Targeting the Synergistic Interaction of Pathologies in Alzheimer's Disease: Rationale and Prospects for Combination Therapy

Abstract: Alzheimer's disease (AD) persists as a paramount challenge in neurological research, characterized by the pathological hallmarks of amyloid-beta (Abeta) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. This review synthesizes the evolving understanding of AD pathogenesis, moving beyond the linear amyloid cascade hypothesis to conceptualize the disease as a cross-talk of intricately interacting pathologies, encompassing Abeta, tau, and neuroinflammation. This evolving pathophysiological understanding parallels a transformation in diagnostic paradigms, where biomarker-based strategies -- such as the AT(N) framework -- enable early disease detection during preclinical or prodromal stages. Within this new landscape, while anti-Abeta monoclonal antibodies (e.g., lecanemab, donanemab) represent a breakthrough as the first disease-modifying therapies, their modest efficacy underscores the limitation of single-target approaches. Therefore, this review explores the compelling rationale for combination therapies that simultaneously target Abeta pathology, aberrant tau, and neuroinflammation. Looking forward, we emphasize emerging technological platforms -- such as gene editing and biophysical neuromodulation -- n advancing precision medicine. Ultimately, the integration of early biomarker detection, multi-target therapeutic strategies, and AI-driven patient stratification charts a promising roadmap toward fundamentally altering the trajectory of AD. The future of AD management will be defined by preemptive, biomarker-guided, and personalized combination interventions.