Addition of humanized APP to humanized APOE mouse model reduces brain size and increases the ratio of cortical representation
Discuss this preprint
Start a discussion What are Sciety discussions?Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
INTRODUCTION
Age, Apolipoprotein E4 ( APOE 4) genotype, and biological sex are major risk factors for late-onset Alzheimer’s disease (LOAD). Neuroimaging is central to its characterization, and preclinical mouse models enable controlled investigation of these factors. To date, humanized APOE 4 has not recapitulated LOAD-relevant brain phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (hAPP) alongside humanized APOE (h APOE ) may therefore improve translational modeling of structural brain changes.
METHODS
Aged mice (mean age = 23.25 months) carrying murine (m) or humanized (h) APP and either murine Apoe or h APOE 3/3, h APOE 3/4, or h APOE 4/4 underwent in-skull ex vivo volumetric MRI. Regional volumes were quantified in absolute terms and relative to total brain volume (TBV). Linear models included APP type, APOE genotype, and sex, with FDR correction applied within contrasts.
RESULTS
Brain volumes were primarily determined by APP background, with hAPP globally reducing total and regional volumes relative to mAPP mice. Across hAPP models, h APOE 4/4 exhibited the greatest brain-wide reductions, which was mitigated by a single h APOE 3 allele. In contrast, mouse APP exerted modest effect in h APOE , with hAPOE4 carriers exhibiting greater total volume without regional specificity. After TBV adjustment, hAPP mice exhibited subcortical vulnerability with relative cortical preservation. Females exhibited larger brain volumes than males, independent of APP or APOE genotype.
DISCUSSION
These findings demonstrate that APP background is a primary driver of mouse brain volume, with hAPP producing global reductions amplified by the h APOE 4/4 genotype. In contrast, h APOE 4 effects in the mAPP background were modest and nonspecific, consistent with normative aging. Together, these results suggest that hAPP and h APOE 4 act synergistically, and that h APOE 4 alone is insufficient to recapitulate AD-relevant brain changes in mice. The hAPP/h APOE 4/4 model yields a brain-wide phenotype consistent with LOAD-associated volumetric patterns, whereas mAPP/h APOE models may better reflect non-pathological aging.
