Alzheimer’s Disease (AD) has long been deemed irreversible. However, a groundbreaking study by scientists from Case Western Reserve University, University Hospitals, and the Louis Stokes Cleveland VA Medical Center reveals that treatment for advanced Alzheimer’s disease can be reversed. Through extensive research on both preclinical mouse models and human brain samples, the team discovered that the brain’s failure to maintain normal levels of nicotinamide adenine dinucleotide (NAD+), the crucial energy molecule of cells, significantly contributes to the onset of Alzheimer’s. Furthermore, sustaining an appropriate NAD+ balance may not only prevent but also reverse the progression of Alzheimer’s disease.
Alzheimer’s disease severity correlates with NAD+ homeostatic dysregulation. Image credit: Chaubey et al., doi: 10.1016/j.xcrm.2025.102535.
Historically, Alzheimer’s disease, the primary cause of dementia, has been regarded as irreversible since its identification over a century ago, and it is expected to impact more than 150 million individuals globally by 2050.
Current therapies focused on amyloid beta (Aβ) and clinical symptoms offer limited benefits, underscoring the urgent need for complimentary and alternative treatment options.
Intriguingly, individuals with autosomal dominant AD mutations can remain symptom-free for decades, while others without Alzheimer’s neuropathology maintain cognitive function despite having numerous amyloid plaques.
These insights indicate potential intrinsic brain resilience mechanisms that may slow or halt disease progression, suggesting that enhancing these processes could enhance recovery from Alzheimer’s disease.
NAD+ homeostasis plays a pivotal role in cellular resilience against oxidative stress, DNA damage, neuroinflammation, blood-brain barrier degradation, impaired hippocampal neurogenesis, deficits in synaptic plasticity, and overall neurodegeneration.
In a recent study, Professor Andrew Pieper and his team from Case Western Reserve University discovered that NAD+ levels decrease significantly in the brains of Alzheimer’s patients, a trend also observed in mouse models.
While Alzheimer’s disease is unique to humans, it can be effectively modeled using genetically engineered mice that carry mutations linked to human Alzheimer’s disease.
The researchers utilized two distinct mouse models: one with multiple human mutations affecting amyloid processing and another with a human mutation in the tau protein.
Both models exhibited Alzheimer’s-like brain pathology, including blood-brain barrier degradation, axonal degeneration, neuroinflammation, impaired hippocampal neurogenesis, diminished synaptic transmission, and excessive oxidative damage.
They also developed cognitive impairments typical of Alzheimer’s patients.
Upon discovering the sharp decline in NAD+ levels in both humans and mice with Alzheimer’s, the scientists investigated whether preserving NAD+ levels before disease onset and restoring them after significant disease progression could prevent or reverse Alzheimer’s.
This research builds upon prior work showing potential recovery by restoring NAD+ balance following severe brain injuries.
The team achieved NAD+ balance restoration using a well-known pharmacological agent, P7C3-A20.
Remarkably, maintaining NAD+ balance not only shielded mice from developing Alzheimer’s but also enabled brain recovery from key pathological changes even when treatment was delayed in advanced disease stages.
Subsequently, both mouse strains fully regained cognitive function, accompanied by normalized levels of phosphorylated tau-217—a recently recognized clinical biomarker for Alzheimer’s disease in humans—confirming the restoration of cognitive function and highlighting a potential biomarker for future Alzheimer’s disease reversal trials.
“We are excited and hopeful about these results,” said Professor Pieper.
“Restoring brain energy balance led to both pathological and functional recovery in mice with advanced Alzheimer’s disease.”
“Observing this effect across two different animal models, driven by distinct genetic causes, reinforces the notion that recovery from progressive Alzheimer’s disease may be achievable through the restoration of brain NAD+ balance.”
These findings encourage a shift in how researchers, clinicians, and patients perceive treatment options for Alzheimer’s disease moving forward.
“The key takeaway is one of hope. Alzheimer’s disease effects may not necessarily be permanent,” noted Professor Pieper.
“Under certain conditions, the damaged brain can self-repair and regain functionality.”
“Through our research, we not only demonstrated a drug-based method for promoting recovery in animal models but also identified candidate proteins in human AD brains that may aid in reversing the disease,” remarked Dr. Kalyani Chaubey, a researcher at Case Western Reserve University and University Hospitals.
While current commercially available NAD+ precursors have been shown to elevate cellular NAD+ to unsafe levels—potentially promoting cancer—the pharmacological approach of this study employs P7C3-A20, which allows cells to maintain optimal NAD+ levels under stress without elevating them excessively.
“This is a crucial consideration for patient care, and clinicians should explore therapeutic strategies aimed at restoring the brain’s energy balance as a viable path toward disease recovery,” Professor Pieper concluded.
For more detailed information, see the study findings published in Cell Reports Medicine.
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Kalyani Chaubey et al. Pharmacological reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in the human brain. Cell Reports Medicine, published online on December 22, 2025. doi: 10.1016/j.xcrm.2025.102535
Source: www.sci.news
