Furthermore, the neuroprotection mechanism of caffeine has not been fully clarified, and the most likely mechanism depends on the ability of caffeine to antagonize A2AR. A series of studies have shown that A2AR antagonists have the ability to reduce Aβ-induced, aluminum chloride (AlCl3)-induced, or glutamate-induced toxicity and inhibit tau hyperphosphorylation which may be implicated in the progression of AD [110,111,112,113]. Here, MAPT is linked to Alzheimer disease.