LAG3 and Cognitive impairment: This work reveals that α‐synuclein (α‐Syn) preformed fibrils enter brain microvascular endothelial cells (BMVECs) via lymphocyte‐activation gene 3 (Lag3)‐dependent endocytosis, causing poly(ADP‐ribose)‐driven cell death of BMVECs, promoting α‐Syn reproduction in BMVECs and destroying the cerebral microvascular system, inducing the damage of cerebral microvessels, neurovascular unit coupling, and blood–brain barrier, then eventually leading to cognitive impairment in α‐synucleinopathies.