Avnish Bhattrai, Adam C Raikes, Roberta Diaz Brinton
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引用次数: 0
Abstract
Introduction: Age, Apolipoprotein ε4 (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 murine Apoe or hAPOE3/3 (hAPOE3-HOM), hAPOE3/4 (hAPOE4-HET), or hAPOE4/4 (hAPOE4-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 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 effects 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, independently 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.
期刊介绍：
Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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