For decades, clinicians and researchers alike have treated Alzheimer’s disease as a one-way street. Once cognition and memory start to fade, conventional wisdom has insisted that the damage reflects irreversible neuron loss.
Startling new research threatens to upend that. In a paper appearing in Cell Reports Medicine, researchers report that rebooting a critical metabolic system in the brain can reverse advanced Alzheimer’s-like disease in mice. The authors report that intervention:
- Curbed inflammation.
- Repaired damaged blood vessels.
- Restored memory.
- And reversed molecular hallmarks of dementia.
“We were very excited and encouraged by our results,” senior author Andrew A. Pieper, MD, PhD, explained. “Restoring the brain’s energy balance achieved pathological and functional recovery in both lines of mice with advanced Alzheimer’s. Seeing this effect in two very different animal models, each driven by different genetic causes, strengthens the idea that restoring the brain’s NAD+ balance might help patients recover from Alzheimer’s.”
Methodology
The work centers on nicotinamide adenine dinucleotide, or NAD⁺, a molecule essential for cellular energy production, DNA repair, and oxidative stress resistance. NAD⁺ levels naturally tumble with age. But the authors of this study demonstrate that this decline is especially pronounced in Alzheimer’s disease.
To prove that (or debunk it), the team turned to two common mouse models of Alzheimer’s disease. One model, known as 5xFAD, develops aggressive amyloid pathology and cognitive deficits. The other, PS19, accumulates mutant tau protein and rapidly declines late in life.
In both models, the researchers waited to intervene until the disease was well established. They then treated the animals with P7C3-A20, an experimental compound that scientists designed to restore normal NAD⁺ homeostasis. Notably, it does so without pushing levels outside of documented norms.
A Pleasant Surprise
The results took the researchers by surprise.
In the 12-month-old 5xFAD mice, six months of treatment normalized brain NAD⁺ levels. It also fully restored performance across multiple memory and learning tests, including object recognition, spatial navigation, and motor coordination. Measures of synaptic plasticity in the hippocampus also bounced back.
The authors also explain that the intervention appeared to turn back the clock on many of the biological features reported to drive cognitive decline. Amyloid plaque burden fell. Pathological tau phosphorylation dropped, including reductions in plasma p-tau217. Blood–brain barrier integrity improved, limiting the leakage of immune proteins into brain tissue. Markers of oxidative stress, DNA damage, and neuroinflammation all dropped.
In the tau-driven PS19 mice – treated at a point when they’re normally nearing death – P7C3-A20 produced meaningful cognitive improvement within weeks and reduced tau pathology, despite ignoring the mutant tau gene itself.
Revelations Could Drive Future Therapies
Although the researchers only tested the drug on animals and cells, they also examined postmortem human brain tissue. Compared with age-matched controls, the brains of Alzheimer’s patients showed about a 30% drop in NAD⁺ homeostasis. The degree of disruption mirrored tau pathology, oxidative damage, synaptic loss, blood–brain barrier breakdown, and neuronal loss.
At the same time, those classified as “nondemented with Alzheimer’s neuropathology” showed gene expression patterns consistent with preserved NAD⁺ regulation. That, the authors argue, points to NAD⁺ balance as a potential biological buffer against cognitive decline.
To move beyond a single compound, the team conducted large-scale proteomic analyses of mouse brains before (and after) disease reversal. They identified nearly four dozen proteins that were abnormally expressed in both mouse and human Alzheimer’s disease. Those proteins reverted to normal levels once the mice were treated.
A Shift in How We Approach Alzheimer’s
If cognitive decline can be reversed in advanced disease—at least in animals—it suggests that Alzheimer’s symptoms may arise less from irrevocable neuron loss than from disrupted cellular support systems that, in principle, can be repaired.
“The key takeaway is a message of hope—the effects of Alzheimer’s disease may not be inevitably permanent,” Pieper, who’s also the director of the Brain Health Medicines Center, Harrington Discovery Institute, added. “The damaged brain can, under some conditions, repair itself and regain function.”
For a field often overshadowed by therapeutic disappointment, this new data represents an optimistic reboot – one that appears to be ready for human trials.
Further Reading
Why Some Alzheimer’s Patients Decline Faster Than Expected
Lipid Deficit Might Explain Higher Alzheimer’s Risk In Women
