A new study from the University of California San Diego has uncovered a hidden cause of Alzheimer’s disease that may lead to a new way to treat it.
Scientists found that a gene called PHGDH, which they had previously linked to the disease, doesn’t just signal risk—it actually helps cause the disease in a surprising way.
This discovery also led to a promising treatment that may slow down Alzheimer’s before it becomes too serious.
Alzheimer’s disease is a brain disorder that affects memory, thinking, and behavior. It’s the most common form of dementia, and it mainly affects older adults. About one in nine people over the age of 65 has it. Scientists have known that certain rare gene mutations can lead to Alzheimer’s, but those cases are the minority.
Most people with Alzheimer’s don’t have those specific mutations. That’s why researchers have been searching for other possible causes—especially for what’s called “spontaneous” Alzheimer’s, which appears without a clear genetic reason.
Dr. Sheng Zhong, a professor at UC San Diego, led a team that previously identified the PHGDH gene as a possible warning sign for Alzheimer’s. They noticed that people with higher levels of this gene’s activity had more serious brain changes linked to the disease.
What wasn’t clear was whether PHGDH was just a warning signal—or if it actually helped cause the damage.
To find out, the researchers ran experiments on mice and mini human brains grown in the lab, called brain organoids. When they reduced the activity of the PHGDH gene, signs of Alzheimer’s disease decreased. But when they increased it, the disease got worse. This showed that the gene was more than just a signal—it was part of the problem.
So what exactly does PHGDH do? Normally, this gene helps make an enzyme that produces serine, a substance important for the brain and the body. Scientists thought maybe this process was what connected the gene to Alzheimer’s. But when they tested that theory, they found no link. This puzzled them—until they discovered something completely unexpected.
Using artificial intelligence (AI) to study the 3D shape of the PHGDH protein, the researchers found a special part of it that looked like the “hands” some proteins use to grab onto DNA and turn other genes on or off.
This was a big surprise, because the gene had never been known to do that. With this new information, they found that PHGDH can turn on two key genes in the brain—and that this process disrupts the brain’s normal function and leads to Alzheimer’s.
This means PHGDH has two jobs. Its first job is making serine, which is helpful and normal. But its second, hidden job—changing how genes are turned on in brain cells—can cause harm. The more PHGDH the brain makes, the more likely this second job will go wrong, leading to Alzheimer’s.
The team then looked for a way to block this harmful second job, without interfering with the helpful one. They found a small molecule called NCT-503, which had already been studied for other reasons. It was weak at blocking PHGDH’s enzyme work (which was good), but it could sneak into the brain and reach the protein’s harmful “DNA-binding” area.
AI helped again by showing how NCT-503 fits into the 3D shape of the protein. When tested on mice with Alzheimer’s, the treatment reduced the disease and improved the mice’s memory and behavior. These results suggest that the drug was successful in blocking the gene’s damaging activity.
There are still limits to the study. Mice aren’t perfect models for human Alzheimer’s, especially the spontaneous kind, so more testing is needed. But the study offers hope. Unlike current Alzheimer’s treatments that target damage already done, this new approach works earlier in the disease process, possibly preventing that damage from happening in the first place.
This research is a major step forward. It reveals how a gene known for one job can have a hidden second job that harms the brain. It also shows how modern tools like AI can uncover these secrets and guide scientists to new treatments.
If future studies confirm these findings, we could be looking at an entirely new way to slow or even stop Alzheimer’s disease before it takes hold.
If you care about Alzheimer’s disease, please read studies about vitamin D deficiency linked to Alzheimer’s and dementia, and strawberries can be good defence against Alzheimer’s.
For more health information, please see recent studies about foods that reduce Alzheimer’s risk, and oral cannabis extract may help reduce Alzheimer’s symptoms.
The research findings can be found in Cell.
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