Kubota Masahito, Bun Shogyoku, Takahata Keisuke, Kurose Shin, Momota Yuki, Iwabuchi Yu, Tezuka Toshiki, Tabuchi Hajime, Seki Morinobu, Yamamoto Yasuharu, Shikimoto Ryo, Mimura Yu, Hoshino Takayuki, Shimohama Sho, Suzuki Natsumi, Morimoto Ayaka, Oosumi Azusa, Hoshino Yuka, Tai Kenji, Aoyagi Hirofumi, Sato Yoshiaki, Kuromitsu Junro, Nakahara Jin, Mimura Masaru, Ito Daisuke
Department of Neurology, Keio University School of Medicine, Tokyo, Japan.
Memory Center, Keio University School of Medicine, Tokyo, Japan.
Alzheimers Res Ther. 2025 Jun 7;17(1):131. doi: 10.1186/s13195-025-01778-8.
Plasma biomarkers offer a promising alternative to amyloid beta (Aβ) positron emission tomography (PET) or cerebrospinal fluid (CSF) biomarkers for diagnosing Alzheimer's disease (AD). This cross-sectional study assessed the utility of multiple plasma biomarkers for diagnosing and staging AD in a Japanese cohort.
The assessed plasma biomarkers included Aβ42/40, phosphorylated tau (p-tau181 and p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL), individually and in combination. Aβ42/40 was measured using the HISCL platform, while all other biomarkers were measured using the Simoa platform. Participants were classified based on Aβ PET imaging and neuropsychological testing into healthy controls (HC), AD continuum (preclinical AD, mild cognitive impairment [AD-MCI], and mild dementia [AD-D]), and non-AD cognitive impairment (CI) groups. Receiver operating characteristic analyses were performed to predict the Aβ PET status, correlation with Centiloid (CL) values and cognitive scores, and biomarker comparisons across AD stages.
Sixty-nine HC, 13 preclinical AD, 38 AD-MCI, 44 AD-D, and 79 non-AD CI participants were included. The area under the curves (AUCs) for predicting Aβ PET status were 0.937 (Aβ42/40), 0.926 (p-tau217), and 0.946 (p-tau217/Aβ42); results of pair-wise DeLong tests revealed no significant differences among these three metrics (all p > 0.05). In the cognitively normal group, the AUCs were 0.968 (Aβ42/40), 0.958 (p-tau217), and 0.979 (p-tau217/Aβ42), while in the cognitively impaired group, they were 0.919 (Aβ42/40), 0.893 (p-tau217), and 0.923 (p-tau217/Aβ42). Among HC and AD continuum participants, CL correlations were - 0.74 (Aβ42/40), 0.81 (p-tau217), and 0.83 (p-tau217/Aβ42). In the HC and AD continuum, Aβ42/40 levels showed a bimodal distribution (cutoff = 0.096), with a shift from high to low occurring at 19.3 CL, compared to the PET positivity threshold of 32.9 CL. P-tau217 exhibited a linear increase with disease progression. All biomarkers correlated strongly with logical memory scores.
Plasma biomarkers, Aβ42/40 and p-tau217, and particularly their ratio (p-tau217/Aβ42), show strong potential as Aβ PET alternatives for AD diagnosis. HISCL-based plasma Aβ42/40 detects Aβ accumulation earlier than Aβ PET visual reading threshold, underscoring its utility as an early diagnostic marker.
血浆生物标志物为诊断阿尔茨海默病（AD）提供了一种有前景的替代淀粉样β蛋白（Aβ）正电子发射断层扫描（PET）或脑脊液（CSF）生物标志物的方法。这项横断面研究评估了多种血浆生物标志物在日本队列中诊断和分期AD的效用。
评估的血浆生物标志物包括Aβ42/40、磷酸化tau蛋白（p-tau181和p-tau217）、胶质纤维酸性蛋白（GFAP）和神经丝轻链（NfL），单独或联合使用。使用HISCL平台测量Aβ42/40，而所有其他生物标志物使用Simoa平台测量。参与者根据Aβ PET成像和神经心理学测试分为健康对照（HC）、AD连续体（临床前AD、轻度认知障碍[AD-MCI]和轻度痴呆[AD-D]）以及非AD认知障碍（CI）组。进行了受试者工作特征分析，以预测Aβ PET状态、与百分位数（CL）值和认知评分的相关性，以及跨AD阶段的生物标志物比较。
纳入了69名HC、13名临床前AD、38名AD-MCI、44名AD-D和79名非AD CI参与者。预测Aβ PET状态的曲线下面积（AUC）分别为0.937（Aβ42/40）、0.926（p-tau217）和0.946（p-tau217/Aβ42）；成对的德龙检验结果显示这三个指标之间无显著差异（所有p>0.05）。在认知正常组中，AUC分别为0.968（Aβ42/40）、0.958（p-tau217）和0.979（p-tau217/Aβ42），而在认知障碍组中，分别为0.919（Aβ42/40）、0.893（p-tau217）和0.923（p-tau217/Aβ42）。在HC和AD连续体参与者中，CL相关性分别为-0.74（Aβ42/40）、0.81（p-tau217）和0.83（p-tau217/Aβ42）。在HC和AD连续体中，Aβ42/40水平呈双峰分布（截断值=0.096），与PET阳性阈值32.9 CL相比，在19.3 CL时从高到低发生转变。P-tau217随疾病进展呈线性增加。所有生物标志物与逻辑记忆评分均密切相关。
血浆生物标志物Aβ42/40和p-tau217，尤其是它们的比值（p-tau217/Aβ42），作为AD诊断的Aβ PET替代物显示出强大的潜力。基于HISCL的血浆Aβ42/40比Aβ PET视觉读取阈值更早地检测到Aβ积累，突出了其作为早期诊断标志物的效用。
