Humanized APP is the primary determinant of regional brain volume in humanized APOE knock‐in mice: a cross‐sectional ex vivo MRI study
Avnish Bhattrai, Adam C. Raikes, Roberta Diaz BrintonAbstract
INTRODUCTION
Age, Apolipoprotein ε4 ( APOE 4) genotype, and biological sex are major risk factors for late‐onset Alzheimer's disease (LOAD), and preclinical mouse models enable controlled investigation of these factors. To date, humanized APOE 4 has not recapitulated LOAD‐relevant brain volume phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP ( h APP) alongside humanized APOE (h APOE ) may therefore improve translational modeling of structural brain changes characterized by neuroimaging.
METHODS
Aged mice (mean age = 23.25 months) carrying murine ( m ) or humanized ( h ) APP and murine Apoe or h APOE 3/3 (h APOE 3‐HOM), h APOE 3/4 (h APOE 4‐HET), or h APOE 4/4 (h APOE 4‐HOM) underwent in‐skull ex vivo volumetric magnetic resonance imaging. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, APOE genotype, and sex, with false discovery rate correction applied within contrasts.
RESULTS
Brain volumes were primarily determined by APP background, with h APP globally reducing total and regional volumes relative to m APP mice. Across h APP models, h APOE 4‐HOM exhibited the greatest brain‐wide reductions, which was mitigated by a single h APOE 3 allele. In contrast, mouse APP exerted modest effects in h APOE , with h APOE 4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, h APP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independently of APP or APOE genotype.
DISCUSSION
h APP induces distinctly smaller brain volumes in this humanized APOE knock‐in model, and h APOE 4 homozygosity amplifies that effect, indicating genotype‐dependent susceptibility. Because this study is cross‐sectional and lacks histopathological confirmation, volume differences may reflect developmental or constitutive effects rather than neurodegeneration. Humanized APP and APOE are therefore necessary but not sufficient to recapitulate the complete volumetric signature of established LOAD. Longitudinal and histological studies are required to determine whether these differences reflect a prodromal trajectory or a developmental effect.