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).

Overcoming System-Level Barriers to Ensure Equitable Access to Anti-Amyloid Therapies

ME: Early on in our experience we had a lot of backups in our infusion centers. We were able to see folks in clinic and have them approved if they wanted to be and we had a long backup. At 1 point, we had over 100 days of backup in our infusion center, sort of unacceptably high. I think that actually led to some innovations in the way we deliver infusion care here. We have sort of a hospital system-wide network of infusion centers and we were able to expedite how our doctors were credentialed at different sites. Now we are able to sort of offer infusions at a host of different sites and that has really opened up our access.

We also were able to extend our infusion center hours, adding weekend hours, adding evening hours. We also were able to create dedicated slots for patients on anti-amyloid antibodies. All those interventions have made a huge impact on our infusion chair access, which I think was an area of success because that was kind of a serious bottleneck early on.

The other sort of insurance barrier is that some insurance carriers require that you be enrolled in a Centers for Medicare & Medicaid Services (CMS)-approved registry, but if you do not have a Medicare beneficiary ID number, ie, you do not receive Medicare as your primary carrier, how can you circle that square? Actually, 1 nice thing is there are a number of national registries, including 1 called ALSnet that we are a part of — that we can enroll our folks with private insurance in ALSnet. It is a national registry and that allows us to kind of check that box first time with these insurance carriers. So that has been another way that we have been able to extend access perhaps to some patients who otherwise you would not be able to access because of an insurance barrier. Those are just a few examples.

Guiding Continuation or Discontinuation of Anti-Amyloid Therapy: Milestones and Individualized Decision-Making

DS: I will say that it is an individualized decision about how a patient is responding, and it is 1 of the more challenging aspects of this. So I think we have already covered safety and I feel that as we now use them and what we have learned in real-world practice, they are manageable. I think many, many clinicians feel that way, so we want your audience to recognize that this is becoming an increasingly comfortable and manageable therapeutic. The decision about how the patient is doing and how long to continue the treatment is something that we are now doing for the first time because we are getting some patients who have been on 18 months of lecanemab treatment, which started early.

I think that if our scoring and our clinical tests — MoCa, MMSE, the routine sort of bedside tests we can do — suggest scores that are considerably worse so that patients have gone from mild to moderate AD, that would be a rational time to discuss with the patient and family, “We are seeing you now go into a state of Alzheimer disease where there is no good peer-reviewed evidence that the medicine really works very well at the stage you have entered.” So patients know that this is a continuum and if they go too far, it is unlikely the medicine will make any difference, but they will still theoretically at least have some risk. Although, the longer you treat, the lower the rate of ARIA goes.

I would say transition to the more advanced stage, not the case from MCI to mild AD if the scores suggest that that is where you are now, one could still continue treatment. But certainly if you are pushing very close to moderate AD, then that is a worrisome event. Of course, if you have had trouble with the therapy, if you have experienced symptomatic ARIA, you might have been discontinued already because the ARIA was moderate in severity and/or it was accompanied by symptoms. Then you would not be recommended to continue the treatment. So there are guidelines, but most importantly, advancement in the trajectory of Alzheimer usually suggests it is time to discuss stopping this therapy.

ME: Yeah, and there are certainly individual circumstances that would prompt a discontinuation despite not being in moderate-stage dementia. It is too much to handle. There are a number of reasons why. We will say in addition to MMSE and MoCa, we also perform a functional screen. We see folks every 6 months, so we do something like an Functional Activities Questionnaire (FAQ) or Quick Dementia Rating System (QDRS). It is sort of a shorter, easier way to get an assessment of one’s functional status. Obviously, the Clinical Dementia Rating (CDR) would be the gold standard, but it can be cumbersome in a time-limited setting. So again, there are times when you need to get that CDR, but other times you can just use a shorter assessment perhaps to get a snapshot of one’s functional status.

LV: Yeah, I think we similarly operationalize that just because what Dr Selkoe was saying, the advancement into a stage into which you will not benefit is really critical. These medicines are not meant to be continued indefinitely throughout every stage of the disease. So thinking about a CDR-2 or moderate dementia and having regular assessments and check-ins in an objective way, but also in an informed way in the patient setting, determining what the stage of the disease is and whether they will continue to benefit I think is sort of critical as we think about continuation.

The other is we do have an 18-month time point, and that is the length of trials that we have. Our goal at our center, our plan is to re-stage patients both biologically and clinically with full staging and then engage in the conversation with them that is informed by the principles that were mentioned earlier about what we know about the drugs, what the rationale is for continuing, and then making a person-centered decision on whether to continue, continue on a reduced frequency, or discontinue based on the drug and the stage of their disease.

I have to say I am pretty unsatisfied with the line of evidence that we have to guide this decision at this point, but we are as I said building this bridge as we are walking on it. The centers across the country that have initiated these therapies are having patients graduate or go beyond the 18-month evidence base from the trials and we are going to learn from them. For any patient that is starting now, I am counseling them. Hopefully we will know more by the time we get to 18 months about what we should do in your specific case and maybe in 5 or 10 years we will have personalized approaches and we will be guided by the biology that we are seeing.

Maybe we will have additional tools in our toolbox with lower rates of ARIA and maybe targeting other proteins and factors in the disease that may be implicated. That is, I think, very forward looking, but I think it is the road that we are driving down. But this is a revolution in our field. This is an involution. We are going from neuropalliative complex care to now treatments, disease-modifying treatments, for Alzheimer disease that are in the clinic and we are implementing them.

People like me — I am an interventional behavioral neurologist now, is what I say. We are going to be the ones at the forefront of this, learning about it, and hopefully turning around and telling everyone else what our experience has been to inform the millions of patients that may benefit from these treatments.

The Evolution of Anti-Amyloid Treatment in Asymptotic A+ Patients With MCI or Mild Dementia: Clinical and Systemic Changes Needed to Support Cognitive Care

DS: We are all very hopeful that the trials, for example, that our colleagues in the AHEAD study (ClinicalTrials.gov identifier: NCT04468659) are running, as well as at Lilly with donanemab, that these will show that treating people before they have clear-cut symptoms and signs of Alzheimer will decrease the number of who advance into clinical impairment. That means that folks who have normal MoCa scores and MMSE scores of 30, those patients already have considerable pathology. We know that for certain. That would be the best place to intervene, as we do in all other chronic diseases and medicine where we can before symptoms occur.

We will see within about 3 to 4 years whether those prevention approaches with the same antibodies we are discussing now — it turns out that as fate would have it, that both lecanemab and donanemab have found their way into prevention studies in people who do not really have clinical Alzheimer disease at this moment.

I suspect that since we already have evidence in published peer-reviewed studies that MCI patients do a bit better both as potentially slowing down the disease and certainly as the risk of ARIA goes down, that people who are completely asymptomatic will have relatively low rates of ARIA and tolerate the medicine and be able to get some patients who do not advance or who would have been expected to advance.

I think that our colleagues in the practice of neurology will become more and more familiar with the possibility of treating people very early. We have emphasized that, all of us, in this entire interview that that is really key. There is no confusion about whether we should take people who are very early, but symptomatic now, including — by the way — subjective symptoms.

There was a time over my long career where we thought of people who had come forward with subjective concerns about Alzheimer, that they were more the worried well. But that is not the case. Subjective concern about memory is turning out to be a sensitive indicator that many of those people might go on to get an Alzheimer or other cognitive disorder.

If patients are subjectively concerned and they are very mild in their symptoms, we want to treat them now, if there are otherwise no contraindications. Certainly, when we think of the outcome of the current prevention studies, almost all of us not only are hopeful, but are pretty much assuming that there is going to be at least a percentage of those individuals who will not decline and who will not go forward. That will be a huge game changer and in terms of the resources needed, society will have to completely change its preparedness and attitude about managing this condition we call Alzheimer. We are going to be doing a lot of screening and potential treatment for people who are not yet symptomatic. It is going to be a real conceptual game changer for our field and for the world.

ME: Yeah, I just cannot emphasize the promise. Obviously, as an optimist perhaps we need to see the data and see if these agents work at these sorts of early symptomatic stages of their illness. But let us assume for a moment that they do work or with the advent of a blood-based biomarker, you can imagine a time in the future where someone maybe reaches a certain age threshold where their likelihood of having a positive AD biomarker is reasonably high, you get that.

If you could get kind of a subcutaneous autoinjector form of an anti-amyloid antibody, you can actually prevent Alzheimer disease from ever occurring in the first place, it would just be an absolute societal game changer. It could change not only the illness and how we think of Alzheimer disease, but also our relationship to aging. Think about how much of aging is the fear of developing Alzheimer. The promise and the optimism underlying these in-stage trials is very, very huge, I would say, and exciting.

LV: I will just briefly add I am an optimist. It is a requirement of being a clinical trialist. We have to believe that we can do something about this disease and I do not see why we cannot. There was a call 50 years ago by Dr Katzman to understand it, to modify the course, and ultimately prevent it. I would say we are two-thirds of the way there and the prevention trials I certainly hope are positive, but I do look at the lessons we are learning from clinical implementation and I am worried about our preparedness for it.

There are not enough cognitive behavioral neurologists. There may not be enough neurologists if we are really talking about screening asymptomatic patients over a certain age. I want to make sure our tools are up to the job to be able to screen and accurately identify patients who are going to be biomarker positive and benefit from treatment. I think it probably behooves every neurologist to learn about these treatments and learn about these tools because I think it is coming that these treatments, more complex treatments and more effective treatments, will be in hand. I actually think we are probably going to have to enlist primary care physicians (PCPs) as well, just given the number of patients that we see. They need to be part of the screening and evaluation process and be able to identify symptoms maybe at an annual wellness visit, maybe with biomarker checks.

Hopefully the drug, which now requires the complex patient selection that you hear, the frequent monitoring, this will become easier. The first generation of donepezil was called tacrine and it was 4 times a day and caused terrible liver toxicity. It was hard to get patients to dose, but now we have a once-a-day formulation that everybody is on, that a PCP feels very comfortable writing.

As these medicines get easier to administer, hopefully safer, we know more about their efficacy — I think that it is going to have to be democratized out into the medical profession because the number of patients that are currently on this medicine does not equal the number of patients that would benefit from them, even at present, even without the prevention trial data.

This discussion was edited for clarity and length.