Aging is the best-known risk factor for many disorders, including neurodegenerative diseases such as Alzheimer's disease (AD). The effect of epigenetic modulation of gene expression on normal aging and in pathological conditions is still unclear, but it is likely it may explain some of the complexity that is characteristic of these processes. Caffeine is a widely consumed psychoactive drug, which is emerging as a protective agent against AD progression and in aging associated deficits. This occurs mainly through the blockade of adenosine A2A receptors, whose expression and function become aberrant throughout aging and in age-related pathologies. Here, we discuss the data supporting the effects of caffeine in AD, focusing on adenosine A2A receptors and epigenetic modulation of gene expression. In addition, we speculate on the potential of caffeine as an epigenetic modulator and the consequences it might have for preventive and therapeutic applications of caffeine in AD.