From Molecular Networks to Medicines: Targeting Complexity in Alzheimer's Disease (AD) Therapy

Alzheimer's disease (AD) is a multidimensional neurodegenerative disease leading to progressive loss of cognitive function and a growing health burden on the world population. Although decades of research have been conducted on this disease, current therapies have limited clinical value, mainly because researchers have not fully incorporated the intricate molecular pathways underlying its development and progression. This review summarizes current knowledge of AD pathophysiology, including amyloid beta (Aβ) dysregulation, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic breakdown. Although the amyloid- and tau-centered paradigms remain prevailing in the field, we note newer molecular targets, including secretase modulators, inflammatory signaling hubs, mitotic and autophagic regulators, epigenetics, and synaptogenesis pathways. We prioritize mechanistic, structural, cellular, and systems levels to facilitate a rational development of therapeutic understanding. The latest trends in medicinal chemistry and computational drug design, multi-target- directed ligands and hybrid scaffolds, as well as in silico ADMET optimization, are also discussed. Furthermore, we discuss the therapeutic aspects of bioinspired analogues of natural products. Lastly, we discuss the ongoing clinical development initiatives, opportunities, and major translational issues. In general, we highlight the need for integrative, mechanism-oriented, and personalized treatment approaches to propel the next generation of AD therapies.