Introduction: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences. Methods:In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio.Results: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve[AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94).Discussion: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD.

Endosomal trafficking has emerged as a defective biological pathway in Alzheimer’s disease (AD), and the pathway is a source of cerebrospinal fluid (CSF) protein accumulation. Nevertheless, the identity of the CSF proteins that accumulate in the setting of defects in AD’s endosomal trafficking pathway remains unknown. Here, we performed a CSF proteomic screen in mice with a neuronal-selective knockout of the core of the retromer complex VPS35, a master conductor of endosomal traffic that has been implicated in AD. We then validated three of the most relevant proteomic findings: the amino terminus of the transmembrane proteins APLP1 and CHL1, and the mid-domain of tau, which is known to be unconventionally secreted and elevated in AD. In patients with AD dementia, the concentration of amino-terminal APLP1 and CHL1 in the CSF correlated with tau and phosphorylated tau. Similar results were observed in healthy controls, where both proteins correlated with tau and phosphorylated tau and were elevated in about 70% of patients in the prodromal stages of AD. Collectively, the mouse-to-human studies suggest that retromer-dependent endosomal trafficking can regulate tau, APLP1, and CHL1 CSF concentration, informing on how AD’s trafficking pathway might contribute to disease spread and how to identify its trafficking impairments in vivo.

Introduction Diagnosis of Alzheimer's disease (AD) based on amyloid beta (A), pathologic tau (T), and neurodegeneration (N) biomarkers in peripheral fluids promises to accelerate clinical trials and intercept disease earlier. Methods Qualification of a Simoa plasma p217+tau assay was performed, followed by clinical utility evaluation in a cohort of 227 subjects with broad A and T spectrum. Results The p217+tau plasma assay was accurate, precise, dilution linear, and highly sensitive. All measured samples were within linear range of the assay, presented higher concentration in AD versus healthy controls ( P < .0001), and plasma and cerebrospinal fluid levels correlated (r 2 = 0.35). The plasma p217+tau results were predictive of central T and A status (area under the curve = 0.90 and 0.90, respectively) with low false +/– rates. Discussion The assay described here exhibits good technical performance and shows potential as a highly accurate peripheral biomarker for A or T status in AD and cognitively normal subjects.

Background: Early and accurate detection and staging is critical to managing Alzheimer’s disease (AD) and supporting clinical trials. Cerebrospinal fluid (CSF) biomarkers for amyloid-β peptides, tau species, and various neurodegenerative and inflammatory analytes are leading the way in this regard, yet there is room for improved sensitivity and specificity. In particular tau is known to be present in many different fragments, conformations, and post-translationally modified forms. While the exact tau species that might best reflect AD pathology is unknown, a growing body of evidence suggests that forms with high levels of phosphorylation in the mid-region may be especially enriched in AD. Objective: Develop an assay for measuring p217tau in CSF. Methods: Here we describe the development and validation of a novel sELISA for measuring CSF tau species containing phosphorylation at threonines 212 & 217, aka p217 + tau, using the PT3 antibody. Results: While the analyte is present at extremely low levels the assay is sufficiently sensitive and specific to quantitate p217 + tau with excellent precision, accuracy, and dilution linearity, allowing good differentiation between diagnostic subgroups. The p217 + tau measurements appear to track AD pathology better than the commonly used p181tau epitope, suggesting superior diagnostic and staging performance. Finally, the assay can also be configured to differentiate antibody-bound versus antibody-free tau, and therefore can be used to measure target engagement by p217 + tau-targeting immunotherapeutics. Conclusion: The assay for measuring p217 + tau described here is highly sensitive, accurate, precise, dilution linear, and shows good potential for identifying and staging AD.

BackgroundSeveral blood phosphorylated tau (P‐tau) species (P‐tau181, P‐tau217, and P‐tau231) have shown high accuracy to detect AD pathology, but a direct comparison of the main blood P‐tau assays in a real‐world memory clinic is needed. The main aim of this study is to perform a head‐to‐head comparison of 9 plasma Tau assays and determine their accuracy to discriminate between symptomatic AD from non‐AD.MethodThis is an observational and cross‐sectional study in the BIODEGMAR cohort, which includes patients presenting with cognitive complaints at the Cognitive Decline and Movement Disorders Unit of Hospital del Mar (Barcelona, Spain). Patients were classified into an AD CSF profile group or a non‐AD CSF profile group according to their CSF Aβ42/P‐tau181 ratio (Lumipulse, Fujirebio), and the discrimination accuracy of 9 plasma Tau assays was tested. All plasma samples were treated identically and measurements were performed in a blinded fashion.ResultA total of 197 participants (109 women [55.3%]; mean [SD] age, 72.3 [5.83] years), were investigated. All plasma Tau biomarkers were significantly higher in the AD CSF profile group than in the non‐AD CSF profile group. For plasma Tau biomarkers, the largest effect sizes were found in plasma Janssen P‐tau217 (r = 0.76), Lilly P‐tau217 (r = 0.73), ADx P‐tau181 (r = 0.73), Lilly P‐tau181 (r = 0.68), and UGot P‐tau231 (r = 0.63). All plasma Tau biomarkers significantly discriminated between patients with an AD CSF profile group from those with a non‐AD CSF profile. The AUC of plasma Tau biomarkers were the following (from highest to lower): Janssen P‐tau217 (0.96; 95% CI, 0.93‐0.99), ADx P‐tau181 (0.94; 95% CI, 0.91‐0.97) and Lilly P‐tau217 (0.94; 95% CI, 0.90‐0.98), Lilly P‐tau181 (0.91; 95% CI, 0.87‐0.96), UGot P‐tau231 (0.88; 95% CI, 0.83‐0.93), Quanterix P‐tau181 (0.80; 95% CI, 0.73‐0.87), UGot P‐tau181 (0.80; 95% CI, 0.73‐0.87), Lilly Total‐tau (0.73; 95% CI, 0.65‐0.81), and ADx P‐tau231 (0.66; 95% CI, 0.58‐0.74).ConclusionThe findings indicate that there are several plasma P‐tau biomarkers that can be used in a memory clinic setting as a stand‐alone biomarker to detect AD pathology in a diverse group of patients presenting with cognitive complaints.