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SUMMARY Brain network dysfunction—including hyperexcitability, altered oscillations, and sleep disruption—is prominent in Alzheimer’s disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fgg γ390–396A mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fgg γ390–396A mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis—currently under clinical evaluation with the humanized antibody THN391— represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026). 110 HIGHLIGHTS Fibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice Fibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice Genetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction Anti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit
Lauderdale et al. (Wed,) studied this question.