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Supporting Information: Figure S1 Figure. S1 -Endogenous tagging of endolysosomal compartments (A) Representative fluorescence microscopy images of CRISPRi-HEK293T cells with RAB7A-mNG 11 endogenously labeled with the split-mNeonGreen system. Cells were treated with AF555-tau fibrils for 22 hours. (B) Representative fluorescence microscopy images of HEK293T cells with mNG 11 -RAB7A (top) or LAMP1-mNG 11 (bottom) endogenously labeled with the split-mNeonGreen system.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder that involves dysregulation of many cellular and molecular processes. It is notoriously difficult to develop therapeutics for AD due to its complex nature. Nevertheless, recent advancements in imaging technology and the development of innovative experimental techniques have allowed researchers to perform in-depth analyses to uncover the pathogenic mechanisms of AD. An important consideration when studying late-onset AD is its major genetic risk factor, apolipoprotein E4 (apoE4). Although the exact mechanisms underlying apoE4 effects on AD initiation and progression are not fully understood, recent studies have revealed critical insights into the apoE4-induced deficits that occur in AD. In this review, we highlight notable studies that detail apoE4 effects on prominent AD pathologies, including amyloid-β, tau pathology, neuroinflammation, and neural network dysfunction. We also discuss evidence that defines the physiological functions of apoE and outlines how these functions are disrupted in apoE4-related AD. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.