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Alzheimer’s Disease: Causes, Symptoms, and Treatments | Dr. David Carr

Episode 75, duration 1 hr 05 mins
Episode 75

Alzheimer’s Disease: Causes, Symptoms, and Treatments | Dr. David Carr

Dr. Carr is a Professor of Geriatric Medicine in the Department of Medicine and Neurology at Washington University at St. Louis. Dr. Carr is a clinician in the Memory Diagnostic Center and Geriatric Assessment Clinic at WU where he maintains an outpatient consulting practice in dementia and geriatric care. He is involved in Alzheimer’s Disease drug trials and was the site PI in the GRADUATE trial and the Green Memory Trial in the WU Alzheimer’s Treatment Unit. He has been and/or currently is a principal investigator or co-investigator on research, national guidelines, and/or educational initiatives related to Alzheimer's and/or medical conditions and driving with funding through NIA, NEI, and Missouri Department of Transportation. He also has been active in consulting work with NHTSA, TIRF, University of Toronto, Medscape, UpToDate and the American Geriatric Society. He has been the primary author or co-author on over 100 peer review manuscripts and chapters, most related to older drivers.

Alzheimer's Disease - Causes, Symptoms, and Treatments - Dr. David Carr

In this episode we discuss:
– How to reduce risk of alzheimers
– Why you should care about azlheimers in your 30s
– How much alcohol is safe for your brain
– How to improve your memory for the long term

00:00:00 – Preventing Alzheimer’s Disease

00:04:09 – The Rising Concern of Dementia Worldwide

00:08:10 – Pathology of Alzheimer’s Disease

00:12:20 – The Usefulness of Testing

00:16:40 – Apoe Genotype and Risk Factors

00:20:34 – Medications for Cognitive Impairment

00:24:37 – The Relationship Between Body Composition and Alzheimer’s

00:28:50 – Hearing Impairment and Alzheimer’s Risk

00:32:39 – The Importance of Deep Sleep

00:36:20 – The Impact of Alcohol on Memory and Cognitive Decline

00:40:35 – Factors for Longevity

00:44:26 – Environmental Factors

00:48:37 – The Problems with Supplements

00:56:40 – Investigating the Impact of Drugs

01:00:44 – Unique Ways to Tackle Diseases

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Dr. Gabrielle Lyon [0:00:01]

Welcome to the Dr.Gabrielle Lyon Show where I believe a healthy world is based on transparent conversations.

In this episode of The Dr. Gabrielle Lyon Show, I’m thrilled to bring to you Dr. David Carr. He is a professor of Geriatric Medicine in the Department of Medicine and Neurology at Washington University at St. Louis. Dr. Carr is a clinician in the Memory Diagnostic Center and Geriatric Assessment Clinic at WashUwhere he maintains an outpatient consulting practice in dementia and geriatrics. He works closely and collaborates with state- and federally-funded older driver research teams. He’s involved in investigations as a principal investigator or co-investigator on research, national guidelines, and/or educational initiatives related to Alzheimer’s as well as other medical conditions and driving. I am telling you, he has been the primary authoror co-author on over 100 peer-reviewed manuscripts, chapters.

Dr. David Carr is truly extraordinary. In this episode, he makes dementia and Alzheimer’s easy to understand. We talk about what dementia is, what it’s not, what are the causes of dementia, what you can do about it, the current practices and potential interventions, andfinally, where geriatrics and memory and aging are going.As always, we make this content free. Please take a moment to do your part and share it. Pay it forward. If you know somebody who is struggling with a family member that has dementia or are concerned about aging parents, please send this episode to them. Let’s all share the information that Dr. Carr has. Please take a moment to rate, subscribe, and pay it forward.

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Welcome to the Dr. Gabrielle Lyon Show. I am here with a veryspecial guest, Dr. David Carr. He is a professor of medicine and neurology, Clinical Director,Division of Geriatrics and Nutritional Science at Washington University in St. Louis, where I did my fellowship, medical directorof multiple different places. One of the reasons why I wanted to have Dr. Carr on is that he is both a clinician and a researcher. Welcome to the show.

Dr. David Carr[0:05:10]

Dr. Lyon, great to see you again. We miss you here in St. Louis. Looks like you’re doing well, you’ve got a new book out. But excited to be here today to talk about the aging brain and what we can do to save those neurons.

Dr. Gabrielle Lyon  [0:05:23]

Let’s talk all about it. Please tell the listeners a little bit about you and your current primary area of focus.

Dr. David Carr  [0:05:32]

I’ve been at Washington University in St. Louis for 30 years. My background was in geriatrics. I obtained my fellowship at Duke University. But I found out very early on when I came back to my university position, very interested in the clinical and research aspects of Alzheimer’s disease and related dementias. So I pretty much have devoted my care, I think it’s fair to say, it’s 50% clinical and 50% research. Some of that is in the area of dementia and driving, but a lot of it is focused on some of the new clinical trials in Alzheimer’s disease where I work closely with my neurology colleagues. My background is internal medicine and geriatrics, but half of my work week for the past few decades has been in neurology per se.

Dr. Gabrielle Lyon  [0:06:23]

It’s incredible. By the way, if you guys are interested, we will put a link to your publication page. It is quite robust. There’s a lot of information in multiple areas, including aging and driving. I’ve heard that by 2050, the total number of people with dementia is expected to rise to 106 million worldwide. Is that true? That certainly seems to be a growing concern.

Dr. David Carr  [0:06:53]

Yes. I think those numbers sound correct. Here in the United States, we’ve been around 5 or 6 million, if you include people not just with dementia but mild cognitive impairment. By mid-century, we’re going to be up around 14 or 15 million if we don’t figure out how to slow this disease down and treat it.

Dr. Gabrielle Lyon  [0:07:16]

You’d mentioned mild cognitive impairment. Why don’t you lay out for people the idea of dementia versus Alzheimer’s, mild cognitive impairment, just briefly, vascular dementia, some of these catch-all phrases that we often use interchangeably.

Dr. David Carr  [0:07:34]

It comes up all the time in our patient interviews and family conferences. We recognize that dementia, although a lay term, has been defined by the American Psychiatric Association and others to be basically a change in one or more cognitive domains that we can not only test for, but we see that’s interfered with social, occupational, indoor activity of daily living function. But we recognize, dementia is a syndrome. If I said, well, I’ve got arthritis, I think people can recognize you can haverheumatoid and lupus and degenerative joint disease, lots of different causes. Dementia is the same way,B12 deficiency, thyroid disease medicines, sometimes depression can mask, so we recognize there’s a lot of different causes for dementia, the syndrome.

Similarly, mild cognitive impairment is a syndrome, but we take away the impairment in activities of daily living. We know you’ve had a cognitive change, we can test for it, but yet it’s not interfering with day-to-day life. So many people are keyed in now.We’re picking up a lot of people with this mild cognitive impairment, where before, I think wejust put it aside as normal aging. But we’re pretty confident, and it’s not all about short-termmemory. We recognize people can have attention deficits, language deficits, personality or behavior impairment, the back part of the brain we call posterior cortical dysfunction. There could be a variety of different things from that standpoint.

Now about 90% of dementias are neurodegenerative orirreversible.About 10% of the time though we investigate, we do find some of those reversible causes; I mentioned thyroid, B12, et cetera.But of the dementias, Alzheimer’s disease, depending on what clinical situation you’re in, probably accounts for about two-thirds of irreversible dementias. But we know that vascular disease or vascular cognitive impairment is the general term, vascular dementia if you meet criteria for dementia is common, and dementiawith Lewy bodies is also a cousinto Alzheimer’s disease and is anothernot uncommon situation where you can have psychosis and Parkinsonism, and things along those lines.

Those are probably the two other types. There are frontal temporal dementia and other rapidly progressive we can get into. But most of the time, we’re dealing with Parkinson-relateddementias, Alzheimer’s disease, or vascular dementia, and often there can be a mix.

Dr. Gabrielle Lyon  [0:10:26]

As it relates to the pathology, Lewy body and the frontal temporal dementias, is there an underlying pathology that we can– let’s say, we’re going to say Alzheimer’s.If two-thirds of the case of dementia, we would consider Alzheimer’s in nature, is there an agreed upon pathology of these diseases?

Dr. David Carr  [0:10:49]

Theresure is. Although it can vary, there are some standards regarding autopsy and the findings. Although there are a variety of different findings in Alzheimer’s disease, two abnormal proteins arethe pathognomonic or the footprint of defining the disorder. One of those is amyloid. Amyloid is a protein that sits outside of the neurons; we call thatextra neuronal. Within inside the brain cell or the neuron, there can accumulate a protein we call tau, and Alzheimer’s disease, specifically phosphorylated tau. We’ve gotten pretty good at measuring these things now that we can actually, in a person, identify if they have significant amounts of these proteins, which help.Most neurodegenerative diseases end up being related to misfolded proteins. Those are the two common ones that we see for Alzheimer’s disease, but there are other proteins that cause brain disease, too.

Dr. Gabrielle Lyon  [0:11:56]

From a perspective of any clinicians listening, if you are looking for amyloid or tau proteins, is this a CSF is cerebral spinal fluid, is this a blood marker? Where are we at as it relates to implementing into practice?

Dr. David Carr  [0:12:16]

We have entered into the era of Alzheimer’s disease biomarkers, and it’s an exciting one. I think it’s fair to say that still a significant number of dementia evaluations don’t necessarily need biomarker studies, but an increasing number of minority of the workups will. I think we are evolving very soon where we’ll simply have a blood test to diagnose Alzheimer’s disease.They’re already here, it’s just a matter of them being approved by the FDA and being validated in other centers. But basically, there are three groups of biomarker tests for Alzheimer’s. One is the PET scan.

The PET scans are of two types; that makes sense; there’s two proteins: there’s the amyloid and there’s the tau.The scan that is most further along to diagnose Alzheimer’s disease is an amyloid PET scan. There are different binding compounds. But this has been documented, evidence based. Right now, as I’m speaking, and this could change today or tomorrow, Medicare hasn’t yet approved those.They can be $5,000, $6,000 out of pocket. Some providers probably are covering them across the country. Given we have a new monoclonal antibodynamedlecanemabthat’s being used to treat Alzheimer’s disease, I think it’s just a matter of time before the insurance companies do cover that. The PET scans are one. We often have research studies where we can get the PET scan covered, but that is a barrier financially.

The second biomarker tests are blood tests. These have popped up all across the country and the globe. Some of them are focused in on amyloid, but many of them now are focused on tau and amyloid, and they may include age in their algorithms, ApoB protein, genotypes. But they’ve become very effective in ruling in or ruling out symptomatic Alzheimer’s disease. We are starting to use one at WashU. It’s called thePrecivityAD2. But there are, like I said, others across the globe that are gaining momentum. If you think about it, that’s what really all of us want. We want to be able towalk into the lab and get a blood test and not have to do the other tests.

The third set of biomarker tests are the spinal tap or lumbar puncture tests. Those are generally covered by insurance. But again, you have to go in and have that done in the clinic.There’s a small risk of infection or bleeding.But I don’t do those; my colleagues in neurology do them. It’s a small flexible needle that are typically in andoutin 20 or 30 minutes,then you can measure the proteins, the amyloid and the tau proteins. Those tests are very good at ruling in and ruling out Alzheimer’s disease. The big question that we asked when patients come in to our dementia clinics, will these tests make a difference? Will they change our management? If the answer is yes, then we figure out how to get them. If not, then we generally don’t pursue them.

Dr. Gabrielle Lyon  [0:15:30]

What if someone were to measure early, let’s say in their 40s? Lots of diseases that we discussed, like cardiovascular disease, even Alzheimer’s, they begin much earlier. Let’s say these amyloid and tau begin to develop, depending on the individual, in their 40s. Would it make sense to measure? Can we slow disease progression? Can we impact the misfolding of these proteins from a lifestyle intervention or even early monoclonal antibody use?

Dr. David Carr  [0:16:05]

That’s a great question. Right now, I don’t think there’d be too many people across the world that would recommend testing in your 40s, unless you’re symptomatic. Now most of Alzheimer’s disease is late onset.Less than 1% is related to what we call familial Alzheimer’s diseasewhere you’ve got an autosomal dominant. That means you can get the disease if it comes from either parent, and you get that specific gene, you can get the disease.In that situation, if you’re symptomatic, it may make sense to get these tests. Most people, if they’re asymptomatic, the test would likely be negative. I think that you probably already know if you have a primary family member with this disease, your risk of getting Alzheimer’s disease is about three-fold. You’re going to want to do healthy lifestyle behaviors given how prevalent it is anyway and also if you have a family history.

Dr. Gabrielle Lyon  [0:17:12]

What about ApoE4? There’s a lot of discussion about that. How common is that testing? Should it be done? What are your thoughts?

Dr. David Carr  [0:17:24]

ApoE4, just to backup, there is a cholesterol-carrying protein that comes in three flavors or three different confirmations, E2, E3, or E4, and you get one, we call it an allele, from each parent. Anybody who gets theE4 allele is at increased risk for developing Alzheimer’s disease. We don’t think it’s a direct effect but more ofa susceptibility gene. If you get a E4/E4 from each parent, then that does put you on a relatively fast track for getting the disease. But the number of people in the population that have a E4/E4 is pretty low,and there’s still a lot of people that end up with cancer or heart disease that never develop Alzheimer’s disease.The general consensus is, we don’t recommend these tests.We do get asked a lot about them, and people cansign up now and get their own ApoE genotype and get it tested. But I think just because you haveE4/E4 doesn’t mean you’re going to get the disease. Even if you had E2 or E2/E2, or E2/E3, it doesn’t mean you won’t get it; your risk is low. I still think you’re going to want to practice healthy lifestyle behaviors.

The one clinical situation that comes up for us now, and we are checking it, is on whether to prescribelecanemab or not. This new monoclonal antibody that was approved by Medicare and the FDA in May of this year, it turns out that one of the risks is cerebral edema or swelling and/or small microbleeds. The question is, how do we know if you’re going to take this antibody, who’s at great risk to have these side effects or not? If you think about it, if you give an antibody to amyloid, it crosses the blood-brain barrier, it’s going to take it out of the brain, but it’ll take it out wherever it is.In a certain number of people, you have a fair amount of this protein that’s in the small capillaries, so when the antibody takes out the protein, they can leak, cause some swelling or some microbleeds.

It turns out if you have an ApoE genotype done, and you are atthe E4/E4 level, or you have one of the E4of the genotype, that you have increased risk for side effects. I had a patient the other day that came in. They were all on board for having lecanemab.They’re interested. We went through the MRI, the exclusions, and all that. Then we got the ApoE genotype testing. He came back a E4/E4. If you look at the data, his risk for having significant side effects from the monoclonal antibody went from 10% to 30%. For them, that was a bridge too far. They said,now that we have that, we’re out.They were in before, but they’re out now.Other people may see that risk and decide to take it, and that’s a shared decision-making situation we need to do.

Dr. Gabrielle Lyon  [0:20:42]

Lecanemabis now available?

Dr. David Carr  [0:20:46]

Yes. Since I think May, we’ve probably got about maybe 12 to 14 people that we’ve started on in our infusion center.

Dr. Gabrielle Lyon  [0:20:58]

That’s fascinating, but certainly not without risk. What about other medications like Aricept and Namenda? When I was there, one of the other physicians—I will give Dr. Byrd a shoutout—was very interested in Axona, some medium-chain triglycerides. Where are we at with Aricept and Namenda and some of these other medications that have been around for quite some time?

Dr. David Carr  [0:21:19]

I think in the general prescribing providers and dementia clinics, whether they’re geriatricians or neurologists, psychiatrists, would still offer that group of drugs, the cholinesterase inhibitors, that boost acetylcholine, like donepezil, rivastigmine,or galantamine,as first-line treatment for early Alzheimer’s disease. Now we wait, actually, until an individual has had dementia to prescribe the drugs, and it seems a little counterintuitive where people are coming in so early now in the mild cognitive impairment phase. They’re like, well, what about donepezil? Well, they’ve done the studies. If you’re at the MCI phase, and you follow people over time, being on a cholinesterase inhibitor or not doesn’t change your progression rate to go on to get dementia and Alzheimer’s disease. And it makes sense.It’s not getting at the targeted pathology like the amyloid or the tau. So we actually wait until somebody meets criteria for dementia. Then if we do believe they have Alzheimer’s disease, we prescribe the drugs.What can we expect out of them?Some mild, symptomatic, modest cognitive stability. I’ve seen people go six months a year, sometimes a couple years relatively stable. At some point, we know people will progress.

The same thing with memantine or Namenda, that’s a drug we typically reserved for more moderate to severe Alzheimer’s disease.To give some of your listeners an idea, they may be familiar with the mini mental status exam; 30 points, perfect score.People that benefit from memantine or Namenda typically score between 3 and 12 on the mini mental, so it’s more for moderate to severe cognitive impairment. Again, the data would suggest some relative, modest cognitive stability over time, six months, a year, a couple of years. Eventually, we know individuals will progress.

Axona is still very interesting.I have a lot of patients that do coconut oil and consume the medium-chain triglycerides.It’s a very interesting theory because itties into what we call Type 3 diabetes.We know that in brain cells, they’re relatively starved for glucose. There’s a decrease in insulin receptors. If you can’t get blood sugar, which is your primary brain fuel, glucose into the brain,why not get breakdowns,ketones, from fat byproducts? It’s had some interest. I think the problem that Axona had as a marketed pharmaceutical, nutritional drug is that they did the smaller study in the hundreds that showed some similar efficacy to some of the prescription drugs. But in phase III trials, we usually are upper in the thousands, so 1,500, maybe 2,000 individuals to be studied. To my knowledge, they never went on and did that. I’ve still had some patients’ families go after it online. I think there’s still a website you can go. But it still hasn’tbeen proven as a solid treatment, I think it’s fair to say, that a lot of people are prescribing.

Dr. Gabrielle Lyon  [0:24:49]

When I was doing my fellowship, we did talk quite a bit about Type 3 diabetes of the brain orthis idea of Alzheimer’s.We spoke about there was a period of time where people tried intranasal insulin. Is that true?

Dr. David Carr  [0:25:05]

I think, at least for the US trial, the big problem with intranasal insulin was the delivery and figuring out a way to consistently have it absorbed and utilized. I think that was the sniff trial, the studyto fight forgetfulness or something like that. But unfortunately, I’m not sure they were ever able to pull it offto my knowledge, even though small studies weren’t able toconfirm efficacy or benefit. But it’s still an interesting theory, andthere’s data to suggest thateven in late life or middle life, if you control blood pressure and diabeteslong term, that you may decrease your decline in cognition. Again, what’s hard about clinical trials is you get six months, you get a year, maybe a year and a half. You and I both know, when you’re in it for the long haul to preserve your brain, you may have to be looking at 5 or 10 years. That’s a long time for investigators to stick with participants, andyou’ve got dropout and people move. These studies are inherently very difficult to pull off especially if the effect is modest from a year-to-year basis.

Dr. Gabrielle Lyon  [0:26:22]

Absolutely. In regard to body composition, where are we at with actionable items that an individual could do to prevent Alzheimer’s? On that note, is mild cognitive impairment reversible, or once an individual has it, that remains? Obviously, it depends on what the cause is, whether it’s hypothyroidism, etc., and maybe a period of lack of sleep. But is there some reversal of mild cognitive impairment, or no, because the pathology is the same?

Dr. David Carr  [0:27:01]

Let me tackle boththe body compositionand whether or not MCI is reversible. We do know in The Lancet article, I would refer many of your listeners to 2020. If they got in and simply looked atLancet dementia prevention, there’s a great review and a great study that looked at the different types of risk factors across one’s lifespan and their attributable risk for future onset of dementia. Obesity was part of that, especially in midlife.Again, all of these things aren’t the answer, but they’re part of the answer. If you meet criteria for obesity, there does appear to be an independent risk factor for future Alzheimer’s disease. What’s the mechanism? Is it again this hyperglycemia and insulin resistance? Is it oxidative stress? Is it inflammation? Is it through cardiovascular disease or diabetes? I mean, there could be a variety of different mechanisms, but trying to keep your body habituswithin a normal range could be a benefit.

I think most of the studies looking at health prevention are just trying to keep things steady and not necessarily improve it, so they’re not declining. Therehave beena few small studies that have looked at improving things. Now, is MCI reversible? Remember, MCI is a syndrome, so within mild cognitive impairment, a presumably 10%, 15% of it could be from B12 deficiency, thyroid disease, sedating medicines like alprazolam or Xanax. There are a subset of those that would be reversible, I think, from a mild cognitive impairment due to Alzheimer’s disease. I’m not aware that would necessarily improve things, but you could potentially stabilize the condition. So maybe you stay at MCI and don’t progress to Alzheimer’s disease, per se.

Now there are other comorbid conditions that can make your recall and cognition worse, for instance, sleep disorders.There’s probably a hazard ratio of three or four for people with obstructive sleep apnea to go on and develop Alzheimer’s disease. We know some people in sleep apnea can have cognitive impairment, typically executive function, etc., so it’s tough. In my dementia clinic, when I see patients, are they symptomatic from their untreated OSA, or are they symptomatic from Alzheimer’s disease? Well, you don’t know until you treat them and get better. Some,maybe a third of my patients, will get better.Their attention will be better. Their memory will be better. A third stay about the same. I can take some comfort in knowing that their trajectory to decline, if they have Alzheimer’s disease, will be slower if they’re effectively treating a primary sleep disorder. We have some data around that. The third may progress,and maybe the sleep disorder didn’t have a component that was symptomatic.But I think that’s an important thing to look at.

Hearing impairment. Oh, my gosh, if you look at this Lancet article, hearing impairment had the strongest association with prospective Alzheimer’s risk than all the other risk factors. It’s fascinating. There’s some data suggesting that if you use hearing aids, and you need them, you may decrease your risk of Alzheimer’s disease, or you may slow your decline if you have it. Now it’s not proven, but suggested by the data. There’s a lot of theories as to why there may be an association. We haven’t quite figured that out, but it is a very compelling association.

Dr. Gabrielle Lyon  [0:31:11]

Why do you think that there is a relationship if you were to pick one thing?

Dr. David Carr  [0:31:16]

I think what many people go to is the socialization. We know that isolation and not getting out and not staying connected is a big risk factor for depression and dementia. We do know that people who are hearing impaired, they tend to shy away from interactions and gatherings, whether it’s oneonone or big groups. So that’s one. The second is there’s a theory that part of the brain, you actually have to get resources from other parts of your brain in order to interpret things. That may put additional stress on the brain to cause it to decline. There are some people who believe some of these situations are, it’s one and the same disease. It’s not really a peripheral hearing impairment, but it’s an auditory comprehension problem that your temporal lobeis having trouble understanding, and so that could be it. Then there’s the overdiagnosis or bias thatpeople with hearing impairment are going to be over diagnosed as having Alzheimer’s disease and doing poorly on tests. But to me, I think it’s the social interaction that Ilook at and see.The other things could be occurring, but I think it’s veryencouraging to know that your quality of life, your mood, and potentially, your brain could be preserved by being able to hear better.

Dr. Gabrielle Lyon  [0:32:42]

Yeah, and that makes a lot of sense. When we talk about sleep, is there a mechanism of action that we know that protects the brain versus that harms the brain? What is some of the data out there on sleep and the effects on brain?

Dr. David Carr  [0:32:59]

There’s a lot of interesting articles online and people have looked at. I’m not sure we’ve necessarily proven all the mechanisms. But one of them that concerns everybody, certainly, if it’s obstructive sleep apnea that’s not being treated, people can get pretty hypoxic at night. It’s pretty impressive how low they can– I just had a patient that was getting down to the 60s and 70s at night, very severe sleep apnea. That’s not normal.People may do 80s and that sort of thing for their saturation. I’m talking about when your saturation levels should be 90 or greater. If you go to bed, and it’s six, seven hours every night, your oxygen level’s dropping, that obviously could have a direct effect on the brain.

The second part of it iswe cycle through our sleep, going tolight sleep, deep sleep, dream sleep, REM, andthen wego through that through the night. The deep sleep is a time when we restore the brain, replenish. That toxic amyloid we’re trying to process, that’s been shown in some very elegant studies that seems to be a time when we’re getting rid of some of the proteins that are causing problems. Every night day in day out, if you go through and impair that deep sleep, you’re robbing your brain an opportunity torestore and get rid of some of the toxins. I think that can be another source. There are other things that people have looked at and tied in, but I think those are probably the two major concerns.Sleep apnea is associated with high blood pressure, and high blood pressure is associated with Alzheimer’s disease, so there may be several ways to tie it in.

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Dr. Gabrielle Lyon  [0:34:43]

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That makes a lot of sense. Number one, all the parents are thinking about how their children or grandchildren should not be sleeping in their room right about now. I know that I certainly am. Alcohol consumption, that’s a big question that people have. It’s a big question that people have with individuals that are aging. What is some of the information regarding alcohol consumption and dementia or dementia risk?

Dr. David Carr  [0:37:26]

You have to be a little cautious in interpreting the data and alcohol and brain health for a couple reasons. One is we’ll never have a randomized trial of alcohol consumption and brain; it’s just not going to happen. But you have to use these case control studies, follow people over time, and there’s a lot of confounding factors that you have to look at.People who drink moremay be smokers and may not exercise, so there’s a lot of things to tease out when you look at the alcohol and brain health literature. The second thing is we don’t define our units the same.If you look at that Lancet article, a unit of alcohol is basically 8 grams, which is very small.In the United States, it’s like 12 to 14 grams of alcohol is a unit, and defined a unit, that would be about 1 to 2 ounces of spirits, about 3 to 4 ounces of wine,and about 12 ounces of beer.That’s a normal beer with normal alcohol. It’s not like a Belgiandubbel or tripel because some of the beers can be pretty alcohol laden.

In general, I would say the bulk of the data suggests that one or two drinks a day are not harmful. Some people, you can find studies that say they’re protective. I’m not quite convinced on the protection, but I don’t think they’re harmful. I think we can say that based on the bulk of the data. But if you have three drinks or more a day, that definitely will increase your risk for dementia and Alzheimer’s disease and/or vascular disease. I’m asked all the time in clinic,where do I stand on alcohol consumption? In general, if I have a patient in front of me that’s already got cognitive impairment, and I think has Alzheimer’s, I try to encourage them not to drink because as we know, age-related changes, small amounts of alcohol, skeletal muscle tends to be down unless you’re hitting the gym and pumping iron.

Small amounts of alcohol can go a long way. When I asked questions to my family, I said, well, if they have one drink, do they get confused? Their gait and balance, are they falling? No.But if you keep probing, you find out a pretty small amount, two or three drinks, they noticed changes in their cognition or gait and balance. I think there’s risks.Some of these folks are still driving for God’s sake and you’re like, whoa, timeout. You’ve got memory problems, and you’re drinking alcohol? Hello. So you got topull it in. But from a prevention standpoint, you’re in midlifeor maybe you’re early 60s, and you’re saying, how much do I drink? I would hold it to one or two a day and notthree a day or 21 or more a week. At that point, I think you’re asking for trouble.

Dr. Gabrielle Lyon  [0:40:21]

I would say that that’s very generous. That’s a very generous amount of alcohol for people. This moves nicely to this concept of cognitive reserve. I’d love for you to talk a little bit about this concept of cognitive reserve. How does this play into the idea that cognitive decline is somewhat modifiable?

Dr. David Carr  [0:40:41]

That ties into this issue of education. Education, similar to hearing impairment, is right up there in preventing Alzheimer’s disease, at least in some of the studies where they’ve looked at people longitudinally.That education is typically looked at in less than45 years of age. There’s been some pretty large studies that have shown that more years of educationare associated with a decreased risk of future Alzheimer’s, even when they adjust for high blood pressure and diabetes and cardiovascular disease. So what’s going on? What are we doing to the brain, if anything?

Some people have said that you’re building up some cognitive reserve. We can define that asa difference between an individual’s clinical picture and their neuro pathology. It’sthe ability to have the mental flexibility and adaptability that enables preservation of activities of daily living, your synapses, your brain things may be stronger, and you may be more resilient to the changes that can occur when the plaques entangles or whatever type of abnormal protein is coming along. It could also be a proxy for late light learning.People who go andstudy longer in school and go to college,they may also be doing activities in their 30s, 40s, 50s, and 60s that are much morebrain friendly from that standpoint.I do thinkit’s hard to knowfrom the standpoint of what’s actually going on, but it appears to be a robust finding. I think it possibly could be related to the strength of the connections that occur and how they may maintain over the lifespan once you’ve started off and done that.That doesn’t mean you should not be active in late life,but a good part of the prevention occurs before age 45 years.

Dr. Gabrielle Lyon  [0:43:09]

So really reading and learning and trying to educate oneself as much as possible.

Dr. David Carr  [0:43:15]

In addition to educational, some people have looked at the occupational complexity. We know that if you do take a job where you’re being much more stressed, that may be stress, but you’re using your brain versussomething that’s very roteand doesn’t require a lot of thought, that may be another example of something that can help build up some cognitive reserve.Leisure activities, I’ve always said, I can’t tell you how many people I’ve seen that are square dancers or ballroom dancers in their 90s that are fit as a fiddle.Their gait and balance are great. They’re running circles around all of us, and they’ve given their life to these.When you think about it, you’ve got both physical activity and all this brain function that you’re having to do to pull off a lot of these activities. I think picking your leisure activities, you do things that are fun, but some of them, especially that combined physical activity and a lot of brain thought could be winners for longevity.

Now I’m a tennis player, and we like to show as we get older, we send around more and more articles that says the average life expectancy gained by playing tennis is 10 years. It’s very interesting to look at. There’s been a lot of studies that have looked at the effect of sports and their longevity. You pick sports, and you gravitate to ones you like.But if you’re trying to prolong your life, you can actually look at those studies and pull them off. They’re quite interesting. Swimming is another one that you can imagine that seems to be associated with longevity.

Dr. Gabrielle Lyon  [0:44:56]

I know some of your colleagues are looking at hormone replacement or at least testosterone replacement. Have you seen any of those kinds of interventions, whether it’s hormone replacement, on improvement in or maintenance or stability of brain function?

Dr. David Carr  [0:45:16]

I have to say, it seems like the field for Alzheimer’s disease has sort ofswung away, and a lot of people are looking atantioxidants and the monoclonal antibodies and things along those lines. The data has been mixed on hormone replacement. I think most people have concluded so far thattestosterone replacement and estrogen replacement, again, a lot of this depends on when it’s happening and over what period of time. It hasn’t been shown to be effective, butnot everybody still feels that way.

I do think there’s still more to be learned about physiologic replacements thatdon’t necessarily will cause thrombosis or cancer or things along those lines. I think there’s also– and I’m not a nutritionist or food expert, but a lot of people are looking at foods as a way toboostcertain hormones and help withthe nutrients and antioxidants, and focus in Mediterranean diet and things along those lines, so soy proteins and things from that standpoint.I think there’s still more to be seen on that area.

Dr. Gabrielle Lyon  [0:46:35]

I do believe that midlife body composition is going to be critical, and then of course, maintaining skeletal muscle mass is important, not just in Alzheimer’s, but aging in general.Sarcopenia,for the patients that we would see in the clinic,I think we’re going to move in a direction where we’re going to be able to protect people earlier from a skeletal muscle standpoint, which would be incredible. It would just be incredible. What about this idea of infection or air pollution, some of the things that maybe are environmental?

Dr. David Carr  [0:47:17]

I think we’ve missed the boat on a lot of these things. Again, going back to the Lancet article, only about 40% of the attributable risk we’ve been able to identify so far. When you think about it, that’s almost more than half.We still don’t know what is contributing to the risk. I think part of this is we haven’t looked at some of our lifelong factors or things that potentially expose us. Pollution is one of those areas. I remember—thisis going back almost 25 years—an Alzheimer’s conference that was hosted at WashU. We had a speaker who came in, and he said, the leading two causes of death in Shanghai, China were COPD and Alzheimer’s disease.They had huge problems with pollution; they may still, I don’t know. But the point was that you can have an environment where you live, and some studies have shown if you live close to some factories and things like that, you may be at risk for Parkinson’s disease or Alzheimer’s disease, etc.

There is an issue there. I think magnetite is one of the compounds that’s in the air, a particulate matter that we can breathe in; nitrous oxide, particulate matter.A lot of different things can come into our body.You wonder about water, too and the different things.We allow so much number of pesticides andinsecticides and things like that in very low amounts, and you say, well, they’re low amounts, they should be safe. But do we really know if you’ve ingested something for 30, 40 years? I mean, these are hard studies to look at, and I do think more people will try to take a look at it and see.We used to think smoking wasn’t a factorbecauseit was protective for Alzheimer’s disease. The original study suggests that it’s because people died from cancer before they had a chance to get their Alzheimer’s disease. But smoking definitely over age 65 yearsis, and a lot of studiesnow haveshownthere’s inflammation and toxins, probably oxidative stress, things along those lines. So it’s not surprising thatpollution can be an issue.I think that you just have to be continuing to be cognizant ofwhere we live, what we live. I mean, there are some times we’ve had these fires that have come down, and people actually wearing masks. So you have to be careful what we breathe.That certainly can be part of the equation.

Dr. Gabrielle Lyon  [0:50:09]

What about neuroprotective compounds like fish oil or caffeine or nicotine, you name it. There’s lots of nootropic-type substances out there.

Dr. David Carr  [0:50:20]

I think they all have some interest from a study standpoint. The tough part, like I said, is to really show efficacy, you’re going to have to follow these compounds over time. So there’s always somebody who can get a little study, basic science, some case control things, that will tout a certain amount. My general rule of thumb is,a lot of these, I can’t recommend just from an evidence-based standpoint. They may be of benefit, but they just haven’t been shown in large trials to be effective. They certainly have some theoretical reasons and some scientific reasons to be helpful. But we also have to be cautious in the supplement industry. We’ve seen that when we’ve tried to do high doses of vitamin A and have problems with either liver disease or cancer. Too much of anything could be bad.

I thinkwhen you look at the blue zones across the worldand people live in their 90s and 100s,certainly some of that’s genetics, and there’s no doubt. But they didn’t get that way takingthis supplement or that supplement. Typically, they’re active, physical activity, they’re social, they’re connected with their environment, they’re eating healthy, they’re sleeping well, so there are certain environmental things that are probably going to be more helpful in the long run to protect your brain than picking out one specific supplement or things along those lines. That’s why I think food and broad-based food diets, you can hit so many different antioxidants and different areas that can be of benefit. It’s hard to just replace that with just one or two supplements.

But the supplement industry is huge. I bet you, 10% of my patients come in takingfive, six, seven, eight different supplements in the hopes that would be helpful.As I tell them,I can’t do a recommendation for and against, except for B12deficiency. We now have strong neurologic correlates, and that can be done by a blood test. But be sure you’ve talked with your pharmacist or your physician about any drug nutrient interactions because those can happen, too.

Dr. Gabrielle Lyon  [0:52:35]

What would your top three be if you were to have to rank things from a protective aspect? Would you say sleep is number one, exercise? How would you personally rank them? Because I will tell you, at WashU, I would say a lot of people are working a lot of hours and may not get a ton of sleep.

Dr. David Carr  [0:52:57]

I would certainly put physical activity up there. We don’t know the exact dose effect, but it’s probably 150 minutes or more a week, and it doesn’t have to necessarily be that vigorous. Walking and getting that amount of regular physical activityI think is a great strategy. What’s nice about that one, not only could it potentially helpdelay the onset of Alzheimer’s or MCI, think about the benefits it has for the cardiovascular system, the musculoskeletal system. I think there’s some great reasons why to adopt exercise.There’s studies on gardening, almst any sport, that just show that being outside and doing some of these natural things we’ve done for years is a huge benefit. My mom, who’s 90 now, she never worked out a day in her life. But you know what, she was a gardener round the clock inside and outside, and she never stopped thatactivity and things on those lines. She had some great genetics, but I do think part of this has to do with again, what’s your leisure activity and how does that stimulate your brain, things along those lines.

Another one we haven’t talked on is stress and depression. There are times where we can’t help ourselves,and we get dealt things either professionally, personally, socially where we’re going to be down. But I think there’s one thing to be said for a bump in the road and another thing to be said if you’re constantly down and being under constant anxiety or depression, then really raise your cortisol levels, stress levels, and we know over time that can be a negative impact on brain and brain health. For those people, getting the healthy lifestyle behaviors, the socialization and the exercise, are some of the best ways to modify that, but getting professional help whether it’s counseling and/or medicines to help cope with some of your stress can be helpful. Now I don’t have data that show that the interventions are necessarily going to be helpful. But we know the association with depression on future brain health can be a negative one. So treating that and addressing it, I think are important.

We already talked a little bitabout the hearing, I think it’s important.Social isolation is the other thing, is being part of your community, having that engagement, whether it’s volunteer work,being involved in programs and having those interactions, I think are huge. They help maintain our social connectedness, but they have positive impacts on cognition, motor skills. I think those are all things that we can look at. In addition, Ihave the top 10 list, and those would–

Dr. Gabrielle Lyon  [0:56:01]

I have your 10 list. I know them exactly. A lot of these questions I’m asking, but I do know the answer, because I have heard them. What about medications that could potentially perpetuate or speed up the process of Alzheimer’s? Are we talking about the same pathology of the misfoldings of these proteins? Is it both the amyloid and tau? Again, we’re talking about a lot of different things. But at the end of the day, is it the influence of these misfolding proteins from the lack of sleep,from medication, etc?

Dr. David Carr  [0:56:34]

You raise a good question that I don’t think has been well studied, and that is, is there a medication we’re taking that could be hurtful long term for cognitive health? One group of medicines that’s come up in the last decade had been those that have anticholinergic side effects. Those could be the overactive bladder agents. Now not all overactive bladder agents are created equal. Don’t go out and stop that, talk with your doctor or pharmacist. But some of them can cause sedation, confusion, memory problems. There can be gastrointestinal or GI drugs that slow down gut activity that can have that. There are certain nausea medicines and antihistamines. That class of drug has been associated with some cognitive impairment. Nowwe don’t know is the cognitive impairment due to the drug and it’s reversible? Is it people already had Alzheimer’s disease, but they became more symptomatic and the drugs brought it out? Or are they actually harming the brain cells and bringing on an Alzheimer’s disease? We don’t know.

But that class of drug along with the benzos, the alprazolams, the Adapins, I think we have to be very cautious on in prescribing and monitoring. I suspect there are other drugs out there, we’re going to find out down the road. Some clever investigator is going to look ata specific drug that’s very common, that may be a problem. We call that post marketing surveillance. Somebody’s just got to go and look at some of these drugs that have been out for a long timeand see if there’s any associations. But those are two classes that we see.

One class of drug that may actually reduce the risk of dementia is warfarin or Coumadin and/or the DOACs, the new novel agents that cancontribute to anticoagulation. We know atrial fibrillation, which is an irregular heart ratesome of your listeners may be aware of, is pretty common in older adults.You get over age 80, 90, it’s not ubiquitous, but it’s common. We do know that atrial fibrillation independently puts you at increased risk for Alzheimer’s disease or vascular dementia. There’s been actually some data that suggested if you treat that, which is evidence based and appropriate treatment, with a blood thinner, you may reduce your risk of Alzheimer’s disease.

This raises the question, how does atrial fibrillation impact the brain to bring on a dementia? And although we don’t know, there are two common theories. One is we know atrial fibrillation can cause clots in the heart, and those clots can break off. Sometimes it can be a major stroke, but sometimes they just maybe small little micro emboli, teeny tiny strokes. One mechanism could be that we’re having micro embolithat are causing problems. But the other is, if you think about it,you’ve got these four chambers working in a very synchronous fashion and pumping your blood and getting things going. But in atrial fibrillation, youlosea couple of the chambers or pumps. Your cardiac output is lower. You may be hypoperfusing, decreasing the blood supply to the brain, and maybe over time, that is an issue. We don’t quite know what the impact is, but we do know treating it, making sure your heart rhythm is under control are important parts. I do think we’re going to see more about this atrial fibrillation being a risk factor for brain disease and prevention by treating it as time goes on.

Nowyou asked the question about infections. For years, nobody would have thought that peptic ulcer disease would have been, at least in part, brought on by bacteria. Now we know H. pylori, andthere can be a bacteria that can hang up and cause inflammation.There’s still a number of investigators, albeit small percentage, that are still studying the hypothesisthat chronic inflammation from infections that continue toharbor inside us, whether it’s a herpes virus or other viruses that harbor down, some people think the amyloid plaque is in response to previous infectionsand that it came aboutto encase it and to cover it. There are some trials looking at antiviral agents inphase I, phase II that people are looking at. So I don’t think we’veruled out. I thinkprobably the majority of experts in the field will say, we don’t think this is infectious. But we said that about peptic ulcer disease, so I thinksome of the biggest breakthroughs are by researchers who look at novel and unique ways to tackle diseases. You could argue, we haven’t done a great job so far of improving it or stopping it. I think more is to be said on this issue of infections, and chronic inflammation, we do believe, across the lifespan can potentially cause problems. We’ve looked at that with dental disease, periodontal disease, heart disease, that sort of thing. So I thinkit’s within the realm of possibility.

The other thing people are looking at is the gut biome. That’s a very exciting area. We know a lot of bacteria hang out there. They may get adjusted if you take a lot of antibiotics or for whatever reason, eat different foods. Some of these bacteria we think may bepositive and helpful, some of them may be harmful. How many of those and what type are causing chronic inflammation over time? That’s a burgeoning area that people are looking at and its relation to brain disease, too, so exciting.A lot of people are looking at different angles.

Dr. Gabrielle Lyon  [1:03:12]

Yeah, it is fascinating. I love what you said about asking a different type of question. Potentially, there are more novel ideas, and we’ve been thinking about these diseases in one capacity.

Dr. David Carr  [1:03:28]

We need it.This disease model ofyou treat, it’s very expensive once people have symptoms, and doing what you’re promoting, Dr.Lyonwith books and programs is,can we back this up and prevent the symptoms from coming on? Because really, if you look at the data, once you start having symptomatic memory impairmentfrom Alzheimer’s disease, you already have a lot of amyloid in your brain. I’m not saying it’s too late, but trying to take it out and actually make a big impact on the disease, in a sense,the horse is out of the barn, backing it up before you get symptoms, and trying to prevent that symptomatic phase is a laudable goal, and I think more to be done on that.

Dr. Gabrielle Lyon  [1:04:15]

Well, thank you, Dr. Carr. I don’t want to keep you too much because again, your colleagues might kill me.

Dr. David Carr  [1:04:23]

The patients and families might be after you.

Dr. Gabrielle Lyon[1:04:28]

What is on the horizon for you? What are you working on now?

Dr. David Carr  [1:04:31]

It’s very interesting. I’m finally trying to bring together the dimension-driving piece and the prevention piece for Alzheimer’s. A colleague of mine, Dr. Babulalat Washington University, puts a car chip at a car,and we’re able to track where people go, and no surprise, in pre-symptomatic Alzheimer’s disease—because we follow people longitudinally in the Alzheimer’s Research Center—those people who drive less appear to be on the fast track to Alzheimer’s disease. They may already be starting to shrink their driving destinations and their social connections. The question is, can we take a group with preclinical Alzheimer’s disease that are already starting to show they’re decreasing their life space? Can we do an intervention to keep them active, to keep them out? Will that delay or prevent the onset of symptomatic Alzheimer’s disease? That’swhere we’re heading from a research standpoint.Now it’s going to be a while before we can actually gear up to do a intervention, but we’ll start off with a small sample and seewhat does that look like? What can we get people to do? How can we do their social interaction?That’sthe next step.

Dr. Gabrielle Lyon  [1:05:59]

Very exciting. Dr. Carr, thank you so much for your time, and I cannot wait to catch up with you later.

Dr. David Carr  [1:06:08]

All right. You’re very welcome. Good luck, everybody there, keeping your brain cells in good shape.

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Dr. Gabrielle Lyon  [1:06:14]

The Dr. Gabrielle Lyon podcast and YouTube are for general information purposes only and do not constitute the practice of medicine, nursing, or other professional health care services, including the giving of medical advice. No patient-doctor relationship is formed. The use of information on this podcast YouTube or materials linked from the podcast or YouTube is at the user’s own risk. The content of this podcast is not intended to substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they may have and should seek the assistance of their health care professional for any such conditions. This is purely for entertainment and educational purposes only.