This transcript was automatically generated from the video recording and may contain inaccuracies, including errors or typographical mistakes.

From Knowledge to Action: Applying the Evolving Science of Alzheimer’s Disease and Cognitive Health in Clinical Practice

Introduction

Lisa Phipps (DCE): Good afternoon, everyone. Thank you so much for joining us today for our webinar, From Knowledge to Action: Applying the Evolving Science of Alzheimer's Disease and Cognitive Health in Clinical Practice.

This is provided by Clinical Care Options doing business as Decera Clinical Education, and is supported by an educational grant from Lilly.

Faculty and Disclosures

We are so pleased to have with us today our two faculty members, Emily Clark, Assistant Professor of Psychiatry and Director of the Memory Care Program Biologics Treatment Center and Associate Director of Alzheimer's Disease Care Research and Education Program at the University of Rochester in Rochester, New York; and Susan Scanland, CEO and Founder of The Dementia Connection, and Clarks Summit, Pennsylvania.

Learning Objectives

Our learning objectives for today are only slightly different for primary care and specialist care.

For primary care, we would like for you to be able to apply evidence-informed strategies, including emerging blood-based biomarkers to support early detection and assessment of cognitive impairment in ageing patients.

For those in specialist care, we want you to be able to implement expert-recommended neurocognitive assessments and emerging diagnostic tools, including blood-based biomarkers, into clinical workflows to enhance early and accurate identification of cognitive decline in ageing patients.

Clinical Case Discussion 1: The Time Before Symptoms

All right. So I am going to go ahead and turn it over to Emily to go over our first case. Please notice that in the bottom of your screen, you have a Q&A box. So you can submit questions so that we can bring those up as our experts are discussing the cases. And we want this to be interactive. So please do submit questions as we're going through each case.

Emily Clark (University of Rochester): Thank you, Lisa. Good afternoon, everybody. Welcome to the talk. We hope you take something valuable away from this afternoon. We're going to get started with our first case. We're going to be illustrating what to do in this time before symptoms.

Patient Case: Christine

So you have Christine coming to your office with concerns about her risk for Alzheimer's disease. This is a 60-year-old woman. She works as a restaurant server. She shares a home with her adult daughter and two teenage grandchildren. Her mother developed dementia at about age 79, so five years before she died at age 84. And Christine was told that this was Alzheimer's disease, but unsure about the diagnosis because at that time there was no biomarker confirmation. So they've always referred to this as Alzheimer's disease.

She also shares that her older brother, who’s now 70, was diagnosed last year with the early stages of Alzheimer's disease. So we can presume we're talking about likely mild cognitive impairment here. And this was confirmed with an amyloid PET scan.

Currently these symptoms are mild but she's noticing some worsening in her brother. And this is leading the family to have more conversations about Alzheimer's disease and considering future care for her brother. Her – she herself is physically active. She's mentally active. She's not noticed any changes in her memory or cognition, but she asks whether or not she should be tested for these early stages of Alzheimer's disease because of her family risk. She also mentions that she's been seeing some headlines in the news about these blood-based biomarkers. And she's curious if this is something that can be done for her.

Pretest 1

So next we've got a pre-test here for you. So we've presented you with this case of this 60-year-old female. She's got no symptoms of cognitive impairment but a decently strong family history of late-onset Alzheimer's disease, with her mother and brother both being diagnosed. What is the best course of action to take here with Christine? Is it:

1. Assess her cognition with a brief tool to confirm lack of impairment;
2. Order a blood-based biomarker testing to detect early signs of Alzheimer's disease pathology;
3. Order genotyping to determine whether she has familial risk factors; or
4. Order brain imaging to detect early signs of neurodegeneration/atrophy.

We’ll again give you a – a few moments here and – and don't be shy. Answer to your best ability because this is all about learning.

All right. So it looks like 54% of you chose A, assess her cognition with a brief tool to confirm lack of impairment. And that is the correct answer. So let's get into why that is the course we would recommend with her.

Discussion

So currently when we are evaluating somebody who is asymptomatic but at risk for Alzheimer's disease, the best course of action is to start with confirming that they are indeed asymptomatic, and if they are, having a baseline assessment, so we can use this for comparison for future evaluations, given her risk to keep a close eye on things.

Right now, blood-based biomarkers are not considered appropriate for asymptomatic individuals. And really this – this reasoning is twofold. First being biomarker testing, particularly our – our plasma biomarkers are not validated in asymptomatic populations, meaning that the validity of these tests really drops off when we expand the use of these tests beyond their intended usage, beyond these individuals who are presenting with symptomatic Alzheimer's disease.

And really these plasma biomarkers like plasma p-tau217 are – are specifically validated for specialty care settings. So we even see – when we're testing symptomatic individuals outside of a specialty care setting, we can see that these – these plasma p-tau217 levels can be less reliable.

So what this means for you is that if you're ordering this on somebody who is asymptomatic, you could be giving them unnecessary distress by revealing a false positive result. Or you could be giving somebody false reassurance in providing them with a negative result that is false. So really, we're not doing anybody any favors one way or the other in testing them in asymptomatic stages right now.

The second justification in not testing is that it is not changing our management right now. We do not currently have any treatment options for individuals who are plasma biomarker-positive but asymptomatic. So really your approach to this population is going to be just the same as seeing somebody with the family history shows at – just kind of at base value you see, she has a family history. She is somebody we would consider to be at risk higher than the general population.

But in terms of our treatment options, there's really not much else we can do about that quite yet. So why not do genetic testing? Why not consider APOE testing?

The answer here is, is basically that – again, it's not changing too much about our management, and we're not really providing a whole lot of valuable information to the patient that while APOE is the strongest genetic risk factor that we know about for late-onset Alzheimer's disease, it does not change our diagnostic assessments that my diagnose – my diagnosis of Alzheimer's does not hinge on that APOE response.

So when we're getting the APOE genotyping, what we're really doing is we're evaluating for risk alleles but not causative alleles. So if you have an individual who has one or two copies of this E4 allele, they're at a higher risk of developing Alzheimer's disease, but Alzheimer's disease is not destined in this population.

So really the only clinical use that we have for – for APOE genotyping is really when we're trying to evaluate somebody for that risk of ARIA in our anti-amyloid therapies or our amyloid-targeted therapies, which we'll get to here in a – a few slides.

Early-Onset vs Late-Onset AD

I'm briefly just going to jump ahead a slide and come back to our slide just to highlight what about genetic testing for determining mutations. So autosomal dominant mutations. That is a different situation. We do know of a select few mutations in Alzheimer's disease that are causative for Alzheimer's disease. These are mutations in the genes APP or amyloid processing protein, Presenilin 1, Presenilin 2. These are mutations that, when present, will lead to Alzheimer's disease.

So genetic testing for these situations is deterministic. However, this is a very uncommon population. We refer to these individuals as early-onset Alzheimer's disease. These are individuals with these mutations who develop symptoms of Alzheimer's disease prior to the age of 65. These are often people who are coming in in their 40s and 50s with symptoms, and their family history, because this is autosomal dominant, is very strong. So in – in each lineage in the family, you're going to see one or multiple people affected by Alzheimer's disease at very young ages.

This is a really interesting area in our field right now because while we would not treat these individuals any differently right now in the clinical setting, so they're asymptomatic but they have this mutation. Doesn't change what I can offer right now in the clinical setting.

However, this is a question being answered by the DIAN-TU study out of Washington University in Saint Louis. What – what the team there is doing is they have collected individuals with these mutations who are asymptomatic and are treating them with – with various treatment options, particularly our anti-amyloid therapies, to see if we can prevent the onset of Alzheimer's disease in this specific – in this specific population. So it's really a very interesting area of our field right now with this development of these amyloid-targeted therapies.

So early-onset, when you hear that term, that is specifically what we're referring to. Most individuals with Alzheimer's disease will fall into that late-onset Alzheimer's disease category. These are individuals older than the age of 65 when their symptoms are presenting. As I mentioned, many of these individuals will have some APOE risk allele before, and these are often multifactorial cases. These are individuals that have a risk, but then something else often kind of tips the scales: lifestyle, exposures to pollutants, medical conditions, medications.

So when we talk about early-stage Alzheimer's disease, we're referring to they’re in the early stages of Alzheimer's disease, but not specifically early onset.

Discussion

Lisa Phipps: Yeah. And I wanted to also bring up a little bit that you did a great job there of distinguishing between early onset and late onset versus early stage. But then also we're talking about early detection, which is another different early. So we have early onset, early detection and early stage. So can you just sort of briefly go like, okay, here are all of the earlies and here's what they mean.

Emily Clark: Absolutely.

Lisa Phipps: Thank you.

Emily Clark: So when we're saying early stages, we are referring to – and I wish I had one of our beautiful graphs that we usually will show, but the – the early pathologic stages of Alzheimer's disease. So what we often will refer to, especially in this context right now, are individuals with, say, mild cognitive impairment due to Alzheimer's disease. They've got mild symptoms of the disease but no functional impairment. Or maybe they're in the mild dementia stages of Alzheimer's disease.

They've got some early impact on their functional independence, but still nonetheless pretty mild symptoms. Thus, usually the population we're referring to when we're talking about early-stage Alzheimer's disease, where again, early onset more refers to the age at which those symptoms present, and late-onset the age at which the symptoms present. So 65 years being kind of that distinguishing factor in – in early-onset versus late-onset.

Did that help explain it a little better?

Lisa Phipps: Yeah, I think so. And then early detection is we're wanting to find it early stage, whether it's –

Emily Clark: Exactly.

Lisa Phipps: Whether the onset is early or late. We want to find it early stage.

Emily Clark: From a time frame standpoint trying to address it early in the disease course.

Lisa Phipps: Right. Great. Thank you very much.

Emily Clark: Absolutely. So I've – I've discussed how, from a treatment, from a diagnostic evaluation standpoint, nothing is going to be much different here with Christine. But how do we frame this for her? How do we talk about how to consider this family history and then her risk?

And what I would explain to her is that this family history indicates that she's certainly at a higher risk compared to our general population. However, it does not mean that she is destined for Alzheimer's disease. So I will usually take this as an opportunity to discuss our modifiable risk factors, to encourage her to focus on the things that she can change. So focusing on the impact of health management, managing blood pressure, cholesterol, diabetes, addressing any sleep problems that she might have.

We know that the glymphatic system is very important to clearance of toxins while we're sleeping, and so we want to make sure people are getting good deep sleep appropriately. And so asking and addressing for problems with insomnia or sleep apnea, focusing on trying to maintain a healthy diet like the Mediterranean or the MIND diet, getting regular exercise, aerobic and strength training, reducing substance use and engaging in regular social activities. All aspects that we know can reduce dementia risk.

How do we counsel patients like this again further? So again, practicing what we just preached in our – in our pre-test that get a cognitive assessment at baseline. See if there's any symptoms. If she truly is asymptomatic, use that as a baseline that you compare against maybe annually to make sure that she is still in this asymptomatic period. But if anything is starting to change, use that as your early detection of something could be wrong and testing for biomarkers and things like that.

Susan, is there anything you'd like to add here?

Susan Scanland (Dementia Connection LLC): Yeah. Emily, thank you so much. You've done such a thorough job of, you know, going through this whole process. We see this so often with the worried well, as we've seen a lot more in the media now with, you know, even famous people coming down with the different dementias.

So this really – you know, it raises awareness that there is an increased risk, but just because of that does not mean you will get Alzheimer's disease. And I love the fact that this patient, Christine, is right where we need to really work on modifiable risk factors. So everything that Emily just mentioned as far as vascular risk factors, especially the incredible importance of exercise. And the good news is that we have – you know, with the late-onset as opposed to the early-onset Alzheimer's disease, we have a lot more wiggle room for prevention.

I've seen some stats that up to 45% of dementias or possibly even Alzheimer's can be prevented with aggressive working on the risk factors. And that's where we, as primary care providers, really need to jump in early, even things like hearing loss. You know, we're hearing now that just the fact that wearing hearing aids, if you've got sensorineural hearing loss will decrease your risk for Alzheimer's disease, you know, with the cognitive processing. In this stressed society we live in, stress management.

Meditation. There's been several forms of meditation that have been found to be helpful and actually changing even structurally some things in the brain and making a difference. You know, we have the – the – there's a new kind of meditation, Kirtan Kriya, and it's actually shown – there was a study back about five years ago showing that it did impact some of the structural things and functional things in the brain.

So being aware of that and, you know, different sorts of, you know, like we said, the MIND diet, caregiver stress, because a lot of times, you know, caregiver stress, even in a younger person can raise one's risk. Social isolation, increasing even at a younger age, your social contacts, cognitive interventions, staying cognitively active in your middle years and so forth.

So a lot of things we can be doing, but exercise, the MIND diet. And they have a fabulous website, theofficialminddiet.com. I really want you as PCPs to impress on your patients, you know, especially with the family history, how important that is. And, you know, good common sense with preventing falls and TBI and those sorts of things. So it's never too early to practice prevention or, you know, watching blood pressure more closely, cholesterol and diabetes and obesity. You know, really toning those in at a younger age, middle age-aged preferred, but it's never too late to improve.

Okay. Anything else you want to add, Emily?

Emily Clark: No. I think that was – that was a wonderful kind of recap of those – those modifiable risk factors that…

Lisa Phipps: Yeah. And – and Susan, it was great that you – you brought up the hearing loss just as Diana put in the chat, evaluate for hearing loss as well. And we had a – someone – Cheryl[?] has put in the tai chi is also excellent, which is great for awareness of your body moving because that's, you know, the whole point of the – the tai chi movements is to pay attention to where your body is going. And that brings in the mindfulness aspect and exercise and it's like low impact. And you know, it's also great for paying – slower moving and balance and all of that sort of thing.

Ronette[?], Susan, has asked if you could spell the meditation that you brought up?

Susan Scanland: Yes, it's K-I-R-T-A-N, Kirtan Kriya. I believe it's K-Y-I-R-A, and it was published – I want to say I have the reference here. It was published in Journal of the Alzheimer's Disease, or one of our favorite journals, of course, back in 2000. Actually, it's been around for a while, 2015. And the author is Khalsa, K-H-A-L-S-A. It's only 12 minutes a day. So even for stressed healthcare providers, which many of us in primary care are, you know, 12 minutes a day to really, you know, lower your risk, you know, and decrease your chances of getting it.

And it was interesting. Yeah, do read the article. Frontal lobes, you know, increased cerebral blood flow.

Lisa Phipps: Yeah.

Susan Scanland: Yeah, it's – it's quite impressive.

Lisa Phipps: Yeah, several people asked about that. So I'm glad that – yeah.

Susan Scanland: It's a great – it's a great. And like I said, 12 minutes a day. We can all make time for that.

Lisa Phipps: Yeah.

Susan Scanland: And then there's the mindfulness-based stress reduction program, which is a wonderful program. You know, it – it's got – it's been proven over 40 years of research based out of Brown University in Mass General. And it's widely used with mindfulness practices once again, you know, and that's been shown also to have an impact on Alzheimer's risk.

So you know, prevention trick, as we – as...

Lisa Phipps: And I want to – I want to make sure that we get through all of our cases. So I think we need to move on to our second case.

Clinical Case Discussion 2: From Risk to Action

We have a question on our – we have another question that I think is probably going to be a good one for this second case. But Martha is asking about, with one first degree relative with early-onset, how exaggerated is the risk of Alzheimer's for this patient? So I don't know if you want to address that now or if you want to wait until we get into the genetics piece of it. Or if you want to go ahead and address that now.

Susan Scanland: I think Emily can have a – a quick answer for that before we jump right in. We talked…

Emily Clark: We actually would consider both of them to be late-onset Alzheimer's disease, since the brother is 70 years old at the time of his diagnosis and symptom presentation. So both are actually late-onset individuals.

Patient Case: Paul

Susan Scanland: Okay. All right. Let's jump to case two. We're going to go a little further down into what happens when symptoms occur. Excuse me. So now we have Paul, who's 72 years old, retired accountant, coming to your office with his wife, and he's noticing things like forgetting the day of the week and words. And as we all do, misplacing things around the house. But his wife is also noticing this decline in his memory and no difficulty in his ADLs. He's doing both the basic ADLs and the instrumental ADLs like driving and cooking and light housekeeping and yard work.

His MoCA has been tested and it's been shown to show basically in the mild cognitive impairment category of 24 out of 30. So I'm going to detail in a minute or so. I had the privilege of working with the Alzheimer's Association with nine other experts across the country on how we need to work up, basically a clinical practice guideline for diagnosis of Alzheimer's and other dementias.

So we've – you know, we spent probably five to seven years on this, and I'm going to share that with you in a minute. But basically a detailed history of cog – like I want to say a cognitive history instead of just a routine history. I want to look at specifically the onset.

One of the symptoms begin what has been the trajectory, what's been the progress of it? How has it impacted on ADL and instrumental ADLs. And IADLs go early on in the late-onset Alzheimer's disease, whereas your ADLs, by the time you hit those, you're moving into the moderate stages. So that's why it's important to clue in on levels of ADLs, because that helps us to categorize.

Also, sometimes dementia and Alzheimer's may present early with mood and behavioral things and social changes. So it's important to know about that. Psych history, know about, you know, what the patient's had and the family has. And don't forget to ask, of course, as we know in this case, in the previous case about the family history of dementia, med history. And there's so many things we need to look at now from illegal substances, herbs, cannabis, alcohol, etc.

Physical exam, but especially on the neuro exam and the gait exam, because just doing the gait exam can help differentiate different types of dementia.

You may not have heard the terms tier one and tier two diagnostic testing, but as one of the authors on that – on that project, I really want to be sure you understand that because it's so important that you, you know, help specialists like Emily by the time you refer them to a cognitive neurologist or a memory center, you've done everything as a primary care provider to diagnose this person with probable Alzheimer's disease. So we're going to talk about that in a minute.

So you're kind of expecting some Alzheimer's disease. But, you know, you just want to send them to someone like Emily or, you know, depending on where you are in the country, it could be anywhere from a one year to even up to a four-year wait for a dementia evaluation. And it's not going to get better. So you really do want to get this right before moving on.

Alzheimer’s Association DETeCD-ADRD Clinical Practice Guideline 2024: Tiered Testing for Cognitive Impairment

So let's just quickly review what's the – they're called the DETeCD, Alzheimer's disease and related disorders, CPG guidelines, which came out in actually early 2005 but finished up in 2004. We looked at core elements. And the first one is you want to establish goals. How are we going to diagnose this with the patient and the care partner? It's so important to have an informant there also just because there could be a lot of denial or confabulation on the part of the person if they come alone.

And we talked about history of the present illness and the multisystem review. And I love starting with cognition and – and function. How function is affected by cognition, because there's a really – really interesting tool called the ECog, the everyday cognition scale. And you don't even have to use it like formally, but I would love – I love to use it by just using it to like, how long has it been since your loved one was able to entertain a meal or to get on a plane and fly, because then you can go backwards and retrospectively almost pinpoint when the problems began. So functional ADL is so important. And I like, you know, the ECog too for that reason.

Cognition, we're not only looking at memory, but language, executive functioning. Are they doing things in the proper sequence. Behavioral, that can show up, and neuropsychiatric, irritability, depression and anxiety may also precede clinical Alzheimer's disease.

Biopsychosocial, we talked about the links between cerebrovascular diseases and neurodegenerative, especially Alzheimer's risk factors. And Emily has covered those beautifully. Social history – and – and so forth.

And the exam. Okay. We can never just diagnose someone based on one blood test or one s-ray. This – what's in the circle has to be done in combination with the diagnostics that we're going to use. We talk about mental status exam. And like I said, you know, for years I've been doing this for 40 – 40-some years. The – you know, the Mini Mental State Exam was – was wonderful and that helps stage Alzheimer's, but it's not great for differentiating MCI, Mild Cognitive Impairment from Alzheimer's disease. So I prefer using the Saint Louis University Mental Status Exam or the MoCA to help differentiate MCI from dementia.

And as we all – you know, the rest of the exam too. And then that's going to basically take us to core six, where we're going to know is there – are they unimpaired like we had with Christine? Do they have subjective cognitive decline, as we are talking about in the current case with Paul? Is there mild cognitive impairment, which there is with Paul? Or is it further down? Is it dementia? And then very important to know by the ADL history and the cognitive history, is this mild versus moderate?

And the reason it's more important to know that now is because now that we have amyloid-targeted therapies – anti-amyloid targeted therapies, you know, with the newer antibody infusions, people are only eligible during the MCI period of Alzheimer's disease only and the mild stage of Alzheimer's disease only, not the other dementias. Because once you hit moderate, you're no longer eligible for that medication. So it's really upon us as primary care providers to catch people before.

You don't say, “Oh, you know” – I mean, if they have symptoms, you don't say, “Oh, let's watch it for a year or two.” You know, it's different when they're asymptomatic like Christine was. But with Paul, we don't – we don't wait because we can lose valuable time in getting them treated.

Alzheimer’s Association DETeCD-ADRD Clinical Practice Guideline 2024: Tiered Testing for Cognitive Impairment

Let's move on. Okay, so here's the tier one and tier two – two testing that we came up in the clinical guidelines. And as you probably are aware, brain MRI without contrast, just to rule out all those problems from NPH to, you know, any CVAs. You know, is there anything else growing, tumors and so forth.

Now, without contrast, and if they can't have an MRI for some reason, a head CT without contrast is, you know, doable too. Labs, CBC with diff, CMP, magnesium, phosphate, TSH, B12, homocysteine, C-reactive protein and ESR.

Now tier two testing, all of those – the tier one should be done on everyone, okay, with suspected cognitive impairment. Tier two, you as the PCP would order this based on what you know about your patient. You would customize these tests. I'm not going to read them all off as you can see them, but you would customize that based on your patient's medical comorbidities or what their presenting symptoms are. For example, Lyme antibodies or whatever.

So you are responsible as PCPs according to these guidelines for tier one and tier two testing. Once you get to the higher tiers, that's when Emily comes in and all of her colleagues who are cognitive neurologists or memory center clinicians. They usually take over, including the Alzheimer's disease biomarkers. And we're kind of at that stage where the science is changing so quickly that, you know, biomarkers will be, you know, standard practice for PCPs. We're kind of in that in-between stage right now.

Pretest 2

Okay. All right. So pre-test two. Okay. So we've got our – our patient here, Paul, and he demonstrates that symptoms and functional impact of MCI. He's got no apparent correctable etiology. We've done the whole tier one and tier two testing, you know, the neuroimaging, you know, the basic MRI and ordered – we've ordered some plasma testing too. And this is showing in, you know, the presence of some Alzheimer's disease, some amyloid pathology.

Okay. Can you diagnose him with Alzheimer's disease? And like I said, there are some primary care providers that are getting into blood-based biomarkers. So let's get – see what you think on this.

1. Yes – the first is yes; blood-based biomarkers can establish Alzheimer's pathology if there is confirmed cognitive impairment;
2. No; confirmation of amyloid pathology with amyloid PET or amyloid CSF is required;
3. No; Alzheimer's diagnosis can only be made by a neurologist or dementia specialist; and
4. No; a new - a full neuropsych evaluation. We talk about neuropsych. That's when they go in for that two-hour testing with a neuropsychologist just to confirm that.

So let's have you answer that. See where you're all at with that and what you think. Maybe not what you're doing, but what you think should be done.

Okay. All right. All right. So most of you, yes, blood-based biomarkers sufficiently establish Alzheimer's disease pathology in the presence of confirmed cognitive impairment. And the rest of you, a good portion of you said, no, you need to correlate it with PET scan or CSF.

So I want to say probably both answers are correct, and – and Emily is – I'm going to ask Emily to elaborate on hers. Because it's really kind of memory center-dependent. Emily, if you want to expand on that with what – you know, what you're experiencing at your clinic or what some of the clinical guidelines for memory specialists are with that.

Emily Clark: We're – we’re really in a really interesting period of – of the diagnosis of Alzheimer's disease. And so while our blood-based biomarkers can be very reliable, I mean, p-tau217 can be up to 90%, even a little bit higher in certain populations. The comfort level is still a little variable depending on the clinicians, the sites, what you're going to do with it.

And so, in most cases, a p-tau217 or a ratio can be sufficient to establish Alzheimer's disease pathology in a symptomatic individual who is meeting that clinical criteria for Alzheimer's disease. However, there are many sites, many specialties – specialists that will still require confirmation with an amyloid PET scan or CSF.

So yes, this is actually – this question has a, you know, possibly two acceptable answers. But we – it’s – it just highlights kind of where we're at in the field right now.

Susan Scanland: Exactly. So really the majority of you got that right because there is correct answers to A and B. But just looking at those answers, I want to clarify Alzheimer's diagnosis can only be made by a neurologist or dementia specialist. That is false. And think about that because, you know, we – if you have to wait for three to four years for a memory center, we don't want to waste that valuable time. Basically, you can assume probable Alzheimer's disease just looking at working up the tier one, the tier two, what's been the trajectory of the illness? And – and like I said, you've ruled out all those, you know, other possibilities of other types of dementia too.

And so important to do that because we don't want to waste valuable time as far as safety things. We're going to talk about that a little bit in the next – next case study, too. Valuable time in treating people with a combination therapy of, you know, cholin – a cholinesterase inhibitors and memantine and definitely, you know, safety issues.

So let's move on from there.

Discussion: Paul

Okay. All right. So what are the most recent updates in diagnostic assessments for Alzheimer's disease pathology?

Okay. Now we know when we refer patients to memory clinics or cognitive neurologists, they use amyloid PET scans, which uses the florbetapir imaging material to visualize plaques in the brain. So you actually see the amyloid plaques in the brain on this imaging.

Amyloid CS – CSF testing for amyloid has been going on for many years. And you know, that's, like I said, a very reliable measure is – you know, is there an amyloid disease present? P-tau ratios, as Emily had mentioned, is now coming into play. Certainly easier to get a blood test than go for, you know, spinal tap. But you know, CSF has been the mainstay for – you know, for years now to confirm diagnoses of actual Alzheimer's disease.

And we're getting new plasma assays coming out that really do correlate strongly with both the – the amyloid PET scans and the CSF testing. So it's a very exciting time in this field for diagnosis and I'm thrilled about it because I've been in this field for 42 years. And I'm glad it's getting even sharper with diagnosis and treatment.

So what's the best clinical practice for ordering and interpreting this?

So once again, you want to go for people who have cognitive impairments, you know, subjective, objective, after ruling out all the etiologies, which we do in our DETeCT clinical practice guidelines. They can be ordered by the PCP while waiting for the specialist availability. And you know, we can get positive results to substitute with the biomarkers as we, you know, confirm those and insurance coverage and so forth, you know, things are being worked on.

Clinical Case Discussion 3: Now What?

So what do we then do after the confirmed Alzheimer's disease diagnosis? So Emily is going to hop in right now, and we're going to kind of wrap up what happens to Paul.

 So let's go on with Paul here. So we've got a positive plasma biomarker assay and we've got objective evidence of cognitive impairment on the MoCA. He’s symptomatically presenting with symptoms of amnestic MCI. You feel comfortable saying that this is mild cognitive impairment likely due to Alzheimer's disease based on all these factors. You're now faced with this challenge that, as Susan highlighted, we face nationwide getting into a specialist. And so unfortunately, that average wait time is around 18 months.

So making an early diagnosis of Alzheimer's disease, early-stage in the disease is falling more and more into primary care clinics. So you plan to bring Paul and his wife in to explain this diagnosis. And knowing his medical history, you suspect that he's a good candidate for these amyloid-targeted therapies, lecanemab and donanemab. So you're definitely wanting to have a meet with a specialist to discuss this treatment option.

Pretest 3

So we have Paul in front of us, 72 years old. He's got supportive biomarkers for Alzheimer's disease. We want to set him up to – to come see a specialist like myself or someone in our clinic, and possibly for amyloid-targeting therapy. What tests did you – could you order that would be most useful for the specialist in considering amyloid-targeted therapies? Is it:

1. An EEG and ECG;
2. ECG and renal function testing;
3. Structural MRI and APOE genotyping;
4. Structural MRI and ECG; or
5. Structural MRI and FDG-PET.

Let's see. Great job everybody. So most people answered correctly. The most useful information for the specialists will be structural MRI and APOE genotyping.

So let's stick on that point for a second. So as I discussed in our case one, APOE genotyping is primarily used clinically for our risk assessment for ARIA with amyloid-targeted therapies. APOE4 carriers have a higher risk of ARIA compared to non-carriers. So it's important for us to be able to ascertain this information when we are providing an informed consent for these treatment opportunities.

APOE4 homozygotes on lecanemab have about a 45% risk of ARIA. And APOE4 homozygotes on donanemab have up to a 55% risk of ARIA. So this – this group of individuals can be very high risk with these treatments. If we're taking a step back and we're looking at heterozygotes. You've got someone who is an E3, E4, you're – you're kind of inching down a little more in terms of the risk that E4 heterozygotes have about a 19% risk of ARIA with lecanemab and about a 30% risk with donanemab.

So really, when we're assessing somebody, when it comes to APOE genotype, we're really looking for those E4 homozygotes. That is – is really what distinguishes somebody when it comes to their risk. So we're always looking for that.

It might be useful for you to know what – what your specialists in your area consider inclusion and exclusion criteria for amyloid-targeted therapies. The appropriate use guidelines for both of these drugs, which are publications that have been released throughout the last few years do not explicitly state that E4 homozygotes should be excluded. However, depending on the comfort level, the experience of – of the specialist in their prescribing practice, some sites have excluded E4 homozygotes from these therapies.

So important for you to know are – are your specialists in your area one of those people. That way you can better prepare your patients. In our clinic, we don't exclude E4 homozygotes, but we do have a very serious discussion about that risk and – and weighing in what is worth it to the patient when we are considering the risks versus the benefits of these therapies?

The – the next point is that structural head MRI. It is also very critical in determining eligibility for these amyloid-targeting therapies. Particularly of interest on these head MRIs, we're looking for pre-existing regions of microhemorrhage, superficial siderosis and looking at that burden of those white matter hyperintensities on MRI.

Depending on the severity of these findings, these can be exclusionary for amyloid-targeting therapies, as these are generally considered to be signals that somebody is carrying a higher vascular burden of amyloid that maybe not necessarily fully diagnostic for cerebral amyloid angiopathy, but possibly somebody who does have a higher deposition in – in their vascular walls.

And so when we administer amyloid-targeting therapies to these individuals, these people are at a higher risk for life-threatening cerebral hemorrhaging and/or edema. And so very, very crucial in this workup process.

Discussion: Paul (cont’d)

So what else can you do during this late period? One key point to – to highlight here is that you can call around to inquire about waitlist cancellations or rapid referral pathways for somebody that you do have biomarker supported. In our clinic, our general waitlist is about eight months for a general memory care assessment. So that's for any type of dementia, presence of dementia, any general concerns.

However, we do fast track individuals for amyloid-targeting therapy if they are considered ideal candidates. So maybe you do have a p-tau217 on them. Or maybe you were lucky and you happen to get an amyloid PET scan covered. Some clinics will offer these fast tracks for people who want to get that opportunity to seek amyloid-targeting therapy. So definitely ask around with your clinics to see is that a pathway and – and how can you best set up your patients to get accepted for something like that?

For reference, with my – my fast track pathway, I can usually get people in, in about two to three months for a consultation for amyloid-targeting therapy. So we try to find niche ways to help as many patients as we can catch them as early as we can, because we know that these drugs are most beneficial the earlier we can get them started.

So – and – and just kind of highlighting who is an ideal candidate that, as I mentioned, there are published guidelines for specialists that – that exhaustively kind of go into what we're looking for. But from a primary care side of things, really the big highlights you want to hit is making sure that these are individuals in those mild stages of Alzheimer's disease. So mild cognitive impairment or mild dementia due to Alzheimer's. You can determine that from our guideline standpoint is somebody who has a 22 or above on an MMSE or about a 17 or above on the MoCA.

Insurances will often use those as cut-off guidelines too. So I have not had very much luck in getting any of my patients scoring below that threshold approved for amyloid-targeting therapy. Unfortunately, many insurances will use that as a very hard and fast rule, no matter what kind of justification I – I try to put in there unfortunately.

Other kind of big things to look out for in considering this population for amyloid-targeting therapy, no anticoagulation. You want to take a look at say like that platelet count. Make sure the platelets are within normal limits. We want, you know, generally medically stable individuals. So no co-occurring bleeding disorders, no severe kidney disease, liver disease, heart disease. No concurrent chemotherapy because we just don't quite know the interactions between our monoclonals and – and some of these chemotherapeutic agents.

So generally you're looking for – for somebody who is relatively healthy, relatively uncomplicated, no anticoagulants, mild stages.

What else could you do during this wait period? Because there's a decent wait period here. You can consider your options for symptomatic treatments in these populations. We know that neuropsychiatric symptoms of – of Alzheimer's disease are very, very common. It is upwards of 80 to 90% of Alzheimer's disease. Individuals will have some neuropsychiatric symptom in the course of their disease.

So SSRIs are usually top of our list. Considering an SSRI for irritability, anxiety, depression are – are really relatively safe, easy treatment option to consider. SSRIs in our geriatric population, your buzzword in terms of our board exams, you're always thinking, look out for hyponatremia.

You start an SSRI, they're falling, they're weak. Always check their sodium levels. You could also consider, especially the acetylcholinesterase inhibitors in these kind of early-stage disease individuals for cognitive benefit. However, that disclaimer is that acetylcholinesterase inhibitors and memantine are only FDA-approved for dementia stages of Alzheimer's disease. In some of our other related dementias, they’re – they're there off-label used if you are trying to administer these in MCI. And you get kind of differing opinions about what's appropriate there or not.

And then otherwise, you – you treat them like you are kind of everybody else. You want to make sure you are maintaining assessing their general medical health, particularly keeping an eye on, again, blood pressure, cholesterol, diabetes, sleep problems, insomnia, sleep apnea. And also it's worth considering getting family involved in these visits. So that way you can routinely assess for safety concerns, discuss kind of potential future planning and support, try to screen for caregiver burnout, connecting them with resources like the Alzheimer's association.

So you really – you're kind of a jack of all trades when it comes to addressing this patient population that you – you are so helpful to this patient and – and these patient families, because there are so many things to be considering here.

And – and Susan, you – you kind of know more than any of us kind of walking people through this – this side of things. What else do you have to add to this?

Susan Scanland: You know, you can never give the caregivers too much support. There are – the Alzheimer's Association has online support groups because we know it's hard for caregivers or family, concerned family members to get to meetings. I even have – I have some colleagues on the West Coast and they've even found in-person support meetings for mild cognitive impairment. And like I said, this is tough, because a lot of times the MCI person is a professional person still at work and the symptoms may show up, you know, in their law practice or medical practice or whatever they're doing.

What Do You Remember?

Another thing I really want to stress for safety is financial exploitation. Because, you know, elders in general are at risk for financial exploitation on the internet, by phone, calling for Social Security numbers. But when you have some cognitive impairment, they are tremendously at risk. So get the family to work with you on protecting the assets they have driving to families and often physicians to hesitate to even bring this up.

But often, if you get a third-party involved, an occupational therapist who does driving assessments or, you know, you know, driving check in general private testers, they – you're not the bad guy then. And – and, you know, disasters can be, you know, averted hopefully, prevented, you know, harm to other people on the road, etc..

We've all heard the stories about people driving the wrong way on the highway. And I actually ran into that myself about 40 years ago when I was new in this field. And it's – it's terrifying. So yeah, never enough prevention for safety. And is the living arrangement a safe place? I've seen a lot of cases where families out of town, they may not realize how impaired the person is, and they're living out in the middle of nowhere and walking in the woods.

So, you know, is the living situation appropriate? Are they driving, protect their finances, you know, get their affairs in order early. That's the quickie. There's many more, but I mean we want to have time to take some questions too. Is there anything else, Emily, you want to add to that?

Emily Clark: No, I think you did a great job. And I mean, I fully agree it's that caregiver support just can never be overstated.

Susan Scanland: Absolutely.

Emily Clark: That providing as much help as many resources as possible. They are always very appreciative and always very much in need because you – you never find somebody who – who is jumping too quickly to tell you about this, that people are often kind of suffering in the background for a long time before they get to a point where they bring it up with you. So trying to screen for it before they bring it up is really helpful.

Susan Scanland: Yeah.

Lisa Phipps: Okay. I am going to go ahead and go through our post-test questions quickly so that we can get through some of the questions that have been rolling in. So let's go ahead and do those.

Posttest 1

So here's our posttest one. Your 60-year-old patient has no cognitive symptoms, but is concerned about her risk of developing Alzheimer's disease because her mother and older brother developed the disease later in life. What is your best course of action at this time? Is it to:

1. Assess her cognition with a brief tool to confirm lack of impairment;
2. Order blood-based biomarker testing to detect early signs of AD pathology;
3. Order genotyping to determine whether she has familial risk factors; or
4. Order brain imaging to detect early signs of neurodegeneration or atrophy.

So what would you do first? Do we assess her cognition with a brief tool, order bio – blood-based biomarker testing or genotyping or brain imaging.

Okay, great. We had some good learning there.

Susan Scanland: Almost 90%. That's great.

Lisa Phipps: Yes.

Susan Scanland: And attention.

Lisa Phipps: Nice big jump.

Posttest 1: Rationale

So yeah, there's the – the rationale and everything there. So our first step is always just to assess with validated tests.

Posttest 2

So post-test two. Your 72-year-old patient has symptoms of mild cognitive impairment. Moca score 24 out of 30 and no apparent correctable etiology. You order plasma testing of p-tau217 amyloid-beta42 ratio, which indicates the presence of AD pathology. As a primary care HCP, can you diagnose him with AD? And now this was the one where there was a little bit of, okay, yes or no, as can a primary care HCP diagnose him? And then the second part of the question is sort of blood-based biomarker sufficient to establish pathology or do you need confirmation? And that was the part where it was kind of like there might be two right answers here. But you know, kind of go with, can a primary care diagnose a person with Alzheimer's disease? So your answers are:

1. Yes; blood-based biomarkers can sufficiently establish AD pathology in the presence of confirmed cognitive impairment;
2. No; confirmation of amyloid pathology with PET or CFS is required;
3. No; AD diagnosis can only be made by a neurologist or dementia specialist; or
4. No; a full neuropsych eval is required.

Susan Scanland: And just to jump in on that, clinical diagnosis is always yes, but pathological diagnosis is what happens when you forward – you know, when you move up to the cognitive neurologist memory specialist. So yeah, so we have like almost different levels of diagnosis, but absolutely, you can clinically diagnose someone with answer A.

Lisa Phipps: Great. Okay.

Susan Scanland: Good.

Lisa Phipps: There you go. Okay.

Posttest 2: Rationale

So yeah, we got the answer there is yes. So again, they kind of talked about the nuances. And Susan just again, kind of said the nuances of clinical versus pathological diagnoses there.

Posttest 3

And the third one. You tentatively diagnose your 72-year-old patient with MCI due to Alzheimer's based on a full cognitive assessment and positive blood biomarker testing. You refer him to a dementia clinic, but the wait time is almost a year. He's interested in receiving amyloid-targeted therapy, if possible. Which tests could you order to be most useful for the specialist in considering treatment?

1. EEG and electrocardiogram;
2. Electrocardiogram and renal function;
3. Structural MRI and APOE genotyping;
4. Structural MRI and EKG; or
5. Structural MRI and FDG-PET.

So what is the specialist most going to find useful in determining whether or not this patient is eligible for amyloid-targeted therapy?

Okay. Got a big – nice big jump there too.

Susan Scanland: Yeah.

Posttest 3: Rationale

Lisa Phipps: So yeah. Yeah.

Susan Scanland: And FDG-PET is especially helpful in determining whether it's frontotemporal dementia versus Alzheimer's. I see some of you still put that, but that's very important if you're thinking about FDG.

Brain Health Hub

Lisa Phipps: Yeah. And so I'm – a couple of questions came in about where could we find information about APOE genotyping? Where can we find out about ARIA risks? Where can we find out about other things? So I wanted to put this slide up here for you. We have a Brain Health Hub on our website and the downloadable slides from this are there. There are other slides from other presentations. There are videos from other presentations, some clinical resources, ClinicalThoughts that dive into some of these other topics for you. So please definitely check out our Brain Health Hub.

Q&A

I know that it's 13:00, so I want to be respectful of everybody's time, but I did want to ask a question. One of these questions that came up real quick was we did talk about falls and we have a question about, I read somewhere that multiple episodes of falling in 65 year olds showing up in emergency departments may be an indicator of Alzheimer's and warrant evaluation. Can you address that very quickly?

Emily Clark: There was a recent publication, I believe a year or two ago, that was looking at individuals and particularly the one I recall was mostly individuals who had Alzheimer's disease were more likely to present with recurrent falls than – than those without Alzheimer's disease. And so a proposed kind of warning sign to say, “Okay, I've got somebody with recurrent falls. Don't know what else going on. Maybe I should screen them cognitively.” But I would take away from it is saying, “You've got somebody who is – who is ageing and they're having recurrent falls, and you can't quite pinpoint any particular problem to them. Consider doing a cognitive screen to see is – is that playing a role into this?”

Susan Scanland: Absolutely. Yeah. And also screen them for Lewy body dementia, because falls are more frequent and more common in dementia with Lewy bodies even than they are with Alzheimer's disease. So yeah, it's not a bad idea to screen for cognition in ER settings.

And also, I just wanted to point out too with the Brain Health Hub, I developed an infographic for all of you to share with your – for people like Christine, who want to work on prevention in their middle ages. I – I went through a lot of literature and came up with about 15-plus risk factors that you can work on to decrease your risk of Alzheimer's disease and also protect your cardiovascular system at the same time for many of them. So please do.

It's a PDF on this website and print as many as you want and share it with your friends, family, everyone who's worried about their brain as they age. It's – it’s a really helpful. I learned a lot from doing it myself. So, all right. Thank you everyone.

Emily Clark: Yeah. Just real quickly I'm mindful of time. Also with the APOE, I did that question. If you're looking for the APOE corresponding results between ARIA and APOE, you can find those on the FDA labels for the drugs. So it's buried in the – in the data there. But it's all there published in the FDA labels.

Lisa Phipps: And then one real quick future-looking question is kind of as with therapies for hep C previously done by only specialists, do you see PCPs one day administering amyloid-targeting therapies?

Emily Clark: It's – it's a really good question. It's very challenging with the ARIA detection and management.

Lisa Phipps: Yeah.

Emily Clark: That I do feel like that will be a barrier. However, we know that these amyloid-targeting therapies are not the end all be all for this disease that we are ever – ever working at small molecule agents that have lower risks associated with them. So I would say it's hard to – hard to foresee the agents we have right now in practice being implemented in primary care. However, I do think that there will be agents that we will be able to administer in primary care in the future. So we're very hopeful.

Susan Scanland: Yeah. They may not always be IV as time goes on in the next, you know, 10 years or so. So it may be easier. Right now it's very labor-intensive to have this sort of, you know, the IV administration. There's just so many things to check. So right now it's done best in specialty clinics that have templates and very, very detailed. In a busy primary care practice right now, I would scratch my head, say how. But – but in the future, who knows? Because, you know, we know Alzheimer's is going to increase and we know the ageing population is going to increase.

So yeah, many challenges ahead, but we're ready to tackle them.

Lisa Phipps: Thank you everyone for joining us today. And thank you, Emily and Susan for a wonderful discussion and presentation. Most appreciated. And again, everyone, check out the Brain Health Hub for a lot of other resources and, you know, recordings of presentations like this. And we will see you all for our next Alzheimer's presentations. Thanks very much. Have a great day.

Emily Clark: Thanks, everyone.

Susan Scanland: Thanks.