You Are What You Eat: Study of Diet and Brain Health Shows Cognitive Benefits from Cheese, Wine and Lamb

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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. I’m here with Dr. Auriel Willette, an assistant professor of food science and human nutrition at Iowa State University. His research focuses on the connections between nutrition and diseases and disorders like Alzheimer’s disease. In November 2020, Dr. Willette published a study in the Journal of Alzheimer’s Disease about how a person’s diet may impact our cognitive abilities later in life, particularly highlighting how certain foods like cheese and red wine were linked to improved cognition later in life. Today on the podcast, we’ll be talking to Dr. Willette about his research on how a person’s diet affects their risk for Alzheimer’s disease, as well as what changes we can make to our diets for a healthier mind. Dr. Willette, welcome to Dementia Matters.

Dr. Auriel Willette: Thanks so much for having me. I appreciate the invitation.

Chin: And you are a former Badger, so welcome back to something Badger-oriented here at UW–Madison.

Willette: Always happy to do anything Badger-related!

Chin: Well, let me start by asking, what sparked your interest in studying the effects of nutrition on the brain and on cognition?

Willette: So, this has been a long touted but little studied area, I guess, of just neurodegenerative diseases where we'll talk about, say for example, how we're supposed to get enough sleep, how we're supposed to eat a balanced diet, so on and so forth, but exactly what that means, that can greatly differ depend on who you ask. More importantly, trying to do not just nutrition research that is high quality and reproducible and rigorous but then overlying on top of that doing cognition correctly, doing studies of brain imaging, and then trying to combine all of those together things can go very wrong, very quickly. So there aren't a whole lot of us out there, but ever since I started work, with rhesus monkeys actually over at the National Primate Center there at UW–Madison, I had a really strong interest regarding how obesity and related problems can affect the brain over time. Throughout all of my work I've found that, even starting decades before potential Alzheimer's onset, there are subtle cognitive and imaging related changes in the brain that we can pick up on that we've been able to find are moderately to, in some cases, strongly correlated with how well we process blood sugar. More recently, we focused on, well, can we look at actual whole foods instead of just certain kinds of diets. Does that have any measurable association because, sure, you can change what your glycemic index looks like or try to control glucose but perhaps it's a lot easier to say, ‘Well, less red meat might be a good idea in your particular case, and maybe more cheese.’ So that's what we've concentrated a lot on in recent years and that's what we're focused on in this paper. It was trying to look at consumption of whole foods and how it was related to changes in cognition over time.

Chin: So one of the things I'm hearing from you is it's very complicated because we talk about nutrition, whether it's micronutrients or whole foods, and then doing proper cognitive testing, how you are doing that and conducting that, and then even those other tests such as brain imaging and biomarkers. You have to put all of that together in the studies that you're doing which is why it has to be so rigorous and scientifically valid if you're going to start making statements about food, which is a really important thing to people.

Willette: Yeah, it is. It's really easy to do, very easy to do incorrectly. (laughs)

Chin: And in the past your research has covered links like you suggested insulin resistance and sugar consumption and Alzheimer's disease. What prompted you to make this broad or broaden your study to focus on overall diet and whole food in particular?

Willette: There's been a lot of work that's come out of Rush University and a couple of other places that really helped pave the way for our better understanding of certain kinds of diet and how that could potentially impact the brain, not impact the brain. For example, the late Martha Clare Morris along with David Bennett really had championed this idea behind like say mediterranean diet or related kinds of diets where we've seen, you know, if a person has a higher Mediterranean Score Index, that's going to be related to cognitive improvement over time or less cognitive decline. I have nothing against the mediterranean diet or any particular diet. That being said, all of them are very specific. They have very specific criteria and so you have a very kind of defined box. Some people are really in tune with what they eat from that perspective. Lots of other people, however, know the kinds of meals that they eat but they might not be able to really categorize them into, you know, ‘Oh I'm really into eating a lot of shellfish, for example, but not so much like fruit.’ It's the case that with whole foods, I think – just in recalling that over the last twenty four hours – it's much easier to recollect rather than saying, ‘Okay over a hypothetical week, how much beef have you eaten?’ So I think for participants, it's easier, if much more time intensive, to do a diet recall, but it offers I think more accurate data. I think that it also offers us a window into different kinds of associations that we might not expect like, for example, growing up as a kid I would always hear you have to eat your vegetables. You can't have two different kinds of starch. If I think we focus on these diet scores – again they're great, but sometimes they might miss these really kinds of unexpected associations that we see. This is the one that continually popped out at me; no matter how we ran the analyses or what kinds of covariates we included, the one kind of food that continuously came up that was associated with not just maintaining cognition over six to ten years, in some cases like actual improvement, was cheese. I would never have thought in 1,000,000 years that the particular food would be related to cognition or if it would be, you know, you kind of expect more saturated fat. Of course it's going to be worse, but yeah, no it was cheese, followed up by lamb, red wine, and a couple of other things. All that really causes, I think, sort of a shift in our focus and that doesn't invalidate anything that we've done with regard to MIND diet studies or DASH or anything else like that. It does open the door for a consideration of maybe certain specific kinds of foods based on their micronutrient composition, anti-inflammatory properties, antioxidant properties. It might be worthwhile to kind of focus on those.

Chin: And before we get into this publication of yours from November 202, can you tell us a bit about some of your prior work in looking at glycemic index or sugar and its effect on cognition?

Willette: Sure. As I like to say, kind of my greatest hits album, really was from around 2015 to 2017-2018 where with the Wisconsin Registry for Alzheimer's Prevention or WRAP, we had looked at insulin resistance or fasting levels of glucose and some other kinds of biomarkers and their relationship to brain glucose uptake, brain atrophy, brain amyloid. Basically doing a series of different analyses to really see if there was some kind of consistent association that we could see in the brain, as well as with cognition, that kind of paired with my interest at the time – still a big interest of mine – which is this problem with regulating energy and specifically how insulin progressively has difficulty regulating the amount of glucose that you have in circulation because, well, of effects of obesity. Yeah, we consistently found that there was an association with higher insulin resistance, for example, and less glucose uptake – and so therefore less ATP, less brain energy broadly speaking – in parts of the prefrontal cortex and the posterior part of the medial parietal lobe, areas that are really important for trying to get relevant memories online, relevant to your particular context, and also getting those memories from long-term storage. What struck me was that we consistently saw this same kind of an association regardless of the scan, regardless of whether it was cross-sectional or whether we had a series of different kinds of scans of something like longitudinal data. It showed this same kind of spatial relationship that seemed to pair really well with not just areas that are sensitive to Alzheimer's disease but also ones that require insulin in order to not uptake all the glucose per se but just to uptake some of it. I kind of liken it to – there are some brain areas that require insulin for, I think, particularly complex cognitive processes. I can't think of anything more complicated than trying to figure out why we're somewhere, what we're supposed to be doing there, how we can react to the environment in real time. So with the WRAP cohort, Ithink we did a number of correlational studies that really kind of established that as a foundation that some people have built on from there. I think really other than that, now we've just tried to tackle really every – every component part of Alzheimer's disease. We had one recent paper looking at tau, for example, and seeing if insulin resistance and glucose was related to tau uptake. Clearly there is an important relationship. The next step, I think though, was to try and see well, how do we incorporate diet? How do we incorporate something that we might be able to, one, more readily understand kind of from a public policy standpoint in general public standpoint, but two also introduce some non-pharmacological kinds of interventions to see if, you know, changing those dietary components might lead to cognitive improvement or at least less cognitive decline.

Chin: Well, thank you for sharing your Dr. Willette’s greatest hits. I like that expression. Now I want to go to that publication, the one in November. It's called “Genetic factors of Alzheimer's disease modulate how diet is associated with long term cognitive trajectories,” and it highlights how a person's diet affects their cognitive ability as they age. Can you tell us a bit about the study and then what you discovered from it?

Willette: Sure. We were interested in looking at a community cohort of people who weren't necessarily enriched for having Alzheimer's disease markers or having a family history of it. We used dietary data, as well as cognitive data from UK Biobank. This is a massive database of wonderful, wonderful information where they have included, among other things, little ambitious goals like trying to scan a 100,000 participants, and not just doing say looking at brain volume but also looking at brain activity as well as some other facets of brain structure and brain function. And it's really remarkable the amount of data that they've collected. So, among other things, they've done a gene chip array in order to look at different kinds of amino acid changes, different base pairs in our genome to allow us in our study to specifically focus on the apolipoprotein gene in particular the ApoE4 haplotype, which is the strongest known genetic risk factor for Alzheimer's disease. From that standpoint, we had a lot of people who over a six to ten year period of time showed some cognitive decline, very steep cognitive decline, in some cases people who had improvement over time, in a specific kind of cognitive function called fluid intelligence – the ability to rationally think through and utilize novel information without prior knowledge. Basically it's kind of the gold standard. We were interested in looking at how these people from the UK, over a span of six to ten years, differed with regard to this two-minute test where they try to answer these GRE-like questions as quickly as possible. ‘Bud is to child as blank is to adult,’ and you have to select, from multiple choice, what the most applicable answer might be. It has some pretty good test-retest reliability. It has some good neuropsychological properties that we felt accurately reflected what was going on with these people. What we did was we took a particular dietary questionnaire looking at diet over a week period of time as opposed to the more fine-grain stuff, which we've since started doing some analyses on. The question was – number one, is there any kind of substantive association with diet and this change in fluid intelligence over time? Number two, did it differ by whether or not you were ApoE4 negative versus ApoE4 positive? We proceeded along with these associations and, among some of the less exciting findings, we found that if you're ApoE4 positive it is important to keep track of exactly how much salt you intake because salt intake was related to worse cognitive function, but only for people who were ApoE4 positive as opposed to negative. So there are little tidbits here and there throughout the report, but again what struck me and why I kept asking the first author, Brandon Klinedinst who's a PhD student in my lab, to keep redoing analyses or trying to splice this in different ways was it kept telling us that cheese was really, really good, that at least as a correlate, it was highly correlated with these changes in fluid intelligence. It wasn't just say, this was – for  the outcome measure, it was on a one to 13 point scale. One point over time would be, you know, a fairly substantive change. This wasn't just, say, like a fifth of a point or half a point. For people who basically ate cheese all the time versus people who never ate cheese, this is a difference over a time of about two points, if I recall correctly. It was fairly substantial. Even for people who ate cheese most of the time or even some of the time, there is something about cheese-eating that wasn't related to socioeconomic status. It wasn't related to racial or ethnic category. It wasn't related to age or sex, but yet it had this powerful association and that was regardless of whether you were ApoE4 negative or ApoE4 positive. The other big one is in order to – for the podcast I'll nerd out a little bit. Basically alcohol in general seems to be bad for cognition but for people who are ApoE4 negative, the more red wine you consumed the better. For people who were ApoE4 positive, as I recall it didn't matter what kind of alcoholic beverages you had – it could be liquor, it could be beer – but that increased consumption was related to better cognitive performance. That being said, in order to simplify things – the way at least I advertise it was to say that – if you, assuming correlation is causation, if you did drink more red wine that that was related to more cognitive benefit, that is less cognitive decline, in some cases modest increases in cognitive performance. Again, we retested that. We looked at all sorts of different covariates and pretty consistently, yeah, we found that cheese, red wine, and lamb were all associated with better cognitive performance.

Chin: I mean, I appreciate you being able to laugh throughout this but that is pretty incredible. And so granted, now I'm interviewing you from Madison, Wisconsin – you know, the cheese state – and so, of course, this is big news for us because good luck getting someone from Wisconsin to not eat cheese. Of course, we want to hear this. We want to know, you know. Then, I appreciate the comment about the alcohol and the fact that you do differentiate those who are ApoE4 positive, thus at risk, versus those that are negative and maintain kind of a standard risk. And so what do you think the mechanism is for all of this, as far as the cheese or as far as the alcohol? I mean, what do you think could be a reason why these are beneficial for people?

Willette: From what we've seen in the literature and based on some preliminary analyses that we've been working on but haven't yet published, we think that it – again, assuming that it is causal, what in essence seems to be happening is there is a lot of antioxidant activity in particular stuff like glutathione is higher in certain kinds of cheeses. So what we've found is it's – cheese in general seems to be good, but in particular it appears to be the so-called hard cheeses. Hard cheeses among other things have higher levels of these various antioxidant and inflammatory biomarkers that can at least suggest why we might see this association because when we think of cheese, initially we think of saturated fat. Curiously enough, I don't know. This might explain in part why people from France are able to eat whatever they want to eat and not suffer from such massive cardiovascular risk so that cheeses are more complicated than we might originally kind of give it credit for, I suppose. For red wine, much the same fashion because, well, all red wine is besides some sulfides and some other preservatives – I mean it's so alcoholic grape juice. Nonetheless, there is a potential molecular basis for kind of what we're seeing. So our next step is to take this existing data and instead of data over a week-long period of time, look at it over 24 hours. We actually now have, in the UK Biobank, markers related to antioxidant activity. We can, at least incrementally, try and see if this initial hypothesis of ours might work out in the data. If it does, great. If it doesn't, then we try and figure something else out, but yeah I believe predominantly it's antioxidant activity. 

Chin: So if you're someone – like for our audience members, if you are someone that you know that has ApoE4 you should be very careful of your salt and it doesn't matter what type of alcohol you drink, that there would still be benefit. If you're not ApoE4, then still be careful with your salt, but not as much of an issue, and red wine in particular seems to be the thing.

Willette: Yeah. Just besides the things that you mentioned, I think there have been several reports out there that have stated, well, increased alcohol consumption might be a bad thing. Other reports say that increased alcohol consumption might be a good thing. The literature is pretty mixed so I'm not necessarily advocating that people go out and buy like twelve bottles of their favorite cabernet right now, but what I am saying is that we, in a very large study, possibly largest of its kind at least based on my knowledge at the time, found an association that we think is pretty clear cut. We would like to follow this up with actual clinical trials to see if something as simple as these dietary changes might be beneficial. Until then, I would say that some of the dietary advice falls along with whatever your doctor might put forward, but there is a potential for actually having some foods that we normally might stay away from, in particular cheese.

Chin: And I'll add to your caveat and say before this interview I did look up to see about the relationship between alcohol and cardiovascular disease, which it seems like alcohol actually at light to moderate amounts can reduce cardiovascular disease. Certainly the field is still mixed on alcohol and cancer risk, where certain types of cancer it does seem there could be a relationship, so you're absolutely right. It depends on what you're looking at. As a geriatrician in clinical practice, we never recommend more than one drink a day whether you're male or female based on our literature, so I agree with you. I'm gonna put that out in the podcast as well. I wonder, how do you reconcile these important findings, particularly the cheese, with things like the MIND diet that say, ‘oh be very careful’. It's actually one of the five that it's to limit or be cautious of cheese.

Willette: I think – and it's been a while since I've dissected it but – they advocate for limiting dairy intake in general but they also then mix. For something like milk, in particular for say like whole milk, again it depends on the sample size when the study was done. It used to be the case that whole milk was considered bad and so then there was this huge push on having 1% and skim milk and so on. Then there was an idea that whole milk is actually better. So with some of the recommendations of the MIND diet, they are geared around, well obviously, what was a staple diet of people around the Mediterranean for thousands of years. I forget what they advocate or what they say about feta cheese, but feta cheese is certainly occasionally used as a garnish in some of their foods. Down around the Mediterranean, it would be unlikely – at least from what I understand, beyond like goats milk and a couple of other products – that dairy would be heavily involved in their diets. Certainly any kind of milk as we know it from cows, but I think the recommendations partly involve this series of associations that we've seen with lower cardiovascular risk, increased longevity, and so on that led to the interest in Mediterranean diet. Some people could certainly correct me on this. I could be wrong, but there was evidence for olive oil potentially being important just because of its antioxidant properties and fat content. The idea of having a lot of vegetables, having a lot of fruits. Certainly I could see all of the dietary components that were included. For the ones that were excluded, however, I think to some degree that might get conflated with at least nutritional information or nutritional recommendations that we had 20 or 30 years ago that we still have to some degree because it is so hard to do nutritional studies correctly – especially correlational ones – where because there was an absence of or at least a relative absence of most kinds of milk as we know, most cheeses as we know it, that with a Mediterranean diet the idea was well, we just simply avoid these foods and you should be good. Myself not being a clinician or a registered dietitian of nutrition, I can't make any firm recommendation one way or the other. All I can say is that adherence to the MIND diet has very consistently been related with better cardiovascular outcomes and stuff like that, but it's always important to remember kind of the context of where some of these – some of these kinds of diets have come from and sometimes the absence of evidence is not the evidence of absence.

Chin: No, that makes sense to me. That makes sense because this is very complicated and one of the first things you said in the beginning is food science is complicated. When you bundle and group certain foods and then study them that makes it even more complicated because we don't know which variable has meaning positive or negative, so I can appreciate that. Based on your findings here and the solid nature, the numbers itself, and the different ways that you try to disprove the finding, it seems very understanding and reliable that cheese is beneficial. I wonder, and for my last question for you, is based on your research on brain health and diet, what dietary changes have you made in your own life and that you might recommend to friends and family about their own brains and protecting or reducing their risk of Alzheimer's disease?

Willette: As we like to say, as an N of 1 – so that means just for what I've done and what's worked for me. Let's see, yeah based on those findings, well because my wife is lactose intolerant I can't test out the cheese part. With regard to red wine, I feel like just beyond alleviation of stress, which especially during the heydays of the pandemic were there on a fairly regular basis, I felt like it led to kind of a mild improvement over time. I also was generally good about not eating processed red meat, buying a lot more chicken, a lot more seafood. For some of the beneficial associations that seem to show up, I did try and act on those in my own life. To what degree they improved or didn't improve things, I know it could be debated but I lost weight, I felt better. It certainly seemed like I was a little bit sharper cognitively, but again, that's just me.

Chin: Well, we'll take that though. So thank you for joining us on Dementia mMatters. We hope to have you on when you have more findings to report.

Willette: Yeah, yeah, I'm really looking forward to getting our future workout where we can dig in and begin to say that hard – it's hard cheese as opposed to just cheese in general, so yeah, I'd love to come back.

Outro: Thanks for listening to Dementia Matters. Be sure to follow us on Apple Podcasts, Spotify, Google Podcasts, or wherever you get your podcasts to be notified about upcoming episodes. You can also listen to our show by asking your smart speaker to play the Dementia Matters podcast. And please rate us on your favorite podcast app -- it helps other people find our show and lets us know how we are doing. Dementia Matters is brought to you by the Wisconsin Alzheimer's Disease Research Center. The Wisconsin Alzheimer's Disease Research Center combines academic, clinical, and research expertise from the University of Wisconsin School of Medicine and Public Health and the Geriatric Research Education and Clinical Center of the William S. Middleton Memorial Veterans Hospital in Madison, Wisconsin. It receives funding from private university, state, and national sources, including a grant from the National Institutes of Health for Alzheimer's Disease Centers. This episode of Dementia Matters was produced by Rebecca Wasieleski and edited by Caoilfhinn Rauwerdink. Our musical jingle is "Cases to Rest" by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's Disease Research Center and Dementia Matters, check out our website at adrc.wisc.edu. You can also follow our Facebook page at Wisconsin Alzheimer’s Disease Research Center and our Twitter @wisconsinadrc. If you have any questions or comments, email us at dementiamatters@medicine.wisc.edu. Thanks for listening.