Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers. We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.

中文翻译：

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APOEε4 载体的蛋白质组学分析表明脂质代谢、补体和淋巴细胞信号转导与认知弹性有关


载脂蛋白 E （APOE） ε4 等位基因是晚发性阿尔茨海默病 （AD） 的最强遗传危险因素。这项病例队列研究使用靶向血浆生物标志物和大规模蛋白质组学来检查允许一些 APOEε4 携带者在老年人中维持正常认知功能的生物学机制。1996 年至 1999 年参加女性健康倡议记忆研究 （WHIMS） 的 APOEε4 携带者和 APOEε3 纯合子如果他们在 80 岁之后仍然没有认知障碍，则被归类为有弹性，如果他们在 80 岁之前或时出现认知障碍，则被归类为无弹性。当参与者认知正常时，对研究入组时 （平均 14 年前） 采集的血液中的 AD 病理学 （Aß42/40） 和神经变性 （NfL， tau） 生物标志物以及 1007 种蛋白质 （Olink） 进行量化。我们确定了区分有弹性和非有弹性的 APOEε4 载体的血浆蛋白，检查了这些关联是否推广到 APOEε3 纯合子，并在英国生物库中复制了这些发现。共纳入 1610 名参与者 （基准年龄：71.3 [3.8 SD] 岁;均为白人;42% APOEε4 携带者）。与弹性 APOEε4 载体相比，非弹性 APOEε4 载体在基线时具有较低的 Aß42/40/tau 比率和较高的 NfL。蛋白质组学分析确定了四种蛋白在弹性和非弹性 APOEε4 载体之间差异表达，FDR 校正的 P < 为 0.05。虽然其中一种候选蛋白，神经元损伤标志物 （NfL），也区分了有弹性的 APOEε3 纯合子，但已知参与脂质代谢 （ANGPTL4） 和免疫信号传导 （PTX3， NCR1） 的其他三种蛋白仅预测有弹性 vs. APOEε4 携带者中的非弹性状态（蛋白质*基因型相互作用-P < 0.05）。这四种蛋白质中的三种也预测了英国生物样本库验证样本中 APOEε4 携带者的 14 年痴呆风险 （N = 9420）。虽然候选蛋白与 AD 病理学的靶向生物标志物几乎没有关联，但蛋白质网络和富集分析表明，自然杀伤 （NK） 细胞和 T 淋巴细胞信号转导（通过 PKC-θ）区分有弹性的 APOEε4 携带者。我们确定并复制了与 APOEε4 携带者认知弹性相关的血浆蛋白质组学特征。尽管 AD 的遗传风险升高，但这些蛋白质与保持认知状态相关的特定免疫过程。未来需要对不同队列进行研究来评估这些结果的普遍性。