Researchers at Rockefeller University have identified a harmful interaction between amyloid beta and fibrinogen that forms stubborn clots, damaging brain blood vessels and sparking inflammation even at low concentrations. This complex disrupts the blood-brain barrier and leads to early signs of neurodegeneration. The findings suggest a new target for early intervention in Alzheimer's disease.
For decades, Alzheimer's disease has been characterized by sticky plaques and tangled proteins in the brain, with recent research highlighting the role of blood vessels in its development. Despite progress, effective treatments remain elusive due to uncertainties in the biological chain of events causing brain cell loss.
New findings from the Patricia and John Rosenwald Laboratory of Neurobiology and Genetics at Rockefeller University reveal a damaging partnership between amyloid beta (Aβ), known for forming plaques, and fibrinogen, a blood clotting protein. When Aβ binds to fibrinogen, it creates clots that resist breakdown, leading to inflammation and vascular damage. This Aβ/fibrinogen complex causes synapse loss, brain swelling, and blood-brain barrier leaks—hallmarks of Alzheimer's—even in very small amounts.
"It takes a larger amount of Aβ or fibrinogen alone to cause serious damage in the Alzheimer's brain," says Erin Norris, research associate professor in Sidney Strickland's lab. "But when the two complex together, you only need very small amounts of each to cause damage. There's a synergistic effect with Aβ and fibrinogen."
The lab has studied this link for nearly 20 years. Earlier work connected the interaction to Alzheimer's progression, a idea once controversial but now supported by field breakthroughs. To assess damage, researchers applied low concentrations of the complex to mouse brain tissue slices and live mice. While individual proteins caused minimal harm, the combination induced major issues, including blood-brain barrier leakage.
"We showed that the complex actually induces blood-brain barrier leakage, when the proteins alone did not," says Research Associate Elisa Nicoloso Simões-Pires. "Disruption of the blood-brain barrier allows for blood proteins to cross into the brain, which lead to additional harm."
Antibodies blocking the binding reduced effects, confirming the complex's role. The study combined in vitro and in vivo methods, yielding consistent results. Mice exposed to the complex showed elevated phospho-tau181, an early Alzheimer's biomarker in humans.
"It's not a simple disease," Simões-Pires adds. "A lot of other factors can induce neurotoxicity, and we certainly do not propose that inhibiting this complex formation would cure AD. But perhaps targeting this complex would alleviate some of the pathologies and be even more effective in combination with other therapies."
These insights point to vascular dysfunction's direct contribution to neurodegeneration and potential early treatments targeting the complex before symptoms appear. The research appears in Alzheimer's journal (2025; 21(5), DOI: 10.1002/alz.70119).