The combined evidence of an increased A2AR expression in hippocampal neurons from humans (aged individuals and AD patients) and from animal models of these physiopathological conditions (Fig. 1; [26, 46, 68]) and the complete rescue of the LTD-to-LTP shift upon A2AR acute blockade stresses out A2AR as a putative pathological mediator involved in calcium dysfunction underlying age- and AD-related cognitive deficits, involving an aberrant recruitment of mGluR5/NMDAR coupled to an altered Ca2+ influx (see Supplementary Fig. 5 for a summary). This evidence concerns the gene ADORA2A and Alzheimer disease.