This Research Topic is a collection of 20 articles that depict a broad representation of the most impactful advances in Alzheimer’s disease (AD) comprehension and therapeutic openings. As it clearly emerges from recent literature, AD is a complex pathology with many different phenotypes and heterogeneous clinical settings. Although in a minority of cases genetic mutations have been linked to its development, for the vast majority of AD patients the triggering event remains to be elucidated. Main hallmarks such as amyloid beta (Aß) plaques and neurofibrillary tangles have been identified, but understanding their exact role on cognitive consequences, timing of appearance, mechanisms of toxicity, and interplay required years of studies, withmany questions still remaining unanswered. To note, the events possibly driving the development of such pathological signs are diverse and much more numerous than expected. For this reason, scientists have been directing their efforts to improving the understanding of the pathways involved in the toxicity mechanisms observed. Indeed, only a profound knowledge of the full process bringing to the different pathological phenotypes will help in figuring out effective treatments and/or preventive actions. With this concept in mind we have developed the present topic, which aims at giving a far-reaching picture of our actual knowledge, from the etiology of AD to mechanistic insights and possible new targets of intervention. Authors present their latest discoveries on a variety of breakthrough AD-related subjects such as inflammation, microbiome, hormones, Aß production and catabolism, and neurovascular unit (NVU) alterations. Notably, the importance of reliable biomarkers as well as the paramount role of global approaches for the treatment/prevention of AD (see multi-interventions), are granted and finely discussed. We present here a summary of the main fields covered by this collection that we believe will constitute critical hints for future research development.