Aydin Aysegul Gungor, Manoj Pranav, Ramadan Faiza, Rajan Sarah, Youssef Elias, Torres Elizabeth B, Bieszczad Kasia M
Biomedical Research Institute of New Jersey, Cedar Knolls, NJ, 07927, USA.
Atlantic Health System, Morristown, NJ, 07960, USA.
bioRxiv. 2025 Aug 11:2025.08.07.669134. doi: 10.1101/2025.08.07.669134.
Hearing has been identified as the largest modifiable mid-life risk factor for Alzheimer's Disease (AD), despite that its link to dementia remains unclear. Here we identify a biomarker of AD risk in an auditory neural signal using the non-invasive, rapidly acquired, and clinically translatable auditory brainstem response (ABR) in normal hearing knock-in rats (Swedish familial AD risk variant to , ; male and female). While ABR morphology has been proposed as a biomarker for AD, we report a novel biomarker derived from multidimensional parametric feature extraction on the distribution statistics of repeated single traces of the ABR that increases its potential for clinical utility with sensitivity and specificity. We report accurate prediction of AD genetic risk in both young and aged animals: rats separate clearly from humanized controls in both sex- and age-dependent manners. Notably, auditory learning in young adulthood normalized the ABR signature in rats with maintained effects into older age, altogether supporting a central neural generator of auditory dysfunction related to AD risk. These preclinical findings show how ABRs could provide a very early biomarker for detection of AD risk and lay the groundwork to test the synergy of auditory and cognitive functions in human dementia.
听力已被确认为阿尔茨海默病（AD）最大的可改变的中年风险因素，尽管其与痴呆症的联系尚不清楚。在此，我们在正常听力的基因敲入大鼠（携带瑞典家族性AD风险变体， ；雄性和雌性）中，使用非侵入性、快速获取且具有临床可转化性的听觉脑干反应（ABR），确定了听觉神经信号中AD风险的生物标志物。虽然ABR形态已被提议作为AD的生物标志物，但我们报告了一种新的生物标志物，它来自对ABR重复单迹分布统计的多维参数特征提取，提高了其在临床应用中的敏感性和特异性潜力。我们报告了在年轻和老年动物中对AD遗传风险的准确预测： 大鼠在性别和年龄依赖性方面均与人类化对照明显区分开来。值得注意的是，成年早期的听觉学习使 大鼠的ABR特征正常化，并在老年期保持这种效果，这完全支持了与AD风险相关的听觉功能障碍的中枢神经发生器。这些临床前研究结果表明ABR如何能够为检测AD风险提供一个非常早期的生物标志物，并为测试人类痴呆症中听觉和认知功能的协同作用奠定基础。
