Alzheimer’s disease (AD) is a prevalent neurodegenerative illness, particularly affecting the elderly population. With over 55 million people worldwide living with dementia, AD stands as the most common form of this condition.
The aging baby-boomer generation in the United States is expected to lead to a rapid increase in AD diagnoses in the coming decades. Additionally, the COVID-19 pandemic has contributed to a 17% increase in Alzheimer’s and dementia-related deaths in 2020.
The financial burden of caring for dementia patients is significant, with billions of dollars spent annually. Early intervention is crucial in slowing disease progression, as it can have a substantial impact on cost-effectiveness. Consequently, there is an urgent need for innovative approaches to diagnose and track AD progression at its earliest stages.
Associating Auditory Processing Disorders with AD
Research suggests that disordered auditory processing could serve as a promising biomarker for AD diagnosis. Several epidemiological studies have demonstrated an association between hearing impairment and AD. In addition to peripheral hearing loss, studies have also identified central auditory processing disorders (CAPDs) in AD patients.
These CAPDs manifest as difficulties in understanding speech amidst background noise, dichotic listening, and sound localization. Prospective studies have even shown that CAPD can precede the onset of AD dementia. Furthermore, impaired gap detection abilities have been observed in AD patients, differentiating them from normal controls and correlating with temporal cortical thinning.
Impaired Inhibitory Function and Central Auditory Hyperactivity
Impaired inhibitory function appears to underlie the relationship between CAPDs and AD. Central auditory hyperactivity, attributed to inhibitory loss, has been reported in patients diagnosed with mild cognitive impairment. By facilitating the transmission of acetylcholine, a neurotransmitter critical in modulating neural activity in the auditory system, it is possible to attenuate this hyperactivity. Pharmacological treatments targeting acetylcholine have shown promise in reducing hearing deficits in noise for AD patients.
Investigating CAPDs and AD Progression
Further investigation is required to understand the underlying relationship between CAPDs and AD. Central auditory hyperactivity could potentially serve as a biomarker for AD diagnosis. Unlike many central auditory processing functions, central hyperactivity can be assessed using non-behavioral tests in rodent models, such as the 5xFAD and APP/PS1 transgenic amyloidosis mouse models.
These models enable researchers to minimize interference caused by AD-related motor deficits. Auditory event-related potentials (auditory ERPs) obtained from the auditory brainstem response (ABR) provide insights into central gain.
By comparing the amplitude of later potentials or waves to that of the first potential derived from the cochlear nerve, greater relative amplitudes in later waves can indicate central hyperactivity. In this study, we investigated the correlation between hearing loss, CAPDs, and AD progression in the 5xFAD and APP/PS1 mouse models, focusing on plaque distribution and auditory pathway amyloid plaque deposition.
Disordered auditory processing, particularly CAPDs, holds promise as a potential biomarker for diagnosing AD. The association between impaired inhibitory function and central auditory hyperactivity suggests a link between auditory processing deficits and AD pathology.
Further research is needed to understand the precise mechanisms underlying this relationship. By investigating AD models in rodents and utilizing auditory ERPs, researchers can gain insights into the correlation between hearing loss, CAPDs, and AD progression.
These findings may contribute to the development of early diagnostic tools and therapeutic interventions for AD, ultimately improving patient outcomes and reducing the societal and economic burden associated with the disease.
Hearing loss in AD and the importance of these studies to patient care
The relationship between hearing loss and AD still remains unclear. Although a large population-based study in South Korea reported significant comorbidity between hearing loss and AD (Chang et al., 2020), studies in small cohorts have yielded mixed results: some studies report increased hearing thresholds in AD patients (Uhlmann et al., 1989; Strouse et al., 1995; Irimajiri et al., 2005; Gates et al., 2008), but others did not (Kurylo et al., 1993; Gates et al., 1995; Idrizbegovic et al., 2011).
We showed that hearing loss severity varied between 5xFAD and APP/PS1 mice (Figure 3), which accumulate amyloid proteins at different rates (Lee and Han, 2013). Those results suggest that differential spatiotemporal amyloid accumulation can affect hearing loss progression in mice. Perhaps a similar differential in human disease could explain why some studies failed to identify significant hearing loss in AD and dementia patients.
Beyond abnormal hearing thresholds, we also observed a unique pattern of pathology progression: the ABR threshold increase was significant at lower frequencies before expanding to higher frequencies (Figure 2). This observation is similar to a previous study, which showed a greater mean difference at 8 and 16 kHz, than at 32 kHz between 5xFAD and WT mice (O’Leary et al., 2017). Given that the DPOAE thresholds remained normal when significant hearing loss manifested (Figure 2), the hearing loss in 5xFAD mice is likely due to auditory neuropathy, which is a common cause of presbycusis.
However, in typical presbycusis, hearing loss is more prominent at high frequencies (Gates and Mills, 2005). Rather than having a synergistic effect with presbycusis, the pattern of hearing loss in 5xFAD mice suggests that amyloidosis contributes to hearing loss by a different underlying mechanism. We speculate that plaque deposition in the central auditory system plays a role in this hearing loss. It has been demonstrated in other animal models that lesions in the brainstem could cause hearing loss and accelerate cochlear aging (Liberman et al., 2014).
A recent clinical study also showed that hearing loss and brainstem size are significantly correlated, but only in the context of AD (Llano et al., 2021). Others have similarly argued that AD-related damage to the central auditory cortices and their linked processing networks can drive central auditory processing disorders, especially by impacting temporal coordination (Johnson et al., 2021). Those studies suggest that auditory brainstem processing disorder can contribute to hearing loss in AD. However, the underlying mechanism of hearing loss in these transgenic AD mice needs further investigation.
In our studies, plaque deposition in the auditory midbrain, including the IC, correlated with a more rapid decline in hearing (Figures 3, 5), which in humans correlates with greater dementia progression (Thomson et al., 2017). We note that AD patients do accumulate plaques and tangles in the IC (Ohm and Braak, 1989; Sinha et al., 1993), and highlight here its importance for individuals with adult-onset hearing loss. The IC is important for lip-reading (Champoux et al., 2006), as it associates visual and auditory input in pre-conscious auditory processing (Gruters and Groh, 2012). We suggest that the existence of plaque in the auditory midbrain could precede a more rapid hearing loss and thus predict a more rapid decline. Further longitudinal studies are needed to determine if this correlation exists.
If it does, such a biomarker would be important for patient care, provided that patients maintain hearing in adulthood. It would help patients to know when they would likely need a hearing aid. Moreover, caretakers who know that patients have difficulties with lip reading can take steps, like communicating medical results in quiet environments, to assist their patients in understanding speech. It could also prompt patients to arrange for greater levels of assistance or acquire a legal guardian. Lastly, changes in ABR metrics over time may be useful to stratify patient populations for later studies testing new treatments.
reference link : https://www.frontiersin.org/articles/10.3389/fnins.2023.1106570/full