Listen Up! The Connections Between Hearing Loss, Hearing Interventions and Cognitive Decline

Transcript

Intro: I’m Dr. Nathaniel Chin, and you’re listening to Dementia Matters, a podcast about Alzheimer's disease. Dementia Matters is a production of the Wisconsin Alzheimer's Disease Research Center. Our goal is to educate listeners on the latest news in Alzheimer's disease research and caregiver strategies. Thanks for joining us.

Dr. Nathaniel Chin: Welcome back to Dementia Matters. Today I'm joined by Dr. Frank Lin, director of the Cochlear Center for Hearing and Public Health and professor of otolaryngology, medicine, mental health, and epidemiology at Johns Hopkins University. Dr. Lin's research has established the association of hearing loss with cognitive decline and dementia and has served as the basis for the 2020 Lancet Commission on Dementia's conclusion that hearing loss is a leading modifiable risk factor for dementia. Today he joins us to talk about the NIH-funded Aging and Cognitive Health Evaluation in Elders study also known as ACHIEVE – very clever – which he serves as the co-principal investigator on. In July 2023, Dr. Lin published his study in the Lancet, which investigated whether treating hearing loss through different hearing interventions could reduce the risk of cognitive decline and dementia in older adults. So Dr. Lin, welcome to Dementia Matters. So to begin, what made you interested in studying modifiable risk factors for dementia, but especially hearing loss?

Dr. Frank Lin: You know Nate, this all began like, I don't wanna go too far back, but you know I did my residency in ENT surgery many, many years ago, and then at that time I had always had a large bent toward public health. Both my parents are public health researchers. I always liked surgery because you get something done and it was a lot of fun, but as I went through my residency though, I'll tell you one clinical observation which always jumped down at me more than anything else, was that if I showed you or you saw an audiogram and it showed basically a mild to moderate loss, which is not uncommon, but that audiogram belonged to an eight year old – let’s say an eight year old girl – that would be critically important. You gotta address it, most insurance companies will cover it. All of a sudden, you scratch off like Annie and now she's not eight and now she's 88. All of a sudden it's met with a collective shrug saying like, “Oh yeah, you have a mild to moderate hearing loss. You know, Annie, you could do something about if you want.” That always jumped out at me as a huge, well massive, clinical paradox. How could the same physiologic impact on hearing be critically important for an eight year old but not for an 88 year old? Part of that was guided, too, by my grandmother. My grandmother had early adult life hearing loss related to streptomycin . She got streptomycin many years ago, so she always has lived with essentially a more marked hearing loss than other people would, but I always grew up with her and I always understood, I saw, witnessed the impact that it had like on her daily life, her daily conversations. I couldn't help but think that that same Annie, eight-year-old audiogram, and my grandmother, how could it not be important and yet the research was never – well I should say the clinical impression was always that it meant nothing. As I delved a little deeper into it and developed some collaborators at the National Institute on Aging and at Hopkins, where I'm based, they’re like,  “You know Frank, you're right. There's actually just not any research on it,” right? It's just an empirical clinical guess, probably because it's so common, hearing loss, but there actually wasn't any research on it.

Chin: Well, I appreciate hearing that story. It’s always fascinating to me how these different parts of your life and your identity come together and then you asking these questions and not getting the responses you need and then, there you go, that's the beginning of your career path.

Lin: And I'll tell you at the same time, Nate, the person I met actually around this time just through a little bit of luck, a little bit of serendipity, is Luigi Ferrucci. Luigi Ferrucci is now the scientific director of the NIA. Back then when I was still with residency, he was the director of the Baltimore Longitudinal Study of Aging at the NIA and we connected because his next-door neighbor happened to be one of my mentors. He's an ophthalmologist, epidemiologist and David Freeedman, my colleague, said, “You know, Frank, you would really benefit from just bouncing some ideas off Luigi”. I was like, “Okay”. [Laughs] So I met Luigi and that's where this all began. I mentioned to him at that point, there was actually – this is crazy to say this – in 1988 or 89, there was a case-control study published in JAMA so classic, bread-and-butter epidemiology, a case-control study of hearing and dementia published in JAMAublished in JAMA1989 showing a dose-dependent relationship between greater hearing loss severity and odds of dementia. From 1989 until when I came across the paper in 2009, nothing had been done. No further research. I mean, you just put in Google Scholar, people cite it, but there's nothing done. Yet, everything would point toward giving a case-control study at the lowest level of sort of epidemiologic evidence. What do you do next? You do a longitudinal study, you go from there, blah, blah, blah, blah. It was never done and I think I had to do a lot with these silos. You know, for me, I'm an ENT surgeon. I know everything about hearing and now I understand a lot about dementia. Back then I understood a little bit, I entered into public health, I had done my PhD at the School of Public Health, but people weren't thinking about that, and people in the dementia, neurology space understood nothing about hearing, right? So it's a classic effect of silos, and it just happened that I was able to bridge that silo with Luigi, who was interested in collaborating, and I was interested in collaborating. Then the rest is sort of the last 15 years of my life actually.

Chin: For background for our listeners though, what is this relationship between hearing loss and cognitive impairment? You talk about a study from the 1980s. What have the studies shown?

Lin: Yeah okay, so going back to that JAMApaper from 1989 or 1980 by Uhlmann and colleagues. It showed, again, hearing as measured with an audiogram. Basically how loud do sounds have to be for you to hear. It's just like a classic clinical measure, just gives you an idea of the function of the inner ear. They found a dose-parallel relationship between greater hearing loss and the odds of dementia, but it’s a case-control study. What the track of research that I began around 2010 in collaboration with Luigi Ferrucci and colleagues at the NIA was beginning to look at that in deeper depth using longitudinal studies, right? So next step, longitudinal study, observational studies of older adults beingfollowed for many many years. In the BLSA, the Baltimore Longitudinal Study of Aging, one of the longest ongoing studies of aging in the United States funded internally by the NIA, coincidentally they had measured hearing on their participants in the early 90s. They did it for a few years until – I'm not joking – the booth broke, the audiometer broke, and they said, “Ah no, one's using the hearing data anyway, let's just stop doing it,” right? But for four years they had very good hearing data. And then, coincidentally – not coincidentally – a big feature of the BLSA study is to focus on aging, especially neurological outcomes, so they had adjudicated dementia diagnoses as well, tracked longitudinally with people followed every two or three years. So the analysis – I got to tell you – is just simple. We did an analysis of looking at baseline hearing, looking at the risk, basically the hazard of incident dementia over time, adjusting for and controlling for age and sex and diet– pretty much any other confounder you could think of we adjusted for. And we saw in that study, which was published in 2011 – back when it was Archives of Neurology, now it's called JAMANeurology – no surprise compared to the case-control study, a dose-dependent effect between greater hearing loss and the risk of being diagnosed with dementia over time. And I say dose-dependent because it was market. It was basically, compared to people with normal hearing, people with a mild, a moderate, or severe hearing loss basically had a twofold, a threefold, and a fivefold increased hazard or risk of dementia. Those are huge risk estimates, as we all know. I'll be honest, when Luigi and I first saw this, it was sort of like an exciting, but “oh no” sort of moment as we’re saying, “Do we really believe this?” right? But you know we did all the sensitivity analyses and it all held up no matter what we did with analyses. It was published in JAMA Neurology, Archives of Neurology back then, in  2011. We were a little guarded about it actually, like “What's gonna happen?”. As you know the hallmark of good science though, Nate, is just replication, replication from people who you don't know at all. So then a year later in Neurology, John Gallacher's group in Oxford, they realized their longitudinal study also had had hearing measured at some point too and and never looked at risk for dementia. They did the exact same analysis basically as us. Lo and behold, same set of results. Since then, it’s been replicated multiple times, so that is a relationship. I guess the next question – I hope you're gonna ask Nate but maybe I’ll ask for you – is why, right? I mean, so what gives here? This is what I spent a lot of my time in 2010 literally going through Psychology and Neurology and books going back all the way back to the sixties. Really thinking about, there were some hypotheses proposed in the original Uhlmann paper from 1989, but they weren't really – it wasn't really thought of that well yet. I basically took a deep dive into it. From my perspective coming at it from, I understand everything about the ear and how the brain processes sound, I did a crash course and really getting a deeper dive with Luigi's help and Susan Resnick’s help looking into dementia and dementia disorders and things like that. And ultimately we – and also with Marilyn Albert, working with her at the time – we hypothesized an initial paper and subsequently sort of codified, a little later in a broader theory-based paper, sort of the three major mechanisms now, which I think probably are well established now – well accepted, I should say – of being the three major mechanisms to which hearing loss increases dementia risk and cognitive decline. The first mechanism gets at the idea of cognitive load. What I mean by that is when you have impaired hearing, what it basically means is that it's not that you can't hear, it's just that your ear is constantly sending a much more garbled signal to your brain because the ear has been damaged progressively. The ear is post mitotic, so it doesn't matter who you are, everyone's hearing gets worse gradually over your lifetime. If the brain is constantly receiving a much more garbled signal from the ear, what essentially has to happen – we know this from the auditory literature – the brain actually reallocates resources to help with hearing. It's like you're constantly shuttling more brain resources to dealing with a much more garbled sound and, in turn, the understanding is that, colloquially, it comes with expense for thinking and memory. But why? The thought there is not so much that hearing loss causes dementia, but hearing loss taps into the cognitive reserve that otherwise could have been used to buffer against amyloid neuropathology, that could have been buffered against microvascular pathology. But that buffer that we all know exists at cognitive reserve, which we know exists many ways, it constantly taxes and taps that buffer. And then, I'll tell you, that goes beyond just theory now. You actually see this on FMRI Studies. You see resource allocation, people even with a mild hearing loss basically using parts of the frontal lobe for auditory processing, which you normally do not need to use, and yet you're seeing that with hearing loss. It's not so much that hearing loss causes dementia, but hearing loss leads to much earlier phenotypic exposure to dementia because you're tapping into that reserve that otherwise could have buffered against known demential pathologies. So, that's one mechanism. The second mechanism – it's interesting because it sounds similar but it's actually completely different and there's actually a line of evidence for this too. It's the idea that auditory deprivation, an impoverished auditory signal sending to the brain, actually does lead to trophic effects on structural atrophy of the brain. And we see this. Actually it's interesting, you can do animal studies. You can section a guinea pig's hearing or give it hearing loss and you actually see the section pathologically, months later, the effects it has on the brain, actually structural loss. You see this in human studies in terms of longitudinal MRI scans, so we've done this in the BLSA and other studies now. You follow a cohort of older adults, people 50, 60 and plus. You see who has hearing loss, who doesn't in the beginning. You'll get their brains in the beginning, not much difference in size cross-sectionally, but if you follow them longitudinally what you see is accelerated rates of atrophy, particularly over the lateral temporal lobe among those with greater hearing loss versus those with normal hearing. Now, again, it gets to the idea maybe very much – I shouldn't say colloquially use or lose it, but in a way auditory deprivation leads to structural atrophies. So that's a second mechanism. Sounds similar but it's actually different, because that second mechanism really implies actually that hearing loss is quote, unquote, possibly directly damaging the brain in terms of its structural integrity, right? The third mechanism is going to be the most intuitive for almost anyone. It's the idea that if you can’t hear well, you may not go out as much. You may not participate as much in conversations. You may not participate as much in cognitively stimulating activities. I mean sounds like common sense, but if you really believe that, I mean, I think many people would agree and the literature is still little all over – I shouldn’t say all over the place, but the logic is inconsistent. No one knows the exact mechanism, but participation in cognitively stimulating activities, social activities, let's just say it's good for the brain. So in the end, it's three mechanisms, none of which are mutually exclusive. It's likely a combination of all three now. What we never knew with these hypotheses in place though is does it actually reflect distally and actually rates of cognitive decline and dementia. And if you believe epidemiological literature, it sure does. I mean to the two now – you mentioned in your really kind introduction the Lancet Commission on Dementia. Out of all known existing potentially modifiable risk factors – I mean theoretically they classify both in their 2017 and their 2020 meta-analyses that hearing loss is singlehandedly the single largest, potentially modifiable risk factor for dementia, purely because of many ways of the risk ratio between hearing loss and dementia in the literature, but also because hearing loss is so common, right? I mean the prevalence of hearing loss doubles with every age decade. By the time you look at seniors 65+, two thirds of everyone over 65 has a hearing loss. It's all of us, right? It's not only a risk factor that is really common, but the risk ratios are large as well.

Chin: You know it's funny, Frank, because I usually will ask researchers, “What's the mechanism?” and there's a lot of pause, because people are very careful, “Well I can't promise” like “It could be this,” but not you. You feel very confident and it all makes sense to me. So, you've given us a lot as background in context. Can you then explain to us, what is the ACHIEVE study that you did? What groups of individuals were you studying? What were you measuring?

Lin: Yeah, thanks Nate. You can imagine all these observational studies to date now I've mentioned before, fairly consistent across studies, greater hearing loss associated with the increased risk of cognitive decline and/or dementia, depending on what the studies measure. A natural corollary to that then as well, does that mean is this just a theoretical like academic tidbit, or does it actually mean, at the population level or the individual level, if someone quote, unquote treated their hearing loss, does that reduce risk of cognitive decline or dementia? That is by no means guaranteed, right? Because when you quote, unquote treat hearing loss with a hearing aid and associated audiological support services, you're not reversing the hearing loss. That hearing loss is still there. I mean, it is a rehabilitative intervention. There is still damage to the cochlea. The cochlea is still sending an impaired signal to the brain. It's just that with a hearing aid and using it well and learning how to use it, you're providing a clear auditory input which can lessen that burden on the brain. Does that actually transfer across, and does that reduce risk? I mean, it’s such a basic question. Okay, hearing loss is related to cognitive decline and dementia, but if you treat it with our existing interventions does it actually reduce risk? Before the ACHIEVE trial – which I’ll get to in a second – we can never answer that because observational studies – you could actually look at these studies. About 20 percent of people on average use hearing aids who have hearing loss and you can look at that data. Do they do better than people who don't use hearing aids? I never talk about this, and I never show it in the papers. They actually do for the most part, right, but you can't believe it though, right? Because you can imagine people who have hearing loss who use hearing aids versus those with hearing loss who don't use hearing aids, they're completely different people, right? People who get hearing aids, they are healthier, they are wealthier, they're more health-conscious, right? All of which would bias toward a positive effect, so certainly you can't contribute causation with intervention from observational study. So, the ACHIEVE trial was a definitive – essentially you can call it technically more of a phase three, this is not a pharmacologic study. It was designed to be a definitive study looking at whether hearing intervention – basically hearing aids and associated audiological support services – does that, versus an education control intervention – basically a general health education control intervention – does that reduce rates of cognitive decline, global cognitive decline, over a three-year period in older adults. These are specifically older adults in the study. The inclusion criteria was 70 to 84-year-old older adults; cognitively intact, basically they have a certain threshold Mini Mental score non-indicative of dementia; and they had to have a mild to moderate level of hearing loss. For t perspective, that is about 50 percent of people – five zero people – 70 to 84 would have that level of hearing loss. This is not extreme. The majority of people have that level of hearing loss. The trial is fundamentally – they got randomized, half got hearing intervention, half got educational control. They were then followed semi-annually with an annual battery of a 45-minute neurocognitive battery, and we looked at rates of cognitive decline. The trial itself was pretty unique. We partnered actually with an existing study called the ARIC study, or the Atherosclerosis Risk In Community studies. This is a study that's been funded by the NHLBI, the Heart, Lung and Blood Institute. It's a very long-standing, observational epidemiologic study. It started thirty-five years ago looking at midlife older adults back then followed to the present day, just looking at how midlife vascular risk factors contribute to late-life vascular disease, basically cardiovascular events. These 16,000 people initially have been followed for almost thirty-five years at four different sites across the country. David Knopman is part of that study. For the last ten years it’s transitioned more to a cognition study. This ARIC study was based off of just a random sample of older adults 30 years ago, been followed to the present day, represent just a general population now at this point with attrition. Fortunately in ARIC though, they have all these protocols. They had the cognitive testing protocols, dementia adjudication overseen by Marilyn Albert and David Knopman, so nesting the trial within there was great. The ACHIEVE trial was based within the ARIC field sites, and then for the ACHIEVE trial we shared a lot of the same existing testing protocols. About a quarter of the nearly thousand people who were recruited to the trial were recruited directly from ARIC. Basically people who were already being followed by ARIC for over 30 years, we saw their hearing, because they were being tested already as part of ARIC's study, and we said, “Hey you could be in the study. Do you want to join?” And they said, “Yeah sure why not, I’ll join the study”. So about a quarter of people came from ARIC participants. The other three quarters of people we basically recruited from a healthy de novo cohort – people who respond to Facebook ads about a study on cognition, aging, and health; eople respond in registries; people interested in cognition studies, and things like that. So two different study populations. One population from ARIC, probably represents much more of a general population. The healthy volunteers, de novo group, representing really… I would say the worried well, in a good way. These are healthy community volunteers interested in an aging study. When we did the trial they are all – nearly thousand people – were recruited from 2018 to 2019. Fortunately, everyone got recruited and randomized before the pandemic hit. They were randomized through hearing intervention versus the education control and then they were then followed for three years with annual measures. This is a global neurocognitive battery that we've been using in ARIC for the last ten years, developed actually originally by David Knopman, Tom Mosley, Marilyn Albert and a bunch of other people involved with ARIC study. We had the last three-year visit at the end of 2022, about three to four months for database lock. We finished database lock in April of 2023. We had the initial trial readout in April 2023. We submit our results to The Lancet mid-June 2023, and it was accepted and published a month later. It's a crazy timeline, it was a hectic few months. Yeah, so it's fundamentally a pivotal – technically I guess you could call it Phase 3 in a way – Phase 3 clinical trial looking at, does treating hearing loss reduce cognitive decline?

Chin: The timeline in the story is fascinating, Frank. And so you're kind of leaving this teaser for our listeners, and I appreciate that from an artistic standpoint. So what did you find?

Lin: Alright, so what do we find? In the primary analysis, which is including everybody in the ARIC cohort and the new, we analyze them all together. Drum roll… no effect of hearing intervention. The three-year rates of global cognitive decline between hearing intervention versus control, basically the same.I'll be honest, I still remember the moment I saw the initial trial read out results in mid April,  and I can't say the word on air but it was like an, “Oh eff” moment. [Laughs] It was like, “Oh god what do we do?”. But – and this is the big, big, big but – one of our pre-specified other analyses that always was pre-planned was that we would replicate the primary cohorts, the primary analysis of global cognitive decline, in the ARIC cohort and the de novo cohort differently because we realize that these two cohorts may be very, very different. That's where the fun stuff is. In the ARIC cohort, you see over three years – statistically significant by far – nearly a 50% reduction in global cognitive decline over three years. In the de novo cohort, over three years hearing intervention was no different. So like, why? Well this, in 20/20 hindsight, makes complete sense. The de novo cohort over three years, the control group, basically had no cognitive decline, right? Because – and it makes sense – these were the healthy volunteers. If you have a healthy volunteer who joins a cognition study, they don't have cognitive decline because they’re too healthy. In three years they really had literally, when I say no cognitive decline, they declined by about 0.15 standard deviation units, so not much. Lo and behold, if the hearing intervention is predicated on reducing cognitive decline, you can't reduce something that's not really declining. In contrast, in the ARIC cohort, the control subjects had about nearly a threefold faster rate of cognitive decline over three years than de novos. They basically had about a 0.4 standard deviation effect size change over three years, which is a lot. 0.5 standard deviations is a lot and they change 0.4 standard deviations over three years in the control group. Lo and behold, in that ARIC cohort with the hearing intervention you see about 50 percent reduction in cognitive decline. I mean, it's really, really stunning, right? So yeah, in the combined cohort, nothing. It was basically the de novos masked everything, right? Actually it's interesting, there are two thoughts. Why do the de novos not decline over three years? One clear thing is that they're likely, honestly, the worried well. These are like high-level people who respond to Facebook ads about cognition and, no surprise, three years they don't decline very much, right? So that's one. And if you look at baseline demographic factors between ARIC versus de novos, de novos had higher education, higher income, lower rates of hypertension and lower rates of diabetes, right? Their baseline cognitive scores were higher than the ARIC’s right? So this all glides in that direction, that all makes sense. Another reason which is really interesting, Nate, that came up a lot when we presented these results of the Alzheimer's Association meeting in Amsterdam was the fact that the de novo cohort was essentially a cognitively-testing naive cohort. As we all know, it has been shown in many, many studies there are true practice effects of cognitive testing that sometimes pan out three to four years later. How much of actually very little cognitive decline over three years – I think 0.16 standard deviation unit change over three years – is somewhat because these people are still getting better at cognitive testing? In contrast, don't forget ARIC with not only their slightly higher risk factors – these people have been followed over 30 years who get routine cognitive testing every one to three years. I mean, you're not – I assume – you're not seeing practice effects anymore after 30 years. What you're observing ARIC may be just much more a true rate of cognitive decline. These are not benefiting from practice effects anymore, whereas de novos could be a combination. They honestly were healthier and had a better cognitive baseline but how much are they still benefiting from practice effects too?

Chin: Right? I think that's a good point, and the fact that you had more of the de novo in your combined group than you did the ARIC.

Lin: Oh yeah, yeah. The de novo, I mean it was like seven or eight de novos to roughly 240 ARICs, right? What's actually really crazy too is that with only essentially 240 ARIC participants that you're seeing that strong of an effect size of just a three-year cognitive change. That even makes it even more impressive, right, that you're seeing a relatively – well it's not small but it's not huge. Even if you had 10,000 people, you look at the treatment effect and it's like, “Oh that's great, but is it really that meaningful?” That's honestly the only reason it’s statistically significant because the 240 is big – it's not that big – but the effect size was large. I mean 48 percent reduction is nothing to sneeze at, right? Another thing I’ll add too which is really interesting too, Nate, that this is brought up by Tom Mosley, who's one the coinvestigatstors. He works at the University of Mississippi and leads the MIND Center there. He found it really personally scientifically compelling too, that the ARIC participants are the ones at greatest risk, right, and yet you're still seeing a benefit because how often do we see interventions where it’s too little, too late for a group, right? The other interesting thing too is that one measure we did at baseline is something called – it's a terrible name – it's called the Hearing Handicap Inventory. It's basically a self-reported scale of communication impairment, right? So Likert scale, “Do you struggle when you go to restaurants?”, “Do you feel embarrassed when you go out in a large group?”, so it's a self-reported communication scale. If you look at those scores at baseline, what's really interesting is that among the ARIC and the de novos at baseline they basically had similar levels of objective hearing. There’s this thing called the Pure Tone Average, about 40, which is the mild to moderate range. They're basically identical; both groups are I think 39.8 and 39.6, but the same levels of objective hearing. But the de novos actually had a much higher level of communication impairment at baseline, and that makes sense. If you're joining a hearing and aging study, you're probably joining it because you wanted free hearing aids so it made sense. Whereas the ARIC participants, their hearing handicapped scores are actually much lower. They're at the level where typically those people you wouldn't think would even want to come in for a hearing aid. Honestly I think they wouldn't, only because they joined the study because they’re already in this other study. The reason I'm saying this is the fact that people who wouldn't even want to come in for hearing aids, who weren't even really noticing that they were having communication issues, were the ones who benefited from this intervention. It sort of blows my mind because it actually guides public health strategies. If you're saying, “Okay just nowadays if people come in and need a hearing aid, we'll pay for it for them,” right? You actually can't go by that strategy in a way. It's almost like you have to reach out to people and say, “Listen, even though you don't feel like you have any problems, your hearing level objectively is at a level where you could possibly really benefit”. So there are a lot of little nuggets here that we’re even just still teasing out.

Chin: It's interesting to think that your initial reaction was one of “Oh no” to like “Wow, look at what we continued to find with this treasure trove of data and the benefit that people actually are experiencing”. And so then as a physician scientist, what does this mean for you when you think about hearing aids as an intervention not only for hearing loss, but as an intervention to prevent dementia in some individuals?

Lin: Well, so dementia as you know is not that common. In the ACHIEVE trial, even though we have adjudicated dementia, there was no effect of three years. No surprise, I mean there are only like a total of 15 cases. There are actually – I think there were fewer cases in the hearing intervention group, but I mean it's like five versus nine and mean nothing to write home about. There are not that many. Clearly, hypothetically if you're reducing cognitive decline you’d think that would carry residual effects to reduce dementia onset many years down the road. That's going to be hard to ever figure out though. What I mean by that is actually the ACHIEVE trial, now that we're finished with the three-year follow-up we've actually – very generously courtesy of the NIH – it's being funded for another three years of follow-up. So we’ll have long term six year results as well too. Maybe we'll be able to answer that in six years because there'll be more cases accruing over the timeline, but I don't know if we ever have the numbers to sort of look at dementia. I mean, fortunately dementia is relatively a rare event in a good way, right? That the definitive evidence of whether treating hearing loss can reduce dementia risk, that I think would be – I mean most dementia trials – don’t forget, for not in a rich cohort for amyloid or anything like that or MCI. Those are two, three, four thousand person studies that really get those numbers and we do not have that in ACHIEVE, so I don't think we'll have a hard outcome of dementia because the numbers will never be there to – going from primary prevention all the way to dementia is really, really hard, right? This is not in a rich population for any people at risk of cognitive decline or dementia at all.

Chin: But at least this study and the data you're talking about, it shows evidence for clinicians to tell their patients, you may benefit from this or there's a 50 percent reduction here in thinking changes later on. I mean, this is going to help people.

Lin: Yeah, yeah, no absolutely, Nate, and I think we can't forget the singular thing here. Hearing interventions, I mentioned, yes without a doubt I think that ACHIEVE trial really shows there could be a very strong way of reducing cognitive decline. Don't forget the whole issue of treating hearing loss in the very beginning is like so you can communicate with mom or dad better or your kids better. You might be a little more active in conversations and all the, let's say, very proximal stuff. Think of that and then yes, distally that has cut care of effects. I mean and fortunately hearing intervention is about as no risk, or low risk. I mean I really can't think of a risk of using hearing aids [laughs] or anything like that, right? I mean maybe – I don't know – I mean theoretically I guess you can give you some ear irritation but it's a no risk intervention, right,hat only has positive upsides, right? It's funny and a lot of people brought this up at the AAIC meeting and I didn't want to answer it because a lot of AAIC now – there's a lot around amyloid-lowering agents, right? Amyloid therapies and there's new results presented there and it really is exciting. I mean, it's really an example of just really good understanding from basic biology, drug development and trials, right? As we all know those therapies are not without risk. So people kept on asking, “Well Frank what do you think about that?” andI'm not touching that with a ten-foot pole. [laughs] But it is – in terms of a no risk intervention that only has carryover benefits on just socialization and communication and, oh yeah, it could confer 50 percent reduction in cognitive decline – it does seem to be a no brainer if you ask me, right? Because, I mean, what is the downside? I don't know. Okay actually, I'll tell one downside and we can go in this way but we don't have to. This is outside the purview of this podcast but it's how I spend a lot of my time now. There's cost. They're bloody expensive, right? That's something years ago, I began working with Congress and the White House National Academies. We got a law passed actually six years ago now, went into effect last year now as some people may realize. Hearing aids are officially over-the-counter in the United States, but it's just the tip of the iceberg. The big companies that are likely planning to enter this space, the big consumer tech companies who could really innovate – these companies like Samsung or companies like Apple – they have not entered yet, but if you look at news reports it's only a matter of time. So that changed the dynamics very quickly of pricing, accessibility, appeal, innovation of hearing technologies that we’re just beginning to see now. Over the next few years, I think you're gonna see a ton of really exciting innovation, accessibility around hearing devices. I mean, tongue and cheek, but are those Airpod Pros you’re wearing or are those hearing aids? Well they could be one and the same, right? I think that makes it very exciting because I think one real risk actually is well “Frank, costs,” right? But I think that is going to be changing very dynamically in the next few years.

Chin: And Frank, you alluded to what my last question is going to be. In this podcast we talk a lot about prevention, avoiding things that are probably negative for our brain. It's a two part question. One, because of the work you do, how careful are you about your hearing? Do you go to concerts, for instance? Do you avoid loud noises?

Lin: [Laughs] Yeah, yeah

Chin: But then really my question for you too is, what do you think of in-ear headphones? You brought up Airpods Pro – and I have nothing for or against Apple – but what do you think about people wearing these devices that are right next to their eardrum?

Lin: Yeah, great questions. I'll answer your more immediate question first. You're younger than me, Nate. I can clearly tell, right? They've been saying this since the early 80s with a Walkman – remember the Sony Walkman? I don’t know if you guys remember that. People have been, all the auditory scientists have been clamoring about this. “Oh my god! everyone's going to go deaf with their Walkmans!” and blah, blah, blah, blah, right? It hasn't happened, and what I mean by that is the Walkmans of forty years ago are far worse than this current generation because back it was an analog device. You could turn that sucker as loud as you want to, right? Every pair of wireless earbuds now function on a digital platform. Yes, you could theoretically turn it way up, but the control settings are much much better now. More importantly, from that whole era of the – actually let's look at the data. The actual data really hasn't borne out. If you look at population prevalence risk estimates of hearing loss in, let's say 40-year-olds nowadays, 30 years after – or maybe 50-year-olds now is, you know, 30 years after Walkmans came out – versus a generation ago. They're really no different. I mean, maybe very, very, very subtly, at best. The reason why it is though, right, is because it doesn't matter who you are, right? Everybody's hearing begins monotonically declining, right? Steady state decline over your entire lifetime beginning roughly you’re age twenty because your inner ear is postmitotic. It does not regenerate. So over a lifetime of noise exposure, aging, genetic susceptibility, everyone loses some hearing. So, yes noise – especially workplace industrial noise, gunfire noise, those big things – that make a difference. Airpods, walkmans, subtly, probably to some degree too, but maybe not actually, right? It's a different order of magnitude than like a generation ago with artillery noise and gunfire noise and factories, right? I don't think it's really being borne full out by the literature. Subtly maybe, but how much does that compare with everything else that affects your hearing of your lifetime? Aging, cardiovascular risk factors which can affect your hearing too. It's probably a relatively small drop in the bucket. It's definitely not good for you, but is it – I think it's probably relatively a drop in the bucket's contribution. I don't put much in store by that necessarily of risk per se. And besides even if it was like what are you going to do about it? Tell my daughter not to use her Airpods? I mean, like let's just get on with it and say we can say all we want but society moves on and lets just like deal with it, right? Your other point about just personal prevention, no that is real. And I shouldn't pooh-pooh it too much because I always say hearing loss is honestly inevitable to some degree, right? Everyone's hearing changes, but you can change that slope to some degree. Listen, the big obvious ones epidemiologically, the big, big risk factors for hearing loss epidemiologically: age, sex, race. Can't do anything about that. Interesting that I mentioned those too. Race is a really interesting one. This is people who – I shouldn’t say race, it's really skin color – people of darker skin have a much, much, much lower risk of hearing loss with aging. That has to do with the corresponding amount of melanin in the cochlea, as in your skin, and that melanin in their ear actually protects in their ear. It's crazy but the risk reduction with skin color – race being a proxy, I guess, for skin color – is huge actually. Anyway, but age, sex, race, can’t do anything about. Sex, you can imagine, women have less hearing loss than men, probably has to do with an environmental indicator. You know men do more stupid stuff, right? But also estrogen might have a protective effect in the inner ear too. But so age, sex, race, let's say you can't do anything about it. The other big ones are noise. We talked about that and that is something you can do about. The general rule of thumb I use in my daily life is that if you are in an environment where at arm's length you have to really raise your voice to be heard, that is a situation where, given enough time, it can be damaging to your hearing. Obviously if you're in the subway platform, it is really loud for the few seconds as the train passes, not as big a deal. But if you're in that subway working as a worker nine hours a day, that can add up, right? Likewise, if you're mowing the lawn that is loud enough that you can't talk someone arm's length, you need to use ear protection. I think that’s just a good rule of thumb anytime you’re in an environment where arm’s length you have to raise your voice to be heard, that environment is theoretically enough to damage your hearing given enough time. If you're gonna be there for a long time, absolutely throw some headphones or earbuds or ear muffs or foam ear plugs in without a doubt. Then the other risk factor to hearing loss, really the only one you can really control I gotta be honest is noise. All the other ones which are shown epidemiologically are basically the cardiovascular risk factors, likely because the same things that lead to microvascular disease of the brain and other parts of the body can lead to microvascularin the inner ear. Again, yes, follow a healthy diet, exercise for your hearing, I guess, but you're doing that anyway. So I don't bother mentioning it because it's almost moot. You're gonna do it for your heart, not for your ear right? The only way unique to the ear is obviously noise, and that is real and that is something that is, honestly, I think easy to deal with. Just if you're going to a concert, just bring some earplugs. If you're using power equipment, throw on a pair of earmuffs. If you're firing guns, wear earmuffs too. Besides that I mean, again, assume you're not in an industry where you really do have to be careful about it. Fortunately there I think there's fifty years now of OSHA protections – Occupational Safety Health Administration protections – around hearing. Obviously not always followed, but I think it's clearly going the right direction. We'll continue to go in the right direction.

Chin: Well I don't know Frank. I think I might tell my patients now, “Go for a run, it's good for your ears too.”

Lin: [Laughs] Sure, yeah.

Chin: So thank you for that advice and really, you know, Frank, thanks for being so great on this podcast. I look forward to the work you're doing. We certainly hope to have you on Dementia Matters again.

Lin: Thanks so much. Nate.

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