A molecule that restores cellular energy stores was able to reverse symptoms of Alzheimer’s disease in mice, potentially paving the way for a new class of therapeutics to treat the devastating disease.
Researchers at Case Western Reserve University in Cleveland analyzed brain tissue from humans with Alzheimer’s and found that those with lower levels of nicotinamide adenine dinucleotide (NAD+), a critical component of cellular metabolism, had more severe disease. After finding a similar correlation in mice with the condition, the scientists gave the rodents a compound called P7C3-A20, which is designed to restore NAD+ to normal levels.
The results, published in Cell Reports Medicine on Dec. 22, showed that P7C3-A20 could not only prevent Alzheimer’s from arising in mice but also boost memory and reduce anxiety in mice that already had advanced stages of the disease.
The therapeutic effect was seen in mice with two different genetic causes of Alzheimer’s, one driven by amyloid protein and another by tau protein.
“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,” Andrew Pieper, M.D., Ph.D., a neuroscientist at Case Western and senior author of the study, said in a Dec. 23 release.
The new treatment approach stops short of elevating NAD+ beyond natural levels, which is known to promote cancer, the researchers wrote in their paper.
Pieper is now working to advance P7C3-A20 through Glengary Brain Health, a Cleveland-based company that he co-founded, according to the release. Pieper’s team had previously found that the investigational molecule could restore cognition in mice with long-term traumatic brain injuries.
Alzheimer’s research has been dominated for decades by the so-called amyloid hypothesis, the idea that telltale clumps of amyloid protein in the brain are what drives the disease. Approved medicines that tackle amyloid, like Eli Lilly’s Kisunla (donanemab) and Biogen and Eisai’s Leqembi (lecanemab), have been dogged by a rare but serious brain bleeding side effect and are also unable to restore lost cognitive function.
“The key takeaway is a message of hope—the effects of Alzheimer's disease may not be inevitably permanent,” Pieper said in the release. “The damaged brain can, under some conditions, repair itself and regain function.”