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Global Insights, Local Impact: Practical Pathways for Integrating Biomarkers in Alzheimer’s CareIntroduction

Malavika Tampi (Alzheimer's Association): Hello, everyone. Welcome to Global Insights, Local Impact: Practical Pathways for Integrating Biomarkers in Alzheimer's Care.

This accredited Continuing Medical Education program is presented by Decera Clinical Education and supported by an educational grant from Lilly.

I am your moderator, Malavika Tampi, Director of Guideline Development at the Alzheimer's Association.

Faculty

I would like to introduce our international panel of expert faculty that we are lucky to have here today:

• Dr. Atsushi Iwata of the Tokyo Metropolitan Institute for Geriatrics and Gerontology;
• Dr. Sebastian Palmqvist from Skane University Hospital and Lund University;
• Dr. Jiong Shi from the University of Science and Technology of China; and
• Dr. Scott Turner from MedStar Georgetown University Hospital.

Thank you all for being here today.

As a note, the faculty will be speaking from their individual clinical opinions. The discussion you will hear should not be considered to represent recommendations from the Alzheimer's Association.

Disclosures

Here you can see all of our disclosures. Please take a moment to review this information.

Learning Objectives

Learning objectives for today will include:

• Evaluating emerging evidence on the clinical utility of blood-based biomarkers to enhance timely and accurate diagnosis of AD;
• Identify appropriate patients for blood-based biomarker testing to support individualized care pathways;
• Apply evidence-based strategies and clinical guidance on biomarker testing to direct clinical decision-making and referrals across the AD care continuum.

Clinical Pathways for ADRD Detection and Diagnosis

Now we are moving into Clinical Pathways for ADRD Detection and Diagnosis.

I will turn the presentation over to Dr. Scott Turner, who will give a brief overview of current clinical detection and diagnostic pathways from a US-based perspective. Dr. Scott?

Dr. Raymond Scott Turner (MedStar Georgetown University Hospital): Thank you for the introduction. Thank you for being here, everyone. I feel it is a different world in Alzheimer's disease because of all the advances that have been made in recent years.

Alzheimer’s Association DETeCD-ADRD Clinical Practice Guideline 2024

How do we get started with an Alzheimer's diagnosis? This was a consensus panel paper published in 2024 looking at seven core elements that are recommended for evaluation of patients with suspected cognitive impairment that might be due to Alzheimer's or other dementing disorder of the elderly.

Core one is establishing shared goals for diagnostic process with the patient and the care partner. Hopefully, everyone is on the same page and seeking a diagnosis for a medical problem.

Then we start, of course, with the history. It is important to get the history from both the patient and the care partner. We often find a very different history. A typical scenario is the patient may just say, nothing wrong with me, normal aging, no problem, and the care partners reporting much more.

The psychiatrist might call this denial. The neurologist might call it anosognosia. It is kind of a lack of awareness of one's own problem. It might also be necessary to separate the care partner from the patient to get a more accurate history, but usually we can do it together.

Then as part of the history, you should focus on cognition as well as function as well as behavior. By behavior I mean like depression, anxiety, insomnia, perhaps psychosis, paranoia, other behavioral changes, which may be presenting sign or symptom of Alzheimer's disease.

Move on to risk factors such as hypertension, diabetes, high cholesterol, family history, traumatic brain injury, history of depression, etc., social history.

Then move on to the examination. With the examination, we would ask you to do some formal cognitive assessment, a validated cognitive test. Obviously, we would like a test such as MMSE or MoCA or SLUMS, which may take five or 10 minutes and you may not have five or 10 minutes, so there are several workarounds. One is to do a brief cognitive assessment that takes only two or three minutes. Another workaround is to set up a different appointment just to do cognitive testing.

Another workaround is that any medical professional in the office could do the cognitive assessment. It does not have to be the MD or DO in the office that does this.

Then moving on to making a diagnosis, is this patient normal aging, normal cognition? Does this patient have subjective memory concerns, mild cognitive impairment, which means cognition declining and worse than before, worse than expected for age and education but intact independence and function? Or now is independence and function impaired? That is moving into dementia category. There is mild, moderate and severe stages.

Then moving on to what may be causing the dementia, the pathologic basis. Obviously, the most often pathology is Alzheimer's disease. There are others as well. This is where the blood tests that you will hear about later are coming into the picture to help with the diagnosis and determining the pathologic basis of the cognitive decline.

Evaluation of Patients With Suspected Cognitive Impairment: Primary Care Setting

This is the recommended flow sheet for primary care setting. I would not spend too much time on this because this is under revision based on the newer technology of the blood tests and how these are helping to make diagnoses and evaluating patients in the clinic.

Obviously, starting with the history, the physical, some cognitive assessment, and then basic blood tests would start the diagnostic evaluation. These would include CBC, chemistry panel, TSH, B12 and perhaps others as indicated, perhaps HIV or syphilis, if there is some risk factor or history of the above.

You may want to consult a neuropsychologist if you are not really confident in your cognitive assessment, or is it unusual or difficult case, perhaps some legal or benefit question hanging over the evaluation.

Then depending on your level of confidence and how much evaluation you have done, you may want to refer to a dementia specialist. Or if you are confident, you can carry on with the workup and get an MRI of the brain. MRI is preferred over CT, but some neuroimaging study to look for structural changes, look for other causes of dementia, especially stroke, tumors and other causes of cognitive decline.

Evaluation of Patients With Suspected Cognitive Impairment: Dementia Subspecialist Setting

If a patient does get to the dementia specialist, and there are other tests that may be considered in addition to the blood tests, of course, which are going to be incorporated into the next version of these flowsheets. The dementia specialists may want to add any other blood tests or CSF tests, would consider a glucose PET scan to distinguish frontotemporal dementia from Alzheimer's disease, may consider a spinal tap looking at proteins in spinal fluid, including A-beta 40/42, tau, phosphorylated tau in CSF.

What also may be considered amyloid PET scan to look for the basis of cognitive decline and to see if this is Alzheimer's disease. Would also perhaps incorporate blood tests to determine whether to screen patients, whether to move on to a spinal tap or an amyloid PET scan.

Of course, the specialist may also consult a neuropsychologist if further cognitive assessment is required, and the neuropsychologist will spend three to four hours with a patient with a standardized set of cognitive tests, with norms for patient's age and education, and provide a report of cognitive abilities.

On the rare patients that have a possible autosomal dominant mutation of Alzheimer's disease, and there are about 200 pedigrees in the world that have a mutation in either APP, presenilin 1 or presenilin 2, may consult a genetic counsellor to discuss genetic testing in these individuals.

Then putting all of this together, the history, the examination, all the biomarker testing to come up with a diagnosis, either a normal subjective cognitive concerns, mild cognitive impairment or dementia, and then coming up with the pathologic basis. For example, you might determine a patient is mild cognitive impairment due to Alzheimer pathology. If the CSF or blood test or amyloid PET scan are indicative of Alzheimer pathology, or we may come up with another diagnosis, such as Lewy body dementia, frontotemporal dementia, vascular dementia, etc..

Traditional and Emerging AD Biomarkers

As I said, this is a brand new world with all of these emerging biomarkers, especially the blood test in recent years. The first biomarkers were really imaging, CAT scan and MRI. These can also get more fancy with volumetrics, quantitative MRI, for example, or functional MRI.

Then PET scans, we have a ligand that looks at glucose uptake, a fluorodeoxyglucose PET scan, which has been available for two or three decades. More recently, amyloid PET and tau PET, where we can see the markers of Alzheimer pathology in vivo in a living patient.

We also looked at proteins in spinal fluid, including A-beta, tau, phosphorylated tau-181, 217, and others.

More recently, the blood tests have really come forth and you will hear much more about them from Dr. Palmqvist. These include A-beta40/42 ratios; phosphorylated-tau-181, 217; neurofilament light or NfL looking at neurodegeneration; GFAP, glial fibrillary acidic protein, looking at gliosis or inflammation in the brain. Then of course, the ratios.

The first FDA-approved plasma test was the ratio of P-tau217 to A-beta 42, which was approved in 2025. Then the second one was P-tau181, which was approved also in 2025.

Up and coming are also lots of digital biomarkers, but we do not really have time to talk about those today.

Trajectories of AD Biomarker Change

Putting all these biomarkers on a timeline or time frame, these are the so-called Jack curves named after Cliff Jack at Mayo Clinic. These are when the biomarkers become abnormal as a function of age. The first one that you see become abnormal is amyloid. A-beta 42 goes down in CSF and plasma and goes up in the brain parenchyma as deposited amyloid as detected by the amyloid PET.

Because this is the first biomarker to become abnormal, we have developed the amyloid cascade hypothesis that the amyloid triggers other pathologies, including phosphorylated-tau aggregates, as tangles, which can be detected in CSF plasma, and tau PET imaging. This leads to death of neurons and spilling of proteins into spinal fluid and then into the blood, such as neurogranin and neurofilament light.

All of this eventually leads to loss of synapses, loss of neurotransmitters, loss of neurons, which can be measured as atrophy on MRI scan, and then eventually all of this leads to cognitive and functional decline.

We also realized that these biomarkers are becoming abnormal 10 to 20 years before the onset of any clinical signs or symptoms.

AA-SNMMI Appropriate Use Criteria for Amyloid and tau PET

This is what the typical amyloid PET scans look like. There are three FDA-approved biomarker amyloid ligand biomarkers. Those are flutemetamol, florbetaben and florbetapir as shown here. The upper images are negative amyloid PET scans.

You can see some non-specific uptake in the white matter tracts in the negative images here. Once you lose the great white junction, that means there is a ligand uptake in the cortex as well, and that indicates a positive amyloid PET scan. You can also see the positive amyloid PET scan has tracer uptake all the way up to the skull. This is how you can read the negative amyloid PET scans from the positive amyloid PET scans. Just by convention, flutemetamol is red in color, the other two in black and white.

On the lower right here is a tau PET image, which you usually do not get tau PET images clinically. These are used for research primarily. At the top is a negative tau PET and the bottom is a positive tau PET image. There is only one FDA-approved tau PET ligand to-date.

2018 NIA-AA Research Framework: AT(N) Classification Scheme

2018, the biomarkers were classified as in the so-called AT(N) classification scheme. A is for amyloid showing aggregated A-beta. A-beta measures in CSF or plasma or amyloid PET imaging. T is the tau or tangles, phosphorylated-tau primarily as measured in CSF and tau PET. Then N stands for neurodegeneration, the spilling of proteins as neurons are dying into the CSF and then into the plasma. This could be total tau as well as neurofilament light. This can be measured by loss of brain volume on MRI and abnormal glucose uptake on a PET scan.

The typical Alzheimer continuum in the lower left on this slide shows that you begin with amyloid positivity, followed by tau positivity followed by neurodegeneration. Then we discovered many patients that do not fit in this pigeonhole. These are called suspected non-amyloid pathology or non-Alzheimer pathology.

Some of these are primarily tau pathology and they are called PART, primarily age-related tauopathy. Many of them have TDP43 aggregates, another protein that aggregates in aging brain. They are amyloid negative and tau negative, and yet they have cognitive decline due to TDP43 aggregates. These are called LATE, limbic-predominant age-related TDP 43 encephalopathy.

2024 NIA-AA Biomarker Categorization

In 2024, this categorization was updated. Now we have T1 and T2 categories for the tau or tangles and T1 are considered diagnostic. These are shown here in the CSF, as well in the plasma primarily p-tau217, which is the best indicator of a positive amyloid PET scan.

These are the diagnostic T1 biomarkers. The T2 are helpful for staging. For example, the microtubule binding region tau-243 in plasma or tau PET imaging. We still have neurodegeneration as neurofilament light and inflammation as GFAP. Now we have added possible co-pathologies such as alpha-synuclein or Lewy bodies that you see with Parkinson's disease and Lewy body dementia, as well as vascular changes which are found on imaging, white matter changes or strokes, frank strokes or lacunar strokes that are found on imaging studies. We often see copathologies in addition to Alzheimer pathologies, particularly in older individuals.

2024 NIA-AA Biomarker Categorization

This is again the 2024 review paper. At the top are the clinical stage, stages zero, I, II, III and IV.

A stage I is the asymptomatic A-plus T-minus and then moving on to the early MCI and MCI and dementia. On the left are the pathologic stages. We start with A, B, C and D. As you go to tau PET positive and the tau spreading throughout the brain.

The typical progression is in the yellow arrow. If you have a lot of co-pathologies, you move the curves to the right and you are much worse clinically than you would expect from your Alzheimer biomarkers. If you have resilience factors such as perhaps an APOE2 gene or a Mediterranean diet, exercise, etc., then you have resilience factors and you look better than you would anticipate from your Alzheimer biomarkers.

Current Evidence for Utility of BBMs in AD Diagnosis and Care

I will turn it over to Dr. Palmqvist now.

Malavika Tampi: Thank you so much, Scott. Go ahead, Sebastian.

Dr. Sebastian Palmqvist (Malmo Lund University): Thank you for that very comprehensive overview. I will now follow-up with more detailed slides on blood-based biomarkers.

What Does Phosphorylated Tau (P-Tau) Measure?

I wanted to start with the basics here. What is it that p-tau is actually measuring? Because p-tau is the most common blood-based biomarkers that is being commercially provided and regulatory approved.

The tau and p-tau is a building block of the microtubule, which is a transporting system in the cell and probably triggered by the buildup of beta amyloid plaques in the brain, we see a hyperphosphorylation and secretion of tau. That hyperphosphorylation can occur at different sites of the tau protein, and that is being denoted by the different numbers that follow p-tau. It could either be p-tau181, p-tau217 or p-tau231. They have slightly different properties which I will get back to.

P-tau is something that we have been measuring in CSF for almost three decades now. The version we are measuring in CSF, and the only commercially available one is p-tau181.

P-tau is independently associated both with a beta amyloid pathology in AD and also the tau tangle pathology. These are statistical associations. P-tau is not measuring either pathologies, measuring something different, but it is associated with these.

Especially in the beginning of the disease, p-tau217 or p-tau in general is much more highly associated with just beta amyloid plaque. As the disease progresses, the association with tau tangle pathology in the brain becomes stronger and stronger.

Trajectories of AD Biomarker Change

Going back to the slide that Scott showed, I just wanted to highlight some aspects from a blood-based biomarker perspective. As you can see time-wise, the changes in plasma is seen almost at the same time as CSF. I would say that maybe the corresponding CSF biomarker is slightly more sensitive.

In terms of increases of different p-tau217 analytes, we see probably the earliest increases in p-tau231 followed by increases in both p-tau181 and p-tau217. As the disease progresses, we continue to see increases in p-tau217. For both p-tau231 and p-tau181, they tend to stabilize and reach a plateau much earlier in the disease process.

P-tau217 Is the Most Promising Across P-Tau Analytes

How do these compare in terms of identifying AD pathology measured either using CSF or amyloid PET?

Below you see the to-date largest meta-analysis of different p-tau181 assays and pooled different P-tau217 assays and 231 assays. As you can see, in the AUCs denoting the discriminative accuracy, you see that the best discriminative accuracy seen for p-tau217.

The reason for the better performance is really explained by the fold increase in p-tau217.

Here is a head-to-head study comparing in the same population different p-tau assays. As you can see, p-tau217 is the clear winner, where you see increases in AD versus non-AD that are about 500% to 600%.

For p-tau181, they do not have the same, not even the regulatory authorized. P-tau181 is in the lower part of this slide or a forest plot.

What About Plasma Aβ42/Aβ40 Ratio?

What about plasma A-beta 42/40? This is good to highlight, because I noticed in the poll that this was the one that you endorsed the most in terms of a standalone blood test. To my knowledge, there is only one approved standalone A-beta 42/40 assay, but it is often incorporated in p-tau assays being reported to the clinicians.

A-beta 42/40 is a bit more tricky to use for clinicians, because in contrast to the 500% to 600% increase we see with p-tau217, there is here only a very small decrease of around 10% to 20%. 20%, I would say, is maybe an overestimation. Usually it is between 10% and 15% decrease. That small difference is because of peripheral beta amyloid that dilutes the contrast between AD and non-AD.

Within a given cohort, the differences could look pretty okay if you look to the panel here to the left, where you have a very precise mass spectrometry A-beta 42/40 assay. Between cohorts, the levels differs quite a lot. That is because beta-amyloid is quite sensitive to how you handle the sample, what kind of tubes you use, and even at what time of day you take the sample. So it makes it much less robust as a standalone biomarker.

It can sometimes provide some supportive value if combined with p-tau217, but is generally not something that is robust to be used on its own.

FDA-Cleared and CE-Marked Lumipulse Cutoffs for Plasma vs CSF

Now that we have both regulatory authorized blood test and CSF test, it is interesting to see how they compare to each other.

Here is a study using amyloid PET as the standard truth or reference standard, and doing a head-to-head comparison of the regulatory approved Lumipulse CSF A-beta 42/40 with the regulatory authorized cut points and comparing it to the FDA-cleared plasma p-tau217 to A-beta 42 using the Lumipulse assay and also the very recently CE mark that is the European corresponding regulatory approval for just plasma p-tau217 and the regulatory approved cut points.

If you see in secondary care, the blood test actually has a slightly higher accuracy than the CSF test or I should say correspondence with amyloid PET. This is driven by more false positives using CSF than plasma.

In primary care, it looks slightly different. For example, A-beta 42 in plasma seems to, at least in this study, be a bit more tricky to measure, could be due to the analytical circumstances in primary care in a less controlled environment, but p-tau217 performs very similar.

What does this mean? Does this mean that sometimes blood test is more accurate than CSF?

No Gold Standard — Only Complementary Reference Standards

I would say no, because the point I would like to highlight here is that CSF A-beta 42/40 and plasma p-tau217 and amyloid PET, they all measure different aspects of the AD pathology, and none of them are more true than the other PET.

It measures non-soluble fibrillar A-beta that has accumulated over time. So it measured what has been happening in the brain. Then we have CSF A-beta 42/40 measuring what is happening right now and what is happening with soluble A-beta species.

P-tau217 or other p-tau species also measure what is happening now, but it measures another aspect of the pathology. In the previous slide, the lower performance of CSF A-beta 42/40 is probably caused by a higher sensitivity, as we saw in the so-called Jack curves or the trajectories starts to increase.

This is very important to think about when you start implementing a blood test, because I know many clinicians in the beginning, they want to follow-up every patient with either CSF or PET to get to know the blood test better. Here I want to emphasize that just because the CSF test or PET test does not show the same thing as the blood test, it does not mean that necessarily the CSF or PET test is more accurate than the blood test.

Alzheimer’s Association Clinical Practice Guideline

I finally want to give some updates from the Alzheimer's Association's Clinical Practice Guidelines on blood-based biomarkers for detecting AD pathology in cognitively impaired individuals within specialized care setting.

Here I am part of a panel consisting of expert clinicians and methodologists who have been working with this for several years now.

Performance Among Blood Tests Using 1 Cutoff

In the first iteration, the panel and the association recommended for using a blood test as a confirmatory test of AD pathology if it reached a sensitivity and specificity of at least 90% and recommended for using a blood test as a triaging test, if it reached a sensitivity of 90% at least, and a specificity of at least 75%.

In the first iteration of the meta-analysis, using just one single cut point, because this was what had been published up until then, we noticed that a few of the tests reached the threshold for triaging tests, but none of the commercially available tests actually reached the threshold for a confirmatory test using just one cut point.

Update in Progress (Tentatively Expected Winter 2026)

We are currently working on an update here. We will still be working on individuals in specialty care with objectively verified cognitive impairment, but we will now focus more on commercially available tests and looking both at the one and two cut-off approach, where the two cut-off approach might help the test to reach a confirmatory status, and also include different ratios because these are the ones being regulatory approved. Still, we are at a stage where we will probably use brand-agnostic recommendations.

2 Clinical Roles: Ruling In vs Ruling Out AD Pathology

We will be also focusing on different scenarios where we either use the test to rule in or rule out and see how the test works in different pre-test or prevalence settings, either where we have a very high suspicion of AD with a clinical phenotype that is typical, where you have a prevalence or pre-test probability of around 75%, or your average specialty care setting, where it is usually around 50% or a younger individual and/or a typical presentation where it goes down to 35%.

With that, I would like to thank for this time and leave it over to Malavika.

Alzheimer’s Association Decision Support Tool for the Use of BBMs for AD Pathology in Primary Care

Malavika Tampi: Thank you so much, Dr. Palmqvist. I just want to also note that the Alzheimer's Association has developed a decision support tool for the use of BBMs in AD pathology in primary care. This should actually be live today. If you want to check out ALZPro, we will have some information later if you are interested in this, but just a note about primary care settings and our resources for those settings.

Next up is Dr. Jiong Shi, who will be presenting BBM data from China. Thank you so much, everyone.

Dr. Jiong Shi (University of Science and Technology of China): Thank you. Glad to be here.

Spotlight on Evolving BBM-Based Diagnostic Workflow in China

I am going to present the spotlight on evolving BBM use in China.

          Head to Head Comparison of BBM in Chinese CLEAR-AD Study

We did a head-to-head comparison to help clinicians to choose which one is the best for the BBM use for Alzheimer's disease.

This study rigorously validates the diagnostic performance of BBM for Alzheimer's disease. The key takeaway is that across multiple testing platforms using either plasma p-tau217 or the p-tau217/A-beta42 ratio consistently demonstrated high and comparable accuracy in identifying A-beta PET positivity.

As you can see on the left, the AUC curve for p-tau217 alone shows excellent predictive power of A-beta PET status. On the right, we see a strong discriminative performance across key clinical groups such as AD versus normal and different MCI subgroups. These findings are significant step toward making the AD diagnosis more accessible and less invasive.

Challenges in the Clinical Application of BBM Testing

While the science is quite promising, especially we talked earlier about the BBM development, we must acknowledge the real-world challenges in implementing BBM. These can be grouped into three main areas:

• Practice;
• Diagnosis; and
• Treatment.

In practice, we need more real-world data and better education of healthcare professionals on how to use these tests.

For diagnosis, we need clear guidelines for interpretation, and we need to build trust in blood test as a valid alternative to either PET or CSF.

For treatment, regulatory framework are still catching up, and we lack tools to effectively stratify patients for specific therapies.

Ultimately, a key challenge remains how do we accurately interpret the results and effectively communicate them to patients.

Potential Application of Plasma P-tau217 Dual Cut-off Model

To address these challenges, we propose a practical two-step diagnostic workflow using the dual cut-off model based on plasma p-tau217. It starts with patients presenting with cognitive impairment symptoms. A simple plasma p-tau measurement is performed. The results are then fed into a risk stratification model to determine the probability of underlying A-beta pathology.

This leads to three possible pathways. For high probable patients, we can make a suspected clinical AD diagnosis and consider specific treatment. For low probability patients, we can rule out AD and investigate other causes, just like Sebastian told earlier about the rule in and rule out.

More crucially, only the intermediate probable group about less than 20% of patients will need further confirmatory tests like A-beta PET. This approach significantly streamlines the diagnostic burden and reduce cost for patients and the healthcare system.

Patient Case Discussions

Malavika Tampi: Thank you so much, Jiong. Now, I would like to invite all faculty to discuss integration of BBM testing into clinical practice, both at the current time and also looking forward to what we might expect in the near future.

We have three patient case scenarios to discuss. What is going to happen as part of this section is that we are going to read through each case presentation slide. There is going to be a poll and we can briefly discuss the poll results. Then we will move into moderated discussion with the panel members.

Patient Case 1: The Primary Care Dilemma

Let us look at our first case. A 68-year-old woman at a routine annual visit presents with her daughter. Her records show inconsistent past management, including history of suboptimal medication adherence and medication regimen has been stable for several years, with report of good recent adherence, and this is something that her daughter has confirmed.

Today, she has borderline indeterminate score on a brief cognitive screener, and when asked, she says she has felt more forgetful lately and her daughter agrees she has noticed some memory problems, but nothing seriously concerning.

The PCP considers BBM testing but is concerned about potential false positives and uncertain how the results should impact clinical decision-making.

Patient Case 1: Discussion

Discussion with our faculty here today. Let us start with the first prompt. What does the evidence say about BBMs in patients with comorbidities that may impact cognitive symptoms and confound diagnostic assessments?

This is going to be open discussion. Faculty please feel free to all chime in and we can move on to the next question once you are done commenting. Go ahead, Sebastian.

Dr. Palmqvist: Maybe I can start about the first bullet point here with comorbidities. In the case the kidney function was highlighted, and I would say looking at the values here, there is no contraindication to order a blood test. Even if it gets down to an EGFR of around 60, the blood tests tend to perform very well. It is only when you go down to maybe around 40 that you see increases and even down to 30, you could see increases of around 100% or so of the concentrations.

Again, you have to remember that the concentration in AD versus no AD is around 500%, 600%. So way higher. What you usually see is that you see a fairly positive test result, or maybe pushing it into the intermediate zone.

Generally regarding other comorbidities that might not affect the p-tau217 concentration, but more cognition. I would say that it is good to start with trying to observe them and see if there are any such comorbidities that could be treated that could affect the cognition first before thinking about a blood test. Just some initial comments.

Malavika Tampi: Scott?

Dr. Turner: Yes, just the initial comments. There was only a brief cognitive assessment done and the results were intermediate or equivocal. I would be reluctant to make any decisions at all about including a blood-based biomarker based on this very quick cognitive assessment with an unclear diagnosis.

The very first thing I would do is at least do a longer cognitive assessment, a more thorough, either MMSE or MoCA or SLUMS. If you do not really want to take the time to do that, perhaps send the patient to a neuropsychologist for a full-blown cognitive assessment. Then based on those results, then I would make a decision whether to do the blood-based biomarker if the cognition is abnormal. Because we do not want to order any biomarkers on someone with normal cognition at this point.

All the recommendations are, if someone is normal, do not get these biomarkers because there is really no treatments yet for normal individuals, even though some may have some Alzheimer pathology and it would just cause unnecessary anxiety at this point.

Clearly, if cognition is abnormal, then I would certainly move on to the blood-based biomarker.

Malavika Tampi: Thank you, Scott. Atsushi?

Dr. Atsushi Iwata (Tokyo Metropolitan Institute for Geriatrics and Gerontology): Yes. I just want to make sure that this patient does not take any angiotensin receptor-neprilysin inhibitors because she has hypertension and that the drug will affect the value of A-beta 42. Just make sure that she is not taking that kind of medicine.

Malavika Tampi: Thank you.

Next prompt. What information would a positive, negative, or indeterminate BBM result provide in this case? This is a question we get asked a lot.

Dr. Palmqvist: I totally agree with what Scott said here. This is very important when trying to answer this part of the discussion, because we do not really know the pre-test probability because we do not know the cognitive status of this individual.

The brief cognitive tests that were shown here, they have a very low sensitivity at the MCI stage. So we first need to get a better understanding of the cognitive stage and, if possible, also the cognitive profile, is it specifically amnestic or not? That makes it much easier to interpret a positive test result, because currently there is a risk of many false positive test results when testing these type of patients.

Dr. Turner: I would say if the patient does have cognitive impairment and the blood-based biomarker was positive or indeterminate, then I would probably move on to an amyloid PET scan. Since not many people are enthusiastic about spinal taps in the United States, we tend to do a lot more proof of amyloid positivity by PET rather than CSF.

Dr. Shi: Yes, I agree with Scott.

Malavika Tampi: Perfect. How would each of these results impact your clinical recommendations for this patient? We went through some further diagnostic pathways. Is there anything that would follow a diagnosis using PET or CSF, for example, that the panel would recommend?

Dr. Turner: If there is cognitive impairment, positive blood-based biomarker or indeterminate and positive amyloid PET scan, then I would start discussing about the possible anti-amyloid therapies that are now available for Alzheimer's disease. See if the patient is interested and see if they are eligible.

Dr. Iwata: I totally agree because this patient has very mild symptoms, who is a very good candidate for anti-amyloid beta therapeutics.

Malavika Tampi: Okay. How do you discuss these nuances with the patient and her daughter? How do you approach shared decision-making in this particular context?

Dr. Palmqvist: At this first point, without any additional examinations, I would carefully explain why it could be difficult to do a blood test, and that it would be very difficult for me to interpret the blood test result before doing, for example, more advanced cognitive testing because many patients can be quite persuasive. They have read about this blood test. They want to take it. So it is very important to explain it that without further evaluation, I cannot interpret the test correctly. That is something that I would explain and use that to motivate additional cognitive testing.

I do not know what do Shi and Scott would do.

Dr. Turner: We synthesize all the data, the history, the examination, all the biomarker tests. We come up with some clinical diagnosis. Then based on the biomarkers available, we come up with a pathologic diagnosis, present all of this information to the patient and the family and just give them lots of education and give them what options may be available as far as any other testing that might be needed or if any other treatments that might be available.

Hopefully, everyone is on the same page, but we often get family members who differ in their opinions.

Malavika Tampi: Atsushi, Jiong, any comments from your side of the world?

Dr. Iwata: Like I said, this patient has a very mild symptoms who is a very good candidate for anti-amyloid beta therapeutics. If they are willing to take the therapeutics, I would recommend them to proceed to amyloid PET or maybe CSF. If they are positive, I would definitely recommend her to take the therapeutics. Of course, we talk about APOE4 status.

Dr. Shi: Yes. In this case, of course, the cognitive testing is very helpful. Also if we use the dual cut-off, that will be helpful too, because if you have a high cut-off, it is likely you can lose in this patient for the diagnosis because she does have cognitive complaints. Maybe there is some A-beta pathology can be validated by the high cut-offs.

Malavika Tampi: Great.

Dr. Turner: I tend to use the blood-based biomarker if it is clearly positive as support for pathologic diagnosis of Alzheimer's disease. If someone is either not interested or not eligible for antibody treatment, I probably would not do an amyloid PET or not do the APOE genotyping to discuss the risks of the anti-amyloid antibody therapy.

I tend to just do history examination, blood-based biomarker. If it is clearly positive, patient clearly has Alzheimer's disease. And no interest or eligibility for antibody, then I would just stop here.

Dr. Shi: Yes.

Malavika Tampi: What we have heard from the faculty here today is the importance of deciding carefully whether to implement a test or not based on the patient's cognition after a test, and then following whatever diagnostic pathways are available and considering eligibility for treatment as well as part of a shared decision-making approach.

Patient Case 2: The Borderline Result

Next patient case, the borderline result. A 55-year-old woman with no major health issues self-referred to the memory clinic, request cognitive evaluation based on intermittent symptoms. These are a couple of things that she says during her visit.

“I often find myself entering a room and forgetting what I had come for. I cannot recall my activities from the last several days without checking back on my calendar. I have always done crosswords, but now I cannot think of half the words.”

Concern due to strong family history of AD, which mother and maternal grandfather developed first symptoms of dementia around age 60 and declined rapidly. After an initial cognitive assessment and interview, there is an indication for mild cognitive impairment.

Diagnostic workup included a commercially available BBM test, for example, a p-tau217 test, which showed indeterminate results. A follow-up appointment is scheduled to discuss these results and next steps.

Patient Case 2: Discussion

Faculty discussion. Let us start with the first point. How can a borderline BBM result best be framed when communicated to a patient? Consider what individual patient factors do you consider in this discussion. For example, anxiety level. This is something that Scott had mentioned before. How do these conversations differ in varying global cultural context? Sebastian, let us start with you.

Dr. Palmqvist: Yes, thanks. Maybe I can start with just explaining to clinicians, this is not how I would explain it maybe necessarily to the patient. I noticed in the poll that the biggest uncertainty thing was how to interpret the results.

Here the term indeterminate was used, and that is seen in some of the regulatory approved texts. We also see for the same type of test results, the term likely positive. What they all mean is that it is an intermediate test result. Using both amyloid PET and CSF p-tau217, we can see that usually the blood test fairly accurately pinpoints the amount of AD pathology in the brain as intermediate.

We are seeing in this group slightly elevated signals on amyloid PET or slightly elevated CSF p-tau217 levels. This is expected from a disease where you see a gradual increase of the p-tau pathology. There is no switch going clearly from normal to abnormal the way you see a switch for CSF A-beta 42/40. There, it is quite drastic, but you have a gradual increase. This is usually what is captured in this intermediate zone. That is explaining it to clinicians.

Maybe I can pause there and we can go over and discuss how to explain it to patients.

Dr. Iwata: I would like to emphasize on the anxiety issues here because intermediate results will probably increase anxiety for the patient. If the patients are so anxious about her amyloid positivity, I would definitely recommend her to take down the PET or CSF in order to confirm the result.

I am not sure if that is going to resolve her anxiety or not, but it could be some of the resolution for her.

Dr. Turner: Just a couple of points on this case. I always try to get the history from the patient, but also someone who knows the patient well. Often patients do not have someone who knows them well and perhaps this is one example of that.

Just like dementia has many causes, MCI also has many causes. She may have clinical MCI, but not necessarily due to Alzheimer's disease. It could be Lewy body, frontotemporal, vascular. Could be something else that is causing the MCI.

Now we have this intermediate blood-based biomarker. I would certainly move on to amyloid PET to see if the MCI is due to amyloid pathology in this case. Then if the amyloid PET is negative, may alleviate some anxiety. If it is positive, then we could start talking about possible therapies.

Dr. Shi: Yes. I agree with Scott. If we have more information from the neuropsych test, for example, whether or not this MCI is amnestic form, from the history sounds like it, but you still need more data from the neuropsychology.

Also in her case, she clearly has family history. Whether or not she truly has the AD pathology, she deserves a confirmatory test.

Malavika Tampi: One question that I have, how would the clinicians on the panel do any differential diagnosis as part of the decision-making process before a blood biomarker is implemented, or would you do it at all?

Dr. Turner: Yes. Obviously, dementia has many causes just like MCI. So there is a very large differential diagnosis. A lot of these are ruled out by the initial blood tests, B12, TSH and other imaging study, the MRI preferably, or the CT scan. Then you are left primarily with the neurodegenerative differential, Alzheimer's, Lewy body, frontotemporal, vascular, other causes of dementia.

Then basically going through the process, including these blood-based biomarkers of trying to come up with an accurate clinical and pathologic diagnosis for the clinical symptoms.

I want to talk about from a Japanese perspective. If I remember correctly, she was a relatively very young female. In the Japanese population, those people tend not to have vascular impairment because male are more vulnerable to vascular component. Because she is young, she is not likely to have PART, primary age-related tauopathy, or any other late diseases.

The chance of having dementia or maybe MCI for her the disease could be Alzheimer's or Lewy body disease. If you can discriminate or differentiate between those two, that would make a pretty much accurate diagnosis for her.

One additional thing I could say about the differential diagnosis here is that, in AD, at this age, at the age of 55, you do not get symptoms from AD pathology without a very clear presence of a high AD pathology burden. Following up with CSF and PET, if it is caused by AD pathology, they will be clearly abnormal.

Here, since already the blood test is only showing intermediate test results, it is not very likely that her MCI stage is caused by AD pathology I would say. Of course in a younger individual like this, I would definitely follow-up with confirmation and they will probably help here because the levels tend to be very high in these individuals, in contrast to older individuals where they are generally lower.

Malavika Tampi: Okay. We know that access to PET and CSF can be variable regionally and even within certain regions. There can be high variability in the accessibility of these diagnostic tests. How do you see access being managed across different scenarios?

In terms of access to amyloid targeting therapies as well, does the patient's interest impact your pursuit of confirmatory testing?

Dr. Turner: I can start with that one. There are some parts of the country that do not have access to PET imaging. There is not much enthusiasm for spinal taps in the United States. Sometimes you may have only a blood test to go on as well as the history and examination.

There have been reports of some patients treating with anti-amyloid antibodies based on a positive blood test alone, supporting a diagnosis of MCI due to Alzheimer pathology or mild dementia due to Alzheimer's disease.

Access is more difficult in patients who are not Medicare eligible. In the United States, some of the insurances are still calling these tests and treatments experimental, so access can be a problem. One workaround is perhaps to see if there is some research study that the patient might qualify for, which would include an amyloid PET or CSF testing. That is another way to try to get at these biomarker results when they are not covered. Of course, self-pay may or may not be an option for some patients to get these results.

If you cannot get any of these, then you can always just see what happens over time. You can re-examine the patient in six months or 12 months, and perhaps repeat blood tests in six months or 12 months and just see what happens over time. I know that is certainly not going to alleviate any anxiety on anyone's part to just watch and wait. If you cannot get anything else, you might be forced to do that.

Malavika Tampi: Any other comments from the faculty before we move on to the next patient case?

Patient Case 3: Different Systems, Different Pathways

Patient case three: different systems, different pathways. In this situation, a 62-year-old man referred to a dementia specialist by a PCP, who tentatively diagnosed early-stage dementia based on patient/informant-reported symptoms and a brief assessment such as an MMSE or MoCA test. In each country, typical workup performed by PCP versus an initial specialist visit may vary, and in each country, typical timeline from PCP presentation to specialty visit may also vary.

Patient and family are interested in amyloid targeting therapies and prefer reimbursable options, but may have some ability and willingness to self-pay. In each country, predominant factors that influence amyloid targeting therapy decision-making may vary. Again, in each country, patient diagnostic pathways may diverge at this point.

In each country, BBMs may be ideally utilized at different points in this patient journey currently or in the future. We are seeing that there is again high variability in how these pathways exist and function across different settings.

Patient Case 3: Discussion

Patient case three, discussion with our faculty. In an ideal system, at which points in the AD diagnostic journey would BBM testing be most clinically useful. What degree of impact would individual patient family preference have on testing decisions. Again, you can think through this in academic research settings versus community clinical practice as well as what is feasible versus what would be ideal in a futures case scenario, depending on where you are.

Dr. Turner: I can start with this one. For this particular individual, I would like to get an MRI of the brain as well for the blood-based biomarker for diagnosis of the mild dementia. If it is positive, it would suggest mild dementia due to Alzheimer's disease. If it is negative, it might suggest dementia due to some other disorder.

The MRI scan, I would like to get to see if there may be eligibility for the antibody treatment if someone has a lot of microhemorrhages indicative of cerebral amyloid angiopathy, they may not be eligible for the antibody, at which point there is no further need for discussion of that option. If the MRI shows eligibility, the blood-based biomarker comes back positive Alzheimer pathology, then I would probably move on to the amyloid PET and the APOE genotyping, presuming that the patient is interested in getting treatment for antibodies.

Obviously, nothing would be done against the patient and family wishes. They would be discussed and presented as an option. If the patient and family agree, then we would move on to these other tests.

Dr. Shi: Yes. I would say, in an ideal system, just like beyond a certain age, we do colonoscopy, we do mammogram, we should have a brain health check-up, like annual check-up, so we get the MRI. See, just like Scott said, we have any cerebrovascular events or risks, and then we can do a simple memory test to see if there is any cognitive impairment. In that scenario, I will incorporate BBM just test for MRI pathology if they do have memory deficit.

I also comment on the first bullet point here. It is a bit difficult and I do not think we will find a solution that maybe fits all healthcare system because secondary care, that is more equal across different regions and countries. There, the purpose is to actually diagnose the patients and rule in and rule out dementia.

In primary care, the role in this evaluation differs quite a lot. In some countries, primary care also diagnosed Alzheimer's disease, and in other countries, they are mainly supposed to refer every patient where they suspect one of these diseases.

Depending on the role of primary care, BBM implementation should differ. I see both advantages and risks. One risk is that we get too focused on Alzheimer's disease. Maybe the PCP thinks that in a case where the patient has MCI, then let us follow-up with a blood test. If it is normal, everything is fine, I do not have to refer the patient. If it is positive, I refer the patient or maybe even diagnosed.

In those cases, the patient still has MCI for a reason. Many of those may be still should be referred to secondary care. Maybe we will, in an ideal system, have different case scenarios where you could test where you should not test.

If you already from the beginning are planning to refer the patient regardless of blood test result, of course, you should not implement it already in primary care, but in other cases where you have decided that this one should not be referred, I have to make a diagnosis in primary care. Then in many of those cases, the BBM will improve the diagnostic accuracy and should be used in primary care. So difficult, and there are many nuances.

Dr. Turner: Yes. It is most useful in the MCI and mild dementia stage. I would not get a BBM on someone with normal cognition. There may be less valuable for the moderate to severe dementia, although it may be helpful for diagnosis. It is not going to be helpful for treatment decision with antibody at that point. I would certainly say MCI and mild dementia is the patient that would get the most value from a blood-based biomarker.

Dr. Iwata: Yes, I totally agree that, because we have to make sure that this is a pathologic biomarker. It is not indicative of any clinical symptoms. This test should be ordered by a doctor to understand what the result means.

One thing I am worried about is that if your patient comes in complaining something about memory, just go directly to blood-based biomarkers without performing any of the clinical diagnosis or clinical evaluation like MMSE or MoCA.

Then if the results come positive, you make a diagnosis of Alzheimer's disease. It should not happen.

Dr. Turner: Yes, I totally agree. The availability of these BBMs now basically requires some cognitive assessment with a validated instrument to be done first to see if it is normal or not normal cognition.

Malavika Tampi: Next question. How well do current healthcare systems in each country accommodate BBM implementation at these ideal stages, and which patient scenarios are likely to be particularly promising or problematic in each country?

Dr. Turner: I can talk about the US. Medicare is providing coverage for the blood-based biomarkers, the amyloid PET. The treatments under the Medicare Advantage sometimes have difficulty with coverage as well as other insurances. It is very insurance specific about coverage. As I said earlier, some feel that these tests and treatments are still experimental and not covered.

If the patient qualifies for Medicare, then that is good. We can get coverage. If they do not and they have Medicare Advantage, then we have to do a lot more hoops to get coverage pre-authorization and appeals and those sorts of things. So it can be problematic to get coverage.

Dr. Palmqvist: Maybe I can follow-up with the European part. Unfortunately, it is not just one system in Europe. There are many different systems. Some are more similar to the reimbursement system seen in the US, and in other countries, such as my own country, Sweden, we do not have any kind of reimbursement system.

There is this lump sum of money in healthcare, which you can per clinic or hospital choose to spend the way you would like. In those cases, it is quite easy. You can order any test you want if you prioritize that for others, and in this case, it is more cheaper than the alternative CSF testing or amyloid PET.

At least for us, it has been very easy to start adopting and implementing in specialty care at least. We are seeing the same across many European countries. It is not a matter of reimbursement or no reimbursement.

For being an AD test quite cheap, it is cheaper than doing a CT or MRI scan and way cheaper than doing amyloid PET. Considering the costs of this disease is quite easy to start implementing.

Dr. Iwata: Japanese perspectives. We have this universal insurance system run by the government. Everyone is insured and covered by the insurance system, which is paid by the government. In this case, we do not have any reimbursed BBM tests yet, but we expect to have this to be reimbursed in the near future, maybe in six months or maybe a year or so.

In that case, I am pretty much sure that the government will restrict the test to ATT implementation only, not for diagnostic purposes, because the government does not want to pay extra money for just for diagnosis. They just want to save money for the payers or payees. This test will definitely be restricted to ATT implementation.

Dr. Shi: Yes. I guess no patient is luckier than the ones in Japan. They are so very well covered. In China, the BBM is partially covered, but neither a PET scan or the MRI treatment are covered. In this sense, if they want to get the diagnosis, BBM is the first way to go.

Even because of the cost, even if it is intermediate or undetermined results, we can wait for six months to get another BBM. That is much easier and accessible than PET scan.

Malavika Tampi: Okay. Thank you. We have heard from all of you around that question. Just one minute. Any inequities or in access or standard of care within country or internationally that are likely to arise as BBMs are integrated? We will spend a minute on this and then we will move on to some wrap-up and then Q&A.

Dr. Turner: There are obviously inequities in every medical area, including this one. There also seem to be some cultural biases that cognitive decline with age is just normal aging. This may apply to some cultures more than others leading to some inequities about when someone presents to a clinic with cognitive concerns. Do you present at the MCI stage or the mild dementia stage or the moderate dementia stage? When do you actually get to clinical presentation?

There is also access problems because there are not enough providers to see all the patients with dementia who need to be seen. One way to work around this is to utilize PAs and NPs in particular, and train them on evaluation and treatment of dementia patients and perhaps working with a specialist to extend and be able to provide greater access to more people with cognitive problems.

Of course, another way to address this is to do an annual screening for older individuals, picking up cognitive deficits in the early-stage as part of a screen. Just like we do all of these cancer screens, we should at some point do cognitive screening annually to pick up early disease in everyone.

Dr. Palmqvist: I agree that there are many inequities in this field, but I do think that the net result of implementing BBMs in the AD diagnostic pathway should be a reduction of inequities, because it should really lead to more patients getting access to a more accurate diagnosis compared to the use of just CSF and PET.

Malavika Tampi: I see Atsushi and Jiong nodding along as well. So we are all in agreement around that point.

Conclusion

Scott, I will be asking you to give us a few key takeaway points and then back to me after that.

What Do We Know? What Do We Need To Figure Out?

Dr. Turner: Okay. Obviously we have learned a lot and now we have these blood-based biomarkers. In the United States, we have two of them that are FDA-approved, and therefore, hopefully covered widely soon, but we still need to figure out a lot. There is still a lot that we do not know. Obviously, these are complementary to history examination, CSF studies, imaging modalities, including MRI and PET.

We have now proven that p-tau217 is the best for predicting amyloid PET positivity, even to the point where there are a handful of patients now being treated with anti-amyloid antibodies based on a blood test alone, supporting the diagnosis of amyloid pathology.

We need more evidence. We need to figure out what the results of these tests are in more diverse populations, and we need to figure out what happens to these test results with comorbidities, for example, decreased renal function.

We have learned that the ratios may be a way to get more accurate results, particularly in someone with comorbidities rather than any single analyte alone. We need to figure out how to work these blood-based biomarkers into our clinical flow both in primary care and in specialty. Of course, we need all of the third party payers to come along with us to provide coverage once we have a proven and validated test, then it really should be covered.

As mentioned before, these blood-based biomarkers are certainly a lot cheaper than spinal tap or PET imaging to make diagnoses and to determine pathologies. We have also learned that having two cut-offs may be better than having one as far as making clinical decisions. Then we have this sometimes around 20% or so of individuals who fall into this intermediate category, which then we say, “Well, what do we do now with these intermediate category patients?”

Obviously, still a lot to learn. There could be other analytes that could be measured in plasma and CSF that may be even better than p-tau217. We have not discovered these yet, and then there are other analytes that are better at staging the disease rather than diagnosing it, such as the MTBR-tau, as we talked about earlier.

Still a lot to learn, still a lot in research, but we have come a long way and now we have these blood-based biomarkers that are available to all clinicians, including primary care, that are helpful in screening, helpful in making decisions, helpful in making diagnoses. We have been using them much longer in research to minimize the number of negative amyloid PET scans, because if the blood-based biomarker is negative, then we would stop there and not get an amyloid PET scan.

The same now applies in the clinic. We may say if the blood-based biomarker is negative, then it is unlikely to be due to Alzheimer pathology and move in a different direction. Certainly come a long way, but still lots to find out.

Practical Pathways for Integrating Biomarkers in Alzheimer’s Care

A few closing thoughts before we move into Q&A. We only have about five minutes for Q&A, but we hope you will join us for region specific discussion. Workshops for the US, Europe and China upcoming in August and September, each led by one of today's faculty.

We also hope to have a Japan-focused workshop, so please continue to check back if you are in Japan.

Q&A

We have a few questions from the audience that I would like to call on our panel around. The first one. Are most neurologists aware of these newer tests and are commercial insurance, Medicare and Medicaid paying for any of these yet? I know the second question we have touched on through Scott. The first part, are most neurologists aware of these newer tests?

Dr. Turner: Most neurologists are aware probably as well as most psychiatrists, geriatricians and probably, maybe even most internal medicine, primary care are becoming aware of these tests if they are not already aware. As I mentioned earlier, if someone is over 65, Medicare is covering. If someone has Medicare Advantage or someone under 65 with other insurances, it is hit or miss at the moment about coverage. So I have to do pre-authorizations, but hopefully improve coverage over time. The trends are in the right direction.

Dr. Palmqvist: Yes. I also agree that most are aware. The problem right now is that very few have actual experience and know how to correctly interpret them, but they are definitely aware of the tests.

Malavika Tampi: One more question. If a patient is found to have amyloid plaques and is interested in amyloid targeting therapy but cannot have MRI due to a VNS or vagus nerve stimulator in the chest. Does that make that treatment impossible?

Dr. Turner: I would say, yes, we have to be able to do MRIs to look for risks of ARIA-based on microhemorrhages that are detectable on MRI, indicative of amyloid angiopathy. We also have to be able to do MRI to look for the ARIA, the ARIA-E, the edema, and the ARIA-H, the hemorrhage. That is a risk known with these anti-amyloid antibodies. If someone cannot get MRIs, then they are not eligible for antibodies.

Malavika Tampi: I see everyone nodding along. Okay, we might have time for one more quick question. Is there a problem with doing a BBM test on a patient with mild CKD or chronic kidney disease, or someone on an ACE inhibitor as well?

Dr. Turner: Sebastian?

Dr. Palmqvist: Yes. No, I can comment on that. Yes. I do not think it is a problem. In patients with lower EGFR, we have to consider, as I mentioned earlier, that we can see some increases. We know quite a lot from other blood tests that we use, like homocysteine, for example. If you have a chronic kidney disease, you tend to see some slight elevations, but you do not see really abnormal levels. That is what to expect with p-tau217.

Yes, you could expect some smaller increases, maybe pushing into the intermediate zone, but you cannot expect an increase of 500% to 600% that you are seeing at the dementia stage.

Malavika Tampi: We do need to wrap up for today. I want to thank all of our faculty for being here and for providing your expert opinions. Thank you so much. To all of our learners for today, thank you so much for joining us, and please enjoy the rest of your day. We will be concluding the session now. Bye, everyone.

Dr. Shi: Bye. Thank you.

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