An iceberg of lost memories

Alzheimer’s is like an iceberg; most disease activity happens slowly below the surface, before you see the first symptoms. Geoffrey Kerchner, Global Development Leader Alzheimer’s Disease at Roche, explains why he has faith in the amyloid theory.
Despite the decade-long history of clinical disappointments in the area of investigational anti-amyloid treatments in Alzheimer’s disease (AD), you are still working in this space. What is keeping you motivated and excited in spite of these failures?

The headlines you often read in the press are “trial failed”, “another Alzheimer’s drug sinks”. But if you take a dive below that surface, the reality I see as a scientist in this field is different. There is progress happening, even if it is slow. But I do see forward momentum in our growing scientific understanding of the disease, both in terms of its complexity but also in terms of how to tailor therapies to patients. Also, from a number of trials with different anti-amyloid molecules, we are seeing a consistent signal of clinical efficacy that, albeit weak, appears to be reproducible. I’m talking about independent sets of observations all pointing in the same direction, namely that amyloid removal and cognitive stabilisation or preservation correlate with each other.

So you still have faith in the amyloid theory of AD causation?

Yes, but we know that Aß deposits in the brain are not the only driver of cognitive decline. The peptide tau, as well as neuroinflammatory changes, represent other key features of AD. What I find really exciting is that we may be able to start combining drugs as we learn what each may contribute in isolation. AD is such a hugely complex illness with so many degenerative activities going on in the brain in parallel that it is highly unlikely that a single drug will be all that patients need.

The aim is not cure in the sense of returning patients to their pre-disease level of cognition, but rather cognitive stabilisation and the prevention of further decline. Ideally you would intervene early in the disease process, when there is still a lot to save. It is hard, but not impossible, to identify patients in the pre-clinical or pre-symptomatic setting. I like to compare AD to an iceberg, where most of the disease activity happens slowly below the surface, before you see the first symptoms. It is only after decades of things taking place silently in the background that the symptoms start to peak above the surface.

What is your vision of the future of AD therapy?

First, I’d like to point out that there is danger in a fixed term like “Alzheimer’s disease” in that it tends to hide an ocean of underlying heterogeneity. What we call AD is probably a spectrum of different overlapping illnesses, characterised by a menu of pathophysiological processes going on in the brain. As we accumulate the tools and better biomarkers, we will be able to tailor a particular combination of therapies that best fit individual patients. It will probably be similar to the situation in oncology, where you take a tumour sample and look for its mutation status, and then you select a portfolio of drugs that will target the different underlying drivers of disease. I think we are on the right path.

A board-certified neurologist, Geoffrey A. Kerchner, MD, PhD, was Assistant Professor of Neurology & Neurological Sciences at Stanford University (Palo Alto, California) for five years. He joined Genentech in 2015 as a Medical Director in Early Clinical Development, where he supported different Alzheimer’s programmes. Parallel to his work at Genentech, he continued to treat AD patients at Stanford’s memory clinic. In October 2018, he took on the role of Global Development Leader for one of Roche’s AD programmes. Geoff says: “It is great to work for a company that shares my passion. My professional focus since the earliest stages of my career has been about trying to make a difference for patients with this dreadful disease”.

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