Alzheimer's disease (AD) is a significant global health challenge, characterized by cognitive decline and neuronal degeneration. The etiology of AD is multifaceted, involving aging, genetics, and environmental factors. Current understanding of AD pathologies includes hypotheses such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Despite advancements in clinical trials and drug development, effective treatments remain limited due to the complex nature of the disease. Recent approvals of aducanumab and lecanemab by the FDA show promise in disease-modifying effects, but long-term efficacy and safety need further validation. The review discusses the current understanding of AD pathogenesis, diagnostic biomarkers, clinical trial updates, and emerging technologies for drug development. It highlights recent progress in selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, PROTACs, and PPI modulators. The goal is to provide insights into the development and clinical application of novel AD drugs. Key mechanisms of AD include the cholinergic hypothesis, which links cholinergic neuron loss to cognitive impairment; the amyloid hypothesis, focusing on Aβ plaque formation; the tau protein hypothesis, emphasizing tau protein aggregation; the neuroinflammation hypothesis, involving chronic inflammatory responses; the oxidative stress hypothesis, highlighting ROS production; the metal ion hypothesis, addressing dyshomeostasis of biometals; the glutamatergic excitotoxicity hypothesis, focusing on NMDA receptor overstimulation; the microbiota-gut-brain axis hypothesis, linking gut microbiota to brain function; and the abnormal autophagy hypothesis, involving disrupted protein clearance. The review also explores signaling pathways linked to AD pathogenesis, such as neuroinflammatory signaling, lysosomal dysfunction, cholesterol metabolism, and mitochondrial dysfunction. These pathways are crucial for understanding the complex interplay of factors contributing to AD and potential therapeutic targets.Alzheimer's disease (AD) is a significant global health challenge, characterized by cognitive decline and neuronal degeneration. The etiology of AD is multifaceted, involving aging, genetics, and environmental factors. Current understanding of AD pathologies includes hypotheses such as the cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. Despite advancements in clinical trials and drug development, effective treatments remain limited due to the complex nature of the disease. Recent approvals of aducanumab and lecanemab by the FDA show promise in disease-modifying effects, but long-term efficacy and safety need further validation. The review discusses the current understanding of AD pathogenesis, diagnostic biomarkers, clinical trial updates, and emerging technologies for drug development. It highlights recent progress in selective inhibitors, dual-target inhibitors, allosteric modulators, covalent inhibitors, PROTACs, and PPI modulators. The goal is to provide insights into the development and clinical application of novel AD drugs. Key mechanisms of AD include the cholinergic hypothesis, which links cholinergic neuron loss to cognitive impairment; the amyloid hypothesis, focusing on Aβ plaque formation; the tau protein hypothesis, emphasizing tau protein aggregation; the neuroinflammation hypothesis, involving chronic inflammatory responses; the oxidative stress hypothesis, highlighting ROS production; the metal ion hypothesis, addressing dyshomeostasis of biometals; the glutamatergic excitotoxicity hypothesis, focusing on NMDA receptor overstimulation; the microbiota-gut-brain axis hypothesis, linking gut microbiota to brain function; and the abnormal autophagy hypothesis, involving disrupted protein clearance. The review also explores signaling pathways linked to AD pathogenesis, such as neuroinflammatory signaling, lysosomal dysfunction, cholesterol metabolism, and mitochondrial dysfunction. These pathways are crucial for understanding the complex interplay of factors contributing to AD and potential therapeutic targets.