Alzheimer's disease has long been considered an irreversible neurodegenerative condition. However, a recently published study in Cell Reports Medicine offers a different perspective: in late-stage Alzheimer's mouse models, researchers successfully achieved pathological reversal and complete cognitive recovery.

This collaborative research between University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center found that an imbalance in NAD+, a key energy molecule in the brain, is a significant factor driving Alzheimer's disease progression.

## Energy Imbalance is Key

NAD+ is a central molecule in cellular energy metabolism, and its levels naturally decline with age. The research team discovered that NAD+ decline is more severe in both Alzheimer's patients and model mice.

The researchers used two different Alzheimer's mouse models: one with amyloid-beta related gene mutations and another with tau protein gene mutations. Both mice exhibited blood-brain barrier damage, neuroinflammation, and cognitive impairments similar to human patients.

## Reversing Late-Stage Lesions

The research team used a drug called P7C3-A20 to restore brain NAD+ balance. Surprisingly, not only did preventive treatment protect mice from developing the disease, but delayed treatment in mice with already advanced lesions also reversed major pathological changes.

"In both different mouse models, restoring brain energy balance achieved both pathological and functional recovery," said Dr. Andrew A. Pieper, the study's senior author. "This reinforces the concept that restoring brain NAD+ balance may help patients recover from Alzheimer's disease."

After treatment, the levels of phosphorylated tau217 in the mice's blood (a clinical biomarker for Alzheimer's) also returned to normal, further confirming disease reversal.

## Cautious Optimism

Some commentators in discussions noted that success in animal experiments doesn't guarantee effectiveness in humans, especially treatments for highly specialized genetically engineered mice often struggle to translate. The fact that this research was published in Cell Reports Medicine rather than top-tier journals like Nature or Science also calls for caution.

However, the research team emphasizes that this at least provides proof-of-concept—that the reversal of Alzheimer's is theoretically possible.

Notably, researchers specifically warned that current NAD+ precursor supplements on the market may raise cellular NAD+ levels to dangerous levels, potentially even promoting cancer. In contrast, P7C3-A20 helps cells maintain NAD+ balance under stressful conditions rather than excessively elevating its levels.

## Future Outlook

This research is prompting a rethinking of Alzheimer's treatment paradigms. "The key message is hope—the impact of Alzheimer's may not be necessarily permanent," said Dr. Pieper. "Damaged brains can self-repair and restore function under certain conditions."

The technology is being commercialized by Glengary Brain Health, a Cleveland company co-founded by Dr. Pieper. The next step will be carefully designed human clinical trials to verify the effectiveness of this treatment approach in patients.

Meanwhile, laboratory research will continue to explore which aspects of brain energy balance are most critical for recovery, and whether this approach is also effective for other age-related neurodegenerative diseases.

**References**: Chaubey K, et al. Cell Reports Medicine (2025). DOI: 10.1016/j.xcrm.2025.102535