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

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 App ^NLF :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.