For more than a century, Alzheimer’s disease (AD) has been described as a one-way road: once the brain begins to degenerate, there is no turning back, only efforts slowing the inevitable. A new study published in Cell Reports Medicine is now challenging that assumption in dramatic fashion.
In a series of rigorous experiments, researchers report that advanced Alzheimer’s disease can be pharmacologically reversed in mouse models. Not prevented. Not merely slowed. Reversed.
How the study worked
To test their hypothesis, the researchers used two well-established mouse models that replicate major features of human Alzheimer’s disease:
- 5xFAD mice, which rapidly develop amyloid-beta (Aβ) plaques, cognitive decline, and brain damage.
- PS19 mice, which primarily model tau protein pathology, another defining hallmark of Alzheimer’s.
Crucially, treatment was initiated not only early, but also after disease was fully established, mimicking advanced Alzheimer’s.
The mice were treated with P7C3-A20, a small-molecule compound known to activate NAMPT, a key enzyme in the NAD⁺ salvage pathway. The drug was administered daily at a dose of 10 mg/kg.
Researchers then evaluated recovery using:
- Memory and learning tests (novel object recognition, Morris water maze)
- Motor and anxiety assessments
- Brain imaging and tissue analysis
- Measures of inflammation, oxidative stress, and blood–brain barrier integrity
- Multiomics (proteomics and transcriptomics) in both mouse brains and human postmortem Alzheimer’s tissue
The results
Mice with advanced Alzheimer’s regained normal memory and learning abilities, performing as well as healthy controls. In both amyloid-driven and tau-driven models, deficits that had already emerged were completely reversed.
Hallmark pathology reduced
- Amyloid plaques were significantly diminished.
- Pathological tau phosphorylation dropped.
- Plasma p-tau217, a biomarker now used in human Alzheimer’s diagnosis, returned to normal levels.
Importantly, the drug did not reduce amyloid production directly, suggesting the brain was clearing toxic proteins through restored cellular processes rather than blunt suppression.
Brain repair at the cellular level
Treatment repaired multiple systems damaged by Alzheimer’s:
- Blood–brain barrier integrity was restored.
- Neuroinflammation dropped sharply.
- Oxidative stress and DNA damage were reduced.
- Hippocampal neurogenesis (the birth of new neurons) rebounded.
- Synaptic plasticity and long-term potentiation, essential for learning, returned.
Energy balance normalized
Alzheimer’s mice showed a 30–45% depletion of NAD⁺. P7C3-A20 restored NAD⁺ to healthy, normal levels, without overshooting, a key safety consideration given concerns around excessive NAD⁺ supplementation.
Even in human brain endothelial cells exposed to oxidative stress, the compound protected mitochondrial function and preserved energy production.
Why NAD⁺ matters
NAD⁺ sits at the crossroads of brain health. It fuels ATP production, supports DNA repair, enables autophagy (the cell’s cleanup system), and regulates stress responses.
In Alzheimer’s disease, amyloid and tau pathology drive chronic stress that drains NAD⁺, leading to mitochondrial failure, inflammation, and neuronal death. The study shows that P7C3-A20 breaks this vicious cycle—not by targeting amyloid or tau directly, but by restoring the brain’s ability to power itself and heal.
This metabolic approach stands in stark contrast to decades of amyloid-centric therapies that have largely failed in clinical trials.
Relevance to human Alzheimer’s
While the experiments were conducted in mice, the team strengthened their case by analyzing human postmortem Alzheimer’s brains. They found that NAD⁺ dysregulation worsens as disease severity increases. Notably, individuals with Alzheimer’s pathology but no dementia (often called “NDAN”) maintained NAD⁺ balance through distinct gene expression patterns.
The researchers identified 46 overlapping proteins between mice and humans that may be critical to reversibility, providing concrete targets for translation into clinical trials.
Commercial development is already underway through Glengary Brain Health, with early-stage human trials anticipated.
Important caveats
Despite the excitement, the authors urge caution:
- Mouse models do not fully replicate sporadic human Alzheimer’s.
- Human data in this study is correlative, not causal.
- It remains unclear whether reversal is possible after extreme neuron loss.
- Long-term safety and off-target effects in humans must be established.
Conclusion
If these findings translate to humans, the implications are profound. Alzheimer’s treatment could shift from damage control to recovery, even after symptoms appear.
For patients, families, and clinicians who have long been told that “nothing can be done,” this research offers something rare in Alzheimer’s science:
