The APOE4 allele is recognized as a significant genetic risk factor to Alzheimer's disease (AD) and influences longevity. Nonetheless, some APOE4 carriers exhibit resistance to AD even in advanced age. Humanin, a mitochondrial‐derived peptide comprising 24 amino acids, has variants linked to cognitive resilience and longevity. Our research uncovered a unique humanin variant, P3S, specifically enriched in centenarians with the APOE4 allele. Through in silico analyses and subsequent experimental validation, we demonstrated a strong affinity between humanin P3S and APOE4. Utilizing an APOE4‐centric mouse model of amyloidosis (APP/PS1/APOE4), we observed that humanin P3S significantly attenuated brain amyloid‐beta accumulation compared to the wild‐type humanin. Transcriptomic assessments of mice treated with humanin P3S highlighted its potential mechanism involving the enhancement of amyloid beta phagocytosis. Additionally, in vitro studies corroborated humanin P3S's efficacy in promoting amyloid‐beta clearance. Notably, in the temporal cortex of APOE4 carriers, humanin expression is correlated with genes associated with phagocytosis. Our findings suggest a role of the rare humanin variant P3S, especially prevalent among individuals of Ashkenazi descent, in mitigating amyloid beta pathology and facilitating phagocytosis in APOE4‐linked amyloidosis, underscoring its significance in longevity and cognitive health among APOE4 carriers.

中文翻译：

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Humanin 变体 P3S 与 APOE4 携带者的长寿相关，并能抵抗 APOE4 诱导的脑病理学

这载脂蛋白4等位基因被认为是阿尔茨海默病 (AD) 的重要遗传风险因素，并影响寿命。尽管如此，一些载脂蛋白4即使在高龄，携带者也表现出对 AD 的抵抗力。护脑素是一种由 24 个氨基酸组成的线粒体衍生肽，具有与认知能力和长寿相关的变体。我们的研究发现了一种独特的护脑素变体 P3S，它在百岁老人中特别富集，具有载脂蛋白4等位基因。通过计算机分析和随后的实验验证，我们证明了护脑素 P3S 和载脂蛋白4。利用一个载脂蛋白4以淀粉样变性为中心的小鼠模型（APP/PS1/载脂蛋白4），我们观察到与野生型护脑素相比，护脑素 P3S 显着减弱了大脑中β-淀粉样蛋白的积累。对用护脑素 P3S 治疗的小鼠进行的转录组学评估强调了其涉及增强β淀粉样蛋白吞噬作用的潜在机制。此外，体外研究证实了护脑素 P3S 在促进淀粉样蛋白 β 清除方面的功效。值得注意的是，在颞叶皮层载脂蛋白4在携带者中，护脑蛋白的表达与吞噬作用相关的基因相关。我们的研究结果表明，罕见的护脑素变体 P3S 在减轻淀粉样蛋白 β 病理学和促进吞噬作用方面发挥着作用，尤其是在德系犹太人血统的个体中普遍存在。载脂蛋白4‐相关淀粉样变性，强调其对长寿和认知健康的重要性载脂蛋白4载体。