
Both mouse models showed complete recovery of cognitive function. This recovery was also reflected in blood tests, which showed normalization of levels of phosphorylated tau-217, a recently approved clinical biomarker used to diagnose Alzheimer’s disease in humans. These findings provided strong evidence of disease reversal and highlighted potential biomarkers for future human clinical trials.
Researchers express cautious optimism
“We are very excited and encouraged by these results,” said Andrew A. Pieper, MD, senior author of the study and director of the Center for Brain Health Medicine at California State University’s Harrington Discovery Institute. “By restoring the brain’s energy balance, pathological and functional recovery was achieved in both strains of mice with advanced Alzheimer’s disease. Confirming this effect in two very different animal models, each driven by a different genetic cause, strengthens the idea that restoring the brain’s NAD+ balance may aid recovery in Alzheimer’s patients.”
Dr. Pieper holds the Maury Mather Professorship in Neuropsychiatry at UH and the Rebecca E. Barkas, MD, DLFAPA, University Professorship in Translational Psychiatry at CWRU. He is a psychiatrist and researcher at the Louis Stokes VA Geriatrics Research, Education, and Clinical Center (GRECC).
Changing perspectives on Alzheimer’s disease
The findings suggest fundamental changes in the way Alzheimer’s disease is approached in the future. “The key takeaway is a message of hope: the effects of Alzheimer’s disease may not necessarily be permanent,” Dr. Pieper said. “Under certain conditions, the damaged brain can repair itself and regain function.”
Dr. Choubey added, “Through our work, we have demonstrated one drug-based method of achieving this in animal models and have also identified candidate proteins in the human AD brain that may be associated with the ability to reverse AD.”
Why this approach differs from supplements
Dr. Pieper cautioned not to confuse this strategy with commercially available NAD+ precursors. He pointed out that such supplements have been shown in animal studies to increase NAD+ to dangerously high levels and promote cancer. The method used in this study instead relies on P7C3-A20, a pharmacological agent that helps cells maintain a healthy NAD+ balance by keeping levels above the normal range even under extreme stress.
“This is important when considering patient care, and clinicians should consider the possibility that therapeutic strategies aimed at restoring the brain’s energy balance may offer a path to disease recovery,” Dr. Pieper said.
Next steps towards human trials
This study also opens the door to additional research and ultimately human trials. The technology is currently being commercialized by Glengarry Brain Health, a Cleveland-based company co-founded by Dr. Pieper.
“This new therapeutic approach to recovery needs to move into carefully designed human clinical trials to determine whether the efficacy seen in animal models also applies to human patients,” Dr. Pieper explained. “Further next steps in laboratory research include identifying which aspects of the brain’s energy balance are most important for recovery, identifying and evaluating complementary approaches to Alzheimer’s disease recovery, and investigating whether this recovery approach is also effective in other forms of chronic age-related neurodegenerative diseases.”
