New Culprit in Early Alzheimer’s: Blood–Brain Barrier Study
Researchers at the Gladstone Institute of Neurological Disease have catalogued 92 proteins that cross the blood–brain barrier. In mice that mimic early Alzheimer’s, the barrier stopped importing protective proteins before it began to leak, according to a study in Cell.
Scientists have found a possible culprit in early Alzheimer’s disease: the blood–brain barrier, which stops importing protective proteins in mice before it begins to leak. The team, led from the Gladstone Institute of Neurological Disease in San Francisco, reported the work in the journal Cell in 2026.
They also mapped 92 proteins that the barrier carries into the brain from the blood.
For decades, researchers viewed the barrier as an impenetrable layer. That view has softened as evidence showed it is more permeable than first thought.
Mapping what gets through
Andrew Yang, a neuroscientist at Gladstone and co-author of the study, and his colleagues developed a technique to label a large array of proteins in the blood. They then tracked which ones entered the brain.
Of the 861 proteins they mapped, 92 crossed into the brain. Most were produced in distant organs, particularly the liver.
The APOA1 finding
The team focused on apolipoprotein A1, known as APOA1, which has been linked to possible protection against Alzheimer’s. Once inside the brain, it prompts brain cells called astrocytes to release cholesterol. Cholesterol helps maintain the synapses, the junctions through which neurons communicate.
How APOA1 crossed the barrier had been unclear until now, Yang said. His team found that two receptors for the protein, SR-B1 and ABCA1, sit on the barrier and on astrocytes. The authors say this suggests how the protein travels from the barrier to the cells that need it.
When the team blocked the ABCA1 receptor in laboratory-grown astrocytes, APOA1 no longer had the same cholesterol-regulating effects.
A different problem comes first
Scientists have long known the barrier breaks down as Alzheimer’s advances, letting harmful molecules leak into the brain. Yang’s team found that another problem appears earlier.
In a mouse model of the disease, the barrier stopped importing protective proteins such as APOA1 before it began to break down. That loss came with fewer neuronal connections, behavioral changes and other early hallmarks of the disease.
“The paradigm in the field has been that the blood–brain barrier is normally impermeable and then becomes leaky as a result of Alzheimer’s disease,” Yang said. His team’s work instead suggests the barrier actively imports proteins the brain needs, and that losing them drives early dysfunction, he added.
Testing extra APOA1 in mice
The researchers then asked whether raising APOA1 in the blood could offset some of the damage. They engineered mice with Alzheimer’s to produce extra APOA1 in the liver.
More of the protein crossed into the brain, and the mice showed fewer Alzheimer’s-related markers. They had less fat build-up in astrocytes and lower levels of inflammatory molecules.
All of these results come from mice and laboratory-grown cells.
