A research team from University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center has reported that restoring brain energy balance could reverse advanced Alzheimer’s disease (AD) in mouse models. Their study, led by Kalyani Chaubey, PhD, and published in Cell Reports Medicine, examined both preclinical mouse models and human AD brains to investigate the role of NAD+, a key cellular energy molecule.
The researchers found that NAD+ levels decline naturally with age and are further reduced in people with Alzheimer’s disease. This pattern was also observed in genetically engineered mouse models designed to mimic AD pathology. The mice developed symptoms similar to those seen in humans with AD, including cognitive impairments and brain changes such as blood-brain barrier deterioration and neuroinflammation.
To test whether maintaining or restoring NAD+ balance could affect disease progression, the team used a pharmacologic agent called P7C3-A20. This compound had previously shown effectiveness in restoring brain function after traumatic brain injury in animal studies. In this new research, preserving or restoring NAD+ balance protected mice from developing AD-related symptoms and even reversed advanced disease. Mice treated after significant disease progression recovered cognitive function and showed normalized levels of phosphorylated tau 217—a clinical biomarker for AD.
"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 at 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 added that these findings suggest a potential shift in how Alzheimer’s treatment is approached: "The key takeaway is a message of hope – the effects of Alzheimer's disease may not be inevitably permanent," he said. "The damaged brain can, under some conditions, repair itself and regain function."
Dr. Chaubey explained further: "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."
Pieper cautioned against using over-the-counter NAD+-precursors because they have been shown to raise cellular NAD+ to dangerously high levels that promote cancer in animal studies. Instead, P7C3-A20 helps cells maintain proper NAD+ balance under stress without excessive elevation.
"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.
The technology is being commercialized by Glengary Brain Health—a Cleveland-based company co-founded by Dr. Pieper—and will be evaluated for translation into human clinical trials.
"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."
