Protein kinases as therapeutic targets in Alzheimer's disease: challenges, insights, and new frontiers.

Alzheimer's disease (AD) remains the leading cause of dementia worldwide, imposing an enormous and growing societal burden with more than 55 million people affected globally. Despite decades of intensive investigation, existing therapeutic options provide only modest symptomatic relief and fail to prevent or slow disease progression, emphasizing the critical need for interventions that target the fundamental molecular mechanisms of neurodegeneration. Pathologically, Alzheimer's disease is characterized by extracellular accumulation of amyloid-β plaques, intracellular neurofibrillary tangles formed by hyperphosphorylated tau, profound synaptic loss, chronic neuroinflammation, and extensive neuronal degeneration. Although amyloid-focused strategies have long dominated drug development, their limited clinical benefit and safety liabilities highlight the multifactorial nature of AD and the need to move beyond amyloid-centric paradigms. Protein kinases have emerged as key integrators of multiple pathogenic processes in AD, governing tau phosphorylation, amyloid precursor protein processing, synaptic signaling, and neuroimmune responses. Aberrant kinase signaling drives tau pathology and propagation, promotes amyloidogenic pathways, disrupts synaptic function, and perpetuates inflammatory cascades. While extensive work on kinases such as GSK-3β, CDK5, JNKs, and CSF1R has firmly established the relevance of kinase dysregulation in AD, no kinase-directed therapy has yet translated into clinical success. This review highlights emerging kinase targets beyond these classical pathways, including Fyn, Casein Kinase 1 Delta (CK1δ), Tau-Tubulin Kinase 1 (TTBK1), and Dual Leucine Zipper Kinase (DLK), which are supported by mechanistic insights and compelling preclinical evidence. Continued advances in brain-penetrant, isoform-selective, and mechanism-driven kinase inhibitor design may enable the development of next-generation disease-modifying therapies for Alzheimer's disease.