A new study led by researchers from University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center has found that restoring the brain’s energy balance can reverse Alzheimer’s disease (AD) in mouse models. The findings were published in Cell Reports Medicine.
The research team, led by Kalyani Chaubey, PhD, investigated whether brains with advanced AD could recover function. They discovered that a decline in NAD+, a key cellular energy molecule, is more severe in people with AD and mouse models of the disease. Maintaining or restoring proper NAD+ balance prevented and even reversed disease symptoms in mice.
The study used two genetically engineered mouse models—one carrying mutations affecting amyloid processing and another with a tau protein mutation. Both developed pathology similar to human AD, including cognitive impairment.
After confirming that NAD+ levels dropped sharply in both human and mouse AD brains, the researchers tested whether maintaining or restoring NAD+ could impact disease progression. They administered P7C3-A20, a pharmacologic agent developed at the Pieper Laboratory, to restore NAD+ balance. The results showed not only prevention but also reversal of pathological changes and full recovery of cognitive function in mice with advanced disease.
Blood levels of phosphorylated tau 217—a biomarker for AD—normalized alongside these improvements.
"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 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 holds several academic positions at UH and CWRU and is involved with clinical research at the Louis Stokes VA Geriatric Research Education and Clinical Center (GRECC).
According to Dr. Pieper: "The key takeaway is a message of hope – the effects of Alzheimer's disease may not be inevitably permanent. The damaged brain can, under some conditions, repair itself and regain function."
Dr. Chaubey noted: "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."
Dr. Pieper cautioned against over-the-counter NAD+-precursors due to their potential risks seen in animal studies: "Currently available over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer." He explained that their approach uses P7C3-A20 "that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels."
"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 developed through this work is being commercialized by Glengary Brain Health based in Cleveland—a 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. He added that future laboratory work will focus on identifying which aspects of brain energy balance are most critical for recovery as well as evaluating complementary approaches for reversing Alzheimer’s disease.
