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In a breakthrough that challenges long-held assumptions about Alzheimer’s disease, scientists have shown that restoring the brain’s energy balance can reverse disease-related damage and fully restore memory in mouse models, even at advanced stages.
The study, published on December 22 in Cell Reports Medicine, found that severe depletion of nicotinamide adenine dinucleotide (NAD+), a molecule essential for cellular energy, plays a central role in driving Alzheimer’s disease. Restoring NAD+ balance repaired brain pathology, normalised disease biomarkers and reversed cognitive decline in mice.
For over a century, Alzheimer’s has been widely viewed as irreversible, leading most research to focus on prevention or slowing progression rather than recovery. The new findings suggest that damaged brains may retain the capacity to repair themselves under the right conditions.
The research was led by Kalyani Chaubey, PhD, of the Pieper Laboratory, with collaborators from University Hospitals, Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center.
By analysing human Alzheimer’s brain tissue and multiple genetically engineered mouse models, the researchers found that NAD+ levels decline far more sharply in Alzheimer’s brains than in normal ageing. This depletion disrupts essential cellular functions and contributes to widespread brain damage.
To test whether the damage could be reversed, the team treated mice with P7C3-A20, a pharmacologic compound developed in the Pieper Laboratory that helps cells maintain healthy NAD+ balance during stress.
The results were striking. Mice treated after developing advanced Alzheimer’s pathology showed repair of major brain damage, including inflammation, nerve fibre degeneration and impaired neuron communication. Both amyloid- and tau-driven mouse models demonstrated complete recovery of learning and memory.
Importantly, blood tests showed normalised levels of phosphorylated tau-217, a clinically approved biomarker used to diagnose Alzheimer’s in humans, strengthening evidence of disease reversal.
“We were very excited and encouraged by our results,” said senior author Andrew A. Pieper, MD, PhD, Director of the Brain Health Medicines Center at University Hospitals. “Restoring the brain’s energy balance achieved both pathological and functional recovery in mice with advanced Alzheimer’s.”
Dr Pieper cautioned against confusing this approach with over-the-counter NAD+ supplements, noting that such products can raise NAD+ to potentially harmful levels linked to cancer in animal studies. The compound used in the study restores balance without exceeding normal levels.
“The key takeaway is a message of hope,” Pieper said. “The effects of Alzheimer’s disease may not be inevitably permanent.”
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While the findings are limited to animal models, researchers say the work opens the door for future human trials. The technology is currently being commercialised by Cleveland-based Glengary Brain Health.
