美国北卡罗来纳大学医学院Priya Palta团队研究了阿尔茨海默病血液生物标志物的变化及其与全因痴呆的关系。该研究于2024年7月28日发表于《美国医学会杂志》。

血浆生物标志物有望识别阿尔茨海默病（AD）神经病理学和神经退行性变，但需要在不同人群中和整个生命过程中进行额外的评估。

为了评估临时血浆生物标志物的变化及其与全因痴呆症、总体和社区居住成年人亚组之间的联系，研究组在美国社区动脉粥样硬化风险研究（ARIC）的1525名参与者中，使用在中年（1993-1995年，平均年龄58.3岁）和晚年（2011-2013年，平均年龄76.0岁）收集的存储样本测量血浆生物标志物；紧随其后的是2016-2019年，平均年龄80.7岁。还评估了中年风险因素（高血压、糖尿病、高血脂、冠心病、吸烟和体育活动）与血浆生物标志物随时间变化的关系。在2011-2013年无痴呆症并在1993-1995年和2011-2013年进行了生物标志物测量的亚人群（N=1339）中评估了具有全因痴呆症事件的生物标志物关联。

使用Quanterix-Simoa平台测量淀粉样β42与淀粉样β40（Aβ42:Aβ40）比值、苏氨酸181磷酸化tau（P-tau181）、神经丝蛋白轻链（NFL）和胶质纤维酸性蛋白（GFAP）的血浆生物标志物。从2012年1月1日至2019年12月31日，研究组从神经心理学评估、半年度参与者或信息提供者接触以及医疗记录监测中确定了全因痴呆症事件。

在1525名参与者（平均年龄58.3[SD，5.1]岁）中，914名参与者（59.9%）是女性，394名参与者（25.8%）是黑人。共有252名参与者（16.5%）患有痴呆症。从中年到老年，观察到Aβ42:Aβ40比值下降，P-tau181、NFL和GFAP增加，携带载脂蛋白和ε4（Apoeε4）等位基因的参与者的生物标志物变化更快。中年高血压与0.15-SD更快的NFL增加和0.08-SD更快的GFAP增加有关；对中年糖尿病的评估NFL快0.11-SD，GFAP快0.15-SD。只有中年AD特异性生物标志物与晚期痴呆有长期联系（每SD低Aβ42:Aβ40比，1.11；95%可信区间，1.02-1.21；每SD高P-Tau181，1.15；95%可信区间，1.06-1.25）。所有老年生命中的血浆生物标志物都与老年痴呆有统计上的显著关联，NFL表现出最大的关联（1.92；95%可信区间，1.72-2.14）。

研究结果表明，AD神经病理学、神经损伤和星形胶质细胞增生的血浆生物标志物随着年龄的增长而增加，并与已知的痴呆风险因素有关。AD特异性生物标志物与痴呆症的关联始于中年，而AD、神经损伤和星形胶质瘤生物标志物的晚年测量都与痴呆症有关。

附：英文原文

Title: Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia

Author: Yifei Lu, James Russell Pike, Jinyu Chen, Keenan A. Walker, Kevin J. Sullivan, Bharat Thyagarajan, Michelle M. Mielke, Pamela L. Lutsey, David Knopman, Rebecca F. Gottesman, A. Richey Sharrett, Josef Coresh, Thomas H. Mosley, Priya Palta

Issue&Volume: 2024-07-28

Abstract:

Importance  Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed.

Objective  To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults.

Design, Setting, and Participants  In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n=1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013.

Exposure  Plasma biomarkers of amyloid-β 42 to amyloid-β 40 (Aβ42:Aβ40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform.

Main Outcomes and Measures  Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance.

Results  Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aβ42:Aβ40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aβ42:Aβ40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14).

Conclusions and Relevance  Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers’ association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

DOI: 10.1001/jama.2024.6619

Source: https://jamanetwork.com/journals/jama/fullarticle/2821670