Calcitonin gene-related peptide (cGRP) receptor antagonists effectively treat migraine through reducing neuroinflammation, vasoconstriction and possibly neurogenesis. Since neuroinflammation is also involved in the pathogenesis of Alzheimer's diseases (AD), we hypothesized and tested if a cGRP receptor antagonist, BIBN 4096 BS (BIBN), has effects on AD pathology. Using an AD mouse model, 5XFAD, with different ages, here we report that the BIBN treatment significantly increased the brain expression of PSD95, a postsynaptic protein, in both young and old AD mice. In parallel, BIBN improved learning and memory in the behavior test in the young, but not old, AD mice. The BIBN treatment reduced α-synuclein aggregation in both young and old AD mice. BIBN significantly decreased neuroinflammatory markers of ionized calcium binding adapter molecules-1 (Iba-1) and the p38 MAPK and NFκB signaling pathways in young, but not old, AD mice. The treatment also reduced the accumulation of amyloid-β (Aβ), and decreased tau phosphorylation through the pathway of CDK5/p25 in young mice only. Our study provides the evidence and suggests that the cGRP antagonists might be a therapeutic target to attenuate the pathological cascade and delay cognitive decline of AD in humans.