Dynamic functional connectivity is modulated by the amount of p-Tau231 in blood in cognitively intact participants.

INTRODUCTION: Electrophysiology and plasma biomarkers are early and non-invasive candidates for Alzheimer's disease detection. The purpose of this paper is to evaluate changes in dynamic functional connectivity measured with magnetoencephalography, associated with the plasma pathology marker p-tau231 in unimpaired adults. METHODS: 73 individuals were included. Static and dynamic functional connectivity were calculated using leakage corrected amplitude envelope correlation. Each source's strength entropy across trials was calculated. A data-driven statistical analysis was performed to find the association between functional connectivity and plasma p-tau231 levels. Regression models were used to assess the influence of other variables over the clusters' connectivity. RESULTS: Frontotemporal dynamic connectivity positively associated with p-tau231 levels. Linear regression models identified pathological, functional and structural factors that influence dynamic functional connectivity. DISCUSSION: These results expand previous literature on dynamic functional connectivity in healthy individuals at risk of AD, highlighting its usefulness as an early, non-invasive and more sensitive biomarker.

Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologies.

INTRODUCTION: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy. METHODS: We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.3 (0.3-14.3) months after CSF collection revealed no co-pathology in 10, concomitant AD in 8, PART in 8, and other co-pathologies in 3 patients. RESULTS: N-terminal p-tau was increased in CJD versus SCD (p < 0.0001) and correlated with total tau (t-tau) in the presence of AD and PART co-pathology (rho = 0.758-0.952, p ≤ 001). Concentrations in CJD+AD were indistinguishable from AD dementia, with the largest fold-change in p-tau217 (11.6), followed by p-tau231 and p-tau181 (3.2-4.5). DISCUSSION: Variable fold-changes and correlation with t-tau suggest that p-tau closely associates with neurodegeneration and concomitant AD in CJD. HIGHLIGHTS: N-terminal phosphorylated tau (p-tau) biomarkers are increased in Creutzfeldt-Jakob disease (CJD) with and without concomitant AD. P-tau217, p-tau231, and p-tau181 correlate with total tau (t-tau) and increase in the presence of amyloid beta (Aß) co-pathology. N-terminal p-tau181 and p-tau231 in Aß-negative CJD show variation among PRNP genotypes. Compared to mid-region-targeting p-tau181, cerebrospinal fluid (CSF) N-terminal p-tau has greater potential to reflect post-mortem neuropathology in the CJD brain.

Evaluating p-tau217 and p-tau231 as Biomarkers for Early Diagnosis and Differentiation of Alzheimer's Disease: A Narrative Review.

The escalating prevalence of Alzheimer's disease (AD) highlights the urgent need to develop reliable biomarkers for early diagnosis and intervention. AD is characterized by the pathological accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Phosphorylated tau (p-tau) proteins, particularly p-tau217 and p-tau231, have been identified as promising biomarker candidates to differentiate the disease progression from preclinical stages. This narrative review is devoted to a critical evaluation of the diagnostic accuracy, sensitivity, and specificity of p-tau217 and p-tau231 levels in the detection of AD, measured in plasma, serum, and cerebrospinal fluid, compared to established biomarkers. Additionally, the efficacy of these markers in distinguishing AD from other neurodegenerative disorders is examined. The significant advances offered by p-tau217 and p-tau231 in AD diagnostics are highlighted, demonstrating their unique utility in early detection and differential diagnosis. This comprehensive analysis not only confirms the excellent diagnostic capabilities of these markers, but also deepens the understanding of the molecular dynamics of AD, contributing to the broader scientific discourse on neurodegenerative diseases. This review is aimed to provide key information for researchers and clinicians across disciplines, filling interdisciplinary gaps and highlighting the role of p-tau proteins in revolutionizing AD research and clinical practice.

Plasma Phosphorylated Tau 231 Increases at One-Year Intervals in Cognitively Unimpaired Subjects.

Background: Plasma biomarkers of Alzheimer's disease (AD) constitute a non-invasive tool for diagnosing and classifying subjects. They change even in preclinical stages, but it is necessary to understand their properties so they can be helpful in a clinical context. Objective: With this work we want to study the evolution of p-tau231 plasma levels in the preclinical stages of AD and its relationship with both cognitive and imaging parameters. Methods: We evaluated plasma phosphorylated (p)-tau231 levels in 146 cognitively unimpaired subjects in sequential visits. We performed a Linear Mixed-effects Model to analyze their rate of change. We also correlated their baseline levels with cognitive tests and structural and functional image values. ATN status was defined based on cerebrospinal fluid biomarkers. Results: Plasma p-tau231 showed a significant rate of change over time. It correlated negatively with memory tests only in amyloid-positive subjects. No significant correlations were found with any imaging measures. Conclusions: Increases in plasma p-tau231 can be detected at one-year intervals in cognitively healthy subjects. It could constitute a sensitive marker for detecting early signs of neuronal network impairment by amyloid.

Day-to-day sleep variability with Alzheimer's biomarkers in at-risk elderly.

INTRODUCTION: Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. METHODS: In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3 ± 5.4; 78 males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. RESULTS: Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-ß (Aß)42, and higher plasma p-tau231/Aß42 were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. DISCUSSION: Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.

Longitudinal changes in the functional connectivity of individuals at risk of Alzheimer's disease.

First-degree relatives of Alzheimer's disease patients constitute a key population in the search for early markers. Our group identified functional connectivity differences between cognitively unimpaired individuals with and without a family history. In this unprecedented follow-up study, we examine whether family history is associated with a longitudinal increase in the functional connectivity of those regions. Moreover, this is the first work to correlate electrophysiological measures with plasma p-tau231 levels, a known pathology marker, to interpret the nature of the change. We evaluated 69 cognitively unimpaired individuals with a family history of Alzheimer's disease and 28 without, at two different time points, approximately 3 years apart, including resting state magnetoencephalography recordings and plasma p-tau231 determinations. Functional connectivity changes in both precunei and left anterior cingulate cortex in the high-alpha band were studied using non-parametric cluster-based permutation tests. Connectivity values were correlated with p-tau231 levels. Three clusters emerged in individuals with family history, exhibiting a longitudinal increase of connectivity. Notably, the clusters for both precunei bore a striking resemblance to those found in previous cross-sectional studies. The connectivity values at follow-up and the change in connectivity in the left precuneus cluster showed significant positive correlations with p-tau231. This study consolidates the use of electrophysiology, in combination with plasma biomarkers, to monitor healthy individuals at risk of Alzheimer's disease and emphasizes the value of combining noninvasive markers to understand the underlying mechanisms and track disease progression. This could facilitate the design of more effective intervention strategies and accurate progression assessment tools.

Phosphorylated tau in Alzheimer's disease.

There is a need for blood biomarkers to detect individuals at different Alzheimer's disease (AD) stages because obtaining cerebrospinal fluid-based biomarkers is invasive and costly. Plasma phosphorylated tau proteins (p-tau) have shown potential as such biomarkers. This systematic review was conducted according to the PRISMA guidelines and aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181), threonine 217 (p-tau217) and threonine 231 (p-tau231) is informative in the diagnosis of AD. All p-tau isoforms increase as a function of Aß-accumulation and discriminate healthy individuals from those at preclinical AD stages with high accuracy. P-tau231 increases earliest, followed by p-tau181 and p-tau217. In advanced stages, all p-tau isoforms are associated with the clinical classification of AD and increase with disease severity, with the greatest increase seen for p-tau217. This is also reflected by a better correlation of p-tau217 with Aß scans, whereas both, p-tau217 and p-tau181 correlated equally with tau scans. However, at the very advanced stages, p-tau181 begins to plateau, which may mirror the trajectory of the Aß pathology and indicate an association with a more intermediate risk of AD. Across the AD continuum, the incremental increase in all biomarkers is associated with structural changes in widespread brain regions and underlying cognitive decline. Furthermore, all isoforms differentiate AD from non-AD neurodegenerative disorders, making them specific for AD. Incorporating p-tau181, p-tau217 and p-tau231 in clinical use requires further studies to examine ideal cut-points and harmonize assays.

Head-to-head comparison of plasma p-tau181, p-tau231 and glial fibrillary acidic protein in clinically unimpaired elderly with three levels of APOE4-related risk for Alzheimer's disease.

Plasma phosphorylated tau (p-tau) and glial fibrillary acidic protein (GFAP) both reflect early changes in Alzheimer's disease (AD) pathology. Here, we compared the biomarker levels and their association with regional ß-amyloid (Aß) pathology and cognitive performance head-to-head in clinically unimpaired elderly (n = 88) at three levels of APOE4-related genetic risk for sporadic AD (APOE4/4 n = 19, APOE3/4 n = 32 or non-carriers n = 37). Concentrations of plasma p-tau181, p-tau231 and GFAP were measured using Single molecule array (Simoa), regional Aß deposition with 11C-PiB positron emission tomography (PET), and cognitive performance with a preclinical composite. Significant differences in plasma p-tau181 and p-tau231, but not plasma GFAP concentrations were present between the APOE4 gene doses, explained solely by brain Aß load. All plasma biomarkers correlated positively with Aß PET in the total study population. This correlation was driven by APOE3/3 carriers for plasma p-tau markers and APOE4/4 carriers for plasma GFAP. Voxel-wise associations with amyloid-PET revealed different spatial patterns for plasma p-tau markers and plasma GFAP. Only higher plasma GFAP correlated with lower cognitive scores. Our observations suggest that plasma p-tau and plasma GFAP are both early AD markers reflecting different Aß-related processes.

Clinical performance and head-to-head comparison of CSF p-tau235 with p-tau181, p-tau217 and p-tau231 in two memory clinic cohorts.

BACKGROUND: Cerebrospinal fluid (CSF) p-tau235 is a novel biomarker highly specific of Alzheimer's disease (AD). However, CSF p-tau235 has only been studied in well-characterized research cohorts, which do not fully reflect the patient landscape found in clinical settings. Therefore, in this multicentre study, we investigated the performance of CSF p-tau235 to detect symptomatic AD in clinical settings and compared it with CSF p-tau181, p-tau217 and p-tau231. METHODS: CSF p-tau235 was measured using an in-house single molecule array (Simoa) assay in two independent memory clinic cohorts: Paris cohort (Lariboisière Fernand-Widal University Hospital Paris, France; n=212) and BIODEGMAR cohort (Hospital del Mar, Barcelona, Spain; n=175). Patients were classified by the syndromic diagnosis (cognitively unimpaired [CU], mild cognitive impairment [MCI] or dementia) and their biological diagnosis (amyloid-beta [Aß]+ or Aß -). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aß1-42/40 ratio, p-tau181 and t-tau] and in-house developed Simoa CSF p-tau181, p-tau217 and p-tau231). RESULTS: High CSF p-tau235 levels were strongly associated with CSF amyloidosis regardless of the clinical diagnosis, being significantly increased in MCI Aß+ and dementia Aß+ when compared with all other Aß- groups (Paris cohort: P ˂0.0001 for all; BIODEGMAR cohort: P ˂0.05 for all). CSF p-tau235 was pronouncedly increased in the A+T+ profile group compared with A-T- and A+T- groups (P ˂0.0001 for all). Moreover, CSF p-tau235 demonstrated high diagnostic accuracies identifying CSF amyloidosis in symptomatic cases (AUCs=0.86 to 0.96) and discriminating AT groups (AUCs=0.79 to 0.98). Overall, CSF p-tau235 showed similar performances to CSF p-tau181 and CSF p-tau231 when discriminating CSF amyloidosis in various scenarios, but lower than CSF p-tau217. Finally, CSF p-tau235 associated with global cognition and memory domain in both cohorts. CONCLUSIONS: CSF p-tau235 was increased with the presence of CSF amyloidosis in two independent memory clinic cohorts. CSF p-tau235 accurately identified AD in both MCI and dementia patients. Overall, the diagnostic performance of CSF p-tau235 was comparable to that of other CSF p-tau measurements, indicating its suitability to support a biomarker-based AD diagnosis in clinical settings.

P-tau231 as a Diagnostic Biomarker for Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

Objective: Some previous studies have shown that cerebrospinal fluid (CSF) levels of p-tau231 were significantly higher in patients with Alzheimer's disease (AD) compared to that in patients with mild cognitive impairment (MCI) and normal control (NC), whereas some other studies did not. Due to contradictory results, we aimed to conduct a systematic review and meta-analysis study on previous investigations to examine the potential role of CSF p-tau231 as a biomarker of AD and MCI. Method: PubMed, Scopus, and Web of Science were searched in March 2021 for studies on the CSF level of p-tau231 in AD, MCI, and NC. The statistical analysis was performed via standardized mean difference (SMD) methodology with a 95% confidence interval. Results: A total of 10 studies including 1141 subjects were included. The present study showed that CSF level of p-tau231 was significantly higher in AD patients compared to that in MCI patients (SMD = 160.94 [11.11, 310.78], P = 0.04) and NC patients (SMD = 436.21 [164.88, 707.54], P < 0.00). Moreover, comparison of MCI and NC showed a significantly higher level of CSF p-tau231 in MCI compared to NC (SMD = 341.44 [59.73, 623.14], P = 0.02). Conclusion: P-tau231 showed to be a valuable biomarker of discrimination AD, MCI, and NC based on our findings. This meta-analysis showed that the CSF p-tau231 can reliably differentiate AD patients from MCI and NC patients. Furthermore, based on our findings the level of CSF p-tau231 was significantly higher in MCI compared to NC. Therefore, p-tau231 can be added to the list of potential biomarkers for the diagnosis of AD and MCI in further studies. However, further investigations are needed to confirm our findings.

Urinary polycyclic aromatic hydrocarbon metabolites, plasma p-tau231 and mild cognitive impairment in coke oven workers.

BACKGROUND: As a group of environmental pollutants, polycyclic aromatic hydrocarbons (PAHs) may be neurotoxic，especially in high-exposure occupational populations. However, the effect of PAHs on mild cognitive impairment (MCI) is still unclear. OBJECTIVE: We aimed to investigate the relationship between PAH metabolites and MCI and to explore whether plasma p-tau231 can be used as a potential biomarker to reflect MCI in coke oven workers. METHOD: A total of 330 workers were recruited from a coke oven plant as the exposure group, and 234 workers were recruited from a water treatment plant as the control group. The concentrations of eleven PAH metabolites and plasma p-tau231 were determined by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) and ELISA. Cognitive function was measured by the Montreal Cognitive Assessment (MoCA) questionnaire. A multivariate logistic regression model and multiple linear regression model were used to analyze the associations of urinary PAH metabolites with the detection rate of MCI, MoCA scores and plasma p-tau231. The dose-response relationships were evaluated using restricted cubic spline models. RESULTS: We found 146 MCI-positive workers in coke oven plant (44.24%), and 69 MCI-positive workers in water treatment plant (29.49%). In addition, the urinary sum of PAH metabolites (Æ©-OH PAHs) was significantly associated with MCI (OR, 1.371; 95% CI:1.102-1.705). Each one-unit increase in ln-transformed Æ©-OH PAHs was associated with a 0.429 decrease in the sum of MoCA, a 0.281 reduction in the visuospatial/executive function and a 9.416 increase in the level of plasma P-Tau231. We found a negative association between plasma P-Tau231 and visuospatial/executive function (ß = -0.007, 95% CI: -0.011, -0.003). CONCLUSION: Our data indicated that urinary Æ©-OH PAHs levels of workers were positively associated with MCI and the level of plasma P-Tau231.

Diagnostic value of serum versus plasma phospho-tau for Alzheimer's disease.

BACKGROUND: Blood phosphorylated tau (p-tau) forms are promising Alzheimer's disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p-tau231 and p-tau181 in paired plasma and serum samples. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker-positive AD and biomarker-negative control participants. METHODS: We studied three independent cohorts (n=115 total): cohorts 1 and 2 included individuals with paired plasma and serum, while cohort 3 included paired serum and CSF. Blood-based p-tau231 and p-tau181 were measured using in-house or commercial single molecule array (Simoa) methods. RESULTS: Serum and plasma p-tau231 and p-tau181 were two- to three-fold increased in biomarker-positive AD versus biomarker-negative controls (P≤0.0008). Serum p-tau231 separated diagnostic groups with area under the curve (AUC) of 82.2% (cohort 3) to 88.2% (cohort 1) compared with 90.2% (cohort 1) for plasma. Similarly, p-tau181 showed AUC of 89.6% (cohort 1) to 89.8% (cohort 3) in serum versus 85.4% in plasma (cohort 1). P-tau231 and p-tau181 correlated slightly better in serum (rho=0.92 for cohort 1, 0.93 for cohort 3) than in plasma (rho=0.88, cohort 1). Within-individual p-tau181 (Quanterix) and p-tau231 concentrations were twice higher in plasma versus serum, but p-tau181 (in-house, Gothenburg) levels were not statistically different. Bland-Altman plots revealed that the relative difference between serum/plasma was larger in the lower range. P-tau levels in paired plasma and serum correlated strongly with each other (rho=0.75-0.93) as well as with CSF Aß42 (rho= -0.56 to -0.59), p-tau and total-tau (rho=0.53-0.73). Based on the results, it seems possible that serum p-tau reflects the same pool of brain-secreted p-tau as in CSF; we estimated that less than 2% of CSF p-tau is found in serum, being same for both controls and AD. CONCLUSIONS: Comparable diagnostic performances and strong correlations between serum versus plasma pairs suggest that p-tau analyses can be expanded to research cohorts and hospital systems that prefer serum to other blood matrices. However, absolute biomarker concentrations may not be interchangeable, indicating that plasma and serum samples should be used independently. These results should be validated in independent cohorts.

A critical appraisal of tau-targeting therapies for primary and secondary tauopathies.

INTRODUCTION: Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. METHODS: We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. RESULTS: The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti-tau monoclonal antibodies have not shown clinical efficacy. DISCUSSION: The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non-specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and post-translational tau modifications.

Diagnostic and prognostic plasma biomarkers for preclinical Alzheimer's disease.

INTRODUCTION: This study involved a parallel comparison of the diagnostic and longitudinal monitoring potential of plasma glial fibrillary acidic protein (GFAP), total tau (t-tau), phosphorylated tau (p-tau181 and p-tau231), and neurofilament light (NFL) in preclinical Alzheimer's disease (AD). METHODS: Plasma proteins were measured using Simoa assays in cognitively unimpaired older adults (CU), with either absence (Aß-) or presence (Aß+) of brain amyloidosis. RESULTS: Plasma GFAP, t-tau, p-tau181, and p-tau231 concentrations were higher in Aß+ CU compared with Aß- CU cross-sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aß+ and Aß- CU; however, no statistically significant differences were observed between the AUCs of GFAP, p-tau181, and p-tau231, but all were significantly higher than the AUC of NFL, and the AUC of GFAP was higher than the AUC of t-tau. The combination of a base model (BM), comprising the AD risk factors, age, sex, and apolipoprotein E gene (APOE) ε4 status with GFAP was observed to have a higher AUC (>90%) compared with the combination of BM with any of the other proteins investigated in the current study. Longitudinal analyses showed increased GFAP and p-tau181 in Aß+ CU and increased NFL in Aß- CU, over a 12-month duration. GFAP, p-tau181, p-tau231, and NFL showed significant correlations with cognition, whereas no significant correlations were observed with hippocampal volume. DISCUSSION: These findings highlight the diagnostic and longitudinal monitoring potential of GFAP and p-tau for preclinical AD.

Clinical and analytical comparison of six Simoa assays for plasma P-tau isoforms P-tau181, P-tau217, and P-tau231.

INTRODUCTION: Studies using different assays and technologies showed highly promising diagnostic value of plasma phosphorylated (P-)tau levels for Alzheimer's disease (AD). We aimed to compare six P-tau Simoa assays, including three P-tau181 (Eli Lilly, ADx, Quanterix), one P-tau217 (Eli Lilly), and two P-tau231 (ADx, Gothenburg). METHODS: We studied the analytical (sensitivity, precision, parallelism, dilution linearity, and recovery) and clinical (40 AD dementia patients, age 66±8years, 50%F; 40 age- and sex-matched controls) performance of the assays. RESULTS: All assays showed robust analytical performance, and particularly P-tau217 Eli Lilly; P-tau231 Gothenburg and all P-tau181 assays showed robust clinical performance to differentiate AD from controls, with AUCs 0.936-0.995 (P-tau231 ADx: AUC = 0.719). Results obtained with all P-tau181 assays, P-tau217 Eli Lilly assay, and P-tau231 Gothenburg assay strongly correlated (Spearman's rho > 0.86), while correlations with P-tau231 ADx results were moderate (rho < 0.65). DISCUSSION: P-tau isoforms can be measured robustly by several novel high-sensitive Simoa assays.

Plasma p-tau231: a new biomarker for incipient Alzheimer's disease pathology.

The quantification of phosphorylated tau in biofluids, either cerebrospinal fluid (CSF) or plasma, has shown great promise in detecting Alzheimer's disease (AD) pathophysiology. Tau phosphorylated at threonine 231 (p-tau231) is one such biomarker in CSF but its usefulness as a blood biomarker is currently unknown. Here, we developed an ultrasensitive Single molecule array (Simoa) for the quantification of plasma p-tau231 which was validated in four independent cohorts (n = 588) in different settings, including the full AD continuum and non-AD neurodegenerative disorders. Plasma p-tau231 was able to identify patients with AD and differentiate them from amyloid-ß negative cognitively unimpaired (CU) older adults with high accuracy (AUC = 0.92-0.94). Plasma p-tau231 also distinguished AD patients from patients with non-AD neurodegenerative disorders (AUC = 0.93), as well as from amyloid-ß negative MCI patients (AUC = 0.89). In a neuropathology cohort, plasma p-tau231 in samples taken on avergae 4.2 years prior to post-mortem very accurately identified AD neuropathology in comparison to non-AD neurodegenerative disorders (AUC = 0.99), this is despite all patients being given an AD dementia diagnosis during life. Plasma p-tau231 was highly correlated with CSF p-tau231, tau pathology as assessed by [18F]MK-6240 positron emission tomography (PET), and brain amyloidosis by [18F]AZD469 PET. Remarkably, the inflection point of plasma p-tau231, increasing as a function of continuous [18F]AZD469 amyloid-ß PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-ß PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-ß PET quartiles 2-4, whereas CSF p-tau217 and plasma p-tau181 increased only at quartiles 3-4 and 4, respectively. Finally, plasma p-tau231 differentiated individuals across the entire Braak stage spectrum, including Braak staging from Braak 0 through Braak I-II, which was not observed for plasma p-tau181. To conclude, this novel plasma p-tau231 assay identifies the clinical stages of AD and neuropathology equally well as plasma p-tau181, but increases earlier, already with subtle amyloid-ß deposition, prior to the threshold for amyloid-ß PET positivity has been attained, and also in response to early brain tau deposition. Thus, plasma p-tau231 is a promising novel biomarker of emerging AD pathology with the potential to facilitate clinical trials to identify vulnerable populations below PET threshold of amyloid-ß positivity or apparent entorhinal tau deposition.

Validation of a prototype tau Thr231 phosphorylation CSF ELISA as a potential biomarker for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques (senile plaques) and intracellular neurofibrillary tangles formed by hyperphosphorylated tau protein. This process leads to neuronal degradation and neuronal death. Phosphorylation of tau protein at threonine 231 (p-tau231) has been shown to be characteristic in post-mortem brain tissue of patients with AD and it can be sensitively detected in cerebrospinal fluid (CSF). Therefore, it may serve as a biomarker to support the diagnosis of AD. In this study, we analysed how well p-tau231 could differentiate between patients suffering from dementia either due or not due to AD by a sandwich enzyme immunoassay. CSF p-tau231 was significantly higher in patients with dementia due to AD than in those with dementia due to other causes. In addition, we studied different factors affecting p-tau231 levels in CSF. We found that apolipoprotein E genotype influences p-tau231 CSF levels. Gender and age did not affect p-tau231 levels in CSF. Our findings indicate that p-tau231 levels in CSF can be a valuable marker for the clinical diagnosis of AD.

Greater specificity for cerebrospinal fluid P-tau231 over P-tau181 in the differentiation of healthy controls from Alzheimer's disease.

Cerebrospinal fluid (CSF) measures of phosphorylated-tau (P-tau) 231 and P-tau181 are two biomarkers for the identification of tau pathology as related to Alzheimer's disease (AD). While both are pathologically validated, their relative diagnostic performances are not well known. This cross-sectional diagnostic study of 87 normal (NL) subjects and 28 AD subjects compared CSF P-tau231 with CSF P-tau181. Logistic regression modeling demonstrated that the P-tau231 was superior to the P-tau181 in the diagnostic classifications. At a fixed 85% sensitivity cutoff, the ROC analysis shows that P-tau231 has greater overall specificity than P-tau181. While both P-tau analytes demonstrated equivalent negative predictive accuracies, P-tau231 yielded significantly fewer false positives. Moreover, P-tau231, but not P-tau181, demonstrated sensitivity to the E4 genotype. A postmortem validation with 9 AD subjects confirmed the superiority of the CSF P-tau231 specificity. This study suggests that P-tau231 has the potential to improve the CSF tau biomarker diagnosis of AD.