So a key question that individuals are interested in when they find out they’re biomarker positive, but they’re still cognitively unimpaired, is how long they have until they develop symptoms of Alzheimer’s disease. Will they develop Alzheimer’s disease symptoms in two years, five years, 10 years? Obviously, those are very different things to consider. So this is something that we’ve been interested in for years...
So a key question that individuals are interested in when they find out they’re biomarker positive, but they’re still cognitively unimpaired, is how long they have until they develop symptoms of Alzheimer’s disease. Will they develop Alzheimer’s disease symptoms in two years, five years, 10 years? Obviously, those are very different things to consider. So this is something that we’ve been interested in for years. And we’ve learned that by putting together longitudinal biomarker data, initially amyloid PET and tau PET data, that we could predict symptom onset. Of course, there’s error in that. It’s not a perfect prediction, but we can get some idea of when symptoms will start. So the next question is, can we do this with blood-based biomarkers? And the basic answer is yes. We can use plasma pTau217, which is a very good marker of amyloid and tau pathology, to develop these biomarker clocks that essentially let us know when this pathology started to accumulate. And it turns out that the age that this pathology starts to accumulate is a very good predictor of when symptoms will start. And something that’s been particularly interesting about this is that if you start to accumulate pathology when you’re young, say 60, it may take 20 years before you develop symptoms. But if you don’t develop this initial accumulation of pathology till you’re, say, 80 years old, much older, it doesn’t take that long to develop symptoms. It starts in maybe five to 10 years. So this is very likely related to the fact that as people get older, they have co-pathologies and decreased brain resilience. Overall, it suggests that a positive biomarker for amyloid in particular, including pTau217, means different things in different people in terms of their risk for developing symptoms. And we have tried to further make these clocks more sophisticated by putting together multiple plasma biomarkers. In general, what we have found is that pTau217 is so good that the other biomarkers aren’t helping that much, although we are working to make these clocks better and better. Right now, these plasma biomarker clocks are performing kind of at the level that we see with familial age at onset in autosomal dominant Alzheimer disease. So we’re talking about R-squared of anywhere from 0.35 to 0.55, 0.6. So that’s at a level where we could use these clocks to improve selection of participants for clinical trials. So that certainly has value. But we would very much like to improve these clocks so that they can be predictive at an individual level. So the eventual goal is to get a blood test, again in someone who’s cognitively unimpaired, and predict within a few years when someone will develop symptoms. And you can imagine that that would be very helpful in considering whether to start someone on treatment or not. And also to develop more sophisticated clinical trials that would be more efficient and not take quite so long to run and cost less money to run so we could test more drugs. So that’s the general idea of these plasma clocks and I do think that they will continue to get better and better and help us to hopefully develop better treatments and clinical care plans.
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