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AD/PD 2022 | What’s the future of Alzheimer’s disease therapeutics?

Adam Fleisher, MD, MAS, Eli Lilly and Company, Indianapolis, IN, shares his thoughts on the future of Alzheimer’s disease drug development, highlighting key approaches under continued investigation. Therapeutics targeting amyloid continue to be a significant area of growth. Ongoing work is aiming to maximize the efficacy of this approach through targeting forms of amyloid other than plaques, such as soluble oligomers. Tau is also an important target for Alzheimer’s disease therapeutics. Designing small molecules and improved delivery methods are a key focus to overcome the challenges of targeting intracellular tau accumulation. Dr Fleisher also highlights inflammation and synaptic dysfunction as important aspects of Alzheimer’s disease pathology that show promise as therapeutic targets. This interview took place at the AD/PD™ 2022 Conference in Barcelona, Spain.

Transcript (edited for clarity)

Beyond that, of course, there’s tau. We believe tau is a bit more of a downstream pathology that is more closely linked to the injury that’s been caused in the brain, the neurodegeneration, and we haven’t quite figured out the optimal way to target tau. It’s challenging in that tau is a much more diverse protein in the way it presents. It is present not only in Alzheimer’s disease, but in various forms and other diseases as well...

Beyond that, of course, there’s tau. We believe tau is a bit more of a downstream pathology that is more closely linked to the injury that’s been caused in the brain, the neurodegeneration, and we haven’t quite figured out the optimal way to target tau. It’s challenging in that tau is a much more diverse protein in the way it presents. It is present not only in Alzheimer’s disease, but in various forms and other diseases as well. So we need to establish specificity for a disease or not, or develop an anti-tau drug that will work on many different disease states.

But it also starts intracellular, inside the cells, inside the neurons, and that’s a harder target, particularly that our technologies have come a long way for large molecules and antibodies, but we need to move beyond that. So I think continuing to develop large molecule approaches to anti-tau continues to be important, but we have to really pivot also and focus on small molecule approaches, mechanisms of action that really get to the key biological mechanisms of the tau pathology, and there are many different approaches to do that.

And in addition to the types of targets on tau, it’s also the approach and the delivery. We need to discover better ways to get our large molecules into the brain past the blood brain barrier. But we also have to look at different approaches beyond antibodies. Like I mentioned, small molecules, but another exciting field right now is genetics. And when I say genetics, it’s not just modifying the genes that cause tauopathies in Alzheimer’s disease, because we know that Alzheimer’s disease is not a monogenetic disease, certainly not a monogenetic tau disease, but we can still use techniques such as siRNA and ASOs and more advanced mechanisms that target the genetics and protein production of these abnormal proteins that can have impact on the disease. So there are many different mechanisms that are being developed as well for what types of molecules that we can target in therapeutics.

But I think the third leg of the third legged stool that we need to talk about in Alzheimer’s disease pathology is inflammation, and particular inflammation, but also oxidation and synaptic dysfunction, if I may go so far to lump those things together. But there are many exciting things going on in neuro inflammation, TREM2 pathways and other pathways that are going to be tremendously important in having a more holistic approach to targeting Alzheimer’s disease.

And in the end, it’s going to be a combination of those things. I think many of us in the field believe that you’re not going to have a single drug cure for Alzheimer’s disease in all likelihood. It’s going to take a multifactorial approach that is hitting all of these pathologic targets, ideally getting into combination studies that hit the two key pathology protein pathologies we know of, both amyloid and tau, doing it at the same time, understanding the sequence, the stage of disease, and when it’s best to address which of those. But also, the neuro inflammation and synaptic toxicity issues that are caused by those pathologies. So calm the brain down, stop the production of amyloid, reduce the misfolding of tau. Hit all of those things together in combination therapy, and I think that’s really the future of Alzheimer’s disease therapeutics.

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Disclosures

Dr Fleisher is a full time employee and shareholder of Eli Lilly and Co