Drs McDade and Sabbagh discuss heterogeneity in Alzheimer’s disease and structural polymorphism and genetic mosaicism seen in patients.
Marwan Sabbagh, MD: Dr McDade, the genomic mosaicism and structural polymorphism of A-beta in patient populations was reviewing grants recently, and I heard about 16 different endophenotypes for Alzheimer’s. Can you comment on the genetic mosaicism and structural polymorphism? Because we will start to see subpopulations as we get better at understanding this disease.
Eric McDade, DO: Yes. As we develop therapies it’ll become increasingly important…, particularly for those therapies that are approved or potentially going to be approved that target amyloid. One of the interesting findings from these trials is that if you use an amyloid immunotherapy at the group level, with therapies like lecanemab and aducanumab and donanemab and gantenerumab that target these plaques, they all do a good job…of lowering amyloid plaques. But you’ll see a rather large range…when you look at the individual-level data. There’ll be individuals in those trials that get the same doses across the trial. One person will have a 60% to 70% reduction in that amyloid PET level, and another may have 20%. One of the things that we are interested in finding out is, is that related to some structural difference within the amyloid plaques and how subsequently the amyloid therapies can target them? And likewise, with some of these biomarkers that we use, like the PET tracers, some of them may bind differently to different forms of the amyloid plaques, which can lead to misdiagnosis or changes in diagnosis. What we understand from a genetic perspective is that there’s a small population, less than 1% of the total population of Alzheimer’s disease, is related to these mutations that are typically inherited in a dominantly inherited form. These mutations essentially all relate to the amyloid beta protein, which is a normal protein within our brains. It’s ubiquitous within neurons. It has important fundamental functions. That leads to an alteration in how that’s processed, and over time that leads to an increased likelihood that the soluble forms of amyloid begin to bind and form these fibrils that lead to the plaques. There’s the autosomal dominant forms that lead to a typical Alzheimer’s-like pathology, but at an early age of onset. And they’re associated with [the] way the amyloid protein is catalyzed. There are also forms that lead to a deposition of a specific type of amyloid that only has a predilection for the vascular system. So, you can have genetic forms of cerebral amyloid angiopathy, and these give us a completely different clinical phenotype than we typically see with Alzheimer’s disease. And again, we don’t fully understand why in these cases where you have these mutations you only get a severe cerebral amyloid angiopathy and strokes, hemorrhagic strokes in particular, whereas in others you get primarily the extracellular plaques that we recognize as related to Alzheimer’s disease. That’s primarily where the genetic mosaicisms lead to these changes. But then also ApoE4, which we know is…the largest genetic risk factor for Alzheimer’s disease, that seems to also contribute to a predisposition towards earlier amyloid deposition and probably is the lipoprotein ApoE4 and how it deals with the processing of amyloid and the binding of amyloid, and subsequently how it can be cleared as well. Those are the major mechanisms that the genetic pathways seem to lead to differences in these A-beta proteins having more of a tendency to bind or to febrilize and cause plaques. And then lastly there are rare mutations that seem to decrease the likelihood that you’ll develop plaques over a lifetime. Again…how that amyloid precursor protein is processed throughout the lifetime leads to a decreased tendency for the protein to develop into these plaques.
Transcript edited for clarity