Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and neuronal loss, with its pathogenesis tightly linked to a “pathological triad”—mitochondrial dysfunction, metabolic dysregulation, and calcium homeostasis imbalance. This triad forms a mutually reinforcing network that amplifies AD pathology, yet its precise causal relationships and clinical relevance remain incompletely understood. Here, we critically synthesize evidence from human studies, animal models, and in vitro systems to dissect how these dysfunctions interact in vivo: mitochondrial structural damage and bioenergetic failure (e.g., reduced cytochrome c oxidase activity) impair ATP production, triggering metabolic reprogramming (e.g., astrocytic Warburg-like glycolysis, lactate shuttle dysfunction) and disrupting calcium buffering via mitochondrial calcium uniporter (MCU) dysregulation. Conversely, metabolic stress (e.g., hyperglycemia-induced mitochondrial overload) and calcium overload (e.g., NMDA receptor hyperactivation) exacerbate mitochondrial damage through reactive oxygen species (ROS) bursts and mitochondrial permeability transition pore (mPTP) opening. These processes are further amplified by amyloid β-protein (Aβ) and tau pathology: Aβ oligomers directly inhibit mitochondrial respiration and activate calcium channels, while hyperphosphorylated tau disrupts mitochondrial trafficking and exacerbates metabolic enzyme dysfunction. We evaluate the clinical translatability of preclinical findings, highlighting inconsistencies (e.g., conflicting results of CoQ10 trials) and gaps (e.g., human-specific metabolic signatures). Finally, we propose a framework prioritizing multi-target therapies that disrupt the triad’s vicious cycle, emphasizing the need for biomarkers to stratify patients based on triad dysregulation patterns.