Iceberg of Lost Memories

Alzheimer’s disease (AD) is like an iceberg, where most disease activity happens slowly below the surface before you see the first symptoms. Geoffrey Kerchner, M.D., Ph.D., Global Development Leader and Associate Group Medical Director at Genentech and Roche, explains why he has faith in the amyloid hypothesis.

Dr. Kerchner, despite the decade-long history of clinical disappointments in the area of investigational anti-amyloid treatments in 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” or “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. I see forward momentum in our growing scientific understanding of the disease, both in terms of its complexity, but also in terms of tailoring therapies for people living with AD.

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 stabilization or preservation correlate with each other.

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

Yes, but we know that deposits of amyloid beta (Aß), which manifest as amyloid plaques in the brain and are a hallmark of the disease, 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 treatment modalities and medicines 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 medicine will be all that people living with AD need.

What is your goal with AD therapy?

The aim is cognitive stabilization 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 people in the early (prodromal, mild cognitive impairment) 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 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, characterized 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 individuals living with AD. It will probably be similar to the situation in oncology, where you take a tumor sample and look for its mutation status, and then you select a portfolio of medicines that will target the different underlying drivers of disease. I think we are on the right path.

A board-certified neurologist, Geoffrey A. Kerchner, M.D., Ph.D., 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 AD programs. Parallel to his work at Genentech, he continued to treat people living with AD at the Stanford Center for Memory Disorders. In October 2018, he took on the role of Global Development Leader for one of Roche’s AD programs.