There is currently no cure for Alzheimer’s disease, the most common form of dementia in the country with an estimated 7.2 million people age 65 and older living with it in the U.S. New research published this week indicates that might change.
“Our results challenge the long-held view that AD is intrinsically irreversible,” said authors of the study published Monday in the Cell Reports Medicine journal. That’s because they were able to reverse certain Alzheimer’s markers in mice.
According to the Alzheimer’s Association, plaques of a protein fragment called beta-amyloid in between nerve cells and tangles of twisted protein fibers called tau that build up inside cells are “prime suspects” in nerve cell death associated with Alzheimer’s. With the destruction of nerve cells comes memory failure, personality changes and other problems that characterize the disease.
Phosphorylated tau 217 (p-tau217), a protein found in tau tangles, has been identified as a biomarker for Alzheimer’s disease. Researchers from Case Western Reserve University, University Hospitals (UH) and the Louis Stokes Cleveland VA Medical Center found that a treatment called P7C3-A20 reduced plasma levels of p-tau217.
This treatment was previously used by the same team to treat traumatic brain injury. In that older study, they found that P7C3-A20 – developed at the Harrington Discovery Institute’s Pieper Lab – restored the balance of nicotinamide adenine dinucleotide, a “coenzyme that plays a central role in energy-producing pathways within cells,” per ScienceDirect.
“Using diverse preclinical mouse models and analysis of human AD brains, the team showed that the brain’s failure to maintain normal levels of a central cellular energy molecule, NAD+, is a major driver of AD, and that maintaining proper NAD+ balance can prevent and even reverse the disease,” said a press release from Case Western Reserve University about the recent study.
It also noted that these NAD+ levels naturally decline across the body as humans age, and even more so in people with Alzheimer’s.
With P7C3-A20 treatment, the older study showed that “restoring the brain’s NAD+ balance achieved pathological and functional recovery after severe, long-lasting traumatic brain injury.” A similar finding came from the new study.
“In advanced disease amyloid-driven… mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD+) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery,” in addition to dropping levels of the tau biomarker, said the study authors.
They explained that restoring NAD+ homeostasis bolsters resilience against disease drivers like plaques and tangles by breaking “the escalating energy demand imposed by ongoing cellular damage,” and that P7C3-A20 is able to promote this homeostasis without exceeding normal ranges.
Alzheimer’s is a condition only found in humans, but mice can be genetically engineered to express genetic mutations known to cause the disease in people, Case Western Reserve explained. For the recent study, researchers used two different mouse models – one with multiple human mutations in amyloid processing and another with a human mutation in the tau protein. Both lines of mice developed brain pathology similar to Alzheimer’s.
“After finding that NAD+ levels in the brain declined precipitously in both human and mouse AD, the research team tested whether preventing loss of brain NAD+ balance before disease onset or restoring brain NAD+ balance after significant disease progression could prevent or reverse AD, respectively,” said Case Western Reserve.
They found that preserving NAD+ not only prevented mice from developing the Alzheimer’s pathology but enabled the brain to fix major pathological events in mice with advanced disease. Both lines of mice fully recovered cognitive function.
“We were very excited and encouraged by our results,” said Andrew A. Pieper, the study’s senior author, a professor at the Case Western Reserve School of Medicine and director of the Brain Health Medicines Center, Harrington Discovery Institute at University Hospitals in Ohio. “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 new idea that recovery from advanced disease might be possible in people with AD when the brain’s NAD+ balance is restored.”
Looking to the future, Pieper and his team said that this research could serve as a foundation for developing therapies that would work to reverse Alzheimer’s pathology and allow for functional recovery. Further studies are expected to assess whether P7C3-A20 “can also fully restore cognitive function following extensive neuronal cell loss in even more advanced disease stages.”
There are “over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer,” Pieper noted. These are not the same as P7C3-A20.
“The key takeaway is a message of hope – the effects of Alzheimer’s disease may not be inevitably permanent,” Pieper said. “The damaged brain can, under some conditions, repair itself and regain function.”
He also said that: “Additional next steps for the laboratory research include pinpointing which aspects of brain energy balance are most important for recovery, identifying and evaluating complementary approaches to Alzheimer’s reversal, and investigating whether this recovery approach is also effective in other forms of chronic, age-related neurodegenerative disease.”
Previously, two treatments that remove beta-amyloid and can slow the development of Alzheimer’s have been made available. However, neither is a cure for the condition.