Some people with high-risk Alzheimer’s gene never get it. Scientists may know why

Some people who carry one of the strongest known genetic risk factors for Alzheimer’s disease go on to develop the condition, others never do. Now, scientists say they have uncovered new clues that could help explain why, potentially opening the door to more personalized prevention and treatment strategies.

An international team led by Michael E. Belloy, an assistant professor of neurology and psychiatry at Washington University School of Medicine in St. Louis, analyzed the genomes of nearly 450,000 people from European, African and Japanese populations.

Belloy told Newsweek, “Apolipoprotein E (APOE4) is found in roughly half of people with Alzheimer’s disease, carrying it does not make the disease inevitable.”

Their findings, published in Alzheimer’s & Dementia, identified dozens of genes that may influence Alzheimer’s risk in people who carry the APOE4 variant.

According to the Alzheimer’s Association, one in three older adults dies with Alzheimer’s disease or another form of dementia.

Whether someone with the APOE4 gene develops Alzheimer’s depends on a mix of factors, including their lifestyle, heart health and other genetic and biological traits.

Belloy said: “Our research focuses particularly on genes and mechanisms in the brain that may naturally counteract the harmful effects of APOE4.

“Some of the genes prioritized in our study may have this protective role, making them compelling starting points for developing interventions that could reduce risk in APOE4 carriers.”

The researchers set out to understand what may be protecting those individuals. Their analysis identified 44 genes linked to Alzheimer’s-related biological processes, as well as potential drug targets that could be explored in future treatments.

One of the strongest signals came from oligodendrocytes, brain cells that produce myelin, a protective coating around nerve fibers that helps brain cells communicate with one another. Many of the genes associated with APOE4 risk were connected to these cells, suggesting that preserving myelin could help protect against the effects of Alzheimer’s disease.

The findings offer further support for a future approach to Alzheimer’s care in which treatments are tailored to the biological mechanisms driving disease in each person, rather than relying on a one-size-fits-all strategy.

Belloy said the “biggest hurdle” is translating the genetic findings into potential treatments.

He said: “Human genetic and molecular data allow us to nominate genes, biological pathways and, in our study, specific brain cell types that appear particularly important.

“However, these findings need to be corroborated in additional studies and tested experimentally to determine which genes are most promising to modify the effects of APOE4.”

Belloy said any promising candidates would still need to go through drug development studies, but he added that the research is helping lay the groundwork for more personalized Alzheimer’s prevention and treatment approaches. He noted that further validation studies are needed before the findings can move forward.

Reference

Zeng Y., Cook N., Yang C., et al. (2026). APOE*4 risk-modifying genes and drug targets in Alzheimer’s disease through cell-type-specific genomic analyses. Alzheimer’s & Dementia, 22. https://doi.org/10.1002/alz.71552

Contact Newsweek editors on this story: Kara Dolman and Shakeema Edwards.