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Alzheimer's disease (AD) is the most common neurodegenerative disorder, and its incidence is relatively high among elderly people, affecting about 1–2% of the population between 60–65 years old and rising dramatically (about 30%) in people aged 80 years or older (Selkoe, 2002). Nowadays, considering the increasing mean life-span of populations in developed countries, the disease is becoming more and more a health concern, and the search for an effective cure has turned into “a real need”. Common signs of AD are difficult to be recognized at the onset of the pathology, primarily because endogenous mechanisms tend to compensate the initial neurodegenerative process. However, when symptoms appear, structural brain damage is already extended and is accompanied by the progressive and relentless deterioration of cognitive functions, which lastly culminate in severe memory loss and dementia. From a biochemical point of view, the typical neuropathological hallmarks of AD range from synaptic/neuronal loss in several areas of the brain, such as the neocortex and hippocampus, to the formation of senile plaques, mainly composed of the neurotoxic amyloid-β peptide (Aβ). According to the well-consolidated “amyloidogenic cascade hypothesis”, the pathogenetic mechanism that drives cognitive decline in AD seems to be triggered by the aberrant processing of the amyloid precursor protein (APP) by β-secretases, that diverts from the physiological cleavage of APP, and that leads to the anomalous accumulation of the noxious Aβ peptide within the brain, culminating in the formation of aggregates within the surrounding brain parenchyma and progressive neuronal death. However, while the exact causative factors that lead to the abnormal Aβ processing in AD remain largely unknown, unanimous consensus claiming that environmental agents act as potential contributing factors to aggravate AD pathogenesis seems to have been reached. Indeed, evidences from our laboratories have strongly suggested that exposure to a broadly used metal, aluminum, may actually promote and (maybe) accelerate the amyloidogenic pathway by increasing oxidative stress mechanisms, reducing antioxidant defense response, and finally by affecting the expression of AD- and stress-related molecules, thereby speeding up the overall degenerative process in AD (Castorina et al., 2010; Giunta et al., 2014). As said, it is therefore of paramount importance to discover new effective drugs able to address this unmet medical need. For the purpose, at least two main routes are available: (1) identify new potential targets to develop drugs able to slow down or arrest disease progression; (2) shed more light into those “old” molecules that have demonstrated proven efficacy in ameliorating many aspects of cognitive deterioration in a number of neurodegenerative conditions but that have been “left aparty” because scientific evidences were apparently controversial. Since the first option may appear the most desirable, many would think this choice is the most appropriate. Unfortunately it is not, and on the contrary, it is the slowest track and the less likely to give the expected results for many reasons. For instance, if an effective molecular target is identified, the steps that would lead to the production of a readily available drug to test into clinical trials are really tortuous, and often not feasible. According to a study conducted by Enna and Williams (2009), only very few high-affinity ligands for potentially attractive molecular targets progress to further evaluation as future drug candidates, and most of these “fortunate ligands” will be even reduced in number after undergoing a series of necessary screening tests. In other cases, molecules directed to specific targets are simply difficult or even impossible to be synthesized as administrable drugs or produce a series of severe side effects. Therefore, despite being a challenging route, the second option to revisit “old drugs” to produce new and more selective drugs remains the most feasible.

The seeming paradox of adenosine receptors as targets for the treatment of Alzheimer′s disease: agonists or antagonists?