Current Series: Advances Treatment Alzheimers Disease

Jeffrey L. Cummings, MD, ScD: In closing, I want people to look into the future a little bit, and Richard, I’ll start with you. How will the future of increasing early diagnosis of AD [Alzheimer disease] and targeted therapies change the treatment of Alzheimer disease?

Richard Isaacson, MD: Just like any chronic disease associated with age, whether we talk about Alzheimer, whether we talk about diabetes, or whether we talk about hypertension, there are always multiple strategies. With high blood pressure, you have the ACE [angiotensin-converting enzyme] inhibitors, you have the ARBs [angiotensin receptor blockers], you have the beta blockers and the calcium channel blockers, but you also have the nonpharmacological approaches. You have the low sodium diet, low carb diet, and the Mediterranean diet. There are all these different interventions plus exercise, and the synergy together is the standard of care.

If I had to use my crystal ball, this would be the same thing with Alzheimer disease. Now, will the amyloid therapies be a pill? Will it be an infusion? We don’t know yet, but we’re going to have those answers. Are we going to start those anti-amyloid therapies when someone has symptoms, when someone is not having symptoms? We don’t know yet, but we’ll have those answers. The first part of this complex puzzle of the multimodal treatment of Alzheimer disease is before us, and in a few years we’ll know. And until that time, we need to keep thinking about other targets as well, whether it’s neuroinflammation or the antiviral approach. Whatever it is from a pharmacological perspective, we’re going to figure that out, too.

And then finally the nonpharmacological strategies. Exercise, when do we need to start it, how much exercise, how much weight training, how much cardio? We don’t know these exact answers. In the next 4, 5, 6, 7, maximum 10 years, we should have a multimodal management plan for Alzheimer disease.

Jeffrey L. Cummings, MD, ScD: That’s great. Marwan, anything to add in terms of your crystal ball of the future management of Alzheimer disease?

Marwan Sabbagh, MD: I want to jump off on Richard’s comment to say that in the fairly near future, we will transform Alzheimer dementia from a terminal disease as we know it to a chronic disease. This is the diabetes and HIV of our time, and I think we will enjoy the success of seeing that happen. I don’t think that’s a generational thing. The idea of curing it, I think that is a generational thing. The idea of preventing it, I think we’re a little bit further out. But the first iteration will be transforming to a chronic disease. The second iteration will be to identify people at risk, so that we can deploy a prevention strategy around those people. We’ve had a run of very negative results. We’ve had a lot of drugs fail in the last 18 months, with real disappointment in the field, real discouragement in the field. But I still think that we’re very close, closer than we’ve ever been. I think that there are ways forward in front of us.

Jeffrey L. Cummings, MD, ScD: Ali, anything that you would add about the future of Alzheimer care?

Alireza Atri, MD, PhD: It is going to go toward precision medicine and personalized medicine. I think we are at a tipping point in some ways of 20 years of work on biomarkers coming together. We have computational power, other ways of actually seeing that. And once we are better at having different biomarkers of whether someone has the disease state, whether this is causing neurodegeneration, whether this is how they may respond to different therapies—once we have a better handle of how to measure those things—I think we can more rapidly look at drugs in combinations. And I think ultimately, it’s going to be a combination of drugs and lifestyle, multiple combinations at different stages. And I think we’ll get there, I agree with you, Marwan. But I think the idea of cure, taking somebody who is in the brain failure stages and reverting the clock back, is something that is many decades away. But I think we can have very meaningful therapies in the next 10 to 15 years that will change the course of this disease.

Jeffrey L. Cummings, MD, ScD: Elaine, how about you, do you have other views of what might happen in the future?

Elaine R. Peskind, MD: A little bit. I think there will be combination therapies, not only addressing amyloid but also tau and perhaps synaptic loss, either to restore synapses, support and grow new synapses. I think there may be mechanisms we know nothing about yet. And I think in the next 10 years that will become much more apparent.

Jeffrey L. Cummings, MD, ScD: I’m with you, Elaine. I think that there’s going to be a broadening of the scope so that we will be getting epigenetic drugs and epigenetic information that may be very useful. This whole new class of senolytics that are addressing cellular aging and may have effects on multiple body systems, including the brain, I think is a very novel and innovative way of thinking about therapeutic intervention.

I think we’re going to see both a focused concerted precision medicine approach in Alzheimer disease, but we’re also going to see importing a lot of information into the Alzheimer disease world as we understand normal aging better and integrate that with pathological aging. This has been extremely informative. Wow, what a session. Before we end this discussion, I’d like to get final thoughts from each of our panelists. Dr Atri, could I ask you for some final thoughts?

Alireza Atri, MD, PhD: I’ll come back to the principles that I think about regarding what can we do now. What we can do now, the first stage is actually to detect and diagnose and, at an earlier stage, empower patients and families to be involved in their own care. The second part is really strategies regarding nonpharmacological care: communication, behavior, environmental changes. The third strategy of the current therapies is pharmacological and taking the bad drugs away, coming up with combinations of lifestyles, and approving medicines to help. The fourth thing is really coming together with the care partner to implement this because implementation really matters. And we need to spread the word that this actually has value.

Then the final component is research, that at every stage we need to be able to understand this stuff. Someone doesn’t wake up one morning and say “I have MCI [mild cognitive impairment]” and the next day they have Alzheimer dementia. This is a continuum over decades, and we need greater engagement from all stakeholders to defeat this disease. This is not something that will be solved by pharma by itself, by academia. We all need to be involved. I’m hopeful and we are learning a lot, and I think we will get there. And I appreciate being part of things like this, so we can educate colleagues and increase engagement, so that people have proficiency and confidence about diagnosing and treating this disease and doing more research.

Jeffrey L. Cummings, MD, ScD: Dr Isaacson, some final thoughts?

Richard Isaacson, MD: To echo your exact points, I think the multimodal management strategy of Alzheimer disease from the spectrum of prevention to treatment will evolve over the next decade or more. And I think it’s an exciting time. I think a lot of people out there are losing hope with the failure after failure, but I don’t see it as that at all. We had to learn. We had to create the baseline and the foundational knowledge to succeed, and I think we have that now.

I also think it’s important to reduce stigma around the disease. If someone is having a memory problem, it’s OK, talk about it. I think in the United Kingdom, in dementia friendly communities, millions of people have been trained on how to interact with a person with dementia. And if someone is lost in a supermarket, well, have a conversation with them and identify that it’s someone with dementia and help them out. I think talking about things from a psychosocial perspective, from a stigma perspective, and getting primary care physicians and specialists to take this seriously are important. If someone has a mild memory glitch, well, it may be nothing but it may be something. The concept of worried well, I don’t know if I love that term anymore. I think if someone is having something, have a conversation, take the next steps, and at least do an evaluation.

Jeffrey L. Cummings, MD, ScD: Good. Dr Peskind?

Elaine R. Peskind, MD: I have a couple of thoughts. One is we shouldn’t forget people who already have Alzheimer disease. More and more research is focusing on secondary prevention and even moving that back a little. I think we shouldn’t forget about providing the best care we can for patients who have the disease, particularly in the later stage of the disease when behavior becomes such a problem. Also I want to mention caregivers. This is a disease that’s often said to cause more suffering in caregivers than it does in the patients themselves. Just remind people to take care of the caregivers. Make sure if they have depression, it’s well treated and provide support services and referral to the Alzheimer’s Association and all the things you need to do for the caregiver.

Jeffrey L. Cummings, MD, ScD: That’s a great reminder. Dr Sabbagh, some final thoughts?

Marwan Sabbagh, MD: Yes, 2. One is that Alzheimer disease can be diagnosed. We need to stop the idea that it’s a diagnosis of exclusion, the imprimatur is to move it toward a diagnosis of inclusion. The biology, technology, and biomarkers exist. They’re just not deployed in medical practice in the United States. Physicians and neurologists in particular need to be informed because they’re coming. Blood tests, CSF [cerebrospinal fluid] tests, and imaging modalities are moving and transforming the landscape in which we can diagnose Alzheimer accurately with greater than 90% accuracy in life, in vivo. And so that will be important, so people don’t have to think they’re guessing.

Second is that Alzheimer disease can be treated. I hear of, over and over again, the futility and nihilism of why bother even diagnosing, because you can’t treat the disease? Nothing makes me more irritated. And I say this to you because people don’t understand what the current treatments can do. They don’t understand that they’re symptomatic treatments. They do not stop the progression. And so when they see the patient getting worse, it’s because they don’t understand that they were going to get worse no matter what. But to understand that it’s treatable, when you treat a patient, their family, and their caregiver who’s in distress; you’re treating their sleep, and their agitation, and their wandering; and you’re bringing social services and support to the patient and their family, that is treating the disease. It’s not just a pill of a cholinesterase inhibitor or an NMDA [N-methyl-D-aspartate] antagonist. All of it is treatment of the disease.

The reason this is important is it’s a paradigm shift. Physicians need to understand treating the disease means that when you have the next drug like a BAN2401, a gantenerumab, or an elenbecestat, that we’re already thinking in a treatment mindset, so that we can just add to our treatment armamentarium a new drug. So the idea is that conceptually we need to embrace the idea that Alzheimer is treatable.

Jeffrey L. Cummings, MD, ScD: Great, thank you. I would add 2 things. One is the multistakeholder collaboration is absolutely essential. And Ali, I think you mentioned this. We’re facing a tsunami and there’s going to be enormous suffering with this disease unless we have better responses to it. And it’s only going to be solved by policy changes and multistakeholder collaborations. And I think we can create a much better future for our patients and our caregivers than we are currently offering them. So thank you all for your contributions to this discussion. On behalf of our panel, we thank you for joining us and we hope you found this Peer Exchange discussion to be useful and informative. Thank you.