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CTAD 2022 | Longitudinal clinical outcomes of tau-PET-positive individuals
Tau-PET imaging using [18F]flortaucipir (FTP) has recently been approved by the US Food and Drug Administration (FDA), and allows for the in-vivo visualization of aggregated tau. Alexis Moscoso Rial, PhD, University of Gothenburg, Gothenburg, Sweden, presents the prevalence and longitudinal clinical outcomes of [18F]FTP-positive individuals across the Alzheimer’s disease (AD) spectrum. In cognitively normal individuals, 8-9% were [18F]FTP positive, indicating that this imaging method aligns well with the onset of clinical symptoms and may be used to predict the onset of symptoms in those that are currently asymptomatic. Furthermore, 1 in 4 individuals who were Aβ-positive unimpaired were shown to also be tau-PET-positive. The overall prevalence in participants with mild cognitive impairment (MCI) and AD dementia was 38/1% and 71.2%, respectively. In all cohorts, tau-PET positivity was highly specific for Aβ pathology (≥95%). For individuals with mild cognitive impairment (MCI), those that were tau-positive had a very high risk (≥90%) of developing dementia within the next 10 years. The tau-PET-positive result can be categorized into moderate or advanced patterns, and current research aims to understand the clinical outcomes of each of these results. This interview took place at the Clinical Trials on Alzheimer’s Disease Congress 2022 in San Francisco.
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Transcript (edited for clarity)
Now we know that tau-PET is probably the specific modality for Alzheimer’s disease pathology that is more closely associated with clinical symptoms. Compared to amyloid, tau is much more closely related to the onset of clinical symptoms, which is what really matters to patients. So for this presentation, I basically gave an overview of the prevalence of tau-PET positivity across different stages of Alzheimer’s disease: preclinical Alzheimer’s disease, which is basically when there’s no symptoms at all, mild cognitive impairment, which is basically mild symptoms, and dementia stage...
Now we know that tau-PET is probably the specific modality for Alzheimer’s disease pathology that is more closely associated with clinical symptoms. Compared to amyloid, tau is much more closely related to the onset of clinical symptoms, which is what really matters to patients. So for this presentation, I basically gave an overview of the prevalence of tau-PET positivity across different stages of Alzheimer’s disease: preclinical Alzheimer’s disease, which is basically when there’s no symptoms at all, mild cognitive impairment, which is basically mild symptoms, and dementia stage. And importantly, I did this using a recently FDA-approved visual interpretation method for tau-PET. That’s one of the key points of our study. So this method is the method that clinicians will be using in their clinical practice to assess tau-PETs. That’s why it’s important for them to understand how frequently we find tau-positive cases in cognitively normal individuals.
This is important to understand how well tau-PET aligns with the presence of the clinical syndrome of Alzheimer’s disease. And we also studied longitudinal outcomes, their absolute risk, the probability of developing Alzheimer’s disease dementia, or mild cognitive impairment in a given timeframe, 10 years for instance, the absolute probability. In terms of prevalence, we basically found that in cognitively normal individuals, there is individuals without any Alzheimer’s disease type symptoms, we found basically that we were able to find positive tau-PET scans there. About 8-9% of the cognitively unimpaired individuals were actually tau-PET-positive. So that, that’s important because that’s a relatively low prevalence, which basically means that tau-PET aligns well with the onset of clinical symptoms. But at the same time, we are able to identify subjects that will develop symptoms really, really soon. And that was the main finding regarding the prevalence.
We also see some quite interesting results in terms of prevalence in mild cognitive impairment and AD dementia cases. We basically saw that the prevalence decreases as a function of age, which probably relates to the presence of co-pathologies, so that can be expected. And in terms of absolute risk of clinical progression of these tau-PET-positive individuals, we found interestingly that for mild cognitive impairment patients, so if you are mild cognitive impairment and you have a tau-PET-positive scan, your risk of developing dementia in the next 10 years is really, really high. If you are between 50 to 70 years of age, the risk of developing dementia in the next 10 years is superior to 90%. This is one of our main findings. In cognitively normal individuals, that’s also important for understanding the relevance of being tau PET-positive. We found that for a typical 70 year old cognitively unimpaired individual, who is amyloid-positive and tau-PET positive, according to this visual interpretation method, the risk of developing mild cognitive impairment or dementia in the next 10 years is about 60%.
So we are talking about here relatively high risks for developing clinical symptoms. We are not talking about small differences in cognitive scales that are difficult to interpret in clinical terms. We are talking about a diagnosis of mild cognitive impairment or dementia, which is relevant, I think. So these were basically the main findings of our study. Basically, with this visual interpretation method, we are able to predict progression, clinical progression in mild cognitive impairment and cognitively unimpaired individuals with preclinical Alzheimer’s disease. And the risk associated to being tau-PET-positive and developing clinical symptoms in the future is relatively high.
In this particular presentation, I just combined both patterns and I only talked about being tau-PET positive. But yeah, then you can separate into moderate and advanced. This is a work in progress, but what we found basically is what really matters is the advanced pattern. So approximately half of the cognitively unimpaired individuals who were tau-positive showed an advanced pattern and the moderate pattern was typically more age related, more prevalent in amyloid-negative individuals. So this specific pattern probably relates not only to Alzheimer’s disease pathology, but also to other conditions such as, I don’t know, probably age related tau pathology. So it is important too, I think, but we still need to confirm this, I think it’s important to classify tau-PET-positive subjects into moderate and advanced patterns because it looks like the advanced pattern is much more dangerous in terms of risk of developing clinical symptoms and having Alzheimer’s disease, compared to the moderate pattern. So the subjects with a moderate pattern seem to be probably, I don’t know, probably other type of pathology, probably more age related and not that much as pure Alzheimer’s disease, let’s say.
In terms of clinical trials, this visual interpretation method for tau-PET is currently being used in the donanemab trial. So this is one of the inclusion criteria for donanemab. You need to be visually tau-PET-positive. So it is important to know that we can find these visually tau PET-positive individuals in cognitively normal individuals, and we can treat these patients as well. At this point, all the prevention trials have focused on amyloid-positive cognitively unimpaired individuals. And probably they assumed that the prevalence of amyloid-positive and also tau-PET-positive individuals in this impaired group was too small. But we actually found that in the A4 study, which is a study that basically enrolls amyloid-positive cognitively unimpaired individuals, one out of four, 25% of the participants were also tau-PET positive, according to this visual method. So that’s a lot. And that might have implications, for instance, for how this subjects respond to an anti-amyloid therapy because they also have advanced type pathology. And that can be one of the implications.
And also for a clinical practice, I think it’s also very important, because again, we are using a visual interpretation method that can be applied by any clinician, and that is clinically approved by the FDA. So that’s one of the key points. And also that being tau-PET-positive, we demonstrated that is associated with a very, very high risk of developing either dementia if you are MCI or developing mild cognitive impairment or dementia if you are cognitively unimpaired. So there is a high risk and this risk, I think it’s clinically relevant. So that’s the relevance in the clinical part.