Researchers uncover how APOE4 damages brain vessels

Alzheimer’s disease is known to cause a gradual decline in memory and thinking. Although damage to the brain’s blood vessels has long been recognized, particularly in people carrying APOE4, the underlying mechanisms have remained unclear and were generally viewed as a consequence of the disease rather than an active driver of its progression.

The researchers published two studies in Cell and Cell Stem Cell, identifying disease mechanisms that may be therapeutically reversible and introducing a new platform of human brain tissue derived from stem cells to accelerate the development of treatments.

First study: APOE4 turns support cells into scar-forming cells

In the first study, published in Cell, the researchers created a single-cell transcriptomic atlas of human brain blood vessels, providing a detailed map of gene activity in the cells that form and support the vessels.

They found that APOE4 transforms pericytes — cells that stabilize small blood vessels and maintain the blood-brain barrier — into myofibroblast-like, scar-forming cells. This process increased vascular fibrosis and the accumulation of amyloid around blood vessels, potentially impairing blood flow and promoting neurodegeneration.

Importantly, blocking TGF-β signaling, a pathway involved in cell communication and tissue remodeling, restored pericyte coverage and reduced vascular fibrosis and amyloid accumulation. The findings were also reproduced in aged APOE4 mice, demonstrating that these effects could potentially be reversed therapeutically.

Joel Blanchard, a co-author of the study, said: “Blood vessel damage is not a late consequence of Alzheimer’s, but an active biological process caused by APOE4 that may be reversible.” He added that the findings “reveal new therapeutic targets.”

The study concludes that APOE4 does more than increase the risk of Alzheimer’s disease: it transforms supportive brain cells into scar-forming cells, damaging blood vessels and promoting harmful accumulation. Blocking TGF-β, however, may reverse this process, opening the door to new treatments.

Second study: Cholesterol disrupts protein clearance

In the second study, published in Cell Stem Cell, the team used miBrains, three-dimensional human brain tissues derived from induced pluripotent stem cells and containing all major brain cell types.

The researchers found that APOE4 causes cholesterol to accumulate in astrocytes, disrupting the lysosomal waste-clearance system — a cellular system responsible for breaking down and removing waste — and reducing the cells’ ability to break down alpha-synuclein, a protein naturally found in the brain.

Instead, the protein clumps together and spreads to neurons, forming harmful deposits.

The second study concludes that APOE4-driven cholesterol accumulation in astrocytes disrupts the waste-clearance system and leads to the buildup of harmful alpha-synuclein. Targeting cholesterol metabolism and lysosomal function could therefore represent a promising therapeutic approach.

The researchers also said the cryopreservable miBrains platform could pave the way for personalized medicine and faster testing of potential treatments.