Abhay Thakur, Rohit Sharma, Sneha Kumari, Dev Prakash, Anjana Devi
Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative condition characterized by the interaction of various molecular, cellular and systemic mechanisms that culminate in synaptic dysfunction, neuronal loss and memory decline. Therapeutic success remains limited despite decades of research, and accumulating evidence suggests that an exclusive focus on single-pathology mechanisms may have contributed to the limited efficacy of many therapeutic strategies. The interplay of pathogenic mechanisms seems to contribute to the disorder in a dynamic and continuous manner, much like the growing evidence supporting a network-based model. This review engages with 30 major pathogenic pathways contributing to AD, including amyloid-β and tau pathology, neuroinflammation, oxidative stress and mitochondrial dysfunction, synaptic and neurotransmitter dysfunction, metabolic and vascular dysfunction, calcium signaling, proteostasis ,gut-brain axis and hormone-related pathways. The study also presents emerging mechanisms such as metal ion dishonesties, prion-like propagation and Wnt/β-catenin Signaling. Particular emphasis is placed on neuroinflammatory and immunometabolism pathways, which mediate the clearance of amyloid, propagation of tau, maintenance of synaptic integrity, and regulation of neurovascular function. In addition, the review examines therapeutic strategies targeting these pathways, including monoclonal antibodies, inflammasome inhibitors, metabolic modulators, and emerging gene- and RNA-based therapies. Multi-target and precision medicine approaches represent promising strategies for potential disease modification, although their clinical efficacy remains under investigation.Overall, this review makes a case for integrative, pathway-based therapeutic models, and multiple approaches may facilitate for drug development, biomarker identification and patient management in Alzheimer's disease.