LATE, Explained

causes of dementia. Whether it be Lewy  body disease or frontotemporal disease, there's so much we have yet to learn about  these neurodegenerative conditions. However, there is one that we know very little about, known  as LATE, or Limbic Predominant Age-Related TDP-43 Encephalopathy, and this is a kind of dementia  that causes problems with memory and thinking due to abnormal clusters of a protein called  TDP-43. Yes, for those who recognize this protein,

it is the same one that causes frontotemporal  disease, but more on that later. Joining us to talk about LATE is Dr. David Wolk. Dr. Wolk is a  professor of neurology and chief of the Division of Cognitive Neurology at the University of  Pennsylvania Perelman School of Medicine. He also serves as the director of the Penn Alzheimer's  Disease Research Center, co-director of the Penn

Institute on Aging and co-director of the Penn  Memory Center. As part of his work, Dr. Wolk focuses on the diagnosis and care of individuals  with a variety of neurodegenerative diseases, and examining biomarkers that differentiate  healthy aging from the earliest transition to Alzheimer's disease and other forms of  dementia. Welcome to Dementia Matters, Dave. Dr. David Wolk: Thank you. It's great to be here. Chin: I'm going to start with a basic question,

but it probably requires a little bit  of time for you. What exactly is LATE?

generic term meaning it affects the brain. It is  really a very newly-defined condition. It was in 2019 that the first pathologic criteria for  LATE came out, and so we're just starting to learn a lot more about that condition. Chin: You used the word pathologic, which I'm glad you did because, for our  listeners, my next question is how has it been identified so far and, now that we've  identified it, do we know how common it is?

Yeah, so the vast majority of work with  LATE has basically been done under the microscope looking at brain tissue where it has been seen  that in these older adults, people more than the age of 80 usually although sometimes younger  than that, and often in conjunction with other diseases like Alzheimer's disease, pathologists  have seen under the microscope TDP-43 in these limbic regions. Somewhat as a surprise in that as  you mentioned earlier, TDP-43 is often thought to

be associated with frontotemporal dementia or  ALS or Lou Gehrig's syndrome. The vast majority of studies have described TDP-43 as building up  in these structures in older adults over time, and when it's been looked at in large populations,  community samples or research samples, about 30-40 percent of people over the age  of 80 will have this condition. In many ways, it's actually a much, much more common condition  than frontotemporal dementia or ALS as connected

to this particular protein. More recently,  there have been attempts to define the condition clinically in addition to pathologically, and so  we're just starting to get a better sense of what it looks like in clinical populations. Chin: Of course, when you say clinical populations, you mean living people. How  are we discussing it or how is it being planned to be diagnosed in living people?  Because usually we're thinking about key

features the same way we have thought about  Alzheimer's. What are the key features of LATE from a clinically diagnostic perspective? Wolk: Yeah. I think just in terms of taking a little bit of a step back, Alzheimer's disease  historically was something that we definitively could make a diagnosis with at autopsy, whereas  there were certain signs and features during life that helped us probabilistically get a  sense of whether or not someone likely had

underlying Alzheimer's disease. I think we're kind  of at the same stage as that with LATE. Now with Alzheimer's, we have all these great markers of  the molecular pathology, the amyloid and tau that builds up in the brain. We don't yet have that  for LATE. What you look for are features that are suggestive of this condition. It turns out it  overlaps quite a bit with Alzheimer's disease. In fact, I think of it as one of the great mimics of  Alzheimer's disease. Because it's affecting memory

areas of the brain it tends to be associated with  significant amnesia. Unlike Alzheimer's disease, the amnesia tends to be a bit more isolated in  individuals relative to other areas of thinking like language, executive functioning, visual  spatial functioning. It tends to be a bit more focused. It also tends to move a bit more slowly  than Alzheimer's disease. There are some features

that we look for on brain imaging. On an MRI  scan or on a FDG PET scan, which is a metabolic scan to measure brain activity, there are certain  patterns that we see that are suggestive of this condition that might help differentiate  it from Alzheimer's disease, including actually generally more severe hippocampal  atrophy in this condition than Alzheimer's, even though we often think of Alzheimer's as  being associated with hippocampal atrophy.

we described. We've also, though, been working  on more formal criteria, clinical criteria that is about to come out. It's accepted, but will  be published, I think, in the next week or two,

where we also place an emphasis on ruling  out Alzheimer's disease in these cases. In individuals who come in with a primarily amnestic  presentation, who have significant atrophy–for example, in their hippocampus on MRI–and don't  have markers of Alzheimer's–they're amyloid negative, for example–most of those cases, many  of those cases are going to have underlying LATE, particularly if they're in the right age range in  their 80s or late 70s and certainly in their 90s.

One is that when patients come to see you, they  want to know what their diagnosis is. I think part of our job as clinicians is to kind of demystify  what is going on with people so that they have a better sense of what's happening in their brain,  what's causing the symptoms they're having, as well as what might happen to them over  time. One reason really that one would want to distinguish LATE from Alzheimer's is it has  prognostic implications. LATE does tend to be,

again, a slower-moving disease than Alzheimer's  disease. Two, on the other side of the coin, we now have therapies for Alzheimer's disease  with immune-based therapies where knowing that you have Alzheimer's is important as well.  Three, I think because of those therapies, there are going to be a lot of patients that come  into us with memory problems who end up not having amyloid evidence of Alzheimer's disease and aren't  candidates for therapies like the anti-amyloid

therapies that are currently approved. Those  individuals, again, will want to know, well, okay, I don't have Alzheimer's, so then what do  I have and what can I expect in the future? Then finally, once we start to be able to identify  people during life as opposed to at autopsy, one can start to learn more richly about how  the disease progresses, get more detailed testing and understanding, learn more about the  genetics and ultimately perform clinical trials

in those individuals. You can't really test  new drugs or things that are targeting this protein or this process without being able to  identify those people in life. It's an important first step to even move on to getting therapies. Chin: Well, then let's talk about the complicated mixed disease where you have multiple pathologies  in the brain. How does copathology with LATE, and other diseases for that matter,  impact Alzheimer's and Alzheimer's

treatments like you just mentioned? Wolk: Yeah. To me, I think this is one of the most important areas within Alzheimer's  disease is that I think we all recognize now that probably the least common form of Alzheimer's  is just Alzheimer's disease alone. Many patients, and up to 50% with Alzheimer's, have concomitant  LATE pathology. There are other pathologies that are also common, like alpha-synuclein, which is  often associated with Parkinson's and Lewy body

disease. It seems pretty clear from the data we  have that when people have these copathologies, the disease tends to progress more rapidly over  time and tends to have sort of mixed features of both Alzheimer's and these other conditions.  Understanding and knowing what the copathologies are in individuals who have Alzheimer's disease  is critically important for understanding, again, what's going to happen with them but also for  us to begin to learn, do some of these new drugs

that target Alzheimer's, how do they impact these  other diseases? It could be the case that people with Alzheimer's and LATE maybe don't respond  so well to these drugs. Maybe in those cases, you might think, all right, well this is not  someone we want to prescribe a drug that has potential side effects if it's not going to help.  On the other hand, I think it's certainly possible because there does seem to be a synergy between  these pathologies that maybe it helps with both

conditions. Maybe these are the patients that  most robustly respond to these drugs. I think it's a really important thing for our field  to begin to grapple with the heterogeneity of Alzheimer's disease, in particular related  to these copathologies, because it really

influences outcomes and ultimately will influence  therapeutics. Hopefully when there are other therapeutics in the future that maybe target  different aspects of all of these diseases, it might allow us to tailor our therapies to  individual patients based on what the sort of

conglomeration is of pathologies that they have. Chin: So you're giving another reason why it's so important to study even our clinic  patients, particularly those that are on these new therapies, so that we can  better understand what's happening in

the brain and how that impacts these outcomes? Wolk: Yeah, absolutely. I think as a director of our Alzheimer's center, that one of  the most important missions now that we have these therapies out there is to actually  learn from what happens to patients with these therapies and to collect as much data as possible,  obviously with patients if they're willing to do so. Although I have found actually many of our  patients are willing to share as much data as

possible when they're on these therapies. We've  built actually a program at Penn around this, where we're collecting research quality imaging  data in all of these patients as they go through the course of therapies, banking blood for  measuring genetics and proteins and other

markers. We're banking spinal fluid if they  happen to get a lumbar puncture and adding in actually additional kinds of measures and tests,  all with the idea that if we could start to learn based on some of the clues that we're getting  about when individuals have these copathologies or other sort of sources of heterogeneity, how  people respond to these drugs. I think LATE, again, is an important player in this  interaction with Alzheimer's disease

and potentially the responsiveness to therapies. Chin: One of the things I hear a lot when I'm out in the community is a phrase of when you've seen  one case of Alzheimer's, you've seen one case of Alzheimer's. While ultimately people progress  through dementia and the changes that happen in

dementia do feel similar as a clinician when you  see multiple patients, it is a unique course. A part of me does wonder, and I'm not asking you to  answer the question, but a part of me wonders if that unique course is because not only a person  is different and has different strengths and therefore different changes, but they could  have different diseases in the brain that we

just haven't been able to identify such as LATE. Wolk: Yeah, I think I totally agree with you. I think trying to understand these copathologies  may be one of the sort of sources of variance across patients that is going to help us better  understand our patients clearly. I used to do a talk where I basically described like three  different cases, all of them really completely different, and each of them were Alzheimer's  disease. The reality is that's not an atypical day

for me in a clinic is to see very varied patients.  I think a lot of it has to do with copathologies. You did mention, perhaps you can  repeat it again, how frequently LATE occurs with Alzheimer's. Then do we know, is LATE  occurring with Alzheimer's more than it occurs with vascular disease and Lewy body disease? Wolk: It occurs–by LATE stage Alzheimer's and about 50 percent of individuals will have TDP 43.  Probably at more early stages, the numbers are a

little bit lower, more like 20, 30 percent. When  we think about people perhaps when they would come to a therapeutic trial, maybe we're talking  a little bit lower than 50 percent, but still certainly a large proportion of those patients. It  occurs pretty frequently also, though, with Lewy body pathology as well. I don't think we really  know exactly the numbers relative to Alzheimer's disease for Lewy body disease. There is some  link with arteriosclerosis and LATE. People who

have small vessel disease are more likely to have  LATE as well. There does seem to be an interaction with a variety of copathologies. In fact, in  Alzheimer's disease when you have one copathology, you're more frequently like to have yet  another pathology than if you don't have a second pathology. There does seem to be  synergy across these different conditions.

I don't want to put you on the spot,  but could you give us an example of someone who might be experiencing the symptoms of  LATE or how you thought it was Alzheimer's ended up being LATE or vice versa? Just so our  audience knows, as a clinician who sees this, what should we expect? What does it look like? Wolk: Yeah, so I've seen a number of patients who

have come in with, for example, mild cognitive  impairment with primary memory issues. We'll do testing on them and when we do sort of standard  tests, they'll show some problems in memory, often sort of modest problems in memory. Generally,  though, pretty good function. Generally, other aspects of thinking are pretty good. You'll get an  MRI scan and you'll see a little bit of atrophy in the medial temporal lobe, sometimes a little more  than maybe you would typically see early in the

course of Alzheimer's disease. Generally in the  past, a lot of those patients we've just said, well, that seems like the early stages of  Alzheimer's, they'll likely progress to a dementia level of impairment. What we've noticed is they  come in a year later and they still kind of look the same. You know, the memory problems, still  functioning well. We're like, OK, it's slow-moving Alzheimer's disease. Then they come in a year  later and a year after that, and they're still

showing kind of memory problems. Maybe the memory  is getting a little bit worse and occasionally a little bit of language problems, but really not  progressing at the rate that we expect to see for Alzheimer's disease and you start getting a  little suspicious about it. Then we've had cases like this where we've since gone on and gotten  an amyloid scan or a lumbar puncture, and then they end up being amyloid negative. Suddenly we're  like, wait, this patient doesn't have Alzheimer's

disease. They have something else affecting their  memory network. They have obvious injury to it. You can see it on a scan. Those cases tend to  be the cases where LATE is the primary driver of their symptoms. Again, I think back to actually  one of the first patients I saw–who I don't know to have LATE, but I really suspected–one of the  first patients I saw at Penn who really had severe memory loss. I mean, constantly asking, why am  I here? Why are we doing this testing? Nothing

else was impaired on our testing. She came in for  about 10 or 15 years. She passed away in her mid to late 90s and never manifested other symptoms  of Alzheimer's. I called her Alzheimer's all the way throughout the entire course and figured  she had passed away from Alzheimer's. Again, we don't have autopsy on her, but now, in  retrospect, she probably had LATE. It was before we really even had that condition defined. Chin: Will you mention the value of amyloid PET

scans, spinal fluid, the future blood-based  biomarkers? Do we have a biomarker? Are we close to having a biomarker for LATE? Wolk: I think we're pretty close, actually. I think there's a couple of really promising  lines of potential biomarkers for TDP-43 more generally. Not just for LATE, but potentially for  other causes of diseases associated with TDP-43. There are something called cryptic peptides. You  know, it sounds kind of funky or crazy. They're

mysterious, if you will. Basically those are  peptides that are produced in the setting of TDP-43 dysfunction because TDP-43 plays a role in  how RNA is processed. When it's not working well, you get proteins that you just generally don't see  in normal health. While the protein levels aren't very high, there's a high signal to noise because  there's not a lot of noise of those proteins in normal individuals. There's been some really  compelling data that those may be really helpful

for measuring this disease in spinal fluid and  potentially even in blood. Then there's this other test looking at little vesicles, extracellular  vesicles that bleb off of neurons and other brain cells that you can actually also measure in  plasma. They serve as cargoes for what's going on in brain cells that you can kind of measure in  the blood. There's been some really compelling data recently. Much of it needs to be replicated,  showing that you can pick up higher levels of

TDP-43 in people who have conditions associated  with it. I think between those two lines, I feel fairly confident that over the next few years, as  the science advances and our detection advances, that we'll be able to have a biofluid-based  biomarker. There are also PET tracers that are in development that we'll also see as well. One  of my concerns with LATE is the amount of TDP in the brain is not so high that it might be hard to  see that visually with a PET scan. That also is a

potential area that we could have a biomarker. Chin: Well, that sounds exciting, and we won't hold you to the number of years. You did answer  my next question, which is what are the next steps or studies in the field? Is there anything else  that you see in the next few years in the realm of LATE that you'd want our listeners to know? Wolk: Yeah, so I think one will obviously be

the development of better biomarkers. I think  we also need to do larger descriptive studies of these patients, as we do have clinical  criteria out there that at least allow us to enrich populations and people who  likely have this condition. I think we need to better sort of characterize those  patients with regard to genetics, biology,

but also just what their cognitive symptoms  and other kinds of behavioral symptoms. I also think because there's so much work in targeting  TDP-43 across frontotemporal dementia and ALS, that potentially some of the drugs that are being  used in that domain could be applied to cases with LATE. I think we hopefully will enter, relatively  quickly, a sort of therapeutic era where we're at least enrolling individuals in clinical trials.  I would hope over the next few years that there

are the beginnings of more clinical trials. Chin: Well, that sounds exciting. All right. With that, I'd like to thank you for being on the show,  and we certainly hope to have you back again.

to End Alzheimer's. All donations go toward  outreach and production. Donate at the link in the description. Dementia Matters is brought to  you by the Wisconsin Alzheimer's Disease Research Center at the University of Wisconsin-Madison.  It receives funding from private, university, state and national sources, including a grant from  the National Institutes on Aging for Alzheimer's Disease Research. This episode of Dementia Matters  was produced by Amy Lambright Murphy and Kaylin

Rowerdink and edited by Eli Gadbury. Our musical  jingle is Cases to Rest by Blue Dot Sessions. To learn more about the Wisconsin Alzheimer's  Disease Research Center, check out our website at adrc.wisc.edu. That's adrc.wisc.edu and follow us  on Facebook and Twitter. If you have any questions or comments, email us at Dementia Matters  at medicine.wisc.edu. Thanks for listening.