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International audience; 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 phenotypesand 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 beenidentified, 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 signsare 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.

Diabetes and metabolic syndrome are associated with the typical American high glycemia diet and result in accumulation of high levels of advanced glycation end products (AGEs), particularly upon aging. AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age‐related diseases, AGEs accumulate in many tissues and are cytotoxic. To date, efforts to limit glycation pharmacologically have failed in human trials. Thus, it is crucial to identify systems that remove AGEs, but such research is scanty. Here, we determined if and how AGEs might be cleared by autophagy. Our in vivo mouse and C. elegans models, in which we altered proteolysis or glycative burden, as well as experiments in five types of cells, revealed more than six criteria indicating that p62‐dependent autophagy is a conserved pathway that plays a critical role in the removal of AGEs. Activation of autophagic removal of AGEs requires p62, and blocking this pathway results in accumulation of AGEs and compromised viability. Deficiency of p62 accelerates accumulation of AGEs in soluble and insoluble fractions. p62 itself is subject to glycative inactivation and accumulates as high mass species. Accumulation of p62 in retinal pigment epithelium is reversed by switching to a lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age‐related diseases, including age‐related macular degeneration, cardiovascular disease, diabetes, Alzheimer's, and Parkinson's, discovery of methods to limit AGEs or enhance p62‐dependent autophagy offers novel potential therapeutic targets to treat AGEs‐related pathologies., AGEs are toxic compounds formed by non‐enzymatic reactions between sugars and proteins. AGEs are prone to aggregate. Insoluble AGEs are efficiently removed via p62‐selective autophagy. The autophagic removal of AGEs is a conserved pathway, and the lack of p62 leads to accumulation of toxic AGEs in mouse and worms. Enhanced autophagy is protective against glycation‐derived damage. p62‐dependent autophagy offers novel potential therapeutic targets to treat AGEs‐related pathologies.

Aging is a major driving force underlying dementia, such as that caused by Alzheimer's disease (AD). While the idea of targeting aging as a therapeutic strategy is not new, it remains unclear how closely aging and age-associated diseases are coupled at the molecular level. Here, we discover a novel molecular link between aging and dementia through the identification of the molecular target for the AD drug candidate J147. J147 was developed using a series of phenotypic screening assays mimicking disease toxicities associated with the aging brain. We have previously demonstrated the therapeutic efficacy of J147 in several mouse models of AD. Here, we identify the mitochondrial α-F-ATP synthase (ATP5A) as a target for J147. By targeting ATP synthase, J147 causes an increase in intracellular calcium leading to sustained calcium/calmodulin-dependent protein kinase kinase β (CAMKK2)-dependent activation of the AMPK/mTOR pathway, a canonical longevity mechanism. Accordingly, modulation of mitochondrial processes by J147 prevents age-associated drift of the hippocampal transcriptome and plasma metabolome in mice and extends lifespan in drosophila. Our results link aging and age-associated dementia through ATP synthase, a molecular drug target that can potentially be exploited for the suppression of both. These findings demonstrate that novel screens for new AD drug candidates identify compounds that act on established aging pathways, suggesting an unexpectedly close molecular relationship between the two., NIH R01AG046153 (D.S) and NIH/NIA SBIR 2R44AG033427 (K.F. and E.R.), the Nomis Foundation (AC), AI104034 and the Della Thome Foundation (PM), Bundy Foundation (DD), the Hewitt Foundation (JG), the Paul F. Glenn Center for Aging Research at the Salk Institute (JG)