A significant scientific breakthrough challenges the long-held paradigm that Alzheimer’s disease (AD) is an irreversible neurodegenerative condition, suggesting instead that damaged brain function might be restorable. For over a century, the prevailing understanding of Alzheimer’s has positioned it as a progressive ailment where cognitive decline is a one-way street, leading research efforts to predominantly focus on preventative measures or strategies to decelerate its relentless march. Despite substantial global investment and decades of intensive investigation, no pharmaceutical intervention has ever been specifically designed with the explicit aim of reversing the disease’s effects and recovering lost cognitive abilities. This deeply ingrained assumption is now being critically re-examined by a collaborative team of scientists affiliated with University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center, who embarked on a pioneering quest to answer a profound question: can a brain already afflicted with advanced Alzheimer’s disease undergo a process of recovery?
At the heart of this transformative research lies a novel approach targeting a fundamental biological failure: the brain’s compromised ability to maintain its energy equilibrium. Published on December 22 in the esteemed journal Cell Reports Medicine, the study, spearheaded by Dr. Kalyani Chaubey of the Pieper Laboratory, meticulously analyzed both human Alzheimer’s brain tissue samples and a variety of preclinical mouse models. Their findings pinpointed a critical deficiency in the cellular energy molecule nicotinamide adenine dinucleotide (NAD+). The research indicates that an impaired capacity to sustain adequate NAD+ levels is a pivotal driver of Alzheimer’s pathology. Crucially, the study demonstrated that not only can maintaining proper NAD+ balance act as a protective shield against the onset of the disease, but it can also facilitate its reversal in experimental settings.
NAD+ is an indispensable coenzyme found throughout the body, including within the brain, and its levels naturally diminish with the aging process. When NAD+ concentrations fall below a critical threshold, cells lose their capacity to execute the essential biochemical processes required for their normal operation and long-term survival. The researchers observed that this age-related decline is markedly exacerbated in the brains of individuals diagnosed with Alzheimer’s disease, a pattern that was consistently replicated in the genetically engineered mouse models used for the study.
To effectively investigate the complexities of Alzheimer’s, which exclusively affects humans, scientists often employ specially bred mice that carry specific genetic mutations known to induce the disease in people. In this particular investigation, two distinct mouse models were utilized. The first group was engineered to harbor multiple human genetic mutations associated with amyloid processing, a hallmark of AD. The second group carried a human mutation affecting the tau protein, another key player in Alzheimer’s pathology. These genetic modifications in the mice were designed to replicate the early and significant pathological hallmarks of human Alzheimer’s disease.
In both of these meticulously constructed mouse models, the presence of these human mutations triggered widespread neurological damage that closely mirrored the pathological landscape observed in human Alzheimer’s patients. This damage manifested as a compromised blood-brain barrier, structural damage to nerve fibers, persistent neuroinflammation, a reduced rate of new neuron formation in the hippocampus (a brain region vital for memory), weakened synaptic communication between neurons, and extensive oxidative stress. Consequently, these mice exhibited severe deficits in memory and cognitive function, strikingly analogous to the symptoms experienced by individuals living with Alzheimer’s disease.
Following the confirmation that NAD+ levels were significantly depleted in the Alzheimer’s-affected brains of both humans and mice, the research team explored two distinct therapeutic windows. They investigated whether bolstering NAD+ levels before the onset of noticeable symptoms could prevent the development of Alzheimer’s pathology. Simultaneously, and perhaps more remarkably, they examined whether restoring NAD+ balance after the disease had already progressed to an advanced stage could lead to a reversal of the existing damage. This investigative strategy was informed by the team’s prior research, published in the Proceedings of the National Academy of Sciences USA, which had previously demonstrated that restoring NAD+ balance could achieve both structural and functional recovery following severe and prolonged traumatic brain injury. For the current study, the researchers employed P7C3-A20, a pharmacologic compound meticulously developed within the Pieper laboratory, specifically engineered to re-establish NAD+ equilibrium within cells.
The outcomes of these experiments were nothing short of extraordinary. While maintaining NAD+ balance effectively protected the mice from developing Alzheimer’s pathology, the results observed when treatment was initiated in mice with already advanced disease were particularly surprising. In these cases, the intervention to restore NAD+ balance enabled the brain to actively repair the substantial pathological damage induced by the underlying genetic mutations.
Both mouse models exhibited a complete restoration of cognitive function. This remarkable functional recovery was further corroborated by blood analyses, which revealed normalized levels of phosphorylated tau 217 (p-tau 217). P-tau 217 has recently gained prominence as a validated clinical biomarker for the diagnosis of Alzheimer’s disease in humans. The convergence of cognitive improvement and biomarker normalization provided robust evidence of disease reversal and illuminated a potential biomarker that could be instrumental in future human clinical trials.
The senior author of the study, Dr. Andrew A. Pieper, MD, PhD, who also serves as the Director of the Brain Health Medicines Center at the Harrington Discovery Institute at University Hospitals, expressed profound excitement and encouragement regarding these findings. He emphasized that restoring the brain’s energetic balance resulted in both pathological and functional recovery in both distinct mouse models exhibiting advanced Alzheimer’s. The fact that this effect was observed across two genetically diverse animal models, each driven by different causal mechanisms, significantly bolsters the hypothesis that therapeutic interventions aimed at restoring the brain’s NAD+ balance could hold promise for human Alzheimer’s patients. Dr. Pieper holds distinguished academic appointments, including the Morley-Mather Chair in Neuropsychiatry at UH and the CWRU Rebecca E. Barchas, MD, DLFAPA, University Professorship in Translational Psychiatry, and also serves as a Psychiatrist and Investigator within the Louis Stokes VA Geriatric Research Education and Clinical Center (GRECC).
These groundbreaking findings herald a potential paradigm shift in the future management of Alzheimer’s disease. Dr. Pieper articulated the core message of hope emanating from this research: "The effects of Alzheimer’s disease may not be inevitably permanent," he stated, adding, "The damaged brain can, under some conditions, repair itself and regain function." Dr. Chaubey further elaborated on the study’s contribution, noting, "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."
It is imperative to distinguish this therapeutic strategy from readily available NAD+ precursor supplements. Dr. Pieper cautioned that while such supplements are designed to increase NAD+ levels, previous animal studies have indicated that they can elevate NAD+ to excessively high concentrations, potentially promoting cancer development. In stark contrast, the methodology employed in this research utilizes P7C3-A20, a specific pharmacologic agent that assists cells in maintaining healthy NAD+ levels during periods of extreme cellular stress, critically without pushing these levels beyond their natural physiological 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," Dr. Pieper advised.
This significant research not only offers a beacon of hope but also paves the way for subsequent investigations and, ultimately, human clinical trials. The proprietary technology is currently undergoing commercialization by Glengary Brain Health, a Cleveland-based enterprise 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. Future laboratory research endeavors will focus on precisely identifying the specific facets of brain energy balance that are most critical for facilitating recovery, discovering and evaluating complementary therapeutic strategies for Alzheimer’s reversal, and exploring the potential efficacy of this recovery approach in other forms of chronic, age-related neurodegenerative disorders.
About the Author
