- For many years, scientists have considered Alzheimer’s disease to be irreversible. For this reason, much research has focused on preventing or slowing disease progression, rather than reversal.
- However, a recent study in mice investigated a compound with neuroprotective properties that may repair damage and recover cognitive function.
- In the animal models of advanced Alzheimer’s disease, the compound could restore levels of a vital cellular energy molecule and reverse disease-related brain damage.
- Although further research is necessary, these findings suggest that treatments aimed at restoring brain energy balance may offer a potential option for reversing cognitive function.
In the United States, more than 7 million adults aged 65 and over are living with Alzheimer’s disease. This progressive condition causes memory loss and cognitive decline. It accounts for 60% to 80% of dementia cases in the U.S.
Nicotinamide adenine dinucleotide (NAD+) is an essential enzyme that has a role in many important cell functions, such as energy metabolism and DNA repair. NAD+ levels naturally decline with age and may relate to a higher risk of age-related diseases, such as Alzheimer’s disease.
Lower levels of NAD+ may contribute to Alzheimer’s disease risk due to an increase in oxidative stress, inflammation, and protein aggregation. As such, research is investigating NAD+ restoration and its potential neuroprotective role.
A research team from Case Western Reserve University, University Hospitals (UH) and the Louis Stokes Cleveland VA Medical Center investigated whether restoring the brain’s energy balance by maintaining NAD+ balance could prevent and even reverse Alzheimer’s disease.
The study, published in
NAD+ is essential for cellular energy and function. A decline in NAD+ levels, which occurs naturally as people age, is a key factor that contributes to Alzheimer’s progression. This reduction can disrupt critical cellular processes necessary for brain function.
The study found this decline is even more pronounced in individuals with Alzheimer’s disease, with human brain samples showing a 30% reduction in NAD+.
The study’s senior author, Andrew A. Pieper, MD, PhD, a professor at the Case Western Reserve School of Medicine and director of the Brain Health Medicines Center, Harrington Discovery Institute at UH spoke to Medical News Today, noting:
“We found that brains from people and mice with Alzheimer’s show much larger disturbances in NAD+ homeostasis, a vital aspect of brain Health, than normal aging causes. That suggested the imbalance might be driving the disease.”
For the study, the research team used two genetically engineered mouse models of Alzheimer’s disease. The mice expressed human gene alterations in either
The accumulation of these proteins plays a significant role in the development of Alzheimer’s disease. The formation of amyloid plaques and tau tangles disrupts communication between neurons, leading to the cognitive decline seen in those with the condition.
Much research has focused on clearing or blocking these proteins, but have not been successful in reversing the damage. In this study, the researchers focused on restoring NAD+ levels instead.
Building on a previous study, the researchers attempted to restore NAD+ balance using a neuroprotective compound known as P7C3-A20.
Pieper noted that :”We previously showed that giving P7C3-A20 long after a traumatic brain injury in mice enabled the brain to stop ongoing neurodegeneration and fully recover normal cognitive function, despite the loss of neuronal brain cells. This led us to ask whether a similar recovery could occur in chronic Alzheimer’s disease.”
This pharmacological agent can help restore NAD+ balance by preventing an excessive breakdown of NAD+ by cells, enabling brain cells to regain energy and recover without depleting NAD+ levels.
Pieper added that “P7C3-A20 is an ideal tool to test this idea because it safely restores and maintains normal NAD+ homeostasis without elevating it to above-normal levels. Thus, we had a way of testing whether fixing NAD+ balance helps the brain recover.”
P7C3-A20 is a synthetic chemical compound that can restore NAD+ levels by activating nicotinamide phosphoribosyltransferase (NAMPT), a crucial enzyme that controls the rate-limiting step in the
In other words, P7C3-A20 helps to recycle important molecules to maintain a sufficient supply of NAD+ for energy and protection.
Pieper explained the mechanism that enables P7C3-A20 to restore NAD+ levels:
“P7C3-A20 readily crosses the blood-brain barrier to safely restore and maintain brain NAD+ homeostasis, which supports DNA repair, reduces oxidative stress and inflammation, and promotes neuronal health and synaptic function.”
The researchers found that maintaining NAD+ levels in the brain could prevent the development of Alzheimer’s in the early stages in these mouse models.
Additionally, models with advanced Alzheimer’s receiving P7C3-A20 displayed significant reversal of disease-related brain damage.
The treatment restored cognitive function and showed biological improvements. These included restored blood-brain barrier integrity, reduced oxidative stress and DNA damage, decreased neuroinflammation, and enhanced synaptic plasticity.
Furthermore, the research teams observed a significant reduction in blood levels of phosphorylated tau 217, a clinical biomarker for Alzheimer’s disease that indicates tau-related brain damage.
Scientists have long considered Alzheimer’s disease to be an irreversible and progressive neurodegenerative condition. However, the results of this study challenge that assumption.
The research suggests that Alzheimer’s disease may not be an inevitably progressive condition and that under certain conditions, the brain may have the capacity to repair itself.
Significantly, the results of the study show that restoring NAD+ levels shows benefit in two distinct models of Alzheimer’s, driven by different genetic causes.
These findings potentially mark a major shift in Alzheimer’s treatment options, suggesting that it may be possible to reverse damage and regain lost function due to the condition.
Additionally, the approach in the study may also help avoid potentially harmful side effects relating to over-the-counter NAD+ supplements.
For example, evidence highlights a possible link between NAD+ supplementation and cancer. Although no evidence currently suggests NAD+ supplements cause cancer, excess NAD+ may fuel cancer cells if they are present.
However, as this method does not supplement NAD+ but instead encourages the salvage pathway, it prevents the risk of elevating NAD+ to levels that could cause harm.
Commenting on the research, Maria C. Carrillo, PhD, Alzheimer’s Association chief science officer and medical affairs lead, said:
This paper reports on a necessary and important scientific step in investigating a fascinating idea — that brain resilience can be enhanced to reverse Alzheimer’s-related damage, or prevent Alzheimer’s-related pathology if started early in the disease process — but the research is still preliminary… the notion that we are seriously investigating the reversal of Alzheimer’s can give everyone a sense of hope that the field is working to create a world without Alzheimer’s and all other diseases that cause dementia.
Although these results are promising, it is important to emphasize that further research is necessary before translating this approach into human clinical trials.
The research team note that the next steps for research will include pinpointing the most crucial aspects of brain energy balance that drive recovery, as well as exploring complementary treatments.
Pieper concluded that “these results were very encouraging because they suggest dementia might not always be irreversible and support testing this approach in people.”
“Because we observed disturbed NAD+ homeostasis in human Alzheimer’s brains and because NAD+ is central to many conserved cellular processes, this strategy has a strong biological rationale for humans. That said, mouse results do not guarantee human success. The next step is well-controlled clinical testing to determine safety and efficacy in people,” he told us.
