Alzheimer's disease (AD), a progressive neurodegenerative disorder, is a leading global health concern for individuals and society. However, the potential mechanisms underlying the pathogenesis of AD have not yet been elucidated. Currently, the most widely acknowledged hypothesis is amyloid cascade owing to the brain characteristics of AD patients, including great quantities of extracellular β-amyloid (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). Nevertheless, the amyloid cascade hypothesis cannot address certain pathologies that precede Aβ deposition and NFTs formation in AD, such as aberrant calcium homeostasis, abnormal lipid metabolism, mitochondrial dysfunction and autophagy. Notably, these earlier pathologies are closely associated with mitochondria-associated membranes (MAMs), the physical structures connecting the endoplasmic reticulum (ER) and mitochondria, which mediate the communication between these two organelles. It is plausible that MAMs might be involved in a critical step in the cascade of earlier events, ultimately inducing neurodegeneration in AD. In this review, we focus on the role of MAMs in the regulation of AD pathologies and the potential molecular mechanisms related to MAM-mediated pathological changes in AD. An enhanced recognition of the preclinical pathogenesis in AD could provide new therapeutic strategies, shifting the modality from treatment to prevention.
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