Bamford Alison R, Adams Jenna N, Kim Soyun, Taylor Lisa M, Tuteja Nandita, McMillan Liv C, Sattari Negin, Chen Ivy Y, Chappel-Farley Miranda G, Escalante Yuritza, Lawrence Alyssa L, Meza Novelle J, Berisha Destiny E, Dave Abhishek, Malhas Rond, Mapstone Mark, Mander Bryce A, Yassa Michael A, Thomas Elizabeth A
Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA; Institute for Interdisciplinary Salivary Bioscience Research, University of California Irvine, Irvine, CA, USA.
Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA; Center for the Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA, USA.
J Prev Alzheimers Dis. 2025 Jun 9:100216. doi: 10.1016/j.tjpad.2025.100216.
Amyloid beta (Aβ) plaque burden, as measured by positron emission tomography (PET), is increasingly being used as a biomarker for Alzheimer's disease (AD) as well as a screening or monitoring tool for clinical trials with amyloid-lowering drugs. However, PET imaging is expensive, invasive and not widely available for all patients, necessitating alternative means to assess brain Aβ accumulation.
In this study, we measured levels of Aβ42, Aβ40 and Aβ38 in saliva samples from cognitively unimpaired older adults (n=93; 61.7 % female; mean age = 70.1 ± 6.6 years) using the Mesoscale Discovery platform, carefully considering preanalytical variables, including timing of sample collection, blood contamination and sample concentration. We next determined the relationships between Aβ peptide levels and Aβ plaque burden within the brain, determined using 18F-florbetapir (FBP) PET.
We found that salivary levels of Aβ38 and Aβ42, but not Aβ40 nor the Aβ42/Aβ40, were significantly positively correlated with the global mean FBP standardized uptake value ratio (SUVR), before and after adjusting for age, sex and time of day of saliva sample collection (r=0.523/0.544, p=0.001/0.002 and r=0.316/0.32, p=0.031/0.044, for Aβ38 and Aβ42, respectively). Similar results were observed when Aβ values were analyzed as a ratio to the total protein levels in each sample and when tested in saliva samples that were collected during a restricted morning time window. Using composite regions which represent cortical regions vulnerable to Aβ accumulation in early, intermediate, and late stages of AD, we found that Aβ38 showed the most robust correlation with FBP SUVRs from early-accumulating brain regions (r=0.510; p<0.001). In contrast to the observed effects in saliva, plasma levels of Aβ42 measured from a subset of the participants showed a significant negative correlation to mean FBP SUVR. Using logistic regression analysis to determine whether any salivary Aβ species could predict brain Aβ burden, we found that salivary levels of Aβ38 in combination with age, sex, sample timing and APOE genotype could predict Aβ-PET positivity with an area under the curve = 0.950 (95 % confidence interval, 0.876-1.0; p<0.0001).
Our findings suggest that salivary Aβ38 and/or Aβ42 could have relevance as a non-invasive, and more widely applicable biomarker, for utility in clinical studies on AD.
通过正电子发射断层扫描（PET）测量的β淀粉样蛋白（Aβ）斑块负荷，越来越多地被用作阿尔茨海默病（AD）的生物标志物，以及用于降低淀粉样蛋白药物临床试验的筛查或监测工具。然而，PET成像价格昂贵、具有侵入性，并非所有患者都能广泛使用，因此需要其他方法来评估脑内Aβ的积累情况。
在本研究中，我们使用中尺度发现平台测量了认知未受损的老年人（n = 93；61.7%为女性；平均年龄 = 70.1 ± 6.6岁）唾液样本中Aβ42、Aβ40和Aβ38的水平，同时仔细考虑了分析前的变量，包括样本采集时间、血液污染和样本浓度。接下来，我们确定了Aβ肽水平与脑内Aβ斑块负荷之间的关系，脑内Aβ斑块负荷通过18F-氟代贝他吡（FBP）PET测定。
我们发现，在调整年龄、性别和唾液样本采集时间后，唾液中Aβ38和Aβ42的水平与全球平均FBP标准化摄取值比率（SUVR）显著正相关，而Aβ40以及Aβ42/Aβ40则不然（Aβ38和Aβ42的r分别为0.523/0.544，p = 0.001/0.002和r = 0.316/0.32，p = 0.031/0.044）。当将Aβ值作为与每个样本中总蛋白水平的比率进行分析时，以及在限制的早晨时间窗口内采集的唾液样本中进行测试时，观察到了类似的结果。使用代表AD早期、中期和晚期易受Aβ积累影响的皮质区域的复合区域，我们发现Aβ38与早期积累脑区的FBP SUVR相关性最强（r = 0.510；p < 0.001）。与唾液中的观察结果相反，从一部分参与者中测量的血浆Aβ42水平与平均FBP SUVR呈显著负相关。使用逻辑回归分析来确定是否有任何唾液Aβ种类可以预测脑内Aβ负荷，我们发现唾液中Aβ38水平结合年龄、性别、样本采集时间和APOE基因型可以预测Aβ-PET阳性，曲线下面积 = 0.950（95%置信区间，0.876 - 1.0；p < 0.0001）。
我们的研究结果表明，唾液Aβ38和/或Aβ42可能作为一种非侵入性且更广泛适用的生物标志物，在AD临床研究中具有应用价值。
