#511 Alzheimer's Disease: Updates in Diagnosis and Treatment

Summary

Curbsiders Internal Medicine Podcast

Episode 511: Alzheimer's Disease — Updates in Diagnosis and Treatment

Release Date: January 12, 2026
Host(s): Dr. Matthew Frank Watto, Dr. Paul Nelson Williams, Dr. Natalie Barrett
Guest: Dr. Halima Amjad, Geriatrician & Dementia Specialist, Johns Hopkins

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Episode Overview

This episode features a deep dive into cutting-edge developments in the diagnosis and management of Alzheimer’s Disease. The Curbsiders are joined by Dr. Halima Amjad, who brings her expertise as a dementia specialist and researcher to discuss:

• Nuances of diagnosing Alzheimer's disease, with a focus on differentiating dementia and MCI
• The emerging role, limitations, and interpretation of plasma-based biomarkers
• Considerations for anti-amyloid therapies, including safety, efficacy, and patient selection
• Controversies and unknowns in the field as practice and evidence rapidly evolve

The hosts also share practical tips, reflect on the complexities of real-world care, and discuss ongoing changes in how internal medicine and primary care should approach dementia and Alzheimer’s in 2026 and beyond.

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Key Topics & Insights

1. Establishing the Diagnosis: Dementia vs. MCI

(06:41–09:59, 12:37–17:14)

• The importance of detailed cognitive and functional history, especially in trained, high-functioning individuals.
• Deficits in delayed recall and short-term memory (moCA/MMSE) are key tip-offs for Alzheimer’s over normal aging.
• Functional history is crucial to distinguish MCI (intact function) from early or mild dementia (some new impairment).

  “It is really the functional impairment that differentiates MCI — mild cognitive impairment — from mild or early stage dementia.”
  —Dr. Halima Amjad (13:20)

• Imaging (especially MRI findings like mesial temporal lobe atrophy) can be suggestive but not diagnostic.
• Co-existing vascular risk factors and imaging findings are common; clinicians must consider them but not over-attribute.

2. Plasma Biomarkers in Alzheimer’s Diagnosis

(23:31–34:12)

• Blood-based biomarkers (notably P-tau217 and the Aβ42/40 ratio) are becoming available but are currently only validated for people with objective cognitive impairment—not for asymptomatic patients or "worried well."

  “All the guidelines… are only indicated for checking them in people who have evidence of cognitive impairment… It is not for the worried well…”
  —Dr. Halima Amjad (23:41)

• Direct-to-consumer testing is rising; clinicians must be prepared to counsel on limitations and appropriate use.
• Blood biomarkers are screening tests — confirmation (e.g., amyloid PET, CSF) is still required before anti-amyloid therapy.
• APOE genotyping often comes up, especially with anti-amyloid therapy eligibility and patient/family concern. It increases risk but is not determinative.

Notable Quote:

“It is okay to defer [blood biomarkers] to a specialist if you’re not comfortable yet... What will we do with the results?”
—Dr. Halima Amjad (25:50)

3. Anti-Amyloid Therapies — Who, When, and How?

(42:37–51:55, 45:14, 52:24–62:47)

• These treatments (e.g., lecanemab, donanemab) are approved only for mild cognitive impairment or early Alzheimer’s—NOT for moderate/severe disease.
• Numerous pre-treatment safety steps:
  • Confirm amyloid positivity (PET/CSF)
  • Rule out excessive microhemorrhages
  • Check APOE genotype due to massively higher ARIA risk in homozygotes (most centers treat this as a contraindication).
  • Screen for stroke, seizure, advanced comorbidities, active immunosuppressant therapy

  “If someone has more than four microhemorrhages... we are looking at the MRI to count the microhemorrhages, make sure there’s no aneurysm or other abnormality, where we would worry about risks.”
  —Dr. Halima Amjad (47:50)

• Therapy requires intense monitoring: frequent MRIs (especially early), and patient ability to tolerate infusions/injections.
• Benefits are real but modest: these therapies slow progression by ~25–30% (~5–7 months over 18 months) but do not halt or reverse disease. Many patients will still decline meaningfully.

  “It’s slowing cognitive and functional decline a little bit. The people receiving these drugs—they still experience decline over time.”
  —Dr. Halima Amjad (58:30)

• Deciding to initiate therapy requires careful discussion about risk, benefit, and patient goals.

4. Anti-Amyloid Drug Safety: ARIA & Other Adverse Effects

(51:55–58:30, 70:30–72:59)

• ARIA: Amyloid Related Imaging Abnormality (edema [ARIA-E] or microhemorrhage [ARIA-H]) is the leading risk; most cases asymptomatic, but can be severe or fatal, especially in APOE4 homozygotes.

  “Most ARIA is asymptomatic… only about 3–6% have symptoms. That’s why MRI monitoring is so important.”
  —Dr. Halima Amjad (52:24)

• Other adverse effects: headaches, infusion reactions. Any new neurological symptom warrants urgent MRI (not CT).
• Ongoing therapy adjustments are being developed as long-term data emerge, especially when patients complete initial 18 months of treatment.

5. The Big Picture: Evolving Practice and Controversies

(58:30–68:51)

• The amyloid theory is not the full answer; drugs remove amyloid, but clinical effects are mild.
• Controversy remains: “Are we just kicking the can down the road?” Are we prolonging early disease or also extending severe stages?
• Long-term management plans undecided for patients after initial therapy – maintenance regimens (infusion/subcutaneous), repeated scans, and the need for protocols still being developed.
• Primary care currently should not be the main site for ordering or interpreting blood-based Alzheimer’s biomarkers unless there is significant expertise; this will likely change as evidence and systems evolve.

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Notable Quotes & Moments

• On Counseling & Patient Support:

  “People will forget what you said, people will forget what you did, but people will never forget how you made them feel. And I think when it comes to dementia care…that’s very true.”
  —Dr. Halima Amjad (05:28)

• On Functionality and Gray Zones:

  “...patients like this…sometimes they'll actually hear from one doctor that they have mild cognitive impairment, someone else will say they have dementia, and actually find myself kind of explaining to them why they might hear different things…”
  —Dr. Halima Amjad (14:36)

• On the State of the Field:

  “We’re living in pretty exciting times when it comes to dementia and Alzheimer’s…blood-based biomarkers…we have disease-modifying treatments…more attention and we’re seeing research translate to changes in clinical care…”
  —Dr. Halima Amjad (73:31)

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Timestamps for Important Segments

• 06:41 – Case introduction & differentiating dementia/MCI
• 13:09 – Functional assessment: when is impairment “dementia”?
• 23:31 – Plasma biomarkers: indications, limitations, patient counseling
• 34:12 – What are these biomarkers, exactly? Types & interpretation
• 42:37 – Biomarker result: next steps, therapy considerations
• 45:14 – Pre-anti-amyloid therapy safety evaluation and eligibility
• 51:55 – ARIA: what is it, how common, who's at risk?
• 58:30 – Amyloid controversy: efficacy and theory challenges
• 64:39 – 18 months of therapy: now what?
• 73:31 – Take-home points from Dr. Amjad

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Summary Take-Home Points

• Diagnosis of Alzheimer’s and appropriate use of new biomarkers require careful clinical context and a specialist’s input; blood tests are for symptomatic patients only.
• Anti-amyloid therapies are a significant advance but carry substantial risks, especially ARIA, and offer only modest slowing of decline in selected early-stage patients.
• Primary care should remain engaged but should seek specialist collaboration until protocols, experience, and evidence mature further. Stay tuned and up to date—this is a rapidly changing landscape.
• Patient/family counseling must set realistic expectations—these are not cures and involve complex safety monitoring.
• Research is ongoing: future directions may include preventive therapy and broader primary care involvement as practice evolves.

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For further information and resources, see show notes and referenced guidelines.

Transcript

[Dr. Matthew Frank Watto]

Hey, before we get to the show, I wanted to remind you to check out our [e-mail] curbsiders. If you haven't signed up yet, sign up now to get ad free episodes, twice monthly, bonus episodes, and a whole bunch of other cool [e-mail] curbsiders Paul, three conspiracy theorists walk into a bar.

[Dr. Paul Nelson Williams]

I feel like I could puzzle this one out. You probably could, but not in a way that won't bore our listeners. All right, go on.

[Dr. Matthew Frank Watto]

You can't tell me that's not a coincidence.

[Dr. Paul Nelson Williams]

That's a good one.

[Dr. Matthew Frank Watto]

Yeah, that's pretty good. Okay.

[Podcast Disclaimer / Narrator]

The Curbsiders podcast is for entertainment, education and information purposes only, and the topics discussed should not be used solely to diagnose, treat, cure or prevent any diseases or conditions. Furthermore, the views and statements expressed on this podcast are solely those of the host and should not be interpreted to reflect official policy or position of any entity, aside from possibly cash, like moral, hospital and affiliate outreach programs, if indeed there are any. In fact, there are non. Pretty much we aren't responsible if you screw up. You should always do your own homework and let us know when we're wrong.

[Dr. Matthew Frank Watto]

Welcome back to the curbsiders. I'm Dr. Matthew Frank Watto, here with my great friend and America's primary care physician, probably the primary care physician, Dr. Paul Nelson Williams. Hey, Paul.

[Dr. Paul Nelson Williams]

Yeah, probably. Hey, Matt, how are you?

[Dr. Matthew Frank Watto]

I'm doing well. Paul, this is an episode. We talked about dementia. We talked about plasma biomarkers, we talked about antibiotics, anti amyloid therapies. Some of the controversy around them, how to monitor it was pretty cool. Our guest was a former schoolmate of mine from elementary school, kindergarten, Dr. Halima Amjad. Yes, we went to kindergarten together and we did not know that until we started recording. Paul, you're going to tell us you're going to introduce our producer in just a second. But before we do that, can you remind people, what is it? Why do they listen to this show? What do we do on Curbsiders?

[Dr. Paul Nelson Williams]

Yeah, I can't speak to why people listen to us, Matt, but I can tell you what we do and what we are. And what we are is the internal medicine podcast. We use expert interviews to bring you clinical pearls and practice changing knowledge. And as you alluded to, we are joined by our producer and co host. For this episode, we are joined by geriatrics fellow and producer extraordinaire, Dr. Natalie Barrett. Dr. Barrett, how are you?

[Dr. Natalie Barrett]

Hi, Paul. Thanks for having me, guys. Today we have a fantastic conversation with our guest Dr. Halima Amjad. Dr. Amjad is a geriatrician, health services researcher and associate professor of medicine in the Division of Geriatric Medicine and Gerontology at the Johns Hopkins University School of Medicine. She serves as a dementia specialist at the Johns Hopkins Memory and Alzheimer's Treatment center and as co director for their Guide Dementia Care Navigation program. Inspired by personal experience with dementia, she leads research focused on improving dementia diagnosis and care, particularly in the primary care setting. Today she'll be teaching us about plasma based biomarkers, antiamyloid therapies and their significance in the diagnosis and treatment of Alzheimer's disease. Without further ado, let's get started.

[Dr. Matthew Frank Watto]

And a reminder that this and most episodes will be available for CME credit for all health professionals through VCU Health at curbsiders.vcuhealth.org Halima, thank you for joining us. And I guess, long time no see. We found out that we went to elementary school together and haven't seen each other since. But the audience wants to know more about you and so do I because we need to catch up. So what is a hobby or interest that you currently enjoy outside of medicine?

[Dr. Halima Amjad]

So enjoy might not be the right word, but I am in that season of life where life is work and family. So I was going to say my biggest interest right now is probably reading parenting books and then unsuccessfully implementing the strategies they have. And the big reason for that is. And actually, Matt, the reason I remembered you because you were a multiple. So I have triplets who are eight and they're a lot to handle. My physician training did not train me for that.

[Dr. Matthew Frank Watto]

Oh, my gosh. Triplets. Yeah, that is. And what's the mix on the triplets there? Is it. What's the mix? Boys, girls?

[Dr. Halima Amjad]

I have identical boys and a daughter.

[Dr. Matthew Frank Watto]

Okay. I mean, children can be feral. I can attest to that personally. So bless you. Well, so what are the kids into these days? I think you said Pokemon. They were watching Pokemon right now? Maybe.

[Dr. Halima Amjad]

Yeah. So they're into Pokemon. They're into reading a book series that I don't love. I think it's like a Diary of a Wimpy Kid is all the rage these days. The boys have started wrestling, so it's loud and chaotic till they sit down and read. So we love that they know how to read now.

[Dr. Matthew Frank Watto]

Yeah. That's good. Just leave some books around, graphic novels, whatever. They'll read. That's fantastic. Okay. You're almost on the other side of it, I guess. I mean, I'm sure having three teenagers at the same age. That's going to be easy.

[Dr. Paul Nelson Williams]

They'll be moving out in 12 years. It's just, it'll be here before you know it.

[Dr. Halima Amjad]

Then there's just the college tuition. We just don't think about that.

[Dr. Matthew Frank Watto]

Paul, anything you'd like to ask about?

[Dr. Paul Nelson Williams]

Sure, yeah. I have no follow up questions regarding the triplets. That's so outside my realm of experience. So instead I will ask you if you would mind sharing with us some advice or feedback either that you've received or that you like to give. Period, end of sentence.

[Dr. Halima Amjad]

Yeah. So some advice that we actually share with a lot of dementia care coordinators and care navigators that we train that I feel like I've taken to when we share it with them is it's actually a Maya Angelou quote that we share with them that people will forget what you said, people will forget what you did, but people will never forget how you made them feel. And I think when it comes to dementia care, talking with patients and caregivers, that's very true. And certainly outside of dementia care too, I think any patients that we interact with, like learners, mentees, staff, just those interactions that we have and the impact that we can have on people if we make them feel heard, seen, you know, often again in the world of dementia, making people feel positive in a tough situation.

[Dr. Matthew Frank Watto]

That'S good advice. And I think, fortunately the bar in medicine in general is pretty low. So it's probably refreshing when they meet somebody that's actually trying to give them a good experience. That's great. Well, Paul, I think we should get to a case from Cash Slack. Natalie, would you do the honors of reading this first case?

[Dr. Halima Amjad]

Of course.

[Dr. Natalie Barrett]

Thanks, Matt. So Mr. E is an 87 year old man with a past medical history of hypertension, hyperlipidemia, pre diabetes, anemia and gout, who presents to your geriatric memory clinic for evaluation. He's sent in by his PCP who suspects Alzheimer's disease. Mr. E scored a 22 out of 30 on his mini mental status exam with deficits in the domain of delayed recall. Blood work including RPR, TSH and B12 were all normal. An MRI of his brain revealed mild small vessel ischemic disease with two microhemorrhages and bilateral atrophy of his mesial temporal lobes.

[Dr. Matthew Frank Watto]

Okay, so Mr. E, here. Halima, anything off the top that you're thinking when you get a case like this?

[Dr. Halima Amjad]

Yeah, so definitely, you know, I know we have sort of his medical history, obviously. Definitely want to get more history on what he's noticing memory wise. Of course we see the MMSE score is a little bit lower if you use a cutoff of 23 or 24, but it's not that much lower considering he's 87. And we know that age affects cognitive test scores. But for me, especially being in a memory clinic setting, just knowing that a primary care provider is concerned about Alzheimer's, of course raises flags for me. And then really wanting to ask more questions about primarily his memory and short term recall would be the things that I would be asking about and wanting to dig in more on. And then certainly I think on the MRI the things that I would be looking for. One, it doesn't sound like he has a lot of vascular disease. That's always something we're looking for. But then also the atrophy that we're seeing, that's kind of in the hippocampal area, the mesial temporal lobes is suggestive and concerning for Alzheimer's, although certainly doesn't make the diagnosis, but sort of makes me wonder about it.

[Dr. Matthew Frank Watto]

And this comment of microhemorrhages, I mean, I think mild small vessel ischemic disease is on like every, it's on like every MRI or CT scan, but the microhemorrhages you don't see as often, that would probably give me pause. But are radiologists starting to put that in now because of the new therapies that are out there?

[Dr. Halima Amjad]

Yeah, definitely. I think everybody's starting to look more closely at MRIs, especially if it's dementia protocol or someone might be a candidate for anti amyloid therapies and they are looking for microhemorrhages and counting them. Definitely we want to see 02 could be hypertension. But the other big thing we're thinking about or thinking more about now with the new treatments is could someone have cerebral amyloid angiopathy where you might see sort of numerous microhemorrhages?

[Dr. Paul Nelson Williams]

So I was going to ask before we even get to the imaging, which I'm glad that this astute primary care doctor just already went with the mri. But before we even get to that point, as we're talking to patients, I know when I'm giving a mini mental status exam like in my heart and brain, I'm just trying to will someone across the finish line to kind of go above the scoring threshold. But I guess when you're evaluating patients, are there any particular domains or anything in the history that kind of makes you lean towards Alzheimer's before you even get to cross sectional imaging or some of the biomarkers and stuff that we'll talk about. What things kind of shunt you in that direction or towards that or down that pathway specifically.

[Dr. Halima Amjad]

Yeah. So definitely history wise, a lot of times people will come in saying, oh, their long term memory is great. Right. It's a spouse, a family member often saying their long term memory is great but their short term memory isn't good. We'll ask about are they repeating themselves, repeating questions, repeating statements or stories, are they misplacing items? That one comes up pretty frequently. Or when you ask, everybody lights up like, oh gosh, they have been losing a lot of things. Right. And even during the appointment. Right. These are often the patients where they're asking me the same question after 10 minutes. That certainly for me is of course a red flag. Right. Of course when we're thinking about MCI or dementia, we're getting that functional history. Is anything getting harder for them? Right. Because where there's normal, just age related memory loss, trying to differentiate that, really getting to that functional history. Then on the testing, really in a typical amnestic presentation of Alzheimer's, really the focus is on that delayed recall. If it's three words on the mmse, five words on the moca, that delayed recall, how do they do there then? Of course they can have deficits in almost any other domain. But that's really what I focus on. It's not, oh, were they one day off on the date as telling as the recall? Or for example, if someone has a high level of education, are they struggling on some aspects that they shouldn't be? Like the subtraction. Although I think I wouldn't do too well on the subtraction myself.

[Dr. Paul Nelson Williams]

I think about this all the time. Even when I was an exhausted resident after a 28 hour shift assessing orientation, I would ask the date and there'd be an internal model panel. I have no idea what day of the week it is or what the actual date is. I don't know how to score this appropriately.

[Dr. Halima Amjad]

Yeah, no, I was going to say there too. We do have to, we're strict on the scoring. But that's where for me, whether it's the moca, the mmse, I look at the overall score. But then also what I'll sometimes tell patients is everybody gets a minus one if they didn't get, they didn't draw the figure correctly. But we've all seen there's the people where there's one line versus oh, they were so close. And to me that's telling. Even if the score score is abnormal. So even Just looking at. That's that same thing. Are they one day off? Are they pretty close versus they're just nowhere in the ballpark.

[Dr. Matthew Frank Watto]

Okay, Natalie, let's get some more history about our patient here, Mr. E. Yeah, sure.

[Dr. Natalie Barrett]

So you review cognitive and functional history and learn that Mr. E is a retired electrical engineer with a bachelor's degree from local university. He's independent in all ADLs and most IADLs, noting new cognitive difficulties with using a computer and directions in unfamiliar places. He and his wife enjoy traveling a lot, and he frequently gets lost. You perform a MOCA and he scores 20 out of 30 with moderate impairment, mostly in delayed recall, executive function, and detention.

[Dr. Matthew Frank Watto]

Halima, let's get into the diagnosis here and what the conversation might be like in that first visit with Mr. E and his wife.

[Dr. Halima Amjad]

Yeah, so getting this additional history is really helpful and I think getting that second cognitive test because the 22 out of 30 on the MMSE was abnormal, but not terribly so. So it's nice to have a different test on a different day to confirm the deficits. And being able to test executive function, being able to retest the delayed recall is helpful. And then. Right. Then differentiating. Okay. There's a subjective cognitive complaint. We're seeing evidence of objective cognitive impairment. Then the next big question, is there functional impairment? And in this patient, it does sound like he's starting to have some trouble. Right? He is driving, but maybe he shouldn't be if he's getting lost. He's an engineer, so he's probably someone who's been great with computers and now he's having trouble. That's where, from my perspective, I would probably classify this patient as having early or mild stage dementia as opposed to mild cognitive impairment. But this, to me, is someone who's in that gray zone. It's really the functional impairment that differentiates MCI mild cognitive impairment from mild or early stage dementia. The two milds is confusing. Maybe it's early stage dementia because there are patients like this where they're managing their finances, but it's all put on auto pay. Right. So they're still independent, but really they're having trouble. And so patients like that too, sometimes they'll actually hear from one doctor that they have mild cognitive impairment. Someone else will say that they have dementia and actually find myself kind of explaining to them why they might hear different things, that there's this sort of gray zone. Especially nowadays when there's all these. Right. You can use gps. There's other ways that you can get around some of the Functions, functional challenges that you're having. But for a patient like this, like I said, I would talk through that. Often the patient is hoping that they just have normal cognitive aging. So I'll usually explain to them kind of the spectrum of cognitive concerns that we're thinking about in a memory clinic setting. I usually explain that most older adults do experience normal cognitive aging. They might have some trouble with attention, with memory, but it's usually mild. It's a nuisance to the person, but not usually noticeable to the person around people around them, and it doesn't affect their activities. Then I'll explain that on the other end of the spectrum is dementia, which is just an umbrella term for cognitive changes that are affecting someone's activities or the things that they're able to do. If it's relevant, I'll actually explain mild cognitive impairment as it falls in between normal cognitive aging and dementia where there's cognitive concerns. We can see objective evidence of cognitive decline or cognitive impairment on testing, but they're still independent. Then usually I'll explain after I've explained that spectrum. Tell them where, based on what I'm hearing, what I'm seeing on the cognitive test, where they fall. This gentleman, I would say that you're an engineer, this test is lower, your test score is lower than we would expect. And you're starting to have some trouble with some activities. And it is usually these higher level activities, computer and driving. And explain that. For that reason, I think that he has early stage dementia. And that usually, of course, leads to that discussion of, well, what could be causing it. And that's where I like to explain that it's an umbrella term because everybody's always asking, like, do I have Alzheimer's or do I have dementia? And trying to help clarify that, although I think I find myself having to explain that multiple times to patients and caregivers. I swear we had this conversation before, but let's have it again, because I think it is just. It's confusing even to doctors, right? Let alone to other people.

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[Dr. Matthew Frank Watto]

And it it in my practice, it seems like a lot of people because I guess vascular risk factors are so common. Oftentimes I'm just wondering, is there a component of vascular dementia in addition to Alzheimer's or how much is the vascular, you know, just this person's metabolic syndrome contributing? Like this guy has all the metabolic stuff, blood pressure, cholesterol, diabetes, gout, you know, so we know he's not metabolically healthy at baseline and that seems to really play into this. Do you talk to people about that, like the metabolic health aspect of it or I guess at the point that they have dementia, maybe it's not as relevant.

[Dr. Halima Amjad]

Well, I think there it's still relevant. And of course, Right. When we talk about the non pharmacologic strategies. Right. The kind of lifestyle strategies that are beneficial for brain health. But I think especially in a patient like this, especially if we haven't done imaging yet. Right. We haven't looked to see whether he has vascular disease or not. Right. Then I would often explain to that. Right. That's one of the reasons that we want to get imaging to be able to sort of better quantify if those kind of metabolic issues or vascular issues might be contributing. Right. Often that's the first step before we start getting into the, you know, the words like Alzheimer's that can scare people away.

[Dr. Matthew Frank Watto]

Sure. And we went through the first case, so we did just to highlight to the audience that we, this person had, they had the basic blood work, RPR, TSH, B12, they had the Imaging this person had a thoughtful workup thinking like is there any reversible cause or is there any other cause for these symptoms? And we didn't find any. So we deliver the diagnosis here to Mr. E and his wife is asking about these new blood tests that she heard about for Alzheimer's. So these plasma biomarkers, can you talk about that? I mean these were a big reason why we wanted to do this episode because I was mentioning to you before we started recording, there are some of these self service labs that are online now and you can get these giant panels and they're doing all these autoimmune tests and infectious tests. And I've now seen that they've started to pop up with these plasma biomarkers for dementia. And I just worry about patients like self serving, ordering these, not having any clinical context and then freaking out and coming to me with like, what does this mean? So you're going to give us the answer?

[Dr. Halima Amjad]

Yeah. So the tests are definitely out there. I'm happy to say that at least in my practice I haven't seen a ton of self serve lab tests. But we know there is some direct to consumer marketing. Of course there's a lot of news around the blood tests, around treatments, so the information is getting out and I definitely do have people coming in asking about it. I think first, after we discuss that I think you have dementia and we start to talk about the different causes, then of course we will talk about what are the ways that we can make a diagnosis of Alzheimer's there. I think it's always important to level set expectations for patients and families. I think especially when it comes to self serve, one piece that's extremely important is that. But really all the guidelines, all the recommendations, even the tests that have been recently FDA approved for the blood biomarkers for Alzheimer's all are only indicated for checking them in people who have evidence of cognitive impairment. So it is not for the worried. Well, it is not for someone who notices memory problems, but scores normal on an MMSE or a MOCA or on full neuropsychological testing. So there you really need to feel comfortable that the, the person has MCI or dementia. Right. There's objective evidence of cognitive impairment. The other important piece is that these are screening tests. So they're not meant to be sort of a standalone, they're not the end of the road, they are the initial screening test. So usually what I will share with patients and caregivers is that I mean we are in an exciting time. So I've been Seeing patients in our memory clinic for 10 years. And when I started out, we didn't have blood tests, we couldn't order amyloid, PET scans. It was all that clinical judgment, or like my spidey sense says, you have Alzheimer's disease. It's exciting now to know that we have tests that can better and more specifically identify Alzheimer's. But I'll often tell patients these tests aren't perfect. They are very good, but we need to be careful and think through ordering the test. The big thing is thinking about what test do we need? And I think the other big question, and certainly if you're thinking about these tests on the primary care side, is what will we do with the results? And I think that's where I would say, even on the dementia specialist, memory clinic side, we've just been using these tests. Really, it's going to be different institution to institution, but probably for the last 12 to 18 months. And we're still sometimes figuring out how to interpret the results, or having at our weekly memory clinic meetings, we're discussing cases, bringing up these results. So, you know, they're good tests. It's exciting to have them, but there's still a lot that we're learning. And that's where I think, right, from a primary care perspective, it is okay to defer it to a specialist if you're not comfortable yet. The other, I think, big, important piece too, especially, for example, if it's the patient's wife asking, is, as we're talking about these tests, making sure that the patient is on board. Because I, in my experience, I see a lot of times the family and the caregivers are all for it, but if you look at the patient, they seem kind of hesitant. So that's where I think it's important, too, to kind of see how they're feeling, right? Are they on board? Are they not? Do they need time to think about it? So I have had some patients where, if I recommend tests, I might even give them the lab slip, but tell them that they can talk more about it, think it through, rather than just rush off and get the test done. So I think it is important to have a conversation. I think this is the type of thing where sometimes it's fine to say, like, you got to come into the office to talk about it. We're not just going to do this, you know, over the phone and, you know, dive in before we've thoughtfully considered, you know, what test to order and what are we going to do with the results of it.

[Dr. Paul Nelson Williams]

And just to emphasize the earlier point, because as opposed to Matt, I don't get a whole lot of people ordering the bazillion tests, but I do have asymptomatic patients, perhaps with a family history of dementia coming in and saying, are these tests, do they have any prognostication, should we order them now? Can they assess my risk of Alzheimer's? Not that I'm having symptoms, but can they predict if I'm going to have them later on? I think just kind of try to plan ahead. But it sounds like there's not a role for that right now. These are just for patients that are having symptoms to kind of help clarify and solidify the diagnosis. Is that correct?

[Dr. Halima Amjad]

Yep, that is correct. And I think there are sometimes I'm honest too, with patients that. Right. That these tests are new. So in a couple of years there might be a role for it in risk prediction in prognostics and sometimes with family members. I'll explain too. Right. Like just keep an eye on the news. Right. If we develop or identify treatments that are effective for preclinical Alzheimer's disease. Right. Then how we're using these markers might change. But right now, how we interpret them, especially in people who don't have objective cognitive impairment, we don't really have good data to guide us. And of course we worry about the false positives.

[Dr. Matthew Frank Watto]

So the idea is that there's 10, 15, 20 years of preclinical Alzheimer's or just dementia. Right. And that if we could find these biomarkers that identify that early, that then maybe we give some of these antiamyloid therapies or something before someone develops dementia and we might prevent it. Is that kind of the gist of what the field is hoping right now?

[Dr. Halima Amjad]

That's what everybody's hoping. The trials are ongoing though, Right. So we don't have the data yet. You know, we expect that in a couple of years we will. The other piece too. And that's where it's always important to tell folks. Right. Again, because we wouldn't have anything to act on. I always think that, that, that's actually a great time to emphasize the lifestyle factors because a lot of middle aged people who have a family history of dementia, a heart attack might not feel as scary. You can get to the cath lab, they'll treat that. But Alzheimer's is scary. Can that get them exercising, eating healthy, treating their obstructive sleep apnea? Really, then using that as the motivation to act on those factors and not worry about blood tests?

[Dr. Matthew Frank Watto]

Yeah, I think it was like 2020, the Lancet had that first article about dementia prevention. And it's all the things that we know we should be doing but that are hard to do, like you just listed. And I think they even have on there, like avoid traumatic brain injuries, Paul, and don't expose yourself to too much air pollution. But it's a lot of just good life advice, I think, in general, for people to stay healthy. The other one that I get asked about, and I do actually, I think we should put a name on these biomarkers. So there's phosphorylated tau proteins, right? There's a couple different ones. I think P Tau217 is the one that's most validated or most in favor right now. And then there's this ratio of amyloid beta 42 to amyloid beta 40. And the idea being that amyloid is involved in the Alzheimer's pathology and that phosphate phosphorylated tau is also involved in, I think, neurofibrillary tangles or plaques in some way. But how do you talk about that part of things? Because I think it also comes up with the CSF studies and some of this pre testing for amyloid therapy, anti amyloid therapies.

[Dr. Halima Amjad]

Yeah, I will say so. That's something I would say when I'm ordering blood tests for patients. I don't necessarily get into the obviously, like the nitty gritty of what test that we're ordering. And I will say, even as a dementia specialist, sometimes I have to look closely at the results to see test was included on this panel, what ratios were they looking at. But big picture, those are the big two buckets of blood tests that you'll see that you can order that there might be combinations of through a lot of the big labs that we use, where with Alzheimer's disease, we're thinking on the brain pathology side, the beta amyloid plaques and then the neurofibrillary tangles that have the phosphorylated tau. So then the sets of of blood tests are picking up on that. And again, it's exciting that we now have sort of lab medicine and immunoassays that can pick this up in the blood when we couldn't before. So typically, yes, you'll see beta amyloid, it's often beta amyloid 42 to 40 ratios where a low level is indicative of or suggestive of. So low levels in the blood, like csf, are indicative of plaques in the brain. And then with P tau, you said it right, which is impressive because like I said, we're still kind of figuring this out in the field is that P Tau217 now is probably the sort of form that's most in favor, that seems to be sort of the most sensitive and specific, that it's a little bit better than say P Tau181, which is the other common form. And those are highly indicative of Alzheimer's disease pathology if they're elevated in the blood. And I think what's important to know there is that they're actually indicative of not just the P tau, but actually a beta amyloid in the brain. The other test that you might see, it's included on some panels is neurofilament light chain. That one is actually less specific. So I know in my patients with Alzheimer's, the NFL, neurofilament light chain is usually not positive unless they're fairly advanced. But I think one interesting feature of neurofilament light chain is actually it tends to be positive more in frontotemporal dementia. Certainly some patients where we're doing these tests or panels of tests where we're thinking about both of those etiologies, Alzheimer's disease and ftd, where then if you see the P tau or the beta amyloid is normal, but the neurofilament light chain is elevated, you might start to think more about frontotemporal dementia with these buckets of tests. Like I said, sometimes we're ordering just P Tau217. Some of the labs will have panels. The Most recently the FDA approved Luma pulse test is actually a P Tau217 to beta amyloid ratio. So again, it's like now there's just bringing about all of these combinations where you have to look at the report really carefully, right? You find yourself looking at what's the reference range, what's the lab interpretation of the results. But it is kind of, again, those kind of broad buckets that you mentioned that those are exactly on point.

[Dr. Matthew Frank Watto]

Okay. And the other one that I wanted to just bring up, which I think it's probably, maybe it's less pertinent, but maybe you get asked about this, the APOE genes, because there's this APOE and then there's various. Everyone has like two copies, right? And you could have a 2, a 3 or a 4 and then some combination of all those. And if you're ApoE, if you have one or two ApoE4 genes, right, that's the one that is associated with increased risk of Alzheimer's. So I think that's the one where I'm getting asked in these, these people, these middle aged people with parents with dementia, some of them are wanting that tested, some of them are not. And that's kind of like, I think that one's somewhat legit, although it's just like if that'll help people keep themselves metabolically healthy and increase their chances and do all the things to not have Alzheimer's. I've ordered it for a couple people. But does that come up in your practice? Or maybe you're just seeing people too far on the other side of the spectrum?

[Dr. Halima Amjad]

Well, it does come up actually, and I think that one's been coming up longer than these other blood tests. Right. Because the other blood Tests are newer, but 23andMe has been around for a while. I know, right. So certainly folks would come in right, where you know, they're worried or. Right. The parent is coming in with memory concerns, but then their child who's bringing them in knows that they have like the child has an ApoE4 allele. So that is more common. I will say we order it now for the anti amyloid therapies. I think I otherwise never have ordered it for a patient. I'll be like, if you want to go out kind of wild west, get it done. And that's really because of. Right. It's that same idea of what do you do with the results with APOE 4. I will often then counsel the person that it is a risk gene, but it's not like an autosomal dominant gene where oh gosh, I have this, I'm going to get Alzheimer's. So even if you have one allele, two alleles. Right. Of ApoE4, it just means that you're at a higher risk. It does not guarantee that you're going to develop Alzheimer's. Right. Folks will say, okay, the relative risk is high, but the absolute risk still isn't that high. So that's where I will usually still focus more on. Again, hey, if you're worried, let's do all of these lifestyle things. And then similarly, if they know they have a gene or two. Right. Because they did some panel or they did 23 and me is just again telling them to keep an eye on the news because there's so much research going on. And if we find treatments for preclinical Alzheimer's, it's Those folks with APOE 4. Some of the studies in preclinical have actually been targeting folks who have APOE4 genes and then doing amyloid scans on that, on that population. So just really Telling people to keep an eye on the field. Right. Because again, right now we don't have any medical medication treatment to offer them. But we might in the future.

[Dr. Paul Nelson Williams]

This will be a long wind up for a question you might not be able to answer. But I guess reading through some of the practice guidelines, these blood based biomarkers specifically they say in terms of triaging, they should be ordered by people who have comfort interpreting them, which kind of leads things sort of wide open. So maybe I'll ask the question a different way. In where you're practicing now, who do.

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You see ordering these?

[Dr. Paul Nelson Williams]

Who has that comfort and expertise? Is this something that's typically ordered in memory clinics and by geriatricians? Do you see this workup starting in the primary care office and then once they come back sort of abnormal or indeterminate, then the patient gets sort of triaged to you? I guess. What are you seeing in terms of what the practice currently looks like? Because I just don't know how to assess feeling comfortable about something. I haven't felt comfortable about any clinical decision in like 15 years. So I don't know. I don't anticipate that starting with any new Alzheimer's blood tests either.

[Dr. Halima Amjad]

Yeah, I mean it's definitely variable. Right. We are getting some patients where their primary care provider ordered it, maybe because they knew they were on their way to memory clinic or. Right. There's always some folks who are braver about ordering new tests, doing new things than I am. But I think in general what we are seeing is that we are definitely using blood based biomarkers, other neurologists are using them. And we see that in the context of we definitely see patients who get worked up by a community neurologist, but then they come to us for consideration for anti amyloid therapy or additional opinion where those neurologists are comfortable ordering the tests. Interestingly, and even within my division, I think the geriatricians who are practicing primary care, some of them are starting to order blood based biomarkers, some are not comfortable even there. I think because I'm a geriatrician who's practicing as a dementia specialist, I'm more comfortable interpreting the results, feeling comfortable on who I should and shouldn't order it on than someone who's practicing more general primary care. And I'll add, I was actually happy over the summer when the Alzheimer's association released their clinical practice guidelines for blood based biomarkers because that really said it should be done in a specialty care setting. But then actually just in October, one of the FDA approved tests is FDA approved for ruling out Alzheimer's in primary care. And I was like, oh. And interestingly, like I've now seen one or two patients where they had a false positive on that rule out test that unfortunately it wasn't ruled out then they have an indeterminate result, got an amyloid PET scan and then we're providing reassurance because actually one patient I saw had to reassure her that you now had this definitive test, your amyloid PET scan is negative. And she was like, what do I do with this P Tau181? I said just ignore it. Like pretend it never happened because you have this now very clean amyloid scan and right. I think to me that's what is right. I think, I don't know if concerning is the right word, but that's where I'm not necessarily in favor of primary care going crazy ordering these tests for broad populations of patients.

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[Dr. Paul Nelson Williams]

I will say maybe we can link this in the show Notes Matt I'm not sure if this was background reading or not, but the AAFP I feel like always does a nice job of kind of summarizing. Yeah, how to frame conversations and there's like a three page sheet on just early detection of Alzheimer's disease and related dementias that really goes through the utility and how to talk to patients about blood based biomarkers and when to consider them. And it's just It's a really nice, straightforward summary for the non expert in terms of at least how to approach the topic, which I. I'm not sure if you've seen that or not, but I found it really helpful.

[Dr. Matthew Frank Watto]

I'd love to see a copy of that. That's great.

[Dr. Halima Amjad]

Yeah, I was gonna say I don't think I've seen that either, but especially if it's like aafp Primary Care Focus. Because right there too, I'm like the conversations I'm having in the setting I'm having them is very different.

[Dr. Matthew Frank Watto]

Natalie, why don't we get on to the next part of the. Part of the case here?

[Dr. Natalie Barrett]

Yeah, sure. So after explaining what plasma biomarkers exist and reviewing their significance with recent therapy advancements, Mr. E and his wife decide to proceed with P Tau217 blood testing. P Tau217 test results elevated. And Mr. E returns to your office to discuss the results.

[Dr. Matthew Frank Watto]

All right, so as you told us, halimao P tau would be elevated and we didn't get the amyloid beta peptides in this one. But can you tell us what would the conversation go from here and how would you talk to them about if they're now interested in anti amyloid therapies?

[Dr. Natalie Barrett]

Yeah.

[Dr. Halima Amjad]

So the P Tau217 being elevated. Right. For me then, especially in the right clinical context, even though it's a screening test. Right. For me, it sort of tells me then that we're dealing with early stage dementia due to Alzheimer's, that I think I wrote this down. The P Tau 217 sensitivity and specificity both is about 88%. So it's a good test. Right. You actually don't necessarily need the beta amyloid ratios. One thing that is relevant in this patient that I think is worth mentioning is he's 87. I will say one thing I am careful about is actually looking at patient's age when I order these tests and write that kind of what is the pre test probability? Because amyloid PET scans, which right now we consider to be the gold Standard, at age 80, about 30 to 40% of cognitively normal older adults will have a positive scan. So I think, especially if you're dealing with someone who's age 80 plus, you want to be sure that you are right, that they've got MCI or early stage dementia, that your clinical suspicion for Alzheimer's is high when you're going into doing the test. But in his case, the history fits. He's got some mild functional impairment. We could see the MRI finding. So to me it puts A bow on it, that, okay, everything is pointing to Alzheimer's disease. And then that's where we talk about. Right. What are the treatment options? What I will usually do. Right. Because the conversations that we have around the new anti amyloid therapies, it's long, it can get very detailed. If you're getting into percentages of risk is first just give patients a general overview of the treatment to get a sense of where they fall on the spectrum. Because we have the elevated P Tau 217. Right. I'm 99% sure this gentleman has Alzheimer's disease. But we would need to do an amyloid PET scan if we were going to proceed with therapy. So there's sort of that initial conversation, then let's get the amyloid PET scan right, do any other tests we need and then have that more detailed conversation around risks, benefits and alternative treatment options.

[Dr. Matthew Frank Watto]

And I was looking for the testing before. There's a whole bunch of contraindications and then there's some testing before. So maybe you can go through that. We mentioned the APOE4 gene before and I think it's. If they're. Is it if they're heterozygotes or homozygotes, I think there's worried about increased bleeding. Right. So that's one of the things where it's like a relative contraindication or some people consider it an absolute contraindication. But can you talk about like, how do you size someone up before you decide like they might be a good candidate or not for the anti amyloid therapies?

[Dr. Halima Amjad]

Yeah. So on that side, that is definitely where we are checking and requiring that patients have APOE genotype testing done if they think that they might pursue treatment. Right. Because that will give us risk information and tell us whether the person is a candidate or not. The FDA label for the medications just has a black box warning for ApoE4 homozygotes. Most, I think probably most institutions, practitioners are not offering the treatment to patients who are ApoE4 homozygotes. But there are some places that are. Right. Because it is. I think you captured it. Well, it's relative contraindication. Some places are treating it, I know certainly in our practice we are treating it as an absolute contraindication because there's a much, much higher risk of ARIA amyloid related imaging abnormalities. For one of the treatment options, lecanemab specifically, if you look at their subgroup analyses for ApoE4 homozygotes, there was actually a greater risk of, of harm than benefit. So on their little forest Plot. There was one group that was on the side of harm, and it was the ApoE4 homozygotes, which is unfortunate because that's the group where we would love to have treatments. Right. They're at higher risk. Their families are at higher risk. So for thinking about whether it's a treatment option, that's definitely part of it. I think often, even before we get the test done, we are thinking through that kind of general eligibility for general eligibility. Right. A couple of big things. One, we have to know they have Alzheimer's disease, and that's where in most patients we're doing an amyloid PET scan, But you can do CSF testing as well. But there we are going beyond the biomarker, beyond the blood biomarker, that we want to feel comfortable that there's amyloid plaque on the brain that we would be clearing with therapy. Disease stage is a huge piece that the person has to have mild cognitive impairment or early stage Alzheimer's. And so we definitely get patients who are moderate stage and asking about whether it's a treatment option. And unfortunately for that group, it's not. Then we're also looking at their medical conditions, that comorbidities certainly play into it, that it's sort of a relative contraindication of do they have stable medical and psychiatric conditions. Right. If they have advanced chronic kidney disease, certainly in our older adult patient populations, we're thinking about life expectancy. Right. The kind of pulling all their comorbidities together. Is it worth treatment? But then definitely on the neurologic side. So if they've had a TIA or a stroke or a seizure in the past year, in the trials, it was. Did they have any of those in the past year? I know some of the appropriate use recommendations and institutional protocols are actually saying if they have any significant seizure history, that they're a higher risk of severe aria, so that they're not treatment candidates. If they have any significant sort of non Alzheimer's neurologic disease. So do they have significant vascular dementia? Do they have. So Lewy body and Alzheimer's often are kind of co. Pathologies. Right. But if you're concerned about Lewy Body, that wouldn't necessarily be a treatment option because of the bleeding risk we're looking at. Do they have bleeding disorders, anticoagulation? I think it depends who you ask. The trials for Donanemab did allow people on stable doses Lecanemab. I think one trial allowed people on stable doses of anticoagulation. The others didn't. So some institutions will not offer Treatments to individuals on anticoagulation. Some might even there, you want stable doses, antiplatelet agents. Aspirin is usually okay. The other thing we think about is, do they have other immune conditions that they're getting treated with, other immunosuppressants, monoclonal antibodies? Because that actually can reduce the efficacy. So I know in the clinical trials and our institutional protocols, if someone's on another immunologic agent, then they would need to be off of it. And that actually comes up a lot for. Because a lot of people are on osteoporosis treatment or I've had patients who have ulcerative colitis. Then you have to kind of weigh the risk and benefits of that treatment versus monoclonal antibodies. And then. Right. One thing that's definitely relevant for this patient, we were talking about those micro hemorrhages. So the clinical trials, and I think even the FDA label talks about if someone has more than four microhemorrhages. And they're certainly like, if they have superficial siderosis, if they've had other hemorrhages that were more than a centimeter, and if they have other sort of brain or vascular, abnormal or cerebral vascular abnormalities other than maybe a stable meningioma. So that's where we are looking at, like, what does the MRI show? If they haven't had in MRI in the past, definitely 12 months, ideally within the last six months, then we're actually usually getting an updated MRI to count the microhemorrhages, make sure that there's no aneurysm or other abnormality, where we would worry about risks. And then big picture is also, can they tolerate MRIs? Can they have MRIs? That's been a challenge for patients who have pacemakers. Can they tolerate infusions? So those, I think, are the things kind of as a checklist that I'm running through. I do think that those are the types of things that if folks in primary care are familiar with it, they might be able to kind of screen out some patients that. Right. If you're pretty sure they're moderate stage, if you see a lot of vascular disease, you know, I've had one patient where she's just such a vasculopath that I said, like, you can't get tpa, and I'm more worried about you having a stroke than. And let's reduce your rate of decline with comorbid Alzheimer's. And that's where I think thinking about their comorbidities. Right. Their medications is definitely where we can sometimes save a Referral, save people kind of going down the pathway. If you're sort of familiar with the eligibility criteria.

[Dr. Paul Nelson Williams]

All right, that is helpful. And we've talked around it and you've even mentioned aria and I think we even sort of said what the acronym stands for. I remember, I think reading about the early studies, like it was A pretty like 30% of patients had some degree of it and like only 5% really needed, like, something catastrophic happened. Like, the numbers seemed kind of scary. I just. Because we're having conversations about risk and benefit, can we define our terms or just. And really sort of. Could you just talk to us a bit more about aria? What it is, what we're worried about and who's. Who's most at risk for it and sort of what that looks like in folks.

[Dr. Matthew Frank Watto]

Yeah.

[Dr. Halima Amjad]

So ARIA is when we talk about these medications as an option for patients, that is the big discussion when we're talking about risk. So ARIA stands for Amyloid related Imaging abnormality, where as a result of removing amyloid plaques, you can get ARIA E, which is edema, so kind of focal edema, or ARIA H, which is hemorrhage, typically micro hemorrhages. And that's something that I'll tell patients too. Right. When we're talking about swelling and bleeding. Right. It's one thing if we're talking about the skin, it's another thing when we're talking about the brain. And so with these treatments, there's definitely a risk of aria. It differs for the two medications that are currently available, that for lecanemab, the overall risk of ARIA. So either ARIA E or ARIA H was about 22% of patients on treatment for donanemab in the original trials. At the original doses, the risk of REO is about 36%. So a lot higher. The reason I specified the dosing is because they now have an FDA approved lower modified dosing protocol where the risk of ARIA E is lower, the hemorrhage risk is about the same as it was in the higher dose. The ARIA E is actually the one we worry about more. So it's kind of the bigger, better, scarier outcome. I think what's always relevant, and we'll explain this to patients, is that most ARIA is asymptomatic. So only about 3 to 6% of patients actually have symptoms. And that's why the MRI monitoring is so important that the majority of ARIA is picked up on MRI and the majority occurs actually in the first couple of months. So there's usually, for each treatment, it's recommended that you either get four or five MRIs sort of on a certain schedule and they're sort of clustered up front. So within the first three to four months of treatment. The rates though also vary. So right when we were talking about APOE4, if you don't have any APOE4 genes, your risk of ARIA is a lot lower if you have ApoE4, if you're ApoE4 homozygous, about a 40% risk of aria, which is huge. There have been deaths. That's actually always something that I mentioned, that it has occurred in the context of aria, in the context of patients receiving tpa, that at least for Donanemab there were three deaths in the clinical trials and lecanemab three deaths in the open label extensions. That's why it's important that patients are aware of the risk. That's why it's important that of course we're doing the MRI monitoring with, with aria. Again, it depends who you ask. The pharmaceutical companies might say, well, most of it's asymptomatic as of right now. We don't think with the sort of, if it's mild to moderate that there's long term sort of adverse effects that it usually does. If you pause treatments, treat it with steroids, it resolves. But I don't know that we have good long term data to suggest that. So. Right, we need to monitor it can have catastrophic side effects. And so I definitely know for some patients and caregivers like that that's too risky. They're happy with how they're doing right now. We obviously talk about the benefits too, and that's something we should talk about as well. But it's when they weigh it, right. For some folks that risk is too high. And that's where I think the Apoe 4 testing is helpful because then we can actually look at specific kind of percentage risks. And again, though it is really mostly for the homozygous that when you look at the non carriers of E4 or having one copy of E4, the risk is nowhere near as high as it is for the ApoE4 homozygous. And of course, right, we touched on the anticoagulation and that's where that intersection comes as well, that if someone's on anticoagulation, there's of course a higher bleeding risk. And we do explicitly tell patients that, right. If they're on treatment, they cannot receive TPA if they have a stroke. We will even sometimes suggest to patients that they wear a medical ID bracelet because. Right. If there's an emergency. Right. And nobody realizes. Right. There have been catastrophic outcomes from that. Interestingly though, and I don't have a great explanation for it, but if you look at the clinical trial data, there was ARIA in the placebo groups and especially in Donanemab, it was like fairly high. But there, I think there may be some element of. Right. These aren't healthy brains. People might have micro hemorrhages, other things. But I feel like I've sometimes presented those slides and I'm like, don't ask me for an explanation. But there was a rate of ARIA in the placebo group.

[Dr. Matthew Frank Watto]

I remember Aducanumab, I think, gave these anti amyloid therapies, maybe a bad reputation. Right. Because it didn't hit its clinical endpoints and then it wasn't going to be approved. And then they kind of fought and then it got approved. And I remember Jerry Powell talking about how they were super skeptical of it. And then lecanemab and Donanemab came around and somewhere along that same timeline there was that discovery that there had been some like amyloid paper from 20 years ago that was. They faked some of their results. And then the whole amyloid hypothesis had come into question. Because these drugs remove amyloid from the brain. We can see that. Right. And the brain even shrinks in size on these drugs, which I think maybe is just the amyloid being removed and then there's more space. But where are we at with that? And do patients actually challenge you with that? Do these drugs actually work? I heard that the amyloid hypothesis is not the real cause of Alzheimer's. I've been confused about that over the past few years because I get different. Some specialists are all in on the anti amyloid drugs and other people are like, no, they don't work.

[Dr. Halima Amjad]

Yeah. So there's definitely ongoing controversy and I think part of that is, right, we're all waiting for more data and longer term data, but definitely how these drugs rolled out with Aducanumab, getting the accelerated approval, but then not meeting clinical endpoints. And we do know, right, between the Aducanumab, the Lecanemab, Donanemab, they're all acting on amyloid, but kind of different parts of the pathway. So it's sort of conceivable that certain some drugs might be clinically effective, whereas other ones aren't. So that definitely introduced the controversy. But even now when you look at the benefits and the risks, there's definitely still questions. I think that's something I actually explained to patients when we're initiating treatment is that these treatments actually tell us that amyloid is not the whole picture of Alzheimer's disease, that we know that these drugs very effectively remove amyloid plaque. There's no controversy on that. If you look at the data, they're very good at reducing amyloid plaque. But then the clinical effects aren't as big as we would expect. Right. It's not stopping the disease, it's certainly not reversing it. Right. It's slowing cognitive and functional decline a little bit. Right. That the people receiving these drugs, they still experience decline over time. So that's always part of that kind of risk, benefit and counseling discussion. And I will actually tell patients that again, that there is controversy and that there is sort of a spectrum of opinions, that there's some doctors, certainly the pharmaceutical companies that will say this is this great disease modifying therapy, we're removing amyloid. Right. And it is exciting that we finally have options. But then on the flip side, there are some individuals, right. Providers who will say, right, the risk is too great, the effect size is small, we don't have long term data yet and aren't prescribing it at all. In my case, and I think most of my colleagues at our memory clinic, I sort of tell patients that we fall in between, that we think there is a role for these medications in the right patient. So weighing the risks and the benefits and making sure that any patient and family that start these treatments, that they're sort of realistic about what it provides. And that's where I think it's just really important that people recognize that they still will experience cognitive and functional decline. We'll use the numbers that you see in the papers in the FDA labels or the news about maybe a 25 to 30% slowing of decline over 18 months. I'll often explain that you might be five to seven months behind someone who didn't have treatment. But I'll often also put that in the context of if it's five to seven months, this is a disease that people can live with for years and decades. On that side too, does five to seven months in MCI or early stage, when you're going to live with this for 20 years, is that meaningful to you? For some people it is. For some people, it isn't. For some folks, knowing I have to get an infusion every two weeks and every month I've got to get all these MRIs and there's this risk of swelling or bleeding in the brain. Some folks will say it's not worth it. Other people will say I'd like to move forward, but again, there we're very careful about who we are offering it to there. I will say it's nice if you have a practice or institutional protocol because then we can simply say we can't get strong armed into it. If you're ApoE4 homozygote, we are not giving you the drug even if you really want it and accept the risk. There are some places that will offer it. There's definitely practice variation there. And then the other thing too, I will explain to patients too, is that we don't have long term data yet. And it's hard because they're in a position where I think in three years, five years, we'll know a lot more about these drugs. They're kind of immediate and long term effects. But these patients and caregivers are making the decision now with the information and sort of short term experiences that we have and the clinical trial data that we have.

[Dr. Paul Nelson Williams]

It's super interesting.

[Podcast Sponsor Voice 1]

Like we'll have long term data.

[Dr. Paul Nelson Williams]

I have to, because like the patients that are selecting by this by necessity have to be relatively well resourced and connected to healthcare and actually be reasonably healthy from the outset. So, like, this is. These are folks that are gonna live for a while, you know, all things being human. So, like, this is really interesting. I have no point to make other than, huh, this is really interesting.

[Dr. Halima Amjad]

Yeah, I think on that side, the other piece that I find super interesting and I think gets ignored is everybody talks about, oh, you get more time in early stage than life. Like, what about moderate stage? What about severe stage? Right. Are these same patients going to live for a longer time in those more advanced stages of Alzheimer's dementia? Right.

[Dr. Paul Nelson Williams]

Are you kicking the can down the road or. Yeah, it's. Gosh, this is fascinating.

[Dr. Matthew Frank Watto]

And you said we think we're not offering it to people with moderate dementia or more advanced dementia just because they probably wouldn't tolerate all these MRIs and things like that and it might just be more futile to offer treatment. We want to intervene as early as possible.

[Dr. Halima Amjad]

Yeah, we definitely want to intervene as early as possible. At least the data that we have and for example, with the Donanemab clinical trials, they actually sort of stratified by people who had sort of differing levels of tau. So maybe pathologically were less and more advanced. And it does seem, at least with the data that we have now, that again, the benefit is sort of small to modest to begin with, but it's also more so the earlier that you treat. So I think there's just concern that there wouldn't be significant benefit in moderate stages. And yes, just the tolerate being able to tolerate the level of monitoring the infusions themselves. Like I know I actually had one patient who started and then within six months of treatment she like she couldn't do it anymore. And you know, she was early, but sort of on that late side of early stage and they just decided not to move forward with completing 18 months.

[Dr. Matthew Frank Watto]

And I think you told us before we went on air that you're starting to get people to this 18 month point now and we have to figure out how we're going to proceed. Will you keep giving the therapy or do we stop and just monitor what's happening right now?

[Dr. Halima Amjad]

Yeah. So this has been and fascinating because even with like patients will ask and I'm like, I'll let you know once we have our protocol in place that, you know, experts are talking. I know there just recently was a CTAD clinical trials and Alzheimer's disease meeting where some data on sort of the open label extensions was being presented. Right. Folks from different institutions were talking. So it's interesting just that we're starting to hit that time point for patients who started receiving treatment sort of of soon after FDA approval. The other piece that's interesting is it might be different for the two drugs that we're using right now. So for lecanemab, which was FDA approved first, right now it does seem like the recommendation is that patients may benefit from maintenance treatment. But maintenance for lecanemab during the sort of 18 months, it's an infusion every two weeks. Once you're in maintenance phase, you can either do an infusion once a month or they actually had FDA approval for a subcutaneous weekly dose. And so I think most of our patients will be switching to that subcutaneous weekly dosing. Right. Then you don't need to go to an infusion center. There's still a risk of ARIA. So then you actually still need MRIs probably every three months, I would say. The other thing that we are doing at the end of 18 months is repeating the amyloid PET scan where we are able to see one. Did they get effect? Right. Did their amyloid plaque burden decrease? About 15 to 20% of people we expect and we are seeing are still amyloid positive but a lower burden. We're repeating MRIs and then putting them on that maintenance. And right now it seems like the recommendation right. From the data that's available, it's not all published yet, but some of it presented or given to the FDA is that individuals on lecanemab should continue maintenance until they hit moderate stage. So if they advance to that point, then you would stop treatment or if they're no longer eligible for other reasons. Right. So then you're still checking off that eligibility criteria and looking for aria. So that's on the lecanemab side. The reason I said it might be different for Donanemab. In Donanemab, they actually repeated amyloid PET scans in the clinical trials and stopped treatment if someone had cleared amyloid. So that's where it's interesting to see if the recommendations end up being different for the different therapies that we have available. So I think still a lot that we're learning and planning and figuring out. Right. And again, I think it's that same piece that in three to five years we'll have a lot more data. And I think we're also looking for the kind of papers to be published. I could see some of the, what the pharmaceutical company has put out about comparing the open label extension, but I think that's right. You really want to see the hard data of how patients are doing, what their rate of decline is. But they're suggesting that the rate of decline, the slopes separate more with time. But again, we still need to see hard data supporting that.

[Dr. Matthew Frank Watto]

Let me catch us up on the case here a little bit. So Mr. E and his wife decided they wanted to proceed and he was started on lecanemab. He had two infusions every two weeks for 18 months. He was monitored with all these brain MRIs and he did not develop Aria. And now they're in the office. His cognitive and functional evaluation are fairly unchanged from the previous Visit. He scores 19 of 30 on the MOCA. And, you know, you just answered it a little bit with lecanemab, like maybe he's going to switch to the subcutaneous weekly dosing. And I guess, is that it for now. Is there anything else you would add for a patient like this when they get to the end of that treatment course there?

[Dr. Halima Amjad]

Yeah, I think for him, like I said, because he's still fairly stable. So it sounds like he's still early stage. His MOCA score hasn't changed. It's not touched upon. But oh no, they say, Right. We talked about. So his functional status is fairly similar. So then for him the recommendation would be maintenance treatment. And I think most patients will elect for the subcutaneous weekly injection rather than infusion. If, you know, if he had experienced rei, I will say there's kind of different protocols for do you stop treatment versus pause? But that might drive whether you keep him on maintenance or not. I think for him, for somebody like him, there wouldn't be too much more that we would do medically outside of just. Right. All the other things that we know are good for brain health. He's got hypertension. Let's make sure that's treated, make sure he's exercising for people who are well. And I guess actually, now that I think about it, would be an option for him. Right. Because we said he's more early stage than mci. You can be on medications like Donepezil, whether you start it later or. Right. Some people are already on it. You can use both. I mean, typically, if I'm starting someone on something like lecanemab or Donanemab, I'm like, let's see how you do that first before we throw on the donepezil. But oftentimes we might put them on. On both. And then certainly too, if someone progresses. Right. And we're saying now you don't meet criteria that we're not going to see more benefit from lecanemab and we're stopping that treatment, then we might also talk about medications like Donepezil and sort of the old school things that we've been using for Alzheimer's for a long time.

[Dr. Matthew Frank Watto]

I guess. One question that we talked about ARIA as a side effect or adverse effect of the. Of lecanemab, Donanemab. But are there any other. More like primary care complaints we might get? Like just, you know, physical symptoms or cognitive complaints that people have on the therapies?

[Dr. Halima Amjad]

So interestingly, I would say one, if you get that type of symptom, you want to do an MRI. Right. So they're scheduled MRIs, but I feel like, Right. If there's any new headache, cognitive concern, dizziness. Right. Low threshold to get additional MRIs. Right. Just because they didn't have one on the scheduled one doesn't mean they couldn't develop Aria. But you can't. Outside of Aria, you can have headaches, you can have some nausea and vomiting. But really, the side effect profile, I know I had someone who fell and I was like, oh, that's right. But we still got an mri. Right. You could fall for other reasons, but it's just. Right. Low threshold, being conservative. But outside of those side effects, ARIA really is the big one. The other one that comes up, but I don't know that you'd see it so much in primary care is infusion reactions that about 20% of people will Experience infusion reactions. It's usually pretty obvious. Hopefully they call the person prescribing the medication and not primary care. But that is something where we, even for people who experience infusion reactions, usually we're just able to treat it with, with premedication, often like a low dose dexamethasone or Benadryl and Tylenol. But I think kind of big picture.

[Dr. Paul Nelson Williams]

Oh, excuse me. Diphenhydramine.

[Dr. Halima Amjad]

Yes. Yeah. So I can. You want me to say that again?

[Dr. Paul Nelson Williams]

I was like, no, you're fine.

[Dr. Matthew Frank Watto]

No, no, no. Yeah, yeah. No, no, I know our CME overlords know that we don't like any medications. So we.

[Dr. Halima Amjad]

Yeah, yeah, I was gonna say, so you can pre treat with dexamethasone, acetaminophen and diphenhydramine to address the infusion reactions. But I think big picture, if there's new neurologic symptoms in someone who's on these treatments, that's where. And you want to get an mri, you want to get it done soon. Because something that's relevant with ARIA is you don't always actually see it on a CT scan. And so you actually want to get an mri. And there too, if they call their neurologist or their dementia specialist, that's where we've talked to our radiologist to make sure these people can get in quickly for MRIs. Right. That they're not waiting a month when we have an urgent concern.

[Dr. Matthew Frank Watto]

All right, well, I'm going to go to my co host here, Natalie, anything we're missing, because we are, we definitely need to wrap it up here. But any, any questions that, that we miss that you think are important or high yield?

[Dr. Natalie Barrett]

I think you guys hit everything. This was great.

[Dr. Matthew Frank Watto]

All right, well, Halima, do you wanna give us two or three take home points, things you really want the audience to remember about this discussion we've just had?

[Dr. Halima Amjad]

Yeah. So I think in general, I think we're living in pretty exciting times when it comes to dementia and Alzheimer's disease and thinking about not just treatment but all the steps, prevention, diagnostics that now we have blood based biomarkers, we can order amyloid, pet CTs, we have new treatments where yes, we have to weigh risks and benefits, but we have disease modifying treatments that we hope will open the door to treatments in the future, including treatments for preclinical Alzheimer's disease. And there's also kind of new models of care. So I think just more attention and we're seeing research translate to changes in clinical care that I think are exciting. I think it's important for all of us, but especially on the primary care side, to stay tuned because I think this field is rapidly evolving. So right now I don't think I would recommend that we're ordering blood biomarkers in primary care unless you are comfortable with addressing results or with the next steps. But I think within the next couple of years we will see that we are ordering blood biomarkers and initiating some of these steps in primary care. But right now it's okay to defer it to a specialist. Do not order these tests if the person does not have objective evidence of cognitive impairment. So MCI or early stage dementia only.

[Dr. Matthew Frank Watto]

I think those are great take home points and we're going to head into our outro. Thank you.

[Dr. Paul Nelson Williams]

This has been another episode of the Curbsiders bringing you a little knowledge food.

[Podcast Sponsor Voice 1]

For your brain hole.

[Dr. Matthew Frank Watto]

Holes.

[Dr. Paul Nelson Williams]

I was hoping Tyler would jump in and say yummy to save me from you saying holes again. But no, here we are, still hungry for more. Join our Patreon and get all of our episodes ad free, plus twice monthly bonus episodes at patreon.com curbsiders you can find our show [e-mail] and sign up for our mailing list to get our weekly show notes in your inbox. This includes our Curbsiders Digest, which recaps the latest practice, changing articles, guidelines and news in internal medicine.

[Dr. Matthew Frank Watto]

I am, I was, I was looking at my puns.

[Dr. Halima Amjad]

Paul.

[Dr. Paul Nelson Williams]

Professional podcasters. Ten years we've been doing this.

[Dr. Matthew Frank Watto]

All right, can you. You can cut that out to our editor please.

[Dr. Paul Nelson Williams]

This all stays in.

[Dr. Matthew Frank Watto]

We're committed to high value practice, changing knowledge and to do that we need your feedback. So please email [e-mail] reminder that this and most episodes are available for CME credit for all health professionals through VCU [e-mail] health.org A special thanks to our writers and producers for this episode, Natalie Barrett, Rachel Miller, Eva Zymanski, and to our whole Curbsiders team. Our technical production is done by Podpaste. Elizabeth Proto does our social media. Jen Watto runs our Patreon. Chris the Chew Manchu moderates our discord. Stuart Brigham composed our theme music. And with all that, until next time, I've been Dr. Matthew Frank Watto.

[Dr. Natalie Barrett]

I've been and Natalie Ann Barrett strong.

[Dr. Paul Nelson Williams]

And as always, I remain Dr. Paul Nelson Williams. Thank you and goodbye.

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