So the idea of this study was basically, we know that the APOEε4 allele is the main genetic risk factor for sporadic Alzheimer’s disease. And although it’s very well established that the carrier ship of the APOEε4 genotype associates with increased Aβ burden, there is much evidence in the last few years showing that APOEε4 also contributes to Alzheimer’s disease pathogenesis through Aβ-independent pathways, such as vascular pathways, tau pathology and many pathways that are independent of Aβ...
So the idea of this study was basically, we know that the APOEε4 allele is the main genetic risk factor for sporadic Alzheimer’s disease. And although it’s very well established that the carrier ship of the APOEε4 genotype associates with increased Aβ burden, there is much evidence in the last few years showing that APOEε4 also contributes to Alzheimer’s disease pathogenesis through Aβ-independent pathways, such as vascular pathways, tau pathology and many pathways that are independent of Aβ. And although let’s say the Aβ-related pathways are much more well established, these other pathways that are independent of amyloid are still poorly understood.
In this study, the idea was that besides increasing Aβ burden, there are studies showing that APOEε4 exacerbates the effects of amyloid on cognition. From animal model studies, there were studies suggesting that perhaps this could occur through tau pathogenesis and because of this, and also considering that cross-sectional studies showing an interaction between the APOEε4 genotype with Aβ on tau pathology, these were cross-sectional studies in humans, here we aim to study the association of Aβ with APOEε4 carriership with tau pathology progression. I think this was the idea here.
So basically here we aim to assess, as I said previously, whether APOEε4 carriership potentiates the effects of Aβ on tau pathology progression. And to do this we studied 104 individuals from the McGill TRIAD cohort across the aging and the Alzheimer’s disease clinical spectrum who had available clinical assessments, the APOEε4 genotype, MRI, Aβ-PET, and also tau-PET at baseline and also follow-up tau-PET. And what we observed was that basically the APOEε4 genotype potentiated the deleterious effects of Aβ on the longitudinal accumulation of tau tangles, mainly in the neocortical regions that were corresponding to Braak 3-6.
And after that what we did was that we aimed to assess whether pathological tau phosphorylation could mediate this APOE-potentiated effects of Aβ burden on the longitudinal accumulation of tau tangles. And for that we assessed pathological phosphorylation using plasma p-tau217 and what we observed was that actually the APOEε4-potentiated amyloid effects on tau tangles were in fact mediated by an increase in plasma p-tau217, suggesting that perhaps these APOEε4 potentiated effects of Aβ on tau tangles occur through tau phosphorylation.
So what’s the clinical relevance of our findings? I think that’s what we always ask ourselves when we see this this tau accumulation, when we have increased tau tangle accumulation, what this means. And what we observed here was that an increased tau accumulation was accompanied by higher rates of cortical atrophy and also higher rates of clinical deterioration.