A recent study indicates that Alzheimer's disease may be reversible, allowing for complete neurological recovery—not merely prevention or deceleration—in animal models.
Summary: A recent study contests the longstanding notion that Alzheimer’s disease is irreversible. Researchers demonstrated that a significant reduction in NAD+—a vital energy molecule—fuels Alzheimer’s pathology in both human brains and mouse models.
Restoring the appropriate NAD+ balance with the drug P7C3-A20 not only prevented the disease in at-risk mice but also reversed advanced pathology, mending brain damage and completely restoring cognitive function. These findings indicate a significant shift in the approach to treating #Alzheimer’s, implying that recovery—not merely slowing the decline—might eventually be possible.
Central NAD+ Failure: Both human and mouse Alzheimer’s brains exhibited a substantial decrease in NAD+, hindering crucial cellular functions.
Reversal Achieved: Restoring NAD+ balance repaired pathology and fully recovered cognition, even in mice suffering from advanced disease.
New Treatment Pathway: The targeted drug P7C3-A20 reinstated healthy NAD+ levels without the risks associated with over-the-counter NAD+ boosters.
Source: University Hospital Cleveland Medical Center
For more than a century, Alzheimer’s disease (AD) has been deemed irreversible. As a result, research has concentrated on preventing the disease or slowing its progression, rather than on recovery.
Despite the expenditure of billions of dollars over decades of research, there has yet to be a clinical trial of a drug for AD aimed at reversing the disease and restoring function.
This image depicts an older woman alongside neurons.
Currently, a research team from University Hospitals, Case Western Reserve University, and the Louis Stokes Cleveland VA Medical Center has questioned this entrenched belief in the field. They investigated whether brains severely affected by advanced AD could experience recovery.
The study, spearheaded by Kalyani Chaubey, PhD, from the Pieper Laboratory, was published today in Cell Reports Medicine.
By examining various preclinical mouse models alongside human brains affected by Alzheimer's disease (AD), the research team demonstrated that the brain's inability to sustain normal levels of a crucial cellular energy molecule, NAD+, significantly contributes to the progression of AD. Furthermore, they found that maintaining an appropriate balance of NAD+ could potentially prevent and even reverse the disease.
As individuals age, NAD+ levels naturally decrease throughout the body, including within the brain. When NAD+ balance is disrupted, cells ultimately lose the ability to perform essential processes necessary for their proper functioning and survival.
In this investigation, the team revealed that the reduction of NAD+ is particularly pronounced in the brains of individuals with AD, a phenomenon that is also observed in mouse models of the condition.
Although AD is a condition specific to humans, it can be effectively studied in laboratory settings using mice that have been genetically modified to express mutations associated with AD in humans. The researchers utilized two distinct models for their study.
One mouse line was engineered to carry multiple human mutations related to amyloid processing, while the other line possessed a human mutation affecting the tau protein.
The pathologies associated with amyloid and tau are among the primary early events in AD, and both mouse lines exhibit brain pathologies that mimic those seen in AD, including deterioration of the blood-brain barrier, axonal degeneration, neuroinflammation, impaired neurogenesis in the hippocampus, diminished synaptic transmission, and extensive oxidative damage accumulation.
These mice also experience significant cognitive deficits that are comparable to those observed in individuals with AD.
Upon discovering that NAD+ levels in the brain dropped sharply in both human and mouse models of AD, the research team investigated whether preventing the decline of brain NAD+ balance prior to the onset of the disease, or restoring NAD+ balance after considerable disease progression, could either prevent or reverse AD, respectively.
This study builds upon their earlier research, published in the Proceedings of the National Academy of Sciences USA, which indicated that restoring the brain's NAD+ balance could lead to both pathological and functional recovery following severe, prolonged traumatic brain injury.
They restored the balance of NAD+ by administering a well-characterized pharmacological agent known as P7C3-A20, which was developed in the Pieper laboratory.
Remarkably, not only did the preservation of NAD+ balance protect mice from developing Alzheimer's disease (AD), but also the delayed treatment in mice with advanced disease allowed the brain to rectify the major pathological events caused by genetic mutations. Furthermore, both strains of mice fully regained cognitive function.
This was accompanied by normalized blood levels of phosphorylated tau 217, a recently approved clinical biomarker for AD in humans, providing confirmation of disease reversal and underscoring a potential biomarker for future clinical trials.
“We were very excited and encouraged by our results,” stated Andrew A. Pieper, MD, PhD, the senior author of the study and Director of the Brain Health Medicines Center at the Harrington Discovery Institute at the University of Houston.
“Restoring the brain’s energy balance led to both pathological and functional recovery in both strains of mice with advanced Alzheimer’s. Observing this effect in two distinct animal models, each driven by different genetic factors, reinforces the notion that restoring the brain’s NAD+ balance may assist patients in recovering from Alzheimer’s.”
Dr. Pieper also holds the Morley-Mather Chair in Neuropsychiatry at the University of Houston and the CWRU Rebecca E. Barchas, MD, DLFAPA, University Professorship in Translational Psychiatry. He serves as a Psychiatrist and Investigator at the Louis Stokes VA Geriatric Research Education and Clinical Center (GRECC).
The findings suggest a paradigm shift in how researchers, clinicians, and patients may approach the treatment of AD in the future.
The primary message conveys a sense of optimism – the impacts of Alzheimer’s disease may not be permanently irreversible,” stated Dr. Pieper. “Under certain circumstances, the impaired brain has the potential to heal itself and restore function.”
Dr. Chaubey elaborated, “Our research demonstrated a drug-based method to achieve this in animal models, and we also identified potential proteins in the human Alzheimer’s disease brain that may be linked to the capacity to reverse the condition.”
Dr. Pieper highlighted that currently available over-the-counter NAD+-precursors have been shown in animal studies to elevate cellular NAD+ to dangerously high levels that could promote cancer.
However, the methodology employed in this study utilizes a pharmacological agent (P7C3-A20) that allows cells to sustain their appropriate NAD+ balance even under conditions of significant stress, without raising NAD+ to supraphysiological levels.
“This is crucial when considering patient care, and healthcare providers should contemplate the possibility that therapeutic strategies focused on restoring brain energy balance could provide a pathway to recovery from the disease,” remarked Dr. Pieper.
This research also promotes further investigation into complementary methods and eventual trials in patients, with the technology being commercialized by Glengary Brain Health, a Cleveland-based company co-founded by Dr. Pieper.
“This innovative therapeutic strategy for recovery must progress into meticulously designed human clinical trials to ascertain whether the effectiveness observed in animal models can be replicated in human patients,” Dr. Pieper clarified.
“Future steps for laboratory research involve identifying which elements of brain energy balance are most critical for recovery, exploring and assessing complementary strategies for reversing Alzheimer’s, and examining whether this recovery method is also beneficial for other types of chronic, age-related neurodegenerative diseases.
Key Questions Addressed:
Q: What did researchers uncover regarding NAD+ in the context of Alzheimer’s disease?
A: They discovered that a significant reduction in NAD+ is a primary factor contributing to Alzheimer’s pathology, leading to disruptions in energy equilibrium and harm to essential brain systems.
Q: Is it possible to reverse the effects of advanced Alzheimer’s by restoring NAD+?
A: Indeed. In two separate mouse models of Alzheimer’s, the restoration of NAD+ levels repaired both structural and functional damage in the brain, resulting in a complete recovery of cognitive abilities.
Q: How does P7C3-A20 differ from typical NAD+ supplements?
A: Unlike over-the-counter NAD+ precursors that may elevate NAD+ to dangerous levels, P7C3-A20 assists the brain in maintaining an appropriate NAD+ balance during stress without inducing harmful increases.