Mitochondrial dysfunction in Alzheimer's disease: mechanisms, pathogenic interplay, and therapeutic opportunities

Alzheimer's disease (AD) remains a major cause of dementia, yet effective disease-modifying therapies are still limited. Although amyloid-β (Aβ) and tau pathology remain core features of AD pathogenesis, they do not fully explain how these pathological alterations drive progressive cellular dysfunction. Increasing evidence suggests that mitochondria are involved at this critical interface. In AD, mitochondrial abnormalities impair energy production, compromise organelle quality control, disrupt calcium (Ca²⁺) homeostasis, and alter communication with the endoplasmic reticulum and glial cells. As these defects accumulate, neurons and glia become less able to maintain metabolic stability, redox balance, and synaptic function. Mitochondrial dysfunction is therefore relevant to AD not as a single isolated lesion, but as a convergent process through which metabolic failure, oxidative stress, mitochondrial DNA damage, inflammatory signaling, and defective cellular maintenance reinforce one another. This perspective also helps explain why disease progression is difficult to reverse once mitochondrial homeostasis has been broadly compromised. At the same time, this framework also points to therapeutic opportunities, as the mechanisms driving the development and progression of mitochondrial dysfunction may be amenable to intervention. However, many mitochondria-centered strategies remain preclinical or have yielded inconsistent clinical benefit. Current evidence supports mitochondrial dysfunction as both a useful mechanistic basis for understanding AD progression and a biologically meaningful, though challenging, therapeutic target.