Deciphering the effects of aging on Alzheimer’s disease based on mitochondrial dysfunction and neuroinflammation

Alzheimer’s disease (AD), a neurological disorder characterized by progressive deterioration of cognitive function, has complex pathogenic mechanisms and lacks curative therapies with proven efficacy. Aging and inflammatory responses, which play indispensable roles in the onset and progression of AD, are closely intertwined with mitochondrial dysfunction. During aging, a series of degenerative alterations, including accumulated mitochondrial DNA (mtDNA) mutations, excessive mitochondrial reactive oxygen species (ROS) accumulation, disrupted mitochondrial quality control (MQC) and disturbed energy metabolism, further induce structural mitochondrial damage. This damage causes the leakage of damage-associated molecular patterns (DAMPs) and activates numerous downstream inflammatory signaling pathways. In brain tissue, inflammatory cytokines, which continuously facilitate blood–brain barrier (BBB) disruption, aberrant activation of microglial cells, tau protein hyperphosphorylation, as well as Aβ accumulation, drive an endlessly amplified neuroinflammatory cascade that leads to irreversible neuronal damage and fuels the initiation and progression of AD. In this review, we clarify the regulatory effects of aging on AD pathogenesis through the mitochondrial dysfunction-chronic inflammation axis and ultimately focus on mitochondrial-targeted therapies, with future outlooks for AD treatment provided.