APP is present on pre- and postsynaptic membranes, where it homo- and heterodimerizes with itself and APP-like proteins (e.g., APLP1/2) (26). Synaptic activity triggers APP endocytosis (8). The activities of the proton pump v-ATPase and the proton leak channel NHE6 determine the kinetics of endosomal acidification. The sequential action of β- and γ-secretases sets the rate of amyloid generation in pre- and postsynaptic endosomal compartments, determining extracellular Aβ concentration and aggregation kinetics. At low Aβ concentrations (left), monomers are prevalent, which stimulates synaptogenesis. As synaptic activity increases and more APP is endocytosed, or as its residence time in poorly acidified endosomes increases (16, 17), more aggregation-prone–form Aβ42 is generated, which readily oligomerizes (right). Aggregated Aβ forms interact with cell surface receptors to suppress the synapse and prevent excitotoxicity. Extracellular oligomers and aggregates are normally degraded by proteases such as insulin degrading enzyme (IDE) and neprilysin, which decrease during aging. If excessive Aβ generation persists, especially in the aging brain, Aβ oligo/polymerization outpaces the degradative capacity and persistent synaptic suppression, i.e. synaptotoxic conditions, ensue. The physiologic “sweet spot” is the point where just enough Aβ is produced to maximize synaptogenesis but not overwhelm its degradation system. This point shifts during aging due to inherently changing, environmentally and genetically determined, metabolic parameters. Therapeutic interventions can be leveraged against this shift, such as amyloid aggregate clearing antibodies (24), v-ATPase boosters such as rapamycin, or NHE inhibitors that can support an ailing proton pump and rebalance endosomal pH homeostasis (16, 17).