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Lucia Gallego Villarejo, Lisa Bachmann, David Marks, Maite Brachthäuser, Alexander Geidies, Thorsten Müller

• The \(\beta\)- and \(\gamma\)-secretase-driven cleavage of the amyloid precursor protein (APP) gives rise to the amyloid \(\beta\) peptide, which is believed to be the main driver of neurodegeneration in Alzheimer’s disease (AD). As it is prominently detectable in extracellular plaques in post-mortem AD brain samples, research in recent decades focused on the pathological role of extracellular amyloid \(\beta\) aggregation, widely neglecting the potential meaning of very early generation of amyloid \(\beta\) inside the cell. In the last few years, the importance of intracellular amyloid \(\beta\) (iA\(\beta\)) as a strong player in neurodegeneration has been indicated by a rising number of studies. In this review, iA\(\beta\) is highlighted as a crucial APP cleavage fragment, able to manipulate intracellular pathways and foster neurodegeneration. We demonstrate its relevance as a pathological marker and shed light on initial studies aiming to modulate iA\(\beta\) through pharmacological treatment, which has been shown to have beneficial effects on cognitive properties in animal models. Finally, we display the relevance of viral infections on iA\(\beta\) generation and point out future directions urgently needed to manifest the potential relevance of iA\(\beta\) in Alzheimer’s disease.