Dennis J. Selkoe, MD (DS): I am Dr Dennis Selkoe. I am a professor of neurology at Harvard Medical School and Brigham and Women’s Hospital.

Michael G. Erkkinen, MD (ME): I am Mike Erkkinen. I am a cognitive behavioral neurologist at the Brigham and Women’s Hospital in Boston.

Lawren VandeVrede, MD, PhD (LV): I am Dr Ren VandeVrede. I am an assistant professor and clinical trialist cognitive behavior neurologist at University of California, San Francisco (UCSF).

Criteria for Anti-Amyloid Treatment: Eligible Candidates With MCI or Mild Dementia Due to Alzheimer Disease (AD)

ME: The main criteria are that these treatments are aimed at early stages of Alzheimer disease. So it is important that we identify people with Alzheimer disease and those who are in the early stages, making sure there is a diagnosis of MCI or mild dementia. Those with later stages of illness would not be eligible. Also, that you have a high suspicion for Alzheimer disease as a main underlying reason for their symptoms. That includes biomarker testing, but that also includes a clinical phenotype that is consistent with Alzheimer disease.

As part of the staging process, there is a requirement that they have a cognitive assessment. In the trials they used a Mini-Mental State Examination (MMSE) score, but in a real-world practice, there are other tests that are often used like a Montreal Cognitive Assessment (MoCa). The trials used a pretty strict cutoff, an MMSE of 22 or higher for lecanemab and 20 or higher for donanemab. But of course there are a lot of reasons why a strict cutoff in real-world practice has some downsides.

Everyone has to have a biomarker of Alzheimer disease that is positive and that is typically either an amyloid scan, a spinal tap, or — increasingly — plasma. Then everyone should have an apolipoprotein E (ApoE) genotype that guides one’s risk of amyloid-related imaging abnormalities (ARIA). There has to be an MRI at baseline. You are really looking for exclusionary features, things like greater than 4 microhemorrhages, areas of superficial siderosis, larger bleeds above 1 cm, evidence of cerebral amyloid angiopathy (CAA)-related inflammation, and a host of other features, things like aneurysms, arteriovenous malformations (AVMs), large-vessel infarcts, and lacunar infarcts, etc, that might exclude someone for other reasons.

Everyone has to have a care partner that they can participate in the treatment with, in the evaluation with, and they can have other neurological or medical conditions that can interfere with the assessment or the ability to participate in treatment or the clinician’s ability to assess the efficacy and safety of treatment. There are a host of those that we can spend some time, if we want to, thinking about. Other things are that people should not be on anticoagulants or systemic immunological suppressants. They have to be able to tolerate an MRI. Those are kind of the main inclusion and exclusion criteria.

DS: Maybe since I practice in exactly the same place as Dr Erkkinen, Lawren, we can turn to you and see if there are any subtle differences in what you have heard from Mike at UCSF.

LV: Dr Erkkinen related, I think, the inclusion/exclusion criteria from the trials in detail and I think especially in the early stages our practice is to adapt these directly as we build an evidence base for the real-world use. Now that we are probably a year and a half into delivering these therapies locally, I think we think about each one and we think about a patient-centered plan, but we are still broadly close to the original intention, which is symptomatic patients with evidence of amyloid with a biomarker that do not have a high risk of ARIA and are likely to benefit from treatment. That means typically targeting earlier stages of the disease.

We do have strict cutoffs for MMSE and MoCa, but we have exceptions that are built in for people with language-variant presentations or people who these tests are not validated in necessarily. We do have exceptions there. Around the imaging I think we are asking ourselves quite a bit about whether these are important for safety or not. We are asking about anticoagulation. We still do not give that, but other centers are. I think there is a natural history experiment happening as these are implemented across the country right now, and we are collecting data from that natural history to guide our future decision making.

We are thinking about things like comorbid conditions, which were excluded from trials, like cancers. There is a whole range of cancer about what is too much precancerous conditions, autoimmune conditions. I think there are still a lot of outstanding questions as you move this into the real world. But for that basic core, “What is the evidence base for the use of these?” I think we still hit pretty closely to those inclusion/exclusion criteria.

DS: I would add that there are appropriate-use recommendations published for both donanemab and lecanemab and actually aducanumab too. I should say that I do not think any of us are prescribing aducanumab since that has fallen by the wayside and has actually been withdrawn by Biogen, so it is really lecanemab and donanemab that we are talking about today.

I think my colleague’s summary of the criteria is quite clear. These clinical syndromes are very important, so I think for practitioners who hear this are really having a sense that this is the trajectory, principally amnestic, although it can also be logopenic, that is, word-finding difficulty anomia syndrome that can be executive dysfunction. But time and again we rely on the canonical, gradually progressive loss of memory often for unimportant things and then gradually for more important things. We want to hear that from the patient and especially from the care partner. That is why the care partner is very important.

I think classical Alzheimer syndrome of amnestic and other associated cognitive disorders cannot be easily explained by another entity like frontotemporal dementia or multiple small strokes, multi-infarct dementia, or Lewy body dementia, etc — most of us who prescribe these medicines have familiarity with the difference between an Alzheimer presentation and non-Alzheimer disorders. But it can be tricky and that is why when we discuss biomarkers today, we will say how the biomarkers of course are necessary to check our clinical judgment.

Distinguishing Early AD From Other Causes of Cognitive Decline: Tools to Help in the Consideration of Anti-Amyloid Treatment

LV: I will say I think as Dr Selkoe pointed out, nothing beats a good history. Listening to the patient, recognizing that the clinical syndrome aligns with our understanding of what the typical and atypical presentations of Alzheimer disease are pretty key. There are clues on neuropsychological testing and neuro-examination. I think review of medication lists are important as well. The MRI I think is helpful.

Part of this is the soul of our field, which is advanced and complex diagnosis. There are a lot of cases of Alzheimer disease that could be unusual, but the great majority do fall within that typical presentation that I think is instantly recognizable to most neurologists and probably to most practitioners out there, just given the prevalence of it.

The challenge is the early detection, as you said, that early subtle case. Is this brain fog actually foreboding something that is to come or is it something maybe that is related to current circumstances or something that might be more addressable and treatable? In those cases, the biomarkers I think could be helpful. We have a lot of new tools that are available in the clinical, blood-based biomarkers, positron emission tomography (PET) biomarkers, standard cerebrospinal fluid (CSF) biomarkers that have decades of use now. I think those are tools that can help us tie the neuropathology that we can confirm to the clinical symptoms we see in the patient. Certainly, interpretation of the MRI is important.

We have additional tools that help us identify other neuropathologies. We have testing for synuclein either in CSF or through skin biopsy. That is helpful to be able to determine that comorbidity is present or maybe an alternate explanation for the clinical symptoms that we have. But I think a lot of it does rely on just good old-fashioned history-taking examination to interpret the findings in the context of the clinical case.

ME: I will add that I think that is right. I think linking a positive biomarker test with a syndrome is the key here to be able to attribute the symptomatology to the biomarker being positive. Are the symptoms caused by Alzheimer disease? One tool that we have using with some regularity is fludeoxyglucose (FDG) PET or extended formal cognitive testing like a neuropsychological assessment if available, even a tau PET scan. One example that comes up with some regularity is a limbic predominant age-related TDP-43 encephalopathy, which in older adults can have an amnestic presentation. If it is amnestic predominant, you might not know: Is this late or is this kind of in the early stages of Alzheimer disease? Things like a neuropsychological assessment, which can help to define the extent of the involvement of the illness or even FDG PET or tau PET can serve a similar function and that can help adjudicate these challenging cases where you have a syndrome and a biomarker, but you want to try to find some extra evidence linking those things.

DS: I might say for the audience we are addressing today that some of the nuances and subtleties that as cognitive neurologists we are used to dealing with all the time are not going to be as relevant or as frontline for many practitioners in the community. One of things I would say all 3 of us feel is that we are hoping to see these therapies used in the appropriate patient, such as we have described today, meeting these criteria that are published and in the label, etc.

That means that practitioners of neurology certainly should become more and more familiar and recognize that they do not need to understand every nuance of the complex presentation of cognitive impairment if they can judge a rather typical history of clinical AD and if they hear from the family that this is a very gradually progressive, slow difficulty principally with memory, but with other symptoms as well in the absence of motor abnormality of any sudden event, stroke, etc, trying again to at least recognize those patients in their practices that have a rather pure Alzheimer-like presentation.

Then the addition of biomarkers that we require, so amyloid PET or CSF biomarkers, the classical ones — that plus that classical history and the ruling out of any obvious other neurologic disorder will give doctors much more confidence that they are giving this medicine to the right people basically.

I might add that the ApoE genotype that we do principally is intended for safety because we know that the key abnormality that develops in people taking these disease-modifying therapies is ARIA, amyloid imaging abnormality, and that is linked to having 1 or 2 alleles of ApoE4. So that is helpful for safety monitoring. It is more likely to happen in Alzheimer disease than in non-Alzheimer disorders. But it is not a specific diagnostic test. It is intended for counseling the patient and family about the risk of ARIA.

I would say that I think all of us except ApoE4 homozygote patients, that is folks with 2 alleles, which has been debatable in the field — some centers including the Veteran’s Administration of the United States and now the recently-approved lecanemab program in Europe from the European Medicines Agency (EMA) are not going to include E4 homozygotes. But some of us do not feel that is necessary or appropriate because those E4 homozygotes have a great risk of developing progressive Alzheimer-type clinical impairment. So we do consider them anyway, but we watch them particularly closely because their 1 or 2 E4 alleles increases their risk of ARIA, including potentially symptomatic ARIA.

Prioritizing Amyloid PET, CSF, and Blood-Based Biomarkers in Confirming Treatment Eligibility

ME: Since the Us Food and Drug Administration (FDA) approved amyloid scans or at least made them more accessible for ordering and for coverage, we have significantly ramped up our use of amyloid scans. You gain a lot of info from amyloid scan. You can get kind of a Centiloid value, which can serve as a nice baseline as you follow the response to treatment in the future. At our center we use amyloid scans probably most.

Historically we have used CSF. Sometimes we will use CSF when there is a plausible alternative etiology, especially something infectious or inflammatory and we want to get a wider data set that you can learn when you get a spinal tap that you cannot get with an amyloid scan. Sometimes if an amyloid scan is qualitatively negative, but there is still high suspicion for Alzheimer disease, we occasionally will get a second AD biomarker, usually in the form of CSF testing, to look specifically for AD. We have found a few cases that way as kind of a secondary biomarker.

We have not adopted a blood-based biomarker at wide scale at our center, although we are interested in doing so and there is good evidence that phosphorylated tau at 217, a moiety, is an effective way at least of helping to sort those who are likely to have AD pathology on a PET scan from those who are not, again, with some perhaps areas of uncertainty in between. I suspect that you will be adopting that at least perhaps as a screen at some point in the future.

LV: Yeah, I would add at our center it was CSF testing prior to the advent of the reversal of the coverage termination by Medicare since now that is widely available. That was August 2023. Really, you saw the lumbar puncture CSF testing go down quite dramatically, but the overall percentage of patients getting a precision diagnosis with biomarkers increased dramatically over the same period I think because of the disease-modifying therapy. It is really about 700% over 1 year.

But lumbar punctures are disincentivized oftentimes. It is hard to find providers. They have to be highly trained; patients have negative stigma about it that I do not think is deserved, but it exists. It is not particularly well compensated, but then you have on the other hand another test that can be performed more than once, amyloid PET, and gives you quantitative information now that we have a Centiloid score that can tell you the amount of amyloid plaque that is there — that certainly in our minds could be used to monitor the response to treatment as it was in trials. So pre- and post-amyloid PET certainly at high resource settings like the ones that we practice at may become the norm.

Blood biomarkers were used quite a bit actually to triage prior to more complicated testing like CSF and PET. But because they are in this hole where they did not have FDA approval or coverage determination, you actually saw patients going right to the more expensive testing and I wonder if that might invert in the future and you might use it as a triage tool prior to the testing.

But I especially see the blood-based biomarkers used maybe in other settings other than highly specialized settings. Like ours were patients maybe undergoing the final confirmatory testing before treatment or maybe getting a pretreatment scan for baseline. You might see the blood-based biomarkers like pTau 217, amyloid beta 42 (Abeta 42) ratio that was just FDA approved. You might see that used in maybe the primary care setting even to identify patients that have high likelihood of Alzheimer disease or to rule out Alzheimer disease and really force the search in other directions for other causes of cognitive symptoms that you might have.

I would say at our center we are mostly seeing amyloid PET used and increasingly we are actually seeing tau PET used to tie the symptoms that we are seeing to clinically relevant or in some ways to determine if the patient may be too biologically advanced to benefit from the treatment, which is a lesson we learned from the clinical trials.

DS: I would add that 1 of the goals that the field has is to make these disease-modifying treatments more accessible and more readily used by neurologists and their patients. So I think that means that the pTau 217 test, which is not perfect — nothing is perfect — but it is very good. It is extremely sensitive and specific for picking up people who are building up amyloid, which is the starting point of the Alzheimer pathobiology.

I think that our listeners can begin to become familiar with ordering pTau 217 with Abeta 42, the new FDA-approved version, and I think that will make it easier to decide if a patient is qualified for lecanemab or donanemab without going to even more expensive — and for society — certainly far more costly diagnostic realm.

I am quite convinced of this. There are a number of papers. There was just an interesting new paper coming out from Washington University, which has a big experience with early disease-modifying therapy treatment. I would say the pTau 217 data they presented and elsewhere as well looks like that test could be very helpful to practitioners in the field that want to say, “Is this patient very likely to have amyloid buildup?” If that biomarker is very clearly abnormal, one could argue and certainly people at Washington University have argued for some time that one does not have to get an amyloid PET scan. I think that is not unreasonable.

This discussion was edited for clarity and length.