Tau368 in cerebrospinal fluid is associated with severity of tau pathology load in the Alzheimer’s continuum

Abstract Background Recent developments in the biomarker field allow Alzheimer’s disease (AD) pathophysiology to be reflected at the preclinical stage. We recently presented an assay targeting tau fragments ending at residue 368, which exhibited a stage‐wise decrease in a ratio with total‐tau. The tau368/T‐tau ratio also correlated with tau positron emission tomography (PET) uptake, and was present in tau tangles. In this study, we aimed to validate these findings in a larger cohort including a larger subset spanning the AD continuum. Method We investigated 129 participants cross‐sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (22 young, 60 cognitively unimpaired (CU) elderly (14 Aβ+), 26 mild cognitive impairment (MCI; 10 Aβ+), 14 AD dementia and 7 frontotemporal dementia (FTD)). For all individuals, [ 18 F]AZD4694 and [ 18 F]MK‐6240 PET were used to index Aβ and tau load (Braak stages) respectively. T‐tau was quantified using ELISA (INNOTEST®) and Tau368 was quantified by an in house Single molecule array (Simoa) assay (Quanterix, Billerica, MA). Spearman rank tests assessed correlation between continuous variables. Linear models tested the effect of tau368/t‐tau ratio on PET summary measures and at the voxel level, always adjusting for age and sex. Result Compared to young controls, we observed a stage‐wise decrease of tau368/t‐tau, with the lowest ratio found in AD dementia (P<0.01), followed by CU‐ (P<0.001), CU+ (P<0.01) and MCI‐ (P<0.001). MCI+ had a lower ratio than CU‐ (P<0.01). Furthermore, there was a strong negative correlation between tau368/t‐tau ratio and PET Braak stages in the whole population (I‐II; ρ =‐0.46, P<0.001, III‐IV; ρ =‐0.44, P<0.001, V‐VI; ρ =‐0.37, P<0.001), in MCI+ (I‐II; ρ=‐0.79, P<0.01, III‐IV; ρ=‐0.84, P<0.01, V‐VI; ρ=‐0.83, P<0.01) and in AD dementia (V‐VI; ρ =‐0.57, P<0.05). Voxel‐wise analysis demonstrated strong correlation between tau368/t‐tau and tau PET ligand uptake in the medial and lateral temporal lobes in cognitively impaired individuals, while no significant association was found in CU. Conclusion We provide further evidence of a stage‐wise decrease in CSF tau368/t‐tau, which tracks cortical tau accumulation only in clinically manifest AD dementia and amyloid positive MCI. These results further support that CSF tau368/t‐tau captures severity of tau pathology within the AD continuum.