Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Mol Neurodegener. 2024 Oct 31;19(1):81. doi: 10.1186/s13024-024-00772-2.
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 (Aß) 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 Aß/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.
载脂蛋白 E (APOE) ε4 等位基因是导致晚发性阿尔茨海默病 (AD) 的最强遗传风险因素。本病例-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研究允许一些 APOEε4 携带者在老年时保持正常认知功能的生物学机制。
1996 年至 1999 年参加妇女健康倡议记忆研究 (WHIMS) 的 APOEε4 携带者和 APOEε3 纯合子，如果他们在 80 岁以上仍保持认知不受影响，则被归类为有弹性，如果他们在 80 岁之前或 80 岁时出现认知障碍，则被归类为无弹性。在参与者认知正常时采集的血液中（平均在研究入组前 14 年），定量检测了 AD 病理（Aβ）和神经退行性变（NfL、tau）生物标志物以及 1007 种蛋白质（Olink）。我们确定了能够区分有弹性和无弹性 APOEε4 携带者的血浆蛋白，研究了这些关联是否普遍适用于 APOEε3 纯合子，并在英国生物银行中复制了这些发现。
共纳入 1610 名参与者（基线年龄：71.3 [3.8 SD] 岁；均为白人；42%APOEε4 携带者）。与有弹性的 APOEε4 携带者相比，无弹性的 APOEε4 携带者在基线时 Aβ/τ 比值较低，NfL 较高。蛋白质组学分析鉴定出 4 种在经过 FDR 校正的 P < 0.05 时有差异表达的蛋白质。虽然候选蛋白之一，神经元损伤标志物（NfL）也能区分有弹性和无弹性的 APOEε3 纯合子，但其他三种蛋白，即参与脂质代谢（ANGPTL4）和免疫信号（PTX3、NCR1）的蛋白，仅在 APOEε4 携带者中预测有弹性与无弹性状态（蛋白*基因型相互作用 P < 0.05）。这四种蛋白中的三种蛋白也可以预测英国生物银行验证样本中 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（通过 PKC-θ）区分了有弹性和无弹性的 APOEε4 携带者。
我们鉴定并复制了与 APOEε4 携带者认知弹性相关的血浆蛋白质组学特征。这些蛋白提示特定的免疫过程在 AD 遗传风险升高的情况下维持认知状态。未来在不同队列中的研究将需要评估这些结果的普遍性。
