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APOE4–Aβ synergy drives brain network dysfunction and neuronal lysosomal-ER proteostasis dysregulation a preclinical Alzheimer’s disease model

Jia Shin,Erica S Brady,Chun Chen,Kelli Lauderdale,Ayushi Agrawal,Yutong Zhang,Xueqiao Jiang,Pranav Nambiar,Jessica Herbert,Dakota D. Mallen,Katie K. Ly,Patrick S. Honma,Zhongyi Guo,Cathrine Sant,Reuben Thomas,Stephanie R. Miller,Inma Cobos,Jorge J. Palop

Published 2025 in bioRxiv

ABSTRACT

Amyloid-β (Aβ) and APOE4 represent two of the strongest pathological and genetic risk factors for Alzheimer’s disease (AD), but how these co-pathogens interact during preclinical stages remains undefined. We addressed this question by developing a humanized knock-in model expressing physiological, endogenously regulated human Aβ and APOE4. Aged AppNLF:APOE4 mice displayed incipient amyloidosis with subtle memory-related changes, consistent with preclinical AD. We found largely distinct, non-overlapping APOE4- and Aβ-driven functional synaptic, sleep, and behavioral alterations. However, at the transcriptomic level, APOE4xAβ had a pronounced detrimental interaction in neuronal populations, whereas glial populations were primarily affected by either genotype. We found APOE4xAβ molecular interactions in neuronal populations, including excitatory and inhibitory cells, converged on a core lysosomal-ER proteostasis axis. We propose that APOE4xAβ interaction produces an early neuronal pathogenic signature, involving the lysosomal-ER proteostasis axis, preceding functional decline and driving disease progression. APOE4xAβ-KI models provide a physiologically relevant platform to study early pathogenesis. Highlights Early synergistic APOE4xAβ interaction emerges predominantly at the transcriptomic level in neurons, but not in glial cells. APOE4 and Aβ drive largely non-overlapping physiological changes in preclinical stages of disease, but converge at the level of network hyperexcitability. APOE4xAβ neuronal synergy converges on a conserved lysosomal-ER proteostasis axis. Humanized APOE4xAβ KI mice provide a physiologically relevant model to dissect early AD pathogenesis in preclinical stages

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