For the first time, scientists at Case Western Reserve University have identified a potential method to reverse Alzheimer’s disease (AD) rather than merely slow its progression. In collaboration with University Hospitals and the Louis Stokes Cleveland Veteran Affairs Medical Center, Dr. Andrew Pieper and Dr. Kalyani Chaubey led the novel research. Titled “Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain,” the study was published in Cell Reports Medicine on Jan. 20.

“For over a century, Alzheimer’s has been considered irreversible,” said Pieper, the director of the Center for Brain Health Medicines of the Harrington Discovery Institute at University Hospitals. According to Pieper, Alzheimer’s causes “profound human suffering and carr[ies] escalating social and economic costs as populations age,” and currently has no known cure.

This breakthrough centers on the brain’s energy balance, regulated by the molecule nicotinamide adenine dinucleotide, or NAD+. Disruptions in NAD+ balance make neurons vulnerable to damage, contributing to neurodegenerative diseases.

“We found a significant impairment in NAD+ homeostasis in post-mortem human AD brains, a finding not previously reported by others, and observed the same deficit in our mouse models,” Pieper said. “Across humans and mice, the extent of NAD+ disruption correlated with disease severity, suggesting impaired NAD+ homeostasis contributes to pathology.”

This insight led the scientists to hypothesize that restoring NAD+ levels could enable damage recovery in AD brains. The key to do so lies in P7C3-A20, an improved version of the neuroprotective compound P7C3, which was originally discovered by the Pieper Laboratory 15 years ago. This therapeutic molecule restores NAD+ to its normal levels and has previously been shown to protect neurons in several neurodegenerative diseases.

After P7C3-A20 treatment, mice with Alzheimer’s had “fully restored cognition to levels indistinguishable from non-diseased controls, accompanied by recovery of learning and memory tasks to normal performance,” Pieper said. “In short, the brains didn’t just stop declining. They rebuilt their structure and function[,] and enabled the mice to regain normal cognitive ability.”

Additionally, pathological signs associated with Alzheimer’s, such as “blood-brain barrier damage, oxidative stress, neuroinflammation and DNA damage [were] prevented by treatment of P7C3-A20 in AD mice,” said Chaubey, the lead research scientist of this project and postdoctoral fellow at the Pieper Laboratory.

The study used two mouse models: amyloid-driven and tau-driven. Amyloid plaques are abnormal clusters of protein between neurons, and tau proteins are normally associated with neuronal structures, but accumulates into insoluble filament tangles in Alzheimer’s. These proteins are major features of Alzheimer’s and both mouse models “established AD-like pathology and cognitive impairment, confirmed by histology, molecular markers and behavioral testing,” said Pieper.

Although the experiments were performed on mice, the research team analyzed  “available human AD databases and tried to find out some common signatures between mice and humans [so] that the study findings can correlate with actual human patients,” Chaubey said. Thus, both mouse models, while imperfect, “recapitulate many core molecular, histological, and behavioral hallmarks,” Pieper said.

Despite compelling pre-clinical data, translating these laboratory results into a clinical setting is expected to be gradual.

“Responsible clinical development takes time,” Pieper said. “Through Glengary Brain Health, [the company Pieper co-founded to commercialize therapies for Alzheimer’s], we are optimizing lead compounds for human trials. We are still realistically a few years before clinical testing can begin and additional years beyond that before any potential implementation, depending on trial results.”

In the meantime, the team is continuing to investigate the ability of P7C3-A20 to reverse brain damage in other brain injuries and age-related neurodegenerative diseases.

For Chaubey, this project was more than a scientific milestone. “Through these results, [for the] first time, we gave some proof of AD reversal,” she said. “It gave hope [to] the patients and their families that one day there is a treatment possibility for those who are suffering. This study is a hope for AD patients worldwide.”