For more than a century, Alzheimer’s disease (AD) has been viewed as an irreversible condition, leading research to focus mainly on prevention or slowing progression rather than recovery. Despite extensive investment, no clinical trial has ever aimed to reverse Alzheimer’s and restore lost brain function.

Challenging this long-standing belief, researchers from University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center investigated whether brains already severely affected by advanced Alzheimer’s could recover. Led by Kalyani Chaubey, PhD, from the Pieper Laboratory, the study published in Cell Reports Medicine revealed that disruption of NAD+, a critical cellular energy molecule, plays a major role in driving Alzheimer’s disease.

NAD+ levels naturally decline with age, but the researchers found that this decline is far more pronounced in the brains of people with Alzheimer’s and in mouse models of the disease. Using two well-established genetic mouse models representing amyloid- and tau-driven Alzheimer’s pathology, the team showed that loss of NAD+ balance contributes to hallmark disease features, including neuroinflammation, synaptic dysfunction, oxidative damage, and severe cognitive impairment.

The researchers then tested whether preserving NAD+ levels before disease onset could prevent Alzheimer’s, and whether restoring NAD+ balance after significant disease progression could reverse it. Using a pharmacologic compound called P7C3-A20, they found that maintaining NAD+ balance not only protected mice from developing Alzheimer’s-like pathology but also reversed major brain damage in mice with advanced disease. Remarkably, treated mice regained normal cognitive function, accompanied by normalization of phosphorylated tau-217 levels, a key clinical biomarker of Alzheimer’s in humans.

According to senior author Andrew A. Pieper, MD, PhD, these findings represent a potential paradigm shift. The results demonstrate that restoring brain energy balance can lead to both pathological and functional recovery, even in advanced Alzheimer’s models. Importantly, unlike over-the-counter NAD+ supplements, P7C3-A20 maintains healthy NAD+ balance without raising levels to potentially dangerous extremes.

The study offers renewed hope that Alzheimer’s disease may not be permanently irreversible. It also opens the door to future human clinical trials and broader exploration of therapies aimed at restoring brain energy balance, with possible implications for other age-related neurodegenerative disorders.

Source: https://news.uhhospitals.org/news-releases/articles/2025/12/study-shows-alzheimers-disease-can-be-reversed-in-animal-models