Given that chronic A1R activation favors activation effect and excitotoxicity occurrence due to receptor internalization (Blum et al., 2003) and that A2AR overactivation leads to memory impairments and AD pathology development (see below), the benefits afforded by a chronic increase of adenosine tone (Lee et al., 2018) are presumably not mediated by receptor-mediated effects. Here, ADORA2A is linked to Alzheimer disease.