Early Age-Related Hearing Loss Investigation (EARHLI): A Randomized Controlled Trial to Assess Mechanisms Linking Early Age-Related Hearing Loss and Alzheimer's Disease and Related Dementias

PROJECT SUMMARY/ABSTRACT This proposal is an early phase II randomized controlled trial (RCT) to obtain preliminary data on mechanisms and efficacy of a hearing aid-based intervention to prevent cognitive decline in those at risk for Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD). The target risk group is 55-75-year old people with early-stage age-related hearing loss (ARHL) and amnestic mild cognitive impairment. The RCT, entitled “Early Age-Related Hearing Loss Investigation (EARHLI)” is in response to PAR-18-877, “Early Stage Clinical Trials for the Spectrum of Alzheimer’s Disease and Age-related Cognitive Decline.” ARHL, the third most common chronic condition in later life, is associated with cognitive impairment/AD/ADRD. This finding has recently been extended to early ARHL (borderline-to-moderate hearing loss [20-55 dB] on pure tone audiometry), which is rarely treated with hearing aids. The mechanisms linking ARHL and AD/ADRD are unknown, but reduced social engagement and changes in brain organization/connectivity have been proposed. A 2020 Lancet Commissions report estimated that eliminating ARHL could be associated with an 8% reduction in new dementia cases, at least as much as well-established risk factors. Yet, 90% of the target population is not treated with hearing aids and there is a dearth of RCTs testing the efficacy of hearing aids in ARHL. While studies have suggested hearing aids improve social engagement, brain organization/connectivity, and, in turn, cognition, there is no RCT evidence supporting these observations. There is one ongoing RCT (ACHIEVE, ClinicalTrials.gov NCT03243422) examining the effect of a hearing intervention on cognition in older adults with more advanced ARHL. EARHLI focuses on early ARHL in middle and early older age, a critical time for AD/ADRD prevention. Unlike ACHIEVE, EARHLI also measures brain organization/connectivity. EARHLI will be a phase II 1:1 RCT of a hearing aid-based intervention versus a comparator (health education program) conducted over 12 months in 150 participants (n=76 undergoing MRI) with early ARHL at risk for AD/ADRD. The overarching hypothesis is that the hearing intervention will lead to improved social engagement and brain organization/connectivity that will lead to improved cognition compared with the comparator arm. This hypothesis will be tested with an intent- to-treat approach comparing the hearing intervention and comparator arms. Aim 1 is to compare change in cognitive performance measured with the Alzheimer’s Disease Cooperative Study Preclinical Alzheimer Cognitive Composite (ADCS-PACC; 1º outcome) and by domain-specific cognitive testing on ADCS-PACC components (0, 6, 12 months). Aim 2 is to compare change in social engagement measured by activity participation (1º outcome) and network size/support (at 0, 6, 12 months). Aim 3 is to compare changes in brain organization/connectivity using task (visual task, auditory regions of interest,1º outcome) and resting-state fMRI, and diffusion-weighted structural connectivity (at 0, 12 months). We will explore whether social engagement and brain organization/connectivity mediate the effects of the intervention on cognitive outcomes.