Scientists Uncover How Alzheimer’s Gene APOE4 Scars the Brain’s Blood Vessels

Scientists have uncovered how APOE4, the strongest genetic risk factor for Alzheimer’s disease, may damage the brain’s blood vessels, identifying a cellular process that could guide future treatment research.

In laboratory studies, researchers at the Icahn School of Medicine at Mount Sinai found that APOE4 can cause pericytes, cells that support and stabilise tiny brain blood vessels, to become cells that make scar tissue.

This change can thicken the vessels and is associated with increased amyloid buildup around them. Amyloid is an abnormal protein linked to Alzheimer’s disease.

The researchers also found that blocking TGF-beta, a protein that helps control how cells behave and how tissues repair themselves, reversed the blood vessel damage in mice carrying APOE4-related changes.

The findings were reported in two studies published in Cell and Cell Stem Cell.

How APOE4 affects the brain’s blood vessels

APOE4 has long been known to increase Alzheimer’s risk, but scientists are still investigating how it contributes to the physical changes associated with the disease.

The new research points to pericytes as an important part of that process. These cells surround small blood vessels and help keep them strong and working properly. In laboratory models, researchers found that APOE4 can push them into a state similar to myofibroblasts, cells that produce scar tissue.

This scarring, known as fibrosis, changes the blood vessels and is linked to increased amyloid buildup around them. This suggests a possible chain of events connecting APOE4 to blood vessel damage, although the findings do not yet show that this sequence occurs in humans.

Researchers reversed the damage in mice

The scientists then focused on TGF-beta, which helps control cell activity and tissue repair.

In laboratory models, blocking the pathway stopped APOE4-related changes in pericytes. In mice, it also reversed the associated deterioration of the brain’s blood vessels.

These results show that the pathway can be changed in experimental systems and in mice. They do not show that the same approach works in people.

The finding gives researchers a specific pathway to investigate as they look for ways to protect the brain’s blood vessel system and potentially limit amyloid buildup.

Joel Blanchard, a co-author of the studies, said the research suggests that APOE4 may actively drive changes in the brain’s blood vessels rather than simply being associated with damage that appears later in Alzheimer’s disease.

The finding is not a cure

The researchers have not shown that Alzheimer’s disease can be reversed in humans.

The reversal was demonstrated in laboratory models and mice, not in human patients. The human findings so far are limited to evidence that the mechanism may be relevant to human disease; they do not establish that blocking TGF-beta would be effective or safe as a treatment.

Human studies will be needed to determine whether the same mechanism operates in people and whether targeting TGF-beta can be done safely.

That distinction matters because a process that can be changed in cells or mice does not automatically become an effective human treatment.

Still, the research gives scientists a more specific target. Much of Alzheimer’s research has focused on amyloid and tau, two proteins closely associated with the disease. These findings add to evidence that the brain’s blood vessels and the cells supporting them may also play an active role in disease development.

The researchers’ proposed sequence is that APOE4 changes pericytes, the altered cells contribute to blood vessel scarring, and the damaged vessels become associated with increased amyloid buildup. This sequence has been supported by laboratory and mouse experiments, but it remains to be confirmed in humans.

If future research confirms the mechanism in humans, interrupting that process could become another avenue for protecting people at risk of Alzheimer’s.

As at the time of this report, the findings represent a laboratory and animal-study discovery rather than a new treatment. But they give researchers a clearer picture of how one of the disease’s most important genetic risk factors may damage the brain’s blood vessel system.