Kaeser SA, Häsler LM, Lambert M, Bergmann C, Bottelbergs A, Theunis C, Mercken M, Jucker M. CSF p-tau increase in response to Aβ-type and Danish-type cerebral amyloidosis and in the absence of neurofibrillary tangles. Acta Neuropathol. 2022 Feb;143(2):287-290. Epub 2021 Dec 28 PubMed.

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  1. This interesting report suggests that CSF t-tau, P-tau181 and -217 are elevated in response to a variety of amyloid species, and that this elevation may occur similarly in mouse models and humans, even if the mice do not develop insoluble tau pathology. The data are supportive of a model whereby amyloid leads to elevated production of soluble tau species, which might potentially be a prerequisite for deposition of insoluble tau species in humans.

    It is encouraging that the relationship between amyloid and soluble tau species can be recapitulated in transgenic mice, thereby providing a model system for understanding the mechanisms by which elevated amyloid leads to elevated tau. 

    However, the relationship between soluble tau species and insoluble tau deposition (NFT and other aggregates) still remains unclear. While there are strong correlations between the two in humans, much work will be needed to understand how these different tau species relate to each other and to the clinical symptoms of tauopathies.  Understanding this relationship will be key for developing more efficient clinical trials and monitoring the response to novel AD therapeutics.

    View all comments by Adam Boxer

  2. Jucker and colleagues again make an important contribution to our understanding of the mechanisms of AD, and the relationships between amyloid and tau. Their results clearly indicate that amyloid is sufficient for p-tau217 and p-tau181 and, together with the time course of changes and effects seen in observational cohorts, begins to indicate the mechanistic links of how amyloid begets tau pathophysiology and ultimately, tau pathology.

    Several recent findings from human studies suggest that there is a sequence of tau changes, starting with amyloid plaques, then p-tau217 and 181, proceeding through p-tau205 and total tau, and then tau aggregation as measured by tau PET. However, it is critical to not conclude causality based on associations, as can happen in human studies without interventions. Longitudinal changes provide more support (e.g., increases in soluble tau concentrations with increasing tau pathology by tau PET); however, these associations are also limited. As seen in the DIAN study, p-tau217 and 181 phosphorylation occupancy decrease during the symptomatic phase of disease, when tau pathology is expected to be increasing. This paradoxical relationship further supports p-tau217 and 181 not being direct measures of tau aggregation pathology, even though overall tau concentrations may still increase.

    With the need to identify tau drugs that impact tau targets, the importance of interpretation of tau biomarkers is critical. For example, when p-tau217 or 181 are lowered with anti-amyloid drugs that remove amyloid, is this a direct downstream effect of amyloid removal, and/or evidence that tau pathology has been altered? The DIAN-TU recently launched a combination trial of an anti-tau and an anti-amyloid antibody, highlighting the need to understand how to measure tau biomarkers related to amyloid removal versus independent anti-tau biological impact.

    The rate of breakthroughs for amyloid and tau biomarkers is already fast and accelerating. We are in a golden age of tracking the molecular signatures of Alzheimer's pathophysiology, and understanding how to interpret these biomarkers will be essential for decision-making in trials and the clinic. This report provides an important insight into the relationships of p-tau to amyloid.

    View all comments by Randall Bateman

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