In these last years, several phase III randomized controlled trials testing promising candidates sharing Aβ depots as target of their action have failed, despite showing some reductions of the brain Aβ charge. The announcements of the negative results have heated the discussion in the field and divided the scientific community between the defenders versus the opponents of the Aβ theory. In the present article, we discuss the limits of these drastic, opposite positions and we propose a novel approach to Alzheimer’s disease (AD). In particular, a “one-fits-all” approach where a single biomarker/process is able to explain the clinical manifestation seems inadequate for AD (as for other conditions of old age). Accordingly, there is an urgent need to overcome the traditional paradigms of “standalone-diseases” (requiring unimodal interventions) in favor of more comprehensive and multidimensional approaches. Specifically, promoting biomarker modeling procedures based on multivariate statistical methodologies may have important implications and advantages in the field of AD and other neurodegenerative diseases.