miBrains open new possibilities: studying how an individual’s neural cells respond to disease, testing potential therapeutics before they’re administered, and exploring why the same disease can look different from person to person at the cellular level.

Donor cells are reprogrammed into induced pluripotent stem cells (iPSCs), which can then be differentiated into each of the six major brain cell types that make up a miBrain. The result is a 3D model that carries that person's own genetic signature, down to the microenvironment.

Together, this work suggests that cerebrovascular damage is not simply a downstream effect of Alzheimer’s, but an APOE4-driven process that actively contributes to disease progression – highlighting the brain vasculature as an important, underexplored target for future therapies.

Blocking TGF-β signaling in APOE4 miBrains restored pericyte coverage and reduced myofibroblasts, vascular fibrosis, and amyloid accumulation. We also replicated these findings in aged APOE4 mice, showing that this vascular pathology can be reversed in our models

Computational analysis of our atlas identified TGF-β signaling as a key driver of this transition. We observed increased TGF-β pathway activity across human tissue, miBrains, and APOE mice, revealing a mechanism connecting APOE4 to cerebrovascular degeneration.

Further experiments confirmed an APOE4-driven pericyte-to-myofibroblast transition, shifting cells that normally support the microvasculature into scar-forming cells that can impair vessel function and promote amyloid accumulation, potentially contributing to neurodegeneration.

We began by creating a single-cell transcriptomic atlas of the brain's vasculature, integrating past data from 220 individuals. In APOE4 carriers, we identified a distinct loss of pericytes alongside the emergence of scar-forming myofibroblast-like cells.

📍Together, this work suggests that cerebrovascular damage is not simply a downstream effect of Alzheimer’s, but an APOE4-driven process actively contributing to disease progression – highlighting the brain vasculature as an important, underexplored target for future therapies.

Blocking TGF-β signaling in APOE4 miBrains restored pericyte coverage and reduced myofibroblasts, vascular fibrosis, and amyloid accumulation. We also replicated these findings in aged APOE4 mice, showing that this vascular pathology can be reversed in our models.

Computational analysis of our atlas identified TGF-β signaling as a key driver of this transition. We observed increased TGF-β pathway activity across human tissue, miBrains, and APOE knock-in mice, revealing a mechanism connecting APOE4 to cerebrovascular degeneration.

Further experiments confirmed an APOE4-driven pericyte-to-myofibroblast transition, shifting cells that normally support the microvasculature into scar-forming cells that can impair vessel function and promote amyloid accumulation, potentially contributing to neurodegeneration.