Multimodal Neuroimaging and Behavioral Characterization of Aged Female APOE4 Knock-In Rats Reveals a Preclinical Alzheimer's Disease Phenotype

Abstract

The apolipoprotein E ε4 allele (APOE4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD) and confers disproportionate risk in women, particularly after reproductive senescence. The brain changes preceding overt neurodegeneration in APOE4 carriers remain incompletely characterized. We conducted neuroimaging and behavioral studies in aged (18-month) female APOE4 humanized knock-in rats and APOE3 controls. Regional brain volumes across 197 areas were quantified by voxel-based morphometry (VBM); white and gray matter microstructure by diffusion tensor imaging (DTI), yielding fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Spatial memory was assessed with the Barnes maze and motor coordination with the beam walk. APOE4 rats showed significantly larger regional brain volumes than APOE3 controls. DTI revealed increased FA in the thalamus, brainstem, and white matter tracts, and reduced FA in the sensorimotor cortex. Across most regions elevated FA was accompanied by reduced ADC, an inverse relationship consistent with cytotoxic edema. Behaviorally, APOE4 rats were significantly impaired on the Barnes maze. Aged female APOE4 knock-in rats exhibit a preclinical AD phenotype: widespread volumetric enlargement across white matter, sensorimotor, and limbic circuits, with microstructural alterations (elevated FA in brainstem, thalamus, and white matter; reduced FA in sensorimotor cortex). This mirrors the imaging and cognitive profile of cognitively normal human APOE4 carriers in preclinical AD and validates the model as a translationally relevant platform for investigating early APOE4-driven pathophysiology and testing preventive interventions.