BACKGROUNDAlzheimer's disease (AD) is the most common cause of dementia worldwide, with apolipoprotein Eε4 (APOEε4) being the strongest genetic risk factor. Current clinical diagnostic imaging focuses on amyloid and tau; however, new methods are needed for earlier detection.METHODSPET imaging was used to assess metabolism‐perfusion in both sexes of aging C57BL/6J, and hAPOE mice, and were verified by transcriptomics, and immunopathology.RESULTSAll hAPOE strains showed AD phenotype progression by 8 months, with females exhibiting the regional changes, which correlated with GO‐term enrichments for glucose metabolism, perfusion, and immunity. Uncoupling analysis revealed APOEε4/ε4 exhibited significant Type‐1 uncoupling (↓ glucose uptake, ↑ perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated Type‐2 uncoupling (↑ glucose uptake, ↓ perfusion), while immunopathology confirmed cell specific contributions.DISCUSSIONThis work highlights APOEε4 status in AD progression manifests as neurovascular uncoupling driven by immunological activation, and may serve as an early diagnostic biomarker.Highlights We developed a novel analytical method to analyze PET imaging of 18F‐FDG and 64Cu‐PTSM data in both sexes of aging C57BL/6J, and hAPOEε3/ε3, hAPOEε4/ε4, and hAPOEε3/ε4 mice to assess metabolism‐perfusion profiles termed neurovascular uncoupling. This analysis revealed APOEε4/ε4 exhibited significant Type‐1 uncoupling (decreased glucose uptake, increased perfusion) at 8 and 12 months, while APOEε3/ε4 demonstrated significant Type‐2 uncoupling (increased glucose uptake, decreased perfusion) by 8 months which aligns with immunopathology and transcriptomic signatures. This work highlights that there may be different mechanisms underlying age related changes in APOEε4/ε4 compared with APOEε3/ε4. We predict that these changes may be driven by immunological activation and response, and may serve as an early diagnostic biomarker.

中文翻译：

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神经血管解偶联评估：APOE 状态是早期代谢和血管功能障碍的关键驱动因素

背景阿尔茨海默病（AD）是全世界痴呆症最常见的原因，载脂蛋白Eε4（APOEε4）是最强的遗传风险因素。目前的临床诊断影像主要集中在淀粉样蛋白和 tau 蛋白；然而，需要新的方法进行早期检测。方法PET成像用于评估衰老C57BL/6J和hAPOE小鼠两性的代谢灌注，并通过转录组学和免疫病理学进行验证。结果所有hAPOE菌株均显示AD表型进展8几个月，雌性表现出区域变化，这与葡萄糖代谢、灌注和免疫力的 GO-term 丰富相关。解偶联分析显示 APOEε4/ε4 在 8 个月和 12 个月时表现出显着的 1 型解偶联（↓ 葡萄糖摄取，↑ 灌注），而 APOEε3/ε4 则表现出 2 型解偶联（↑ 葡萄糖摄取，↓ 灌注），而免疫病理学证实了细胞特异性贡献讨论这项工作强调了 AD 进展中的 APOEε4 状态表现为由免疫激活驱动的神经血管解偶联，并且可以作为早期诊断生物标志物。 我们开发了一种新的分析方法来分析 PET 成像18F-FDG 和64衰老 C57BL/6J 和 hAPOEε3/ε3、hAPOEε4/ε4 和 hAPOEε3/ε4 小鼠的两性 Cu-PTSM 数据用于评估称为神经血管解偶联的代谢灌注曲线。 该分析显示，APOEε4/ε4 在 8 个月和 12 个月时表现出显着的 1 型解偶联（葡萄糖摄取减少，灌注增加），而 APOEε3/ε4 在 8 个月时表现出显着的 2 型解偶联（葡萄糖摄取增加，灌注减少），这与免疫病理学和转录组学特征。 这项工作强调，与 APOEε3/ε4 相比，APOEε4/ε4 与年龄相关的变化可能存在不同的机制。我们预测这些变化可能是由免疫激活和反应驱动的，并且可以作为早期诊断生物标志物。