Breakthroughs in molecular medicine have positioned the amyloid-β (Aβ) pathway at the center of Alzheimer’s disease (AD) pathophysiology. While the detailed molecular mechanisms of the pathway and the spatial-temporal dynamics leading to synaptic failure, neurodegeneration, and clinical onset are still under intense investigation, the established biochemical alterations of the Aβ cycle remain the core biological hallmark of AD and are promising targets for the development of disease-modifying therapies. Here, we systematically review and update the vast state-of-the-art literature of Aβ science with evidence from basic research studies to human genetic and multi-modal biomarker investigations, which supports a crucial role of Aβ pathway dyshomeostasis in AD pathophysiological dynamics. We discuss the evidence highlighting a differentiated interaction of distinct Aβ species with other AD-related biological mechanisms, such as tau-mediated, neuroimmune and inflammatory changes, as well as a neurochemical imbalance. Through the lens of the latest development of multimodal in vivo biomarkers of AD, this cross-disciplinary review examines the compelling hypothesis- and data-driven rationale for Aβ-targeting therapeutic strategies in development for the early treatment of AD.

By integrating convergent protein engineering and rational inhibitor design, we have developed an in vivo conditional protein knockout and͞or manipulation technology. This method is based on the creation of a specific interaction interface between a modified protein domain and sensitized inhibitors. By introducing this system into genetically modified mice, we can readily manipulate the activity of a targeted protein, such as ␣-Ca 2؉ ͞calmodulin-dependent protein kinase II (␣CAMKII), on the time scale of minutes in specific brain subregions of freely behaving mice. With this inducible and regionspecific protein knockout technique, we analyzed the temporal stages of memory consolidation process and revealed the first postlearning week as the critical time window during which a precise level of CaMKII reactivation is essential for the consolidation of long-term memories in the brain. C urrent-inducible and region-specific gene knockout techniques are powerful for molecular and temporal analysis of biological processes (1, 2). However, because the inactivation event occurs at the DNA level, manifestation of any phenotype depends on the turnover rate of the existing protein, which takes days or weeks. This inherently slow process has excluded precise investigation of many in vivo biological processes that occur within minutes and hours. Therefore, it is highly desirable to develop new types of techniques that can direct the knockout event at the protein level, rather than at the DNA level, for achieving almost instantaneous effects. Furthermore, the molecular specificity of such a knockout should surpass the conventional pharmacological inhibitors. We decided to explore methods to integrate the molecular and regional specificity of genetics with the high temporal resolution of chemical inhibition for the development of an inducible, reversible, and regionspecific protein knockout technique.Such a technique would be valuable for elucidation of molecular mechanisms underlying various temporal stages of brain function such as memory processes. The N-methyl-D-aspartate (NMDA) receptor has been established as a crucial molecular switch for synaptic plasticity (3, 4) and for memory formation (1,(5)(6)(7)(8). At the molecular level, long-term memory was widely assumed to be stored in the form of synaptic structural changes resulting from a single molecular cascade triggered by learning. However, this ''single cascade hypothesis'' has its conceptual difficulties in accounting for long-term memory formation in the brain. For example, the time scale of a single molecular cascade (typically between hours to days) is too short for describing the hippocampus-mediated consolidation process that is known to occur over a timescale of week(s) in rodents (9-12) and years in humans (13-15). Moreover, synaptic structures in the adult brain are dynamic, and synaptic proteins such as the NMDA receptor are known to be degraded within 5 days in the brain of freely behaving animals (1). Thus, it raises fundamental concerns whether any struc...