Furthermore, the cognitive impairment and cerebral microvascular injury caused by α‐Syn PFFs were reversed by deletion of endothelial cell‐specific Lag3 in vivo; therefore, our study provides the key evidence for the inference that cerebral microvascular injury induced by α‐Syn fibrils independently exacerbates cognitive impairment in α‐synucleinopathies. Here, LAG3 is linked to Cognitive impairment.