The role of hearing loss in cognitive impairment and Alzheimer’s disease pathology

PROJECT SUMMARY
Alzheimer’s disease (AD) is a large and growing worldwide public health epidemic. Because there is no cure
for AD, much clinical effort is focused on interventions targeting potentially modifiable risk factors. Recent
epidemiological studies have identified hearing loss (HL) as a major modifiable risk factor for AD. These
findings have prompted debate over whether HL specifically accelerates AD pathology, or if the link instead
reflects shared risk factors such as age, genetics, or metabolic conditions. Because human studies are
necessarily correlational, an animal model is necessary to determine whether HL specifically influences AD
pathology. We address this question in Aim 1 using the E4FAD mouse model of AD, which is homozygous for
the most prevalent genetic AD risk factor (ApoE4) and co-expresses five additional familial AD mutations. We
will determine whether HL induced by cochlear ablation accelerates AD pathology, including hallmark
accumulations of amyloid β (Aβ) as plaques and phosphorylated tau (p-tau), as well as increased neuronal
hyperactivity and reductions in memory-related sharp wave ripples (SWRs). Because these pathologies
emerge first within entorhinal cortex (EC) and hippocampus (HC), we will assess cognitive impairment (CI)
reflecting EC-HC dysfunction (e.g., spatial memory). The expected results will be informative for clinical best
practices, e.g., by suggesting whether prevention and treatment of HL could itself mitigate AD, or if instead
targeting a common cause is needed to address both HL and AD. Independent of these outcomes, recent
studies in rodents have shown HL causes long lasting CI reflecting HC dysfunction. Although the underlying
mechanisms remain poorly understood, they may include side effects of noise exposure in rodents (e.g.,
elevated stress hormones in HC), as well as psychosocial factors in humans (e.g., communication difficulty and
social withdrawal). However, recent rodent studies have documented CI following HL induced without noise
exposure (e.g., cochlear ablation), implicating mechanisms other than psychosocial factors and noise side
effects. A leading candidate mechanism in such cases is disrupted neuronal activity in the EC-HC which could
result from altered input from the auditory pathway following HL (e.g., decreased sound-related activity and
increased spontaneous hyperactivity). We address this possibility in Aim 2 through longitudinal physiology
recordings in EC-HC and auditory cortex (ACtx) before and after HL induced by cochlear ablation. We will
examine whether hyperactivity emerges in EC-HC in parallel with upstream ACtx, quantify possible reductions
in SWRs, and determine whether functional connectivity is altered between EC-HC and ACtx. The expected
results will clarify mechanisms of HL-induced CI and may suggest clinical responses to both HL and CI (e.g.,
pharmacological attenuation of hyperactivity). Collectively, our proposal will resolve outstanding unresolved
questions surrounding the role of HL in HC dysfunction including AD-related pathology. These findings will be
highly relevant to large clinical populations suffering disability due to AD and HL.

Grant Number: 5R01AG078132-04
NIH Institute/Center: NIH
Principal Investigator: James Bigelow