About one in nine people over 65 have Alzheimer’s — and the number is growing quickly.
Without an existing cure, researchers are racing to find ways to prevent and treat the disease, which kills more than breast cancer and prostate cancer combined.
Thanks to a flurry of advancement in this field, scientists have uncovered two new ways Alzheimer’s can possibly be managed in the future.
The first is by harnessing a powerful genetic mutation that reduce the harmful build up of a protein in the brain. The second opens the door to retuning a healthy layer of protective fat to nerve fibers, keeping signaling between cells functional.
Both studies could be first steps in developing therapies for Alzheimer’s in the future.
Blocking toxic build up
One of the best ways to research Alzheimer’s is examining folks with a common gene variant called APOE4 — one in four carry it. And though these carriers face at least two times (and up to 12 times) the risk of developing Alzheimer’s, not everyone does.
The difference between who does and doesn’t get this irreversible disease holds the key to future prevention and treatment.
Researchers from Columbia found that some people with the APOE4 variant also had another mutation on their FN1 gene, a gene that gives instructions for making fibronectin.
Fibronectin is essential for the body to build tissue, so everyone has a copy of this gene. But the vital protein becomes a problem when it builds up around blood vessels, getting in the way of normal signaling.
This can lead to a dysfunctional blood-brain barrier, allowing harmful substances into the brain and making it harder to clear waste. This is often seen in APOE4 carriers that get Alzheimer’s.
But the rare FN1 mutation Columbia researchers identified seemed to do the opposite: keep fibronectin under control. In one experiment, they found that zebrafish with this mutation had much lower fibronectin build up compared to those without the mutation.
This finding suggests several possible treatments, including preventing that extra fibronectin from building up. “This new study takes us from a genetic clue to a disease mechanism,” author Caghan Kizil said. “And with [the mechanism], ideas for how to reproduce that natural protection.”
Protecting and reversing loss of protective fat
Researchers from MIT found a new pathway called Wnt that gets disrupted in folks carrying APOE4.
They found that those with APOE4 suppressed Wnt signaling, leading to a build up of fat inside oligodendrocytes, which make myelin, the fatty protective insulation around nerve fibers.
Enough myelin protection around nerve fibers is critical for proper communications between cells. Without it, lipids can build up in the brain without ever going to where they’re needed.
With faulty oligodendrocytes, less myelin is made. This is one of the first signs of Alzheimer’s before other symptoms appear.
What’s even more notable though, is that MIT researchers found a way to correct this.
They found they could inhibit an enzyme called GSK3b, lowering fat buildup in those critical oligodendrocytes, making them work better and produce more myelin, better protecting the nerve fibers.
The authors believe that in the future, drugs could be developed to restore the Wnt pathway to produce more myelin. The key is an experimental compound called CHIR99021, which inhibits GSK3B.
This research “not only provides new insights into cellular pathways contributing to lipid metabolism defects, but really also has the potential to provide new targets for drug development,” said author Li-Huei Tsai.
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