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• Posted March 29, 2024

Mutation Helps Even Carriers of 'Alzheimer's Gene' Avoid Alzheimer's

A genetic mutation that boosts cell function could protect people against Alzheimer's disease, even if they carry another gene mutation known to boost dementia risk.

The newly discovered mutation appears to protect people who carry the APOE4 gene, which increases risk of Alzheimer's, researchers said.

The protective mutation causes cells to produce a more powerful version of humanin, a tiny protein that plays an important role in cellular function.

Humanin levels are higher in people who have reached the age of 100 despite carrying the APOE4 gene, which predisposes people to early death as well as Alzheimer's, researchers discovered.

Humanin produced by this variant also effectively cleared amyloid beta from the brains of lab mice carrying APOE4, researchers report.

“This new study sheds light on resilience genes that help people live longer and partially explains why some people at high risk for developing Alzheimer's disease are spared,” said senior study author Dr. Pinchas Cohen, dean of the University of Southern California (USC) Leonard Davis School of Gerontology.

The gene variant that causes higher levels of humanin is called P3S-humanin, researchers said.

This variant is thought to be extremely rare, and is found primarily in people of Ashkenazi Jewish descent, researchers said.

Mitochondria, the energy powerhouse of cells, produce humanin to protect against cellular aging and stress, according to a 2023 review in the journal Biology.

Humanin has been shown to protect brain health, and can reduce inflammation and stress, the review says. It also can improve blood sugar metabolism and insulin resistance, two contributing factors to type 2 diabetes.

For the new study, researchers examined more than 500 healthy centenarians, near-centenarians and their children.

They found that about 12% of centenarians of Ashkenazi descent carried the P3S variant, compared to less than 0.2% of others.

Brain function tests among centenarians with the APOE4 gene found that those who also carried the PS3-humanin gene outperformed those who didn't, suggesting that the humanin variant blunted some of their Alzheimer's risk.

Between 40% and 60% of people diagnosed with Alzheimer's carry the APOE4 gene, according to the Alzheimer's Association.

Researchers then turned to mice genetically engineered to carry a humanized APOE4 gene. They found that treatment with PS3 gene-produced humanin resulted in a marked reduction of amyloid beta in the brains of the mice.

Treatment with standard humanin protein also resulted in some decrease of amyloid beta, but the effect was more powerful with the genetic variant, researchers said.

Amyloid beta plaques are a hallmark of Alzheimer's disease.

Analysis showed that PS3-derived humanin allows it to bind more effectively with the APOE4 gene, researchers said.

“This humanin P3S, when made by mitochondria, actually binds the protein product of APOE4 very tightly. This seems to help clear away harmful amyloid-beta, which builds up in the brains of people with Alzheimer's,” said lead researcher Brendan Miller, a postdoctoral scientist at the Salk Institute for Biological Studies.

“Our experiments showed that this protein variant could be a reason why some people with the risk-gene avoid Alzheimer's and maintain good brain health into old age,” Miller added in a USC news release.

Future Alzheimer's drugs might target APOE4 by using insights gained from PS3-derived humanin, Cohen said, and humanin also might be used to help people resist other age-related diseases.

The new study was published March 22 in the journal Aging Cell.

More information

The Alzheimer's Association has more on genetic risk for Alzheimer's.

SOURCE: University of Southern California, news release, March 23, 2024