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Barthélemy NR, Li Y, Joseph-Mathurin N, Gordon BA, Hassenstab J, Benzinger TL, Buckles V, Fagan AM, Perrin RJ, Goate AM, Morris JC, Karch CM, Xiong C, Allegri R, Mendez PC, Berman SB, Ikeuchi T, Mori H, Shimada H, Shoji M, Suzuki K, Noble J, Farlow M, Chhatwal J, Graff-Radford NR, Salloway S, Schofield PR, Masters CL, Martins RN, O'Connor A, Fox NC, Levin J, Jucker M, Gabelle A, Lehmann S, Sato C, Bateman RJ, McDade E, Dominantly Inherited Alzheimer Network. A soluble phosphorylated tau signature links tau, amyloid and the evolution of stages of dominantly inherited Alzheimer's disease. Nat Med. 2020 Mar;26(3):398-407. Epub 2020 Mar 11 PubMed.
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Lund University
The finding that early changes in soluble tau, including increased phosphorylation, start in parallel with Aβ aggregation is very interesting. This shows how closely integrated the key hallmarks of AD are, even in the earliest stage of the disease. It is intriguing that these events appear to precede widespread development of aggregated tau (and corresponding atrophy and cognitive impairment) by several years.
Further studies are now needed to understand the cellular mechanisms that may link the early changes in aggregated Aβ with the changes in soluble tau, and with downstream events in AD. For example, it will be important to clarify if the biomarker changes in soluble tau are on a causal pathway that leads to development of aggregated tau. If we can establish such links, it would argue for anti-tau interventions in individuals with CSF signs of soluble tau alterations, but without pathological tau PET. Alternatively, the changes in soluble tau may represent a biochemical epiphenomenon that may be very useful for diagnostic purposes (perhaps especially when measured in plasma or serum) but without major importance for disease progression.
Overall, I think the findings are very much in line with previous findings from us and others on the associations between CSF p-tau with tau PET, which have suggested that changes in soluble tau may occur before significant tau PET changes (e.g. Mattsson et al., 2017; Mattsson et al., 2018). We also have new results from patients with sporadic AD, patients with MAPT-mutations, and from transgenic AD-mice, that are strongly convergent with the findings by Barthélemy et al. We describe these results in a paper currently in press in Science Advances, scheduled for publication in April.
References:
Mattsson N, Schöll M, Strandberg O, Smith R, Palmqvist S, Insel PS, Hägerström D, Ohlsson T, Zetterberg H, Jögi J, Blennow K, Hansson O. 18F-AV-1451 and CSF T-tau and P-tau as biomarkers in Alzheimer's disease. EMBO Mol Med. 2017 Sep;9(9):1212-1223. PubMed.
Mattsson N, Smith R, Strandberg O, Palmqvist S, Schöll M, Insel PS, Hägerström D, Ohlsson T, Zetterberg H, Blennow K, Jögi J, Hansson O. Comparing 18 F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease. Neurology. 2018 Jan 30;90(5):e388-e395. Epub 2018 Jan 10 PubMed.
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