Sound-evoked auditory neurophysiological signals are a window into prodromal functional differences in a preclinical...

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 Amyloid precursor protein, App ^S; 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: App ^S rats separate clearly from humanized controls in both sex- and age-dependent manners. Notably, auditory learning in young adulthood normalized the ABR signature in App ^S 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.