Mutations Are Linked to Lower Odds of Alzheimer Disease

Random changes in certain genes that cause blood-forming stem cells to accumulate when unchecked and have been shown to increase tenfold the risk of developing blood cancer may also be associated with a reduced risk of Alzheimer disease (AD).

“Our hypothesis was that these mutations would be associated with an increased risk of Alzheimer’s disease, but we found an overall 35% to 40% reduced risk for Alzheimer’s, although this is an association and does not address causality.” Siddhartha Jaiswal, MD, of Stanford University, said in a statement.

The mutation, known as clonal hematopoiesis of indeterminate potential (CHIP), is common with aging and are acquired rather than inherited.

CHIP is found in at least 10% to 20% of individuals over the aged 70 years, and previous studies have shown that individuals with CHIP have about a 1% chance per year of developing leukemia or another blood cancer and are at nearly double the average risk for heart disease.

CHIPS has no signs or symptoms and is generally detected only when an individual undergoes genetic testing for another condition, such as a solid tumor or an unexplained low blood count.

Available treatments could temporarily improve symptoms, such as memory loss, but they do not stop the brain damage that worsens the disease overtime. Although there is no specific gene that has been identified to cause late-onset AD, carrying a variant form of the Apolipoprotein E (APOE) gene affects an individual’s risk of developing the disease.

“APOE has several different forms. . The ones most relevant to Alzheimer are e2, which decreases risk; e3, which has a neutral effect on risk; and e4, which significantly increases risk,” Jaiswal said.

“In our study, if people had the protective e2 form of the gene, CHIP did not seem to have any effect. But for carriers of e3 and e4, the risk reduction associated with CHIP was comparable to or greater than that of APOE e2,” Jaiswal said.

Investigators analyzed anonymized data from 5730 individuals who had contributed blood samples to 1 of 2 large, ongoing precision medicine studies: the Alzheimer's Disease Sequencing Project, sponsored by the National Human Genome Research Institute and the National Institute on Aging, and Trans-Omics for Precision Medicine or TOPMed, sponsored by the National Heart, Lung, and Blood Institute.

They matched data for individuals who carried an APOE mutation and a CHIP mutation. The 2 cohorts were about 60% female, with an range from approximately aged 60 to 80 years. Individuals were also predominantly white.

They found that there was an association between CHIP mutations and a lower likelihood of developing AD or changed in the brain typically seen in individuals with the disease.

Investigators also examined brain tissue samples from autopsies performed on 8 donors who had CHIPS; 6 of them were cognitively normal when they died.

They identified the CHIP mutation in cells known as microglia, a type of neuroglia located throughout the brain and spinal cord.

“Our thinking now is that the job of the microglia may be to clear out the toxic lumps of protein that accumulate in the brains of people with Alzheimer. As we age, normal microglia may do this less well, but something about the CHIP mutation may allow the mutated microglia to continue effectively performing this task,” Jaiswal said.

“Proving this, and figuring out what it is about the CHIP mutation that exerts this protective effect, could ultimately lead to the development of new treatments for Alzheimer’s disease,” he said.

There is a long-standing suspicion that inflammation could play a role in the development of AD, and though the findings show an association between the presence of the CHIP mutation and a reduced risk for AD, the investigators have not proven that the mutation directly explains the potential for reduced risk of the disease, Jaiswal said.

Reference

Mutations that heighten the risk for blood cancers and heart disease are associated with lower odds of Alzheimer’s disease. American Society of Hematology. News release. December 11, 2021. Accessed December 13, 2021. Email.