Digging Deep into Alzheimer Disease: How Electron Microscopy Helps Elucidating Its Pathogenesis.

Alzheimer disease (AD), first described by Alzheimer and Perusini in the early twentieth century, is a devastating neurodegenerative disorder without a definitive cure. Unraveling the subcellular alterations underlying AD is essential to elucidate disease mechanisms, track progression, link cellular abnormalities to functional deficits, and develop therapeutic strategies aimed at preventing, slowing or reverting the disease course. Electron microscopy (EM) has been pivotal in this field since the 1960s, when Terry and Kidd characterized the ultrastructure of amyloid-beta (Aβ) deposits and paired helical filaments (PHFs) composed of hyperphosphorylated tau. Over the decades, conventional transmission and scanning EM have been complemented by advanced approaches such as volume EM (vEM), cryo-electron microscopy (cryo-EM), and cryo-electron tomography (cryo-ET). These techniques enable three-dimensional reconstructions, minimize fixation artifacts, and provide near-native, near-atomic resolution insights into AD pathology. EM has also revealed critical contributions of other subcellular compartments to AD pathogenesis, including synapses, mitochondria, lysosomes, the blood-brain barrier, iron deposits, and inflammatory machinery. Importantly, EM studies extend beyond human tissue, encompassing animal models, cell cultures, and synthetic assemblies, thereby allowing cross-system comparisons that highlight conserved pathological features. By integrating data from diverse experimental settings, EM provides a uniquely comprehensive view of the AD subcellular landscape. This makes it an indispensable tool not only for dissecting disease mechanisms but also for guiding the rational design of therapeutic molecules with potential disease-modifying effects. This review synthesizes the state of knowledge on EM-based studies of AD, emphasizing their central role in advancing both mechanistic understanding and translational approaches.