Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by memory loss and cognitive decline, predominantly in the elderly (Alzheimer Disease International et al., 2015). Although amyloid-β peptide (Aβ), particularly in its oligomeric forms, has long been linked to AD pathogenesis (Chen 9:1205-1235 2017, Gaspar 2 394-400 2010), the mechanisms underlying its cellular toxicity remain unclear. Mitochondrial dysfunction is a consistent feature of AD (D’Alessandro 107:102713 2025), yet how Aβ drives these alterations is not fully understood. This review integrates recent evidence showing that Aβ accumulates on mitochondrial membranes (Cenini 21:3257-3272 2016, Manczak 23:5131-5146 2006, Sirk 5:1989-2003 2007), providing a mechanistic link between amyloid pathology and mitochondrial damage. We discuss how membrane-associated Aβ disrupts mitochondrial protein import by impairing the translocase of the outer membrane (TOM) complex (Cenini 21:3257-3272 2016, Sirk 5:1989-2003 2007) and interferes with voltage-dependent anion channel 1 (VDAC1) (Smilansky 52:30670-30683 2015), a key regulator of metabolite exchange and apoptosis. We further emphasize the role of mitochondria-associated membranes (MAMs) as critical sites for Aβ generation and transfer to mitochondria, where dysregulated cholesterol metabolism may amplify MAM activity and Aβ accumulation (Area-Gomez and Schon 38:90-96 2017, Monaghan 2:240287 2025). Altogether, we propose that mitochondrial membrane localization of Aβ is a central mechanism linking amyloid pathology to mitochondrial dysfunction in aging, highlighting new directions for mitochondria-targeted therapeutic strategies in AD.
