Alzheimer's disease (AD) is the most common form of dementia, posing significant global challenges due to its complex etiology involving aging, genetics, and environment. Current understanding of AD pathogenesis includes multiple hypotheses such as the cholinergic, amyloid, tau, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. However, the interplay among these factors and the primary initiators of AD remain unclear. Most clinical drugs have been ineffective or caused adverse effects, but recent approvals of aducanumab and lecanemab show potential for disease-modifying effects. These drugs require further validation for long-term efficacy and safety. AD is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), along with neuroinflammation, synaptic dysfunction, mitochondrial and bioenergetic disturbances, and vascular abnormalities. Clinically, AD is marked by amnestic cognitive impairment, with symptoms progressing from depression and anxiety to severe memory loss and behavioral issues. Comorbidities like hypercholesterolemia, hypertension, diabetes, and cardiovascular diseases exacerbate AD's impact. The connection between comorbidities and AD pathology is an active area of research. The cholinergic hypothesis suggests that cholinergic neuron damage in the nucleus basalis of Meynert leads to cognitive impairments. AChE inhibitors like donepezil and rivastigmine are used but have limited efficacy and side effects. The amyloid hypothesis posits that Aβ accumulation is a key factor in AD, with APOE ε4 being a major genetic risk factor. Aβ aggregates are toxic, causing neuroinflammation, oxidative stress, and mitochondrial dysfunction. Recent drugs like aducanumab and lecanemab aim to reduce Aβ burden but require further validation. The tau protein hypothesis highlights tau hyperphosphorylation and aggregation in NFTs, leading to neuronal dysfunction. Tau aggregation is influenced by post-translational modifications and interacts with microglia, exacerbating AD pathology. Neuroinflammation, driven by microglial activation and pro-inflammatory cytokines, contributes to AD progression. Oxidative stress, caused by metal ion dyshomeostasis and mitochondrial dysfunction, damages neurons and exacerbates AD. The metal ion hypothesis links metal accumulation to Aβ and tau pathology, with iron and copper playing significant roles in oxidative stress and neuronal death. The glutamatergic excitotoxicity hypothesis suggests that excessive glutamate signaling through NMDA receptors leads to neuronal damage. The microbiota-gut-brain axis hypothesis indicates that gut microbiota influences brain function through the gut-brain axis, with dysbiosis contributing to AD. Abnormal autophagy disrupts cellular homeostasis, leading to Aβ and tau accumulation. Recent research focuses on autophagy-stimulating drugs and novelAlzheimer's disease (AD) is the most common form of dementia, posing significant global challenges due to its complex etiology involving aging, genetics, and environment. Current understanding of AD pathogenesis includes multiple hypotheses such as the cholinergic, amyloid, tau, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, and abnormal autophagy. However, the interplay among these factors and the primary initiators of AD remain unclear. Most clinical drugs have been ineffective or caused adverse effects, but recent approvals of aducanumab and lecanemab show potential for disease-modifying effects. These drugs require further validation for long-term efficacy and safety. AD is characterized by amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), along with neuroinflammation, synaptic dysfunction, mitochondrial and bioenergetic disturbances, and vascular abnormalities. Clinically, AD is marked by amnestic cognitive impairment, with symptoms progressing from depression and anxiety to severe memory loss and behavioral issues. Comorbidities like hypercholesterolemia, hypertension, diabetes, and cardiovascular diseases exacerbate AD's impact. The connection between comorbidities and AD pathology is an active area of research. The cholinergic hypothesis suggests that cholinergic neuron damage in the nucleus basalis of Meynert leads to cognitive impairments. AChE inhibitors like donepezil and rivastigmine are used but have limited efficacy and side effects. The amyloid hypothesis posits that Aβ accumulation is a key factor in AD, with APOE ε4 being a major genetic risk factor. Aβ aggregates are toxic, causing neuroinflammation, oxidative stress, and mitochondrial dysfunction. Recent drugs like aducanumab and lecanemab aim to reduce Aβ burden but require further validation. The tau protein hypothesis highlights tau hyperphosphorylation and aggregation in NFTs, leading to neuronal dysfunction. Tau aggregation is influenced by post-translational modifications and interacts with microglia, exacerbating AD pathology. Neuroinflammation, driven by microglial activation and pro-inflammatory cytokines, contributes to AD progression. Oxidative stress, caused by metal ion dyshomeostasis and mitochondrial dysfunction, damages neurons and exacerbates AD. The metal ion hypothesis links metal accumulation to Aβ and tau pathology, with iron and copper playing significant roles in oxidative stress and neuronal death. The glutamatergic excitotoxicity hypothesis suggests that excessive glutamate signaling through NMDA receptors leads to neuronal damage. The microbiota-gut-brain axis hypothesis indicates that gut microbiota influences brain function through the gut-brain axis, with dysbiosis contributing to AD. Abnormal autophagy disrupts cellular homeostasis, leading to Aβ and tau accumulation. Recent research focuses on autophagy-stimulating drugs and novel