To this day, Alzheimer's disease is one of the most frightening health conditions that people face in their older years.
The devastating illness deteriorates your brain's ability to think, remember things and can even alter your behaviour.
While some studies have discovered that engaging in a pretty gross habit or reaching a daily step count can reduce the risk of developing Alzheimer's disease (AD), for over a century, scientists have considered it an irreversible illness. This is why research has focused on preventing or slowing its progression, rather than recovery.
However, a new study challenges this long-held belief by testing whether brains already severely afflicted with advanced AD could recover.
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A research team from Case Western Reserve University, University Hospitals and the Louis Stokes Cleveland VA Medical Center studied diverse preclinical mouse models and analysis of human AD brains. The research was published online on 22 December in Cell Reports Medicine.
Led by Kalyani Chaubey from the Pieper Laboratory, the team found that the brain’s failure to maintain normal levels of the central cellular energy molecule NAD+ is a major driver of AD. More specifically, maintaining proper NAD+ balance can prevent and even reverse the disease, the scientists revealed.
As people get older, NAD+ levels decline naturally across the body and brain. When NAD+ balance deteriorates, cells lose their ability to carry out the essential functions needed for operation and survival.
Chaubey and her team's research showed that the decline in NAD+ is significantly worse in the brains of AD patients, with the same pattern appearing in mouse models of the condition.
In the study, the scientists used two mouse models. The first carried multiple human mutations affecting amyloid processing, while the other had a human mutation in the tau protein.
For context, amyloid and tau pathology are among the earliest major developments in AD progression. Both mouse lines also exhibited the severe cognitive decline characteristic of human Alzheimer's patients.
This wasn't the team's first success with NAD+. Previously, the team published research (in the Proceeding of the National Academy of Sciences USA) showing that restoring NAD+ balance helped the brain recover from serious traumatic injury.
To restore NAD+ levels, they used a compound called P7C3-A20, a drug developed in the Pieper lab. Incredibly, they found that maintaining healthy NAD+ levels prevented mice from developing Alzheimer's disease. Not only that, but when they gave the treatment to mice already suffering from advanced AD, their brains remarkably repaired the severe damage caused by the disease-causing genes.
Moreover, both groups of mice fully recovered their cognitive function, accompanied by normalised blood levels of phosphorylated tau 217, a recently approved clinical biomarker of AD in people. Blood levels returning to normal provided solid proof that the disease had reversed.
“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 UH. "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.”
Going forward, the team hopes their results will change the way researchers, clinicians, and patients think about treating AD.
“The key takeaway is a message of hope - the effects of Alzheimer's disease may not be inevitably permanent,” Pieper concluded. “The damaged brain can, under some conditions, repair itself and regain function.”