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Preprint WatchModerateAugust 26th, 2026

Humanized APP is the primary determinant of regional brain volume in humanized APOE knock-in mice: a cross-sectional ex vivo MRI study

Bhattrai, A.; Raikes, A. C.; Brinton, R. D.

Humanized APP background, rather than humanized APOE genotype, is the primary determinant of total and regional brain volume in aged humanized APOE knock-in mice, which bears on how APOE4-stratified preclinical models are used to justify APOE4-targeted clinical development.

Moderate contradiction

1 prior failure

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This preprint reports that in aged humanized knock-in mice, brain volume phenotypes track the APP background rather than the APOE genotype, and that humanized APOE4 on its own did not recapitulate late-onset Alzheimer's structural changes. Claidex holds one APP failure on file, valiltramiprosate-alz801-app-apoe4-alzheimers-phase3-efficacy-failure, a Phase 3 efficacy failure in early Alzheimer's disease restricted to APOE4 homozygotes. The two sit uncomfortably together. If the preclinical models used to argue that APOE4 homozygotes are a mechanistically distinct and enrichable population are dominated by APP rather than by APOE, then the stratification logic behind APOE4-restricted trials rests on a weaker model foundation than assumed. Any new programme proposing APOE4 enrichment should state which preclinical model supports the enrichment and whether that model separates APP from APOE effects.

Abstract excerpt

INTRODUCTION: Age, Apolipoprotein E4 (APOE4) 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 APOE4 has not recapitulated LOAD-relevant brain volume phenotypes. Given the central role of amyloid precursor protein (APP) in LOAD pathogenesis, incorporating humanized APP (hAPP) alongside humanized APOE (hAPOE) 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 either murine Apoe or hAPOE3/3 (hAPOE3-HOM), hAPOE3/4 (hAPOE4-HET), or hAPOE4/4 (hAPOE4-HOM) 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, hAPOE4-HOM exhibited the greatest brain-wide reductions, which was mitigated by a single hAPOE3 allele. In contrast, mouse APP exerted modest effect in hAPOE, 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: hAPP induces distinctly smaller brain volumes in this humanized APOE knock-in model, and hAPOE4 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.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.