San Francisco’s Gladstone finds the brain’s protective barrier stops importing helpful blood proteins early in Alzheimer’s-like disease in mice

The blood-brain barrier, the lining of the brain’s blood vessels that keeps most substances out, also works as a delivery system that brings at least 92 helpful proteins from the blood into the brain, and that delivery fails early in an Alzheimer’s-like disease in mice, scientists at the Gladstone Institutes in San Francisco reported Nov. 11 in the journal Cell.

The finding suggests Alzheimer’s disease may partly begin outside the brain, when supplies from the body are cut off.  If that holds in people, treatments could someday work by boosting helpful proteins made elsewhere in the body, the researchers said.  “Alzheimer’s disease may not start entirely inside the brain,” said Andrew Yang, the Gladstone investigator who led the study.

What they found

• Of 861 blood proteins the team tracked in mice, 92 crossed into the brain.  Most were made in distant organs, especially the liver.
• Each protein went to particular kinds of brain cells, which the researchers likened to a ZIP code system.
• One liver protein, apolipoprotein A1, or APOA1, travels to astrocytes, star-shaped support cells, and switches on a process that keeps connections between nerve cells healthy.  Failure of that process has been linked to higher Alzheimer’s risk.
• In mice bred to develop an Alzheimer’s-like disease, the barrier stopped importing APOA1 and other protective proteins before it started leaking harmful ones.  Lost nerve-cell connections and behavior changes came with it.
• Mice engineered to make extra APOA1 in the liver got more of it into their brains and showed fewer signs of the disease.

Why it matters

For a century scientists treated the barrier mainly as a physical boundary, Yang said.  It was already known to break down and leak harmful proteins into the brain as Alzheimer’s progresses.  This study points to an earlier failure:  helpful deliveries stop first.  The team says the map could also help design ways to carry drugs across the barrier into the brain more efficiently.

How it works

The researchers chemically tagged the full set of mouse blood proteins without changing how they work, put them back into the bloodstream, then checked brain tissue to see which tagged proteins had crossed.  Co-authors included scientists at UC San Francisco, the Buck Institute for Research on Aging in Novato, Emory University and two Hong Kong institutions.

Limits

All of the experiments were in mice, including mice engineered to mimic parts of Alzheimer’s disease.  The study does not show that the same failure happens in people or that raising APOA1 would help patients.  No treatment has been tested.

Sources:  Gladstone Institutes news release, Nov. 11, 2026; Zhou et al., “The blood-brain barrier imports diverse plasma proteins for neuroprotection disrupted early in Alzheimer’s models,” Cell (2026).