LAUSR

Phosphorylated tau (p-tau) species in bodily fluids are among the most reliable molecular biomarkers for differential diagnosis and progression monitoring of Alzheimer’s disease (AD) [3]. The ATN research framework stages AD patients based on three classes of readouts, amyloid (A), tau (T) and neurodegeneration (N) including cerebrospinal fluid (CSF) and imaging biomarkers [6]. CSF p-tau together with positron emission tomography (PET) for tau are suggested biomarkers of tau pathology. While tau PET is clearly related to tauopathy by tracing brain neurofibrillary tangles, for p-tau it is less clear whether it reflects or rather anticipates early tangle formation. Several studies could show that the increase of fluid-based tau phosphorylated at threonine 181 (p181tau) and tau phosphorylated at threonine 217 (p217tau) is an early event of AD pathogenesis driven by β-amyloid deposition in brain [1, 3]. The tight link between β-amyloid deposition and CSF p-tau is also consistent with recent clinical data using anti-Aβ antibody Donanemab; concomitant with a reduction in Aβ plaques, plasma p217tau decreased while tauopathy still progressed, although at a slower rate [8]. However, whether β-amyloidosis per se, i.e. in the absence of neurofibrillary tangles and neuronal death, is sufficient to raise p-tau levels in the CSF is not clear [3]. We quantified endogenous p181tau in CSF samples of APPPS1 transgenic (tg) mice (see also Supplementary Methods, online resource) that do not develop neurofibrillary tangles or extensive neuron loss [9]. CSF p181tau in APPPS1 tg mice showed an age-dependent increase reaching a plateau at threeto four-fold higher levels in aged compared to 1.5-month-old mice (Fig. 1a). In non-tg littermates, CSF p181tau exhibited a biphasic profile with a transient drop reminiscent of CSF total tau (t-tau) levels in non-tg mice [10]. Total tau (t-tau) measured in the same CSF samples also plateaued in aged APPPS1 tg mice (Supplementary Fig. 1, online resource). The p181tau/t-tau ratio initially dropped but overall remained stable at 7–8% (Fig. 1b). CSF p181tau strongly correlated with CSF t-tau levels (Fig. 1c). We then used an immunoassay which allows the quantification of tau phosphorylated at threonine 217 with or without adjacent phospho-epitopes (“p217 + tau” [12] (see also Supplementary Methods, online resource). P217 + tau also showed an age-dependent increase and reached a plateau, although at 14to 16-fold higher levels compared to 1.5-month-old APPPS1 tg animals (Fig. 2a). The p217 + tau/ t-tau ratio was unchanged up to 6 months of age but started to increase thereafter (from 5 to 14%) becoming significant at 18 months of age (Fig. 2b). A strong correlation was observed between CSF p217 + tau and t-tau levels (Fig. 2c). Thus, overall changes in CSF p181tau, p217 + tau and t-tau tightly follow the Aβ deposition reported in this mouse model starting at 1.5 months with a plateau around 18 months of age [9, 10, 13]. The magnitude of the CSF p-tau increase is comparable to the p-tau increase observed in AD patients [7]. In AD, soluble p-tau also reaches its highest level in the phase of maximal cerebral amyloid load, but seems to decrease thereafter, presumably due to the occurrence of neuron loss during disease progression [1]. To test whether the increase of CSF p-tau is specific to the aggregation of Aβ or rather a shared consequence of different types of cerebral amyloidosis, we then assessed tau in the CSF of ADanPP tg mice, a model of Danish amyloidosis as seen in Familial Danish Dementia * Stephan A. Kaeser [email protected]