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Age-related hearing loss and cognitive decline — The potential mechanisms linking the two

  • Yasue Uchida
    Correspondence
    Corresponding author at: Department of Otorhinolaryngology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
    Affiliations
    Department of Otorhinolaryngology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan

    Department of Otorhinolaryngology, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan
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  • Saiko Sugiura
    Affiliations
    Department of Otorhinolaryngology, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan

    Toyota Josui Mental Clinic, 86-2 Minamidaira, Josui-cho, Toyota, Aichi, 470-0343, Japan
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  • Yukiko Nishita
    Affiliations
    Section of National Institute for Longevity Sciences − Longitudinal Study of Aging, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan
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  • Naoki Saji
    Affiliations
    Center for Comprehensive Care and Research on Memory Disorders, National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu, Aichi, 474-8511, Japan
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  • Michihiko Sone
    Affiliations
    Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, Aichi, 466-8550, Japan
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  • Hiromi Ueda
    Affiliations
    Department of Otorhinolaryngology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan
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Open AccessPublished:August 31, 2018DOI:https://doi.org/10.1016/j.anl.2018.08.010

      Abstract

      The amount of attention to age-related hearing loss (ARHL) has been growing, not only from the perspective of being one of the most common health conditions affecting older adults, but also from the perspective of its relation to cognition. Results from a number of epidemiological and laboratory studies have demonstrated a significant link between ARHL and cognitive decline. The Lancet International Commission on Dementia, Prevention, Intervention, and Care has estimated that mid-life hearing loss, if eliminated, might decrease the risk of dementia by nine percent, since hearing loss is a modifiable age-associated condition linked to dementia. Despite numerous research efforts, elucidation of the underlying causal relationships between auditory and cognitive decline has not yet reached a consensus.
      In this review article, we focused on the hypotheses of etiological mechanisms between ARHL and cognitive decline: (1) cognitive load hypothesis; (2) common cause hypothesis; (3) cascade hypothesis; and (4) overdiagnosis or harbinger hypothesis. Factual evidence obtained in previous studies was assessed to understand the link between ARHL and cognitive decline or dementia. Additionally, an overview of the conceivable effects of hearing intervention, e.g., hearing aids and cochlear implants, on cognition were presented, and the role of hearing aid use was considered for the relevant hypotheses.
      We should continue to strive for social enlightenment towards the importance of ‘hearing well’, and cultivate a necessity for hearing screening among patients at risk of cognitive decline.

      Keywords

      1. Introduction

      According to the results from the most recent Global Burden of Disease (GBD), hearing loss has become the third leading cause of years lived with disability (YLDs) and a major concern for global health, especially in the elderly population [
      • Collaborators GDaIIaP
      Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016.
      ]. The attention to age-related hearing loss (ARHL) has been growing from the perspective of its relation with cognition. Numerous studies, including systematic review articles and meta-analyses, have shown a link between ARHL and cognitive decline, impaired performance across cognitive domains, and increased risk for dementia diagnosis [
      • Thomson R.S.
      • Auduong P.
      • Miller A.T.
      • Gurgel R.K.
      Hearing loss as a risk factor for dementia: a systematic review.
      ,
      • Zheng Y.
      • Fan S.
      • Liao W.
      • Fang W.
      • Xiao S.
      • Liu J.
      Hearing impairment and risk of Alzheimer’s disease: a meta-analysis of prospective cohort studies.
      ,
      • Loughrey D.G.
      • Kelly M.E.
      • Kelley G.A.
      • Brennan S.
      • Lawlor B.A.
      Association of age-related hearing loss with cognitive function, cognitive impairment, and dementia: a systematic review and meta-analysis.
      ,
      • Wei J.
      • Hu Y.
      • Zhang L.
      • Hao Q.
      • Yang R.
      • Lu H.
      • et al.
      Hearing impairment, mild cognitive impairment, and dementia: a meta-analysis of cohort studies.
      ,
      • Ford A.H.
      • Hankey G.J.
      • Yeap B.B.
      • Golledge J.
      • Flicker L.
      • Almeida O.P.
      Hearing loss and the risk of dementia in later life.
      ]. Loughrey et al. analyzed the results of 36 unique studies with an estimated 20,264 unique participants based on inclusion criteria in a meta-analysis, and estimated the association between ARHL and cognitive function, cognitive impairment, and dementia. A significant association was found for cognitive impairment [odds ratio (OR), 1.22; 95% confidence interval (CI), 1.09–1.36] and dementia [OR, 1.28; 95%CI, 1.02–1.59] among the prospective cohort studies, and a small but statistically significant association between ARHL and 7 cognitive domains, such as episodic memory and processing speed, among the cohort studies.
      At the 2017 Alzheimer’s Association International Conference in London, a novel lifespan-based model of dementia risk was reported by the Lancet Commission on Dementia Prevention, Intervention, and Care and simultaneously published in Lancet [
      • Livingston G.
      • Sommerlad A.
      • Orgeta V.
      • Costafreda S.G.
      • Huntley J.
      • Ames D.
      • et al.
      Dementia prevention, intervention, and care.
      ]. Hearing loss was positioned as the largest potentially modifiable risk factor for dementia among nine health and lifestyle factors. The Lancet Commission found that mid-life hearing loss, if eliminated, might reduce the risk of dementia by nine percent.
      The underlying causal mechanisms leading to the connection between the two are not well understood. Since dementia is the greatest global challenge for health and social care in societies with high longevity like Japan, it is important to develop preventive measures against dementia and to scrutinize the potential causal contribution of hearing loss. In this article, we introduce various hypotheses linking hearing loss with cognitive decline and dementia [
      • Fulton S.E.
      • Lister J.J.
      • Bush A.L.
      • Edwards J.D.
      • Andel R.
      Mechanisms of the hearing-cognition relationship.
      ,
      • Stahl S.M.
      Does treating hearing loss prevent or slow the progress of dementia? Hearing is not all in the ears, but who’s listening?.
      ,
      • Wayne R.V.
      • Johnsrude I.S.
      A review of causal mechanisms underlying the link between age-related hearing loss and cognitive decline.
      ,
      • Lin F.R.
      • Albert M.
      Hearing loss and dementia — who is listening?.
      ], and discuss the impact of interventions, such as hearing aid use, on the delay of the progression of cognitive impairment.

      2. Cognitive load hypothesis

      Cognitive load theory, which was developed in 1998 by psychologist John Sweller, originated in educational psychology [
      • Sweller J.
      • Ayres P.L.
      • Kalyuga S.
      Cognitive load theory.
      ], and now become one of the most important concepts for teachers to know. The cognitive load while carrying out a task is the cognitive effort or amount of information processing required by an individual to perform the task. The basic idea of cognitive load theory in education is that if a learning task requires too much capacity, learning will be hampered because our cognitive capacity in working memory is limited. In the educational science, to optimize the use of working memory capacity and to avoid cognitive overload are recommended in an instructional system design [
      • Jong T.d
      Explorations in learning and the brain: on the potential of cognitive neuroscience for educational science.
      ].
      For an individual with hearing loss, listening effort, which refers to the attention and concentration required to understand speech, must be always present. The cognitive load hypothesis theorizes that hearing loss leads to degraded auditory signals, greater cognitive resources being required for auditory perceptual processing, and diversion from other cognitive tasks to effortful listening, eventually resulting in cognitive reserve depletion (Fig. 1A) [
      • Stahl S.M.
      Does treating hearing loss prevent or slow the progress of dementia? Hearing is not all in the ears, but who’s listening?.
      ,
      • Wayne R.V.
      • Johnsrude I.S.
      A review of causal mechanisms underlying the link between age-related hearing loss and cognitive decline.
      ,
      • Lin F.R.
      • Albert M.
      Hearing loss and dementia — who is listening?.
      ,
      • Tun P.A.
      • McCoy S.
      • Wingfield A.
      Aging, hearing acuity, and the attentional costs of effortful listening.
      ,
      • Martini A.
      • Castiglione A.
      • Bovo R.
      • Vallesi A.
      • Gabelli C.
      Aging, cognitive load, dementia and hearing loss.
      ]. For hearing-impaired individuals, this is similar to performing ‘dual tasks’ at the same time, as assumed in Lavie’s cognitive load theory [
      • Lavie N.
      Perceptual load as a necessary condition for selective attention.
      ,
      • Lavie N.
      Distracted and confused? Selective attention under load.
      ]. When dual tasks are performed together under conditions of high load for the primary task, decrements to the performance of the secondary task will be observed when processing capacity is exceeded [
      • Lavie N.
      Perceptual load as a necessary condition for selective attention.
      ].
      Fig. 1
      Fig. 1(A) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Cognitive Load Hypothesis. (B) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Common Cause Hypothesis. (C) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Cascade Hypothesis. (D) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Overdiagnosis or Harbinger Hypothesis.
      Fig. 1
      Fig. 1(A) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Cognitive Load Hypothesis. (B) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Common Cause Hypothesis. (C) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Cascade Hypothesis. (D) Potential mechanism linking hearing loss and cognitive impairment and conceivable effect of intervention with hearing aids — Overdiagnosis or Harbinger Hypothesis.
      An excessive cognitive load dedicated to auditory perceptual processing in everyday life causes brain structural changes and neurodegeneration relevant to the detriment of other cognitive processes; subsequently, a vicious cycle is created in which the cognitive resources available for auditory perception may be reduced. The cognitive load in hearing-impaired individuals diverts cognitive resources away from other cognitive processes such as working memory. Hypothetically, this could lead to cognitive decline.
      Scientific evidence for this cognitive load hypothesis, i.e., the hypothesis that hearing loss could increase listening effort during speech perception, is limited at the current moment.
      Ohlenforst et al. performed a systematic review to address the following two research questions: (1) does hearing impairment affect listening effort; and (2) can hearing aid amplification affect listening effort during speech comprehension? [
      • Ohlenforst B.
      • Zekveld A.A.
      • Jansma E.P.
      • Wang Y.
      • Naylor G.
      • Lorens A.
      • et al.
      Effects of hearing impairment and hearing aid amplification on listening effort: a systematic review.
      ] Among the 41 relevant studies from a total of 7017 articles that were characterized by their diversity regarding the assessment of listening effort, including subjective, behavioral, and physiological measurements, the experimental setups applied, stimuli used, and participants included, the authors concluded that the results of the review indicated that published listening effort studies lack consistency and standardization across studies, and have insufficient statistical power. Only the results from the statistical Sign test on the outcome of electroencephalographic (EEG) responses to acoustic stimuli as an assessment of listening effort indicated that hearing-impaired listeners show higher listening effort than normal-hearing listeners. Though the quality of evidence was moderate for the EEG data, the authors found the evidence to be of low quality in the dual-task paradigm studies and of very low quality in the Visual Analog Scale (VAS) and pupillometry studies.
      Van Engen and McLaughlin have reviewed the efficacy of using eye tracking and pupillometry to investigate cognitive effort during listening in many difficult situations [
      • Van Engen K.J.
      • McLaughlin D.J.
      Eyes and ears: using eye tracking and pupillometry to understand challenges to speech recognition.
      ]. Eye tracking utilizes the nature that people tend to spontaneously direct their line of sight to those elements which are most closely related to the meaning of the word currently heard. As to pupillometry, in general, the pupils dilate as cognitive tasks become more difficult. The authors summarized that eye tracking has proven to be an invaluable tool for studying communication challenges, and that pupillary responses in younger and older adults and in populations with hearing loss appear to indicate greater cognitive load as speech becomes less intelligible.

      3. Common cause hypothesis

      The common cause hypothesis assumes the existence of a common factor that is responsible for age-related deterioration in cognitive and non-cognitive processes, and proposes that age-related declines are shared across multiple and seemingly-disparate functions. According to this hypothesis, both hearing loss and cognitive impairment are the results of a common neurodegenerative process in the aging brain (Fig. 1B) [
      • Stahl S.M.
      Does treating hearing loss prevent or slow the progress of dementia? Hearing is not all in the ears, but who’s listening?.
      ,
      • Wayne R.V.
      • Johnsrude I.S.
      A review of causal mechanisms underlying the link between age-related hearing loss and cognitive decline.
      ,
      • Lin F.R.
      • Albert M.
      Hearing loss and dementia — who is listening?.
      ]. In its original conception, the hypothesis stated that sensory acuity can be an indicator of the physiological integrity of the aging brain [
      • Lindenberger U.
      • Baltes P.B.
      Sensory functioning and intelligence in old age: a strong connection.
      ]. In the development of ARHL, various functional and structural changes occur both peripherally and centrally, including degeneration of the stria vascularis, loss of hair cells and primary afferent neurons, and alterations of the central auditory pathways such as a reduction in neurons of the cochlear nucleus and changes in neurotransmitter release [
      • Tavanai E.
      • Mohammadkhani G.
      Role of antioxidants in prevention of age-related hearing loss: a review of literature.
      ]. Most cases of ARHL exhibit a mixture of these pathological changes occurring in the peripheral and central auditory pathways to various degrees.
      Both ARHL and dementia are multifactorial and heterogeneous. Risk factors vary and coexist. For example, the potential common etiological factors include microcirculatory insufficiency, general physical health, genetics, and oxidative stress.
      Cardiovascular disease and cerebrovascular disease are known to be dementia risk factors [
      • Livingston G.
      • Sommerlad A.
      • Orgeta V.
      • Costafreda S.G.
      • Huntley J.
      • Ames D.
      • et al.
      Dementia prevention, intervention, and care.
      ,
      • Snowdon D.A.
      • Greiner L.H.
      • Mortimer J.A.
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      • Greiner P.A.
      • Markesbery W.R.
      Brain infarction and the clinical expression of Alzheimer disease. The Nun Study.
      ]. Vascular brain injury, including stroke and microvascular infarct, not only leads to vascular dementia, but occurs more commonly in older individuals with Alzheimer’s disease (AD) than in those without AD. Additionally, a significant association between moderate to severe hearing loss and stroke was observed in older participants in a population-based survey [
      • Gopinath B.
      • Schneider J.
      • Rochtchina E.
      • Leeder S.R.
      • Mitchell P.
      Association between age-related hearing loss and stroke in an older population.
      ]. Vascular risk factors such as atherosclerosis, smoking, and diabetes have an impact on both hearing and cognition [
      • Livingston G.
      • Sommerlad A.
      • Orgeta V.
      • Costafreda S.G.
      • Huntley J.
      • Ames D.
      • et al.
      Dementia prevention, intervention, and care.
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      • Freitas P.
      • et al.
      Cardiovascular risk factors are correlated with low cognitive function among older adults across Europe based on the SHARE database.
      ,
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      • et al.
      Vascular health indices and cognitive domain function: Singapore longitudinal ageing studies.
      ,
      • Uchida Y.
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      Is there a relevant effect of noise and smoking on hearing? A population-based aging study.
      ,
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      • Sugiura S.
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      • Shimokata H.
      Diabetes reduces auditory sensitivity in middle-aged listeners more than in elderly listeners: a population-based study of age-related hearing loss.
      ,
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      • Sugiura S.
      • Ando F.
      • Shimokata H.
      • Nomura H.
      • et al.
      The impact of arterial sclerosis on hearing with and without occupational noise exposure: a population-based aging study in males.
      ,
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      • Bos D.
      • Ikram M.A.
      • Sabayan B.
      • et al.
      Coronary heart disease, heart failure, and the risk of dementia: a systematic review and meta-analysis.
      ,
      • Chang J.
      • Ryou N.
      • Jun H.J.
      • Hwang S.Y.
      • Song J.J.
      • Chae S.W.
      Effect of cigarette smoking and passive smoking on hearing impairment: data from a population-based study.
      ,
      • Gates G.A.
      • Cobb J.L.
      • D’Agostino R.B.
      • Wolf P.A.
      The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.
      ].
      Apolipoprotein E (APOE) is a gene strongly associated with neurodegenerative conditions. Although there are reports that the APOE ε4 allele, which predisposes a susceptibility to AD, is also associated with hearing loss, these data are inconsistent [
      • Kurniawan C.
      • Westendorp R.G.
      • de Craen A.J.
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      Gene dose of apolipoprotein E and age-related hearing loss.
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      • Mener D.J.
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      • Yaffe K.
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      • Helzner E.P.
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      • et al.
      Apolipoprotein E allele and hearing thresholds in older adults.
      ,
      • Dawes P.
      • Platt H.
      • Horan M.
      • Ollier W.
      • Munro K.
      • Pendleton N.
      • et al.
      No association between apolipoprotein E or N-acetyltransferase 2 gene polymorphisms and age-related hearing loss.
      ].
      The brain harnesses chemically diverse reactive species to perform heterogeneous signaling functions; therefore, the brain is susceptible to oxidative stress. A recent review article provided a detailed explanation as to why the brain is susceptible to oxidative stress [
      • Cobley J.N.
      • Fiorello M.L.
      • Bailey D.M.
      13 reasons why the brain is susceptible to oxidative stress.
      ]. Among a complex interconnected myriad of reasons regarding the brain vulnerability to oxidative stress, 13 of the reasons discussed in the review were unsaturated lipid enrichment, glucose, mitochondria, calcium, glutamate, modest antioxidant defense, redox active transition metals, neurotransmitter auto-oxidation, and RNA oxidation. As well, numerous studies have demonstrated that reactive oxygen species play an important microcirculatory role in auditory processing, and that mitochondrial DNA deletion (mtDNA) and subsequent cellular apoptosis play a main role in the pathophysiology of the inner ear and the central auditory pathway [
      • Tavanai E.
      • Mohammadkhani G.
      Role of antioxidants in prevention of age-related hearing loss: a review of literature.
      ,
      • Kamogashira T.
      • Fujimoto C.
      • Yamasoba T.
      Reactive oxygen species, apoptosis, and mitochondrial dysfunction in hearing loss.
      ,
      • Yamasoba T.
      • Lin F.R.
      • Someya S.
      • Kashio A.
      • Sakamoto T.
      • Kondo K.
      Current concepts in age-related hearing loss: epidemiology and mechanistic pathways.
      ,
      • Someya S.
      • Prolla T.A.
      Mitochondrial oxidative damage and apoptosis in age-related hearing loss.
      ,
      • Seidman M.D.
      Effects of dietary restriction and antioxidants on presbyacusis.
      ].
      In this hypothesis, hearing loss is thought to occur simultaneously with cognitive impairment as the result of a neuropathological cause; therefore, there is no direction of causality, with neither hearing loss nor cognitive impairment causing the other [
      • Stahl S.M.
      Does treating hearing loss prevent or slow the progress of dementia? Hearing is not all in the ears, but who’s listening?.
      ].

      4. Cascade hypothesis

      Aggravated peripheral hearing affects brain structure directly via impoverished sensory input (Fig. 1C). Animal studies have demonstrated that impoverished auditory signals and reduced stimulation from an impaired cochlea can cause brain neuropathological alterations [
      • Park S.Y.
      • Kim M.J.
      • Kim H.L.
      • Kim D.K.
      • Yeo S.W.
      • Park S.N.
      Cognitive decline and increased hippocampal p-tau expression in mice with hearing loss.
      ,
      • Xie R.
      Transmission of auditory sensory information decreases in rate and temporal precision at the endbulb of Held synapse during age-related hearing loss.
      ]. Human studies have also shown that ARHL is associated with smaller brain volume and that hearing impairment causes accelerated rates of brain atrophy [
      • Lin F.R.
      • Ferrucci L.
      • An Y.
      • Goh J.O.
      • Doshi J.
      • Metter E.J.
      • et al.
      Association of hearing impairment with brain volume changes in older adults.
      ,
      • Rigters S.C.
      • Bos D.
      • Metselaar M.
      • Roshchupkin G.V.
      • Baatenburg de Jong R.J.
      • Ikram M.A.
      • et al.
      Hearing impairment is associated with smaller brain volume in aging.
      ,
      • Golub J.S.
      Brain changes associated with age-related hearing loss.
      ,
      • Peelle J.E.
      • Troiani V.
      • Grossman M.
      • Wingfield A.
      Hearing loss in older adults affects neural systems supporting speech comprehension.
      ]. Cross-sectional studies have found that elderly individuals with audiometric-defined hearing loss have decreased volumes in their primary auditory cortex and/or total brain volume. Peelle et al. conducted two studies: a functional magnetic resonance imaging study examining the effects of hearing ability on neural activity and a voxel-based morphometry study examining the relationship between hearing ability and cortical brain volume [
      • Peelle J.E.
      • Troiani V.
      • Grossman M.
      • Wingfield A.
      Hearing loss in older adults affects neural systems supporting speech comprehension.
      ]. They found that individual differences in hearing ability predicted the degree of language-driven neural recruitment in bilateral superior temporal gyri (including primary auditory cortex), thalamus, and brainstem, and that there was a significant linear relationship between hearing ability and gray matter volume in the primary auditory cortex. The authors suggested that modulations of neural activity related to sensory loss appear to impact the resources required to perform higher-level cognitive operations, supporting a resource-allocation framework.
      Experience-dependent neuroplasticity is a fundamental property of the brain; therefore, for better or worse, the brain has the capacity to change in response to environmental stimuli and learning [
      • Kleim J.A.
      • Jones T.A.
      Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage.
      ]. The use-it-or-lose-it theory also applies to auditory signal processing. If one does not continue to use his or her listening and processing abilities, he or she might lose those abilities. It is considered to be plausible that peripheral hearing deterioration in the elderly plays a causal role in reducing gray matter volume in the auditory cortex [
      • Peelle J.E.
      • Troiani V.
      • Grossman M.
      • Wingfield A.
      Hearing loss in older adults affects neural systems supporting speech comprehension.
      ]. Furthermore, a “two-hit model (referred to as the ‘multiple hit’ or “sequential hit” model)” may exist in the brain, leading to less severe latent brain pathology (first hit) that is due to other causes (e.g., amyloid-beta accumulation, neurofibrillary tangles, and microvascular disease) [
      • Lin F.R.
      • Albert M.
      Hearing loss and dementia — who is listening?.
      ].
      In individuals with hearing loss, verbal communication failure can severely limit social integration, and a decrease in socialization is known to occur subsequent to social isolation [
      • Mick P.
      • Kawachi I.
      • Lin F.R.
      The association between hearing loss and social isolation in older adults.
      ,
      • Dawes P.
      • Emsley R.
      • Cruickshanks K.J.
      • Moore D.R.
      • Fortnum H.
      • Edmondson-Jones M.
      • et al.
      Hearing loss and cognition: the role of hearing AIDS, social isolation and depression.
      ], loneliness [
      • Palmer A.D.
      • Newsom J.T.
      • Rook K.S.
      How does difficulty communicating affect the social relationships of older adults? An exploration using data from a national survey.
      ], apathy [
      • Sugawara N.
      • Sasaki A.
      • Yasui-Furukori N.
      • Kakehata S.
      • Umeda T.
      • Namba A.
      • et al.
      Hearing impairment and cognitive function among a community-dwelling population in Japan.
      ], and depression [
      • Amieva H.
      • Ouvrard C.
      • Meillon C.
      • Rullier L.
      • Dartigues J.F.
      Death, depression, disability and dementia associated with self-reported hearing problems: a 25-year study.
      ,
      • Rutherford B.R.
      • Brewster K.
      • Golub J.S.
      • Kim A.H.
      • Roose S.P.
      Sensation and psychiatry: linking age-related hearing loss to late-life depression and cognitive decline.
      ,
      • Kiely K.M.
      • Anstey K.J.
      • Luszcz M.A.
      Dual sensory loss and depressive symptoms: the importance of hearing, daily functioning, and activity engagement.
      ]. Research indicates that perceived social isolation is a risk factor for poorer overall cognitive performance, faster cognitive decline, poorer executive functioning, increased negativity, and depressive cognition [
      • Cacioppo J.T.
      • Hawkley L.C.
      Perceived social isolation and cognition.
      ]. Depression and social isolation may mediate the relationship between hearing loss and cognitive impairment. These detriments related to hearing loss can cascade directly or indirectly, leading to cognitive impairment.

      5. Overdiagnosis or harbinger hypothesis

      One of possible mechanisms for the link between hearing loss and cognitive decline is overdiagnosis, in which degraded hearing, rather than cognitive function, impacts performance on certain neuropsychological tests. Accumulating evidence suggests that hearing loss could result in the overestimation of the level of cognitive impairment [
      • Dupuis K.
      • Pichora-Fuller M.K.
      • Chasteen A.L.
      • Marchuk V.
      • Singh G.
      • Smith S.L.
      Effects of hearing and vision impairments on the Montreal Cognitive Assessment.
      ,
      • Jorgensen L.E.
      • Palmer C.V.
      • Pratt S.
      • Erickson K.I.
      • Moncrieff D.
      The effect of decreased audibility on MMSE performance: a measure commonly used for diagnosing dementia.
      ]. Since verbal instructions or tasks that rely considerably on hearing are used during cognitive assessments, individuals with hearing difficulty are sometimes at a disadvantage. The selection of tests for cognitive measures that are heavily loaded for verbal skills is not appropriate for individuals with hearing difficulty; however, even when the response mode of a measure is nonverbal, instructions for tasks can be complex or difficult to perceive for the hearing-impaired. Any degree of hearing loss can affect functioning and test performance for neuropsychological assessments [
      • Hill-Briggs F.
      • Dial J.G.
      • Morere D.A.
      • Joyce A.
      Neuropsychological assessment of persons with physical disability, visual impairment or blindness, and hearing impairment or deafness.
      ]. One study examined the effects of simulated hearing loss on Mini-Mental State Examination (MMSE) scores in a sample of cognitively healthy young adults [
      • Jorgensen L.E.
      • Palmer C.V.
      • Pratt S.
      • Erickson K.I.
      • Moncrieff D.
      The effect of decreased audibility on MMSE performance: a measure commonly used for diagnosing dementia.
      ]. The results showed that reduced audibility significantly affected MMSE performance, and it was inferred that audibility alone could affect the diagnosis of dementia. Hearing-impaired individuals may be vulnerable to the overdiagnosis or even misdiagnosis of cognitive impairment despite having normal cognitive function (Fig. 1D).
      Testing of “central auditory processing” (CAP) may act as a harbinger of AD during the pre-symptomatic period (Fig. 1D) [
      • Gates G.A.
      • Cobb J.L.
      • Linn R.T.
      • Rees T.
      • Wolf P.A.
      • D’Agostino R.B.
      Central auditory dysfunction, cognitive dysfunction, and dementia in older people.
      ,
      • Gates G.A.
      • Anderson M.L.
      • Feeney M.P.
      • McCurry S.M.
      • Larson E.B.
      Central auditory dysfunction in older persons with memory impairment or Alzheimer dementia.
      ,
      • Gates G.A.
      • Anderson M.L.
      • McCurry S.M.
      • Feeney M.P.
      • Larson E.B.
      Central auditory dysfunction as a harbinger of Alzheimer dementia.
      ,
      • Idrizbegovic E.
      • Hederstierna C.
      • Dahlquist M.
      • Kämpfe Nordström C.
      • Jelic V.
      • Rosenhall U.
      Central auditory function in early Alzheimer’s disease and in mild cognitive impairment.
      ,
      • Swords G.M.
      • Nguyen L.T.
      • Mudar R.A.
      • Llano D.A.
      Auditory system dysfunction in Alzheimer disease and its prodromal states: a review.
      ]. Recent findings have shown that both peripheral and central auditory system dysfunction occur in the prodromal or early stages of AD. Hearing loss manifested as central auditory dysfunction, as investigated through methods such as dichotic listening tasks, can be a harbinger of AD. Dichotic listening tasks related to CAP reflect the everyday life difficulties experienced during comprehending speech in noisy backgrounds or competing speakers. Initial cognitive decline has been reported to be potentially concealed behind symptoms treated as hearing loss. Screening for peripheral and central auditory dysfunction, especially central auditory tests in at-risk populations, is recommended as a low-cost and effective means to identify precursors to AD pathology [
      • Gates G.A.
      • Anderson M.L.
      • McCurry S.M.
      • Feeney M.P.
      • Larson E.B.
      Central auditory dysfunction as a harbinger of Alzheimer dementia.
      ,
      • Swords G.M.
      • Nguyen L.T.
      • Mudar R.A.
      • Llano D.A.
      Auditory system dysfunction in Alzheimer disease and its prodromal states: a review.
      ].

      6. Conceivable effect of hearing intervention — consideration based on respective hypotheses

      Do hearing aids (or cochlear implants) beneficially affect cognitive function in the hearing-impaired elderly? Although this is a matter of concern from long ago, it is also a difficult theme to prove. The evidence demonstrating the impact of hearing aids on cognitive function is limited and inconsistent.
      Several randomized controlled trials (RCTs) have studied the impact of hearing aids on cognitive ability. During a 4-month trial period, Mulrow et al. conducted a follow-up for 188 participants who were identified as being hearing impaired through screening, and who were randomly assigned to receive either a hearing aid or join a waiting list [
      • Mulrow C.D.
      • Aguilar C.
      • Endicott J.E.
      • Tuley M.R.
      • Velez R.
      • Charlip W.S.
      • et al.
      Quality-of-life changes and hearing impairment. A randomized trial.
      ]. They found a small but significant improvement in cognitive performance, as assessed by the Short Portable Mental Status Questionnaire, in subjects who received hearing aids compared with those assigned to the waiting list.
      A large-scale randomized controlled interventional trial, called the Aging and Cognitive Health Evaluation in Elders (ACHIEVE), was initiated in November 2017 in the United States [
      • Deal J.A.
      • Albert M.S.
      • Arnold M.
      • Bangdiwala S.I.
      • Chisolm T.
      • Davis S.
      • et al.
      A randomized feasibility pilot trial of hearing treatment for reducing cognitive decline: results from the aging and cognitive health evaluation in elders pilot study.
      ]. The full-scale ACHIEVE trial is designed to follow 850 subjects for 3 years of follow-up to determine the efficacy of best practices for hearing intervention in reducing cognitive decline in hearing-impaired older adults. Since many studies using various approaches have been attempted with small sample sizes, unbiased evaluation in a fully powered trial is needed.
      The cognitive benefit of hearing aids was evaluated in 51 patients with AD over the age of 65 years in a multicenter double-blind randomized placebo-controlled trial [
      • Nguyen M.F.
      • Bonnefoy M.
      • Adrait A.
      • Gueugnon M.
      • Petitot C.
      • Collet L.
      • et al.
      Efficacy of hearing aids on the cognitive status of patients with alzheimer’s disease and hearing loss: a multicenter controlled randomized trial.
      ]. The primary endpoint was a change from baseline of the Alzheimer’s Disease Assessment Scale-Cognitive subscale after a 6-month period. No significant effect of hearing aid use was observed after 6 months of follow-up in 38 patients with AD and hearing loss.
      Cochlear implantation in elderly patients is difficult to investigate with a large sample size. A prospective longitudinal study performed in 10 tertiary referral centers in France evaluated cognitive function before, 6 months after, and 12 months after cochlear implantation in 94 patients between the ages of 65 and 85 years using a battery of 6 tests [
      • Mosnier I.
      • Bebear J.P.
      • Marx M.
      • Fraysse B.
      • Truy E.
      • Lina-Granade G.
      • et al.
      Improvement of cognitive function after cochlear implantation in elderly patients.
      ]. The authors reported that more than 80% of the patients (30 of 37) with the poorest cognitive scores before implantation improved their cognitive function 12 months after implantation, and concluded that hearing rehabilitation using cochlear implants in the elderly was associated with improvements in impaired cognitive function.
      A cross-sectional, but very large-scale, study was performed using the UK Biobank data set [
      • Dawes P.
      • Emsley R.
      • Cruickshanks K.J.
      • Moore D.R.
      • Fortnum H.
      • Edmondson-Jones M.
      • et al.
      Hearing loss and cognition: the role of hearing AIDS, social isolation and depression.
      ]. Associations between hearing loss, cognitive performance, social isolation, depression, and hearing aid use were analyzed using structural equation modeling with data from 164,770 adults between the ages of 40 and 69 years. Hearing aid use was associated with better cognition independent of social isolation and depression. The effect of hearing loss on cognition remained significant independent of hearing aid use, implying that the effect of hearing loss on cognition is only partly mediated through hearing aid use. Social isolation was associated with both poorer cognition and poorer hearing.
      Since age-related cognitive decline is a slowly progressing change, short-term evaluation is insufficient to assess whether a certain interventional strategy is valid in preventing cognitive decline. A few studies have investigated the long-term effects of hearing aids, with varying results [
      • Dawes P.
      • Cruickshanks K.J.
      • Fischer M.E.
      • Klein B.E.
      • Klein R.
      • Nondahl D.M.
      Hearing-aid use and long-term health outcomes: hearing handicap, mental health, social engagement, cognitive function, physical health, and mortality.
      ,
      • Amieva H.
      • Ouvrard C.
      • Giulioli C.
      • Meillon C.
      • Rullier L.
      • Dartigues J.F.
      Self-reported hearing loss hearing aids, and cognitive decline in elderly adults: a 25-year study.
      ,
      • Maharani A.
      • Dawes P.
      • Nazroo J.
      • Tampubolon G.
      • Pendleton N.
      • group S-CW
      Longitudinal relationship between hearing aid use and cognitive function in older Americans.
      ].
      One study, the Epidemiology of Hearing Loss Study (EHLS), assessed longitudinal data from adults from 48 to 92 years of age living in Beaver Dam, Wisconsin, USA [
      • Dawes P.
      • Cruickshanks K.J.
      • Fischer M.E.
      • Klein B.E.
      • Klein R.
      • Nondahl D.M.
      Hearing-aid use and long-term health outcomes: hearing handicap, mental health, social engagement, cognitive function, physical health, and mortality.
      ]. Individuals with hearing impairment but no hearing aids at the pre-baseline time point were included. A total of 666 subsamples of EHLS participants were assessed at baseline, five years prior to baseline, and five and 11 years after baseline. At 11 years post-baseline, there were no significant differences observed between the hearing aid users and the non-users in any of the cognitive tests. The rate of incident cognitive impairment during the 11-year follow-up was 11.1% for the hearing aid users versus 15.5% for the non-users. No statistical significant difference was observed (p = 0.49).
      The other report was a French epidemiological study called the Personnes Agées QUID (PAQUID) cohort, in which 3670 community-dwelling individuals aged 65 years and older were included [
      • Amieva H.
      • Ouvrard C.
      • Giulioli C.
      • Meillon C.
      • Rullier L.
      • Dartigues J.F.
      Self-reported hearing loss hearing aids, and cognitive decline in elderly adults: a 25-year study.
      ]. The association between self-reported hearing loss, hearing aid use, and decline in MMSE score over a 25-year follow-up period was assessed. Although hearing loss was significantly associated with a lower score on the MMSE and greater cognitive decline during the 25-year follow-up period, the cognitive decline of individuals who wore hearing aids was not significantly different from that of controls. The authors interpreted the findings as implying that hearing aid use attenuates the cognitive decline accelerated by hearing loss since elderly adults with hearing loss who used hearing aids had similar rates of cognitive decline as those with no hearing impairment.
      Another study was the Health and Retirement Study, which was part of the SENSE-Cog multi-phase research program in the United Kingdom. In this study, 2040 adults aged 50 years and older took part before and after using hearing aids [
      • Maharani A.
      • Dawes P.
      • Nazroo J.
      • Tampubolon G.
      • Pendleton N.
      • group S-CW
      Longitudinal relationship between hearing aid use and cognitive function in older Americans.
      ]. The association between hearing impairment and cognitive trajectories was investigated over 18 years. The authors reported that hearing aid use was positively associated with episodic memory scores, and that the decline in episodic memory scores was slower after using hearing aids than before.
      The results of these previous studies have not been consistent. It is unclear why it has proven difficult to verify that the use of hearing aids prevents the cognitive decline related to hearing loss despite a number of epidemiological studies showing evidence that hearing impairment is associated with adverse cognitive status. Consideration of the respective hypotheses for the potential causal mechanisms is shown in Fig. 1A–D.
      If the cognitive load hypothesis is valid, hearing aid use should reduce the effort required for auditory processing, thereby rendering diversion from cognitive tasks unnecessary, halting the progression of brain atrophy, and retaining cognitive resources (Fig. 1A). If the common cause hypothesis is valid, the development of cognitive impairment should progress independently from hearing intervention. Even when hearing aids are of great benefit in reducing hearing difficulty, the effect should not contribute to the prevention of cognitive impairment (Fig. 1B). If the cascade hypothesis is valid, constant input from the periphery should be retained with the use of a hearing aid. In accordance with the principle of experience-dependent plasticity, the lifelong ability for structural and functional brain reorganization should adjust to the changes in the external or internal environment, even in the mature adult brain [
      • May A.
      Experience-dependent structural plasticity in the adult human brain.
      ]. Restoring communication abilities may help to improve social interactions (Fig. 1C). It has been reported that one can prevent cognitive decline and delay the onset of dementia by maintaining strong social connections [
      • Hsiao Y.H.
      • Chang C.H.
      • Gean P.W.
      Impact of social relationships on Alzheimer’s memory impairment: mechanistic studies.
      ,
      • Qiu C.
      • Fratiglioni L.
      Aging without dementia is achievable: current evidence from epidemiological research.
      ]. Hsiao et al. reviewed the impact of social behaviors on the progression of cognitive deficit in animal models of AD and described a mechanistic scheme that explains how social isolation exacerbates cognitive impairment and how social interaction with conspecifics rescues AD-related memory deficits. Through cellular mechanisms and epigenetic regulation, AD mice can improve cognitive function if they are accompanied by and interact with conspecifics. The overdiagnosis hypothesis could represent reality to some extent. Through the use of hearing aids, accurate neuropsychological test performance becomes possible, and the risk of overdiagnosis or misdiagnosis can be reduced (Fig. 1D). With respect to the harbinger hypothesis, the question of whether hearing intervention has the potential to delay the development of dementia requires further investigation.
      Mixed dementia is a condition in which abnormalities characteristic of more than one type of dementia occur simultaneously. It is said that the frequency of mixed dementia may be underestimated [
      • Korczyn A.D.
      Mixed dementia — the most common cause of dementia.
      ]. Postmortem studies have revealed that the brains of the elderly commonly exhibit extensive co-occurrence of multiple pathologies such as arteriolosclerosis, Alzheimer pathologies, hippocampal sclerosis, Lewy body pathology, and cerebral amyloid angiopathy [
      • Qiu C.
      • Fratiglioni L.
      Aging without dementia is achievable: current evidence from epidemiological research.
      ]. Additionally, among the hypothetical mechanisms, there may be multiple that apply to an individual. The hypothesis that multiple mechanisms are mixed at various ratios for each individual is shown in Fig. 2. Demonstration of the cognitive benefits of hearing aid use could be complicated by such heterogeneity.
      Fig. 2
      Fig. 2The hypothesis that multiple mechanisms occur at various ratios for each individual.

      7. Conclusions

      While life expectancy has been extended on a global scale, the burden of hearing loss and dementia has become higher than ever. Multiple epidemiological and basic science studies have shown evidence that hearing loss is an independent modifiable risk factor for the development of cognitive decline and dementia. The beneficial effects of hearing aid use on cognitive function are likely modest; therefore, it is necessary to confirm the effects through further investigations that involve larger sample sizes and long-term observation. We should continue to strive for social enlightenment towards the importance of ‘hearing well’, and cultivate a necessity for hearing screening among patients at risk for cognitive decline.

      Disclosure statement and funding

      This work was supported in part by the Japan Society for the Promotion of Science KAKENHI (grant number 26502016 ); the Research Funding for Longevity Sciences from the National Center for Geriatrics and Gerontology, Japan (grant numbers 28-2 and 28-40 ); the Japan Agency for Medical Research and Development ( 18dk0310085 ); and the Ministry of Health, Labour and Welfare of Japan (grant number Special Research H29-015 ).
      The funding sources had no role in the study design, conduct of the study, writing of the manuscript, or decision to submit for publication.

      Acknowledgements

      The authors sincerely thank Dr. Akinori Nakamura and other brain scientists at the Department of Clinical and Experimental Neuroimaging, National Center for Geriatrics and Gerontology, for advice and expertise on earlier versions of the manuscript.

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