Ng Ted K S, Beck Todd, Boyle Patricia, Dhana Klodian, Desai Pankaja, Evans Denis A, Rajan Kumar B
Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, Illinois.
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois.
JAMA Netw Open. 2025 May 1;8(5):e258903. doi: 10.1001/jamanetworkopen.2025.8903.
Scarce population-based data exist on whether APOE4 modifies associations of blood-based neurodegenerative biomarkers with cognitive decline, particularly in a diverse, biracial population of community-dwelling older adults without dementia.
To assess whether APOE4 carrier status is associated with an accelerated rate of cognitive decline in older adults without dementia and with elevated neurodegenerative burden.
DESIGN, SETTING, AND PARTICIPANTS: This 20-year prospective cohort study started in 1993 and was conducted through 2012 on the South Side of Chicago among community-dwelling older adults without dementia from the longitudinal biracial Chicago Health and Aging Project. The interaction of APOE4 carrier status with prospective associations of serum neurodegenerative biomarkers with global cognitive decline was examined using a mixed-effects regression model, adjusting for demographics and chronic health conditions. Statistical analyses were conducted from June 2024 to January 2025.
APOE4 carrier status and serum biomarker levels for total tau (t-tau), neurofilament light (NfL) chain, and glial fibrillary acidic protein (GFAP) measured with a Quanterix Neuroplex kit at baseline.
Cognitive decline calculated from composite global cognition scores across study waves.
Among 1038 community-dwelling older adults (mean [SD] age, 77.1 [5.9] years; 615 Black [59.2%] and 423 White [40.8%]; 651 female [62.7%]), there was a mean (SD) of 12.8 (3.4) years of education and 343 individuals (33.0%) were APOE4 carriers. Higher levels of blood-based neurodegenerative biomarkers (ie, t-tau, NfL, and GFAP) were associated with a faster rate of cognitive decline among APOE4 carriers than noncarriers. Specifically, compared with noncarriers, APOE4 carriers had annual rates of cognitive decline per 1-log10 unit higher levels in t-tau and GFAP that were accelerated by a β (SD) of -0.03 (0.02) (P = .046) and -0.07 (0.03) (P = .02), respectively. Similarly, compared with noncarriers and participants in the lower NfL tertile, APOE4 carriers with middle and upper tertiles of NfL levels experienced accelerated cognitive decline, with a β (SD) of -0.04 (0.02) (P = .006) and -0.03 (0.02) (P = .07), respectively, although the difference was not significant for upper tertiles.
This study found that higher levels of neurodegeneration (t-tau), axonal injury (NfL), and reactive astrocytes and neuroinflammation (GFAP) biomarkers were associated with accelerated cognitive decline in genetically susceptible APOE4 carriers. These findings highlight the association of APOE4 with exacerbation of neurodegenerative processes, with not only significant implications for understanding and tracking the progression of neurodegenerative diseases, but also a call for inclusivity of APOE4 status in scientific investigations and clinical trials.
关于APOE4是否会改变血液中神经退行性生物标志物与认知衰退之间的关联，基于人群的数据稀缺，尤其是在一个多样化的、无痴呆症的社区居住老年混血人群中。
评估APOE4携带者状态是否与无痴呆症老年人认知衰退加速率以及神经退行性负担增加有关。
设计、背景和参与者：这项为期20年的前瞻性队列研究始于1993年，于2012年在芝加哥南区对来自纵向混血的芝加哥健康与衰老项目的无痴呆症社区居住老年人进行。使用混合效应回归模型，在调整人口统计学和慢性健康状况的基础上，研究APOE4携带者状态与血清神经退行性生物标志物与整体认知衰退的前瞻性关联之间的相互作用。统计分析于2024年6月至2025年1月进行。
基线时使用Quanterix Neuroplex试剂盒测量的APOE4携带者状态以及总tau（t-tau）、神经丝轻链（NfL）和胶质纤维酸性蛋白（GFAP）的血清生物标志物水平。
根据各研究阶段的综合整体认知评分计算认知衰退情况。
在1038名社区居住老年人中（平均[标准差]年龄为77.1[5.9]岁；615名黑人[59.2%]，423名白人[40.8%]；651名女性[62.7%]），平均（标准差）受教育年限为12.8（3.4）年，343人（33.0%）为APOE4携带者。与非携带者相比，APOE4携带者中血液中神经退行性生物标志物（即t-tau、NfL和GFAP）水平较高与认知衰退速度更快有关。具体而言，与非携带者相比，APOE4携带者中t-tau和GFAP每升高1-log10单位，其每年的认知衰退率分别加快β（标准差）为-0.03（0.02）（P = 0.046）和-0.07（0.03）（P = 0.02）。同样，与非携带者和NfL水平处于较低三分位数的参与者相比，NfL水平处于中、高三分位数的APOE4携带者认知衰退加速，β（标准差）分别为-0.04（0.02）（P = 0.006）和-0.03（0.02）（P = 0.07），尽管高三分位数的差异不显著。
本研究发现，较高水平的神经退行性变（t-tau）、轴突损伤（NfL）以及反应性星形胶质细胞和神经炎症（GFAP）生物标志物与基因易感性APOE4携带者的认知衰退加速有关。这些发现凸显了APOE4与神经退行性变过程加剧之间的关联，这不仅对理解和追踪神经退行性疾病的进展具有重要意义，也呼吁在科学研究和临床试验中纳入APOE4状态。
Zotero 插件