We found that the E4NLF model isolates physiological APOE4xAβ interactions that mirror asymptomatic amyloidosis staging, including incipient plaques by 14–15 months of age (>50 years equivalent for human)57, subtle preclinical memory deficits by 20–22 month (>65 years equivalent for human)57, APOE4- and Aβ-dependent gliosis, and preclinical functional abnormalities in sleep and brain hyperactivity. Here, APOE is linked to amyloidosis.