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To assess the variations and diagnostic performance of serum biomarkers of neurodegenerative diseases. In this monocentric prospective study, neurofilament light (NFL), T-tau, p-tau181, p-tau217, Aβ40, and Aβ42 were measured in serum collected from orthopedic patients (control group, n=114) and patients in the neurology department (n=69) previously diagnosed with Alzheimer's disease (AD, n=52), parkinsonian syndromes (n=10), and other etiologies of neurodegeneration (non-AD, n=7). In the control group, serum NFL, T-tau, p-tau181, p-tau217, and Aβ40 significantly increased with age, independently of sex. NFL (p=0.0078), p-tau217 (p<0.001) were significantly increased with neurodegeneration when compared to controls, with only p-tau217 significant in the multivariate analysis (p<0.001). Multivariate regression analysis accounting for age highlighted a significant increase of p-tau217 (p<0.001) in the AD subgroup. NFL was significantly increased in the non-AD patients (p<0.001), and in the parkinsonian syndromes subgroup (p=0.016) when compared to negative controls. Serum p-tau181 and p-tau217 were significantly correlated with CSF p-tau181 (Spearman's coefficients of 0.43 and 0.48 respectively, n=40). Areas under the ROC curves for the identification of patients with neurodegenerative diseases were 0.62 (0.54–0.70) for NFL, 0.62 (0.54–0.71) for T-tau, 0.83 (0.76–0.89) for p-tau217, and 0.66 (0.58–0.74) for Aβ40. Serum biomarkers can help identify patients with neurodegenerative disease and may be a valuable tool for care and orientation. Phosphorylated tau p-tau217 is a promising blood biomarker for AD and NFL for other etiologies. [ABSTRACT FROM AUTHOR]

Background: Among the Alzheimer's disease (AD) biomarkers measured in blood, phosphorylated forms of tau (p-tau) have been shown to exhibit a particularly high diagnostic potential. Here, we performed a comprehensive method comparison study, followed by evaluation of the diagnostic performance of eight recent plasma p-tau immunoassays targeting different tau phosphorylation sites, different tau fragments, and that are measured by two distinct platforms. Methods: We enrolled a cohort of 40 patients with AD at the stage of dementia (AD-dem) characterized by positive CSF A + T + profile, and a control group of 40 cognitively healthy participants (Control), to conduct a comprehensive method comparison for three plasma p-tau181 and five plasma p-tau217 assays run on the Simoa® HD-X™ or Lumipulse® G600II/G1200 platforms. Design of the compared assays differed in regard to: (1) tau phosphorylation site targeted by the capture antibody (T181 or T217), and (2) epitope of the pan-tau detector antibody (N-terminal or mid-region). For each of the assays we determined precision and analytical sensitivity parameters and used Passing-Bablok regression and Bland-Altman plots for pairwise comparison of p-tau181 or p-tau217 assays. Subsequently, we evaluated the diagnostic accuracy of all the assays for discrimination between AD-dem and Control groups. Results: We found a strong, positive correlation between all the measurements. Fixed and/or proportional bias was observed for each of compared p-tau181 assay pairs or p-tau217 assay pairs. While both plasma p-tau181 and p-tau217 levels were significantly increased in AD-dem vs. Control groups as measured by all assays, higher median concentration AD-dem/Control fold change and AUC values were observed for p-tau217 (assays range: fold change 3.72–6.74, AUC 0.916–0.956) compared with p-tau181 (assays range 1.81–2.94, AUC 0.829–0.909), independently of the platform used. No significant differences were observed between diagnostic performance of p-tau181 assays or p-tau217 assays targeting tau N-terminus or mid-region. Conclusions: Although all plasma p-tau measurements enabled discrimination between clinical groups, p-tau217 assays showed the highest robustness, independently of the pan-tau detector antibody targeting N-terminal or mid-region, and independently of the platform used. Considering the observed method disagreement in measured absolute concentrations, we stress the need for development of certified reference material, harmonizing measurements across different platforms. [ABSTRACT FROM AUTHOR]

Abstract Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by brain aggregation of β-amyloid (Aβ) peptides and phosphorylated tau (P-tau) proteins. Extracellular vesicles (EVs) can be isolated and studied for potential roles in disease. While several studies have tested plasma-derived EVs in AD, few have analyzed EVs from cerebrospinal fluid (CSF), which are potentially more closely related to brain changes. This study included 20 AD patients and 20 cognitively unimpaired (CU) participants. Using a novel EV isolation method based on acoustic trapping, we isolated and purified EVs from minimal CSF volumes. EVs were lysed and analyzed by immunoassays for P-tau217 and P-tau181. Isolation was confirmed through transmission electron microscopy and the presence of EV-specific markers (CD9, CD63, CD81, ATP1A3). Nanoparticle tracking analysis revealed a high variance in EV distribution. AD patients exhibited increased P-tau181 and decreased P-tau217 in EVs, leading to a higher EV P-tau181/P-tau217 ratio compared to CU. No significant differences in EV counts or sizes were observed between AD and CU groups. This study is the first to use acoustic trapping to isolate EVs from CSF and demonstrates differential P-tau content in AD-derived EVs, warranting further research to understand the relationship between these EV changes and brain pathology.

Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P‐tau181), a recognised AD biomarker, has been described to reflect early‐stage cortical amyloid‐β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P‐tau181 at the pre‐clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P‐tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted‐mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)‐Aβ load. In addition, the P‐tau181‐linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ− and CN Aβ+ individuals. Significant positive associations of medium‐ and long‐chain acylcarnitines (ACs) were observed with P‐tau181 in the entire cohort, CN Aβ− and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation‐mediated energy metabolism pathways. However, in CN Aβ−, additional linear associations of P‐tau181 were observed with muscle metabolism and nitric oxide homeostasis‐associated metabolites. Upon investigating the P‐tau181‐linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium‐ and long‐chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET‐Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET‐Aβ status in older adults. Therefore, plasma P‐tau181‐linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross‐sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by brain aggregation of β-amyloid (Aβ) peptides and phosphorylated tau (P-tau) proteins. Extracellular vesicles (EVs) can be isolated and studied for potential roles in disease. While several studies have tested plasma-derived EVs in AD, few have analyzed EVs from cerebrospinal fluid (CSF), which are potentially more closely related to brain changes. This study included 20 AD patients and 20 cognitively unimpaired (CU) participants. Using a novel EV isolation method based on acoustic trapping, we isolated and purified EVs from minimal CSF volumes. EVs were lysed and analyzed by immunoassays for P-tau217 and P-tau181. Isolation was confirmed through transmission electron microscopy and the presence of EV-specific markers (CD9, CD63, CD81, ATP1A3). Nanoparticle tracking analysis revealed a high variance in EV distribution. AD patients exhibited increased P-tau181 and decreased P-tau217 in EVs, leading to a higher EV P-tau181/P-tau217 ratio compared to CU. No significant differences in EV counts or sizes were observed between AD and CU groups. This study is the first to use acoustic trapping to isolate EVs from CSF and demonstrates differential P-tau content in AD-derived EVs, warranting further research to understand the relationship between these EV changes and brain pathology. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) leaks can lead to serious complications if left untreated, making rapid and accurate diagnosis essential. Biomarkers such as β2-transferrin (B2TRF) and β-trace protein are used to detect CSF leaks, but their limitations warrant the exploration of alternative markers. This study investigates the potential of phosphorylated tau at threonine 181 (p-tau181) as a biomarker for CSF leaks. Methods: Samples from 56 subjects were analyzed for B2TRF and p-tau181 using immunoaffinity blotting and chemiluminescent enzyme immunoassay, respectively. Data analysis included Mann–Whitney test to assess the overall difference in median p-tau181 concentrations between B2TRF positive and negative patients and a receiver operating characteristic (ROC) curve analysis to determine optimal p-tau181 cutoff values for predicting B2TRF positivity. Results: p-tau181 levels were significantly higher in B2TRF positive samples compared to negative samples (p < 0.001). ROC analysis showed high diagnostic performance for p-tau181, with an optimal cutoff of 13.22 pg/mL providing 92.0% sensitivity and 93.1% specificity. Excluding hemolyzed samples improved further the diagnostic performances, maintaining high sensitivity (90.9%) and achieving perfect specificity (100.0%). Conclusions: This study highlights the potential of p-tau181 as a valuable biomarker for the detection of CSF leaks due to its high diagnostic accuracy and practical advantages over the current biomarkers. The characteristics of p-tau181 assay being both quantitative and rapid, with high diagnostic accuracy, suggest that it could be a valuable tool for the detection of CSF leaks. Further research are now needed to validate these findings. [ABSTRACT FROM AUTHOR]

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 (Aβ) co‐pathology.N‐terminal p‐tau181 and p‐tau231 in Aβ‐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. [ABSTRACT FROM AUTHOR]

Objective To investigate the correlations of serum Aβ1-42, P-Tau181, and Hcy levels with sleep disorders in patients with Parkinson's disease (PD). Methods A total of 80 PD patients were divided into a normal sleep group (< 7 points) and a sleep disorder group (≥ 7 points) based on the evaluations with Pittsburgh Sleep Quality Index (PSQI). Univariate and multivariate logistic regression analyses were performed to investigate the correlations between the levels of serum Aβ1-42, P-Tau181, and Hcy levels and sleep disorders. Receiver operating characteristic (ROC) curves were used to analyze the efficacy parameters of different indicators in predicting sleep disorders in those patients. Results Univariate and multivariate logistic regression analyses showed that serum Aβ1-42 and Hcy were protective and independent risk factors for sleep disorders in the PD patients, respectively (P < 0.05). The predictive AUCs of serum Aβ1-42 and Hcy levels for sleep disorders in the PD patients were 0.757 (95% CI: 0.652 ~ 0.861) and 0.796 (95% CI: 0.688 ~ 0.905), respectively. Conclusion The levels of serum Aβ1-42 and Hcy in PD patients are closely related to sleep disorders. Therefore, they can be used as predictive factors for clinical diagnosis of PD with sleep disorders. [ABSTRACT FROM AUTHOR]

Abstract We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer’s Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1–40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP−) when they were A−, A+/T−/N−, or A+/T−/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP− patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn’s k = 0.50, p

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer's Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1–40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP−) when they were A−, A+/T−/N−, or A+/T−/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP− patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn's k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology. [ABSTRACT FROM AUTHOR]

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer's Coordinating Center's Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer's disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer's patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p‐tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non‐amnestic MCI/dementia), and Aβ‐PET in Hispanic and non‐Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three‐hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ‐PET. P‐tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ‐PET[+] and Aβ‐PET[‐] (AUC = 0.86). P‐tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p‐tau181 than non‐Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p‐tau181 informs etiological diagnosis of cognitively impaired Hispanic and non‐Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non‐Alzheimer's contributions to memory loss. Highlights: Alzheimer's biomarkers were measured in Hispanic and non‐Hispanic older adults.Plasma p‐tau181 related to amnestic cognitive decline and brain amyloid burden.AD biomarker associations did not differ between Hispanic and non‐Hispanic ethnicity.Hispanic individuals may be more likely to have non‐Alzheimer causes of memory loss. [ABSTRACT FROM AUTHOR]

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‐β (Aβ)42, and higher plasma p‐tau231/Aβ42 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. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Objectively-defined subtle cognitive decline (Obj-SCD) and plasma phosphorylated-tau181 (p-tau181) are promising early Alzheimers disease (AD) markers. However, associations between Obj-SCD and p-tau181, and their combined prognostic potential, are unknown. METHODS: Baseline and 4-year longitudinal p-tau181 changes were compared across cognitively unimpaired (CU; n = 402), Obj-SCD (n = 199), and mild cognitive impairment (MCI; n = 346) groups. CU and Obj-SCD participants were further classified as p-tau181-positive or negative. RESULTS: CU and Obj-SCD has lower baseline p-tau181 than MCI and did not differ from one another. Longitudinally, Obj-SCD had the steepest p-tau181 increase. Obj-SCD/p-tau181-positive participants had the fastest rates of amyloid accumulation, cognitive decline, and functional decline. CONCLUSIONS: Despite assumptions that cognitive changes invariably follow biomarker changes, early neuropsychological difficulties may emerge before/concurrently with plasma p-tau181 changes. Combining Obj-SCD and p-tau181, two potentially accessible early markers, was associated with the faster declines in AD-related outcomes.

Background: Elevated tau phosphorylation has been linked to the Apolipoprotein E (APOE) ɛ4 allele, which is considered one of the most significant genes related to Alzheimer's disease (AD). However, it is uncertain whether the impact of increased plasma tau phosphorylated at threonine 181 (p-tau181) on memory and executive function decline would be greater among APOEɛ4 carriers. Objective: To investigate the effects of plasma p-tau181 and APOEɛ4 on memory and executive function. Methods: The longitudinal analysis included 608 older adults without dementia (aged 72±7 years; 47% female; follow-up period of 1.59±1.47 years) from the ADNI dataset, including 180 individuals with normal cognition and 429 individuals with mild cognitive impairment. Linear mixed-effects models were utilized to assess the contributions of APOEɛ4 status and plasma p-tau181 to longitudinal changes in memory composite score and executive function composite score. Results: At baseline, the APOEɛ4+/Tau+ group exhibited poorer performance in memory composite score and executive function composite score, and an elevated load of cerebrospinal fluid Aβ and tau pathologies. To further understand longitudinal changes, we compared groups directly based on plasma p-tau181 and APOEɛ4 status (four groups: APOEɛ4–/Tau–, APOEɛ4–/Tau+, APOEɛ4+/Tau–, APOEɛ4+/Tau+). Both the memory composite score and executive function composite score showed a significantly greater decline in the APOEɛ4+/Tau+ group than in all other groups. Conclusions: Our findings indicate that there is an interaction between plasma p-tau181 levels and APOEɛ4 status, which contributes to the longitudinal changes of memory and executive function in older adults without dementia. [ABSTRACT FROM AUTHOR]

Introduction: This study aimed to determine the efficacy of combining plasma phosphorylated tau (p‐tau)181, amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts. Methods: Biomarkers were measured using a single‐molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE‐V). Results: In the Asan cohort, after adjusting for age and sex, p‐tau181 (AUC = 0.854) or APOE ε4 status (AUC = 0.769) distinguished Aβ status with high accuracy. Combining them or adding NfL and Aβ42/40 improved model fitness. The best‐fit model included the plasma p‐tau181, APOE ε4, NfL and Aβ42/40. The models established from the Asan cohort were tested in the KBASE‐V cohort. Additionally, in the KBASE‐V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC = 0.768) and mild cognitive impairment (MCI) (AUC = 0.997) participants. Conclusions: Plasma p‐tau181 showed a high performance in determining Aβ‐PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC. [ABSTRACT FROM AUTHOR]

Abstract 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 [Aβ]+ or Aβ $$-$$ - ). Both cohorts included detailed cognitive assessments and CSF biomarker measurements (clinically validated core AD biomarkers [Lumipulse CSF Aβ1–42/40 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 Aβ+ and dementia Aβ+ when compared with all other Aβ− 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.

Objective: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes. Methods: This pilot study comprised two independent cohorts. The first cohort--part of a Traumatic Head Injury Neuroimaging Classification (THINC) study--with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort--with a mean age of 19 years--comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay. Results: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05). Conclusion: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions. [ABSTRACT FROM AUTHOR]

Abstract Introduction This study aimed to determine the efficacy of combining plasma phosphorylated tau (p‐tau)181, amyloid beta (Aβ)42/Aβ40, neurofilament light (NfL), and apolipoprotein E (APOE) genotypes for detecting positive amyloid positron emission tomography (PET), which is little known in the Asian population, in two independent cohorts. Methods Biomarkers were measured using a single‐molecule array (Simoa) in a cohort study (Asan). All participants underwent amyloid PET. Significant changes in the area under the curve (AUC) and Akaike Information Criterion values were considered to determine the best model. The generalizability of this model was tested using another cohort (KBASE‐V). Results In the Asan cohort, after adjusting for age and sex, p‐tau181 (AUC = 0.854) or APOE ε4 status (AUC = 0.769) distinguished Aβ status with high accuracy. Combining them or adding NfL and Aβ42/40 improved model fitness. The best‐fit model included the plasma p‐tau181, APOE ε4, NfL and Aβ42/40. The models established from the Asan cohort were tested in the KBASE‐V cohort. Additionally, in the KBASE‐V cohort, these three biomarker models had similar AUC in cognitively unimpaired (AUC = 0.768) and mild cognitive impairment (MCI) (AUC = 0.997) participants. Conclusions Plasma p‐tau181 showed a high performance in determining Aβ‐PET positivity. Adding plasma NfL and APOE ε4 status improved the model fit without significant improvement in AUC.

We examined whether plasma p-tau181 and p-tau217 are specific biomarkers of pathologically confirmed Alzheimer's disease (AD). In particular, we investigated the utility of plasma p-tau for differentiating AD from primary age-related tauopathy (PART), as well as AD with mixed pathologies. Data came from 269 older adults who participated in the Religious Orders Study or the Rush Memory and Aging Project. Blood samples were collected during annual clinical evaluations. Participants died and underwent brain autopsy. P-tau181 and p-tau217 were quantified in the plasma samples proximate to death (average interval before death: 1.4 years) using Lilly-developed MSD immunoassays. Uniform neuropathologic evaluations assessed AD, PART, and other common degenerative and cerebrovascular conditions. Plasma p-tau217 was more strongly correlated with brain β-amyloid and paired helical filament tau (PHFtau) tangles than p-tau181. Both p-tau markers were associated with greater odds of AD, but p-tau217 had higher accuracy (area under the ROC curve (AUC): 0.83) than p-tau181 (AUC: 0.76). Plasma p-tau markers were almost exclusively associated with AD pathologic indices with the exception of cerebral amyloid angiopathy. Compared to p-tau181, p-tau217 showed a higher AUC (0.82 versus 0.74) in differentiating AD from PART. For either p-tau, we did not observe a level difference between individuals with AD alone and those with mixed AD pathologies. In summary, plasma p-tau181and p-tau217 were specifically associated with AD pathological changes. Further, our data provide initial evidence that p-tau217 may be able to differentiate between AD and PART in individuals with comparable burdens of tau tangle pathology. These results demonstrate the specificity of p-tau217 for AD, supporting its use to identify patients suitable for anti-AD therapies including β-amyloid immunotherapies. [ABSTRACT FROM AUTHOR]

ObjectiveThe aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes.MethodsThis pilot study comprised two independent cohorts. The first cohort—part of a Traumatic Head Injury Neuroimaging Classification (THINC) study—with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort—with a mean age of 19 years—comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay.ResultsConcentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690–0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT−/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT−/MRI−, n = 111) findings and UIC (P-values < 0.05).ConclusionThese findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay's performance as a possible early diagnostic biomarker for mTBI/concussions.

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 β-amyloid (Aβ) 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 Aβ 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 Aβ load. All plasma biomarkers correlated positively with Aβ 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 Aβ-related processes.

Objective: To investigate the relationship between serum uric acid(UA), interleukin-6(IL-6), phosphorylated Tau181(P-tau181) and cognitive function, daily living ability and prognosis in patients with Alzheimer’s disease(AD). Methods: From May 2018to January 2021,98 patients with AD(AD group) who were admitted to Ninth People’s Hospital, Shanghai Jiaotong University School of Medicine and Huangpu Branch of Ninth People’s Hospital,Shanghai Jiaotong University School of Medicine and 71 healthy volunteers for outpatient physical examination(control group) were selected, serum UA, IL-6 and P-tau181 levels were detected, and the cognitive function of patients was assessed with the Mini Mental State Examination(MMSE) and Montreal Cognitive Assessment Scale(MoCA),and the ability of daily living of patients was assessed with the Barthel index(BI). All patients were followed up for 1 year after discharge, and the adverse prognosis during the follow-up period was counted. Pearson correlation analysis showed the correlation between UA, IL-6, P-tau181 and MMSE, MoCA, BI. Multivariate Logistic regression analysis showed the risk factors of poor prognosis in patients with AD. Results: Serum UA level, MMSE, MoCA score and BI in the AD group were lower than those in the control group(P＜0.05), while IL-6 and P-tau181 levels were higher than those in control group(P＜0.05). Serum UA level in patients with AD was positively correlated with MMSE, MoCA score and BI(P＜0.05), while IL-6 and P-tau181 levels were negatively correlated with MMSE, MoCA score and BI(P＜0.05). Multivariate Logistic regression analysis showed that long-term bed rest, stage of AD dementia, high level of IL-6 and high level of P-tau181 were risk factors for poor prognosis of patients with AD(P＜0.05), and high level of UA was protective factor(P＜0.05). Conclusions: The serum UA level in patients with AD is decreased, and the IL-6 and P-tau181 levels are increased,which are related to cognitive dysfunction, decreased ability of daily living and poor prognosis. The detection of serum UA, IL-6 and P-tau181 can assist in evaluating the condition and prognosis of AD. [ABSTRACT FROM AUTHOR]

Background: Recent data support beta‐synuclein as a blood biomarker to study synaptic degeneration in Alzheimer's disease (AD). Methods: We provide a detailed comparison of serum beta‐synuclein immunoprecipitation – mass spectrometry (IP‐MS) with the established blood markers phosphorylated tau 181 (p‐tau181) (Simoa) and neurofilament light (NfL) (Ella) in the German FTLD consortium cohort (n = 374) and its relation to brain atrophy (magnetic resonance imaging) and cognitive scores. Results: Serum beta‐synuclein was increased in AD but not in frontotemporal lobar degeneration (FTLD) syndromes. Beta‐synuclein correlated with atrophy in temporal brain structures and was associated with cognitive impairment. Serum p‐tau181 showed the most specific changes in AD but the lowest correlation with structural alterations. NfL was elevated in all diseases and correlated with frontal and temporal brain atrophy. Discussion: Serum beta‐synuclein changes differ from those of NfL and p‐tau181 and are strongly related to AD, most likely reflecting temporal synaptic degeneration. Beta‐synuclein can complement the existing panel of blood markers, thereby providing information on synaptic alterations. Highlights: Blood beta‐synuclein is increased in Alzheimer's disease (AD) but not in frontotemporal lobar degeneration (FTLD) syndromes.Blood beta‐synuclein correlates with temporal brain atrophy in AD.Blood beta‐synuclein correlates with cognitive impairment in AD.The pattern of blood beta‐synuclein changes in the investigated diseases is different to phosphorylated tau 181 (p‐tau181) and neurofilament light (NfL). [ABSTRACT FROM AUTHOR]

Introduction: Plasma amyloid beta (Aβ)1‐42/Aβ1‐40 ratio, phosphorylated‐tau181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) are putative blood biomarkers for Alzheimer's disease (AD). However, head‐to‐head cross‐sectional and longitudinal comparisons of the aforementioned biomarkers across the AD continuum are lacking. Methods: Plasma Aβ1‐42, Aβ1‐40, p‐tau181, GFAP, and NfL were measured utilizing the Single Molecule Array (Simoa) platform and compared cross‐sectionally across the AD continuum, wherein Aβ‐PET (positron emission tomography)–negative cognitively unimpaired (CU Aβ−, n = 81) and mild cognitive impairment (MCI Aβ−, n = 26) participants were compared with Aβ‐PET–positive participants across the AD continuum (CU Aβ+, n = 39; MCI Aβ+, n = 33; AD Aβ+, n = 46) from the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (AIBL) cohort. Longitudinal plasma biomarker changes were also assessed in MCI (n = 27) and AD (n = 29) participants compared with CU (n = 120) participants. In addition, associations between baseline plasma biomarker levels and prospective cognitive decline and Aβ‐PET load were assessed over a 7 to 10‐year duration. Results: Lower plasma Aβ1‐42/Aβ1‐40 ratio and elevated p‐tau181 and GFAP were observed in CU Aβ+, MCI Aβ+, and AD Aβ+, whereas elevated plasma NfL was observed in MCI Aβ+ and AD Aβ+, compared with CU Aβ− and MCI Aβ−. Among the aforementioned plasma biomarkers, for models with and without AD risk factors (age, sex, and apolipoprotein E (APOE) ε4 carrier status), p‐tau181 performed equivalent to or better than other biomarkers in predicting a brain Aβ−/+ status across the AD continuum. However, for models with and without the AD risk factors, a biomarker panel of Aβ1‐42/Aβ1‐40, p‐tau181, and GFAP performed equivalent to or better than any of the biomarkers alone in predicting brain Aβ−/+ status across the AD continuum. Longitudinally, plasma Aβ1‐42/Aβ1‐40, p‐tau181, and GFAP were altered in MCI compared with CU, and plasma GFAP and NfL were altered in AD compared with CU. In addition, lower plasma Aβ1‐42/Aβ1‐40 and higher p‐tau181, GFAP, and NfL were associated with prospective cognitive decline and lower plasma Aβ1‐42/Aβ1‐40, and higher p‐tau181 and GFAP were associated with increased Aβ‐PET load prospectively. Discussion: These findings suggest that plasma biomarkers are altered cross‐sectionally and longitudinally, along the AD continuum, and are prospectively associated with cognitive decline and brain Aβ‐PET load. In addition, although p‐tau181 performed equivalent to or better than other biomarkers in predicting an Aβ−/+ status across the AD continuum, a panel of biomarkers may have superior Aβ−/+ status predictive capability across the AD continuum. HIGHLIGHTS: Area under the curve (AUC) of p‐tau181 ≥ AUC of Aβ42/40, GFAP, NfL in predicting PET Aβ−/+ status (Aβ−/+). AUC of Aβ42/40+p‐tau181+GFAP panel ≥ AUC of Aβ42/40/p‐tau181/GFAP/NfL for Aβ−/+. Longitudinally, Aβ42/40, p‐tau181, and GFAP were altered in MCI versus CU. Longitudinally, GFAP and NfL were altered in AD versus CU. Aβ42/40, p‐tau181, GFAP, and NfL are associated with prospective cognitive decline. Aβ42/40, p‐tau181, and GFAP are associated with increased PET Aβ load prospectively. [ABSTRACT FROM AUTHOR]

Background: Plasma phosphorylated‐tau181 (p‐tau181) represents a novel bloodbased biomarker of Alzheimer's disease pathology. We explored clinicians' experience of the utility of plasma p‐tau181 in Camden and Islington Memory Services. Methods: Patients were identified by their clinician as appropriate for p‐tau181. Their p‐tau181 result was plotted on a reference range graph provided to clinicians. This was discussed with the patient at diagnostic feedback appointment. Results: Twenty‐nine participants' plasma p‐tau181 samples were included (mean age 74 SD 8.5, 65% female). Nine clinicians participated in the study. Eighty‐six percent of clinicians found the p‐tau181 result to be helpful and in 93% of cases it was clearly understandable. The p‐tau181 result was useful in making the diagnosis in 44% of cases. Conclusions: Plasma p‐tau181 is a feasible test for use in memory services and acceptable to clinicians. Clinician feedback on utility in dementia diagnoses was mixed. Further work is required to provide education and training in understanding and interpreting ambiguity in biomarker results. [ABSTRACT FROM AUTHOR]

New diagnostic methods have been developed for the early diagnosis of Alzheimer’s disease (AD) with the primary purpose of intercepting the transition-phase (mild cognitive impairment, MCI) between normal aging and dementia. We aimed to explore whether the five-word test (FWT) and the mini-mental state examination (MMSE) are predictive for the early diagnosis of MCI due to AD (AD-MCI). We computed ROC analyses to evaluate the sensitivity and specificity of MMSE and FWT in predicting abnormal CSF (t-Tau, p-Tau181, Aβ1–42) and amyloid-PET biomarkers. AD-MCI patients showed lower MMSE and FWT scores (all p < 0.001) than non-AD-MCI. The best predictor of amyloid plaques’ presence at amyloid-PET imaging was the encoding sub-score of the FWT (AUC = 0.84). Both FWT and MMSE had low/moderate accuracy for the detection of pathological CSF Aβ42, t-Tau and p-Tau181 values, with higher accuracy for the t-Tau/Aβ1–42 ratio. In conclusion, the FWT, as a single-domain cognitive screening test, seems to be prompt and moderately accurate tool for the identification of an underlying AD neuropathological process in patients with MCI, supporting the importance of associating biomarkers evaluation in the work-up of patients with dementing neurodegenerative disorders.

Background: The diagnostic and prognostic performance of the novel fluid biomarkers brain-derived tau (BD-tau) and phospho-tau217 (p-tau217) in Creutzfeldt-Jakob disease (CJD) is not defined., Methods: We measured cerebrospinal fluid (CSF) and plasma BD-tau, p-tau217, p-tau181, total tau (t-tau), neurofilament light (NfL), and 14-3-3 in 100 CJD patients, 100 with non-prion rapidly progressive dementia (np-RPD), 92 with mild cognitive impairment due to Alzheimer's disease (AD-MCI), and 55 healthy controls (HC)., Results: Plasma BD-tau performed comparably to plasma t-tau but had lower performance than CSF t-tau (p < 0.001) and 14-3-3 (p = 0.014) in CJD versus np-RPD differential diagnosis. Plasma BD-tau diagnostic accuracy increased when ratioed to plasma p-tau217, matching CSF 14-3-3. Plasma BD-tau levels were associated with survival (p < 0.001), outperforming t-tau and NfL., Discussion: Plasma BD-tau is a valuable marker for CJD prognostication. In the clinical setting, the plasma BD-tau/p-tau217 ratio provides an accurate, fast marker supporting the clinical diagnosis of CJD., Highlights: The increase of plasma BD-tau levels parallels that of CSF t-tau in CJD. CSF p-tau217 levels are significantly increased in CJD, reflecting a prion-specific secondary tauopathy. Plasma p-tau217 shows a distinct profile than CSF p-tau217 in CJD. Plasma BD-tau/p-tau217 ratio is as accurate as CSF 14-3-3 in distinguishing CJD from np-RPDs, including AD. BD-tau represents a valuable blood-based biomarker for CJD prognostication., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Abstract 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

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with dementia and is a serious concern for the health of individuals and government health care systems worldwide. Gray matter atrophy and white matter damage are major contributors to cognitive deficits in AD patients, as demonstrated by magnetic resonance imaging (MRI). Many of these brain changes associated with AD begin to occur about 15 years before the onset of initial clinical symptoms. Therefore, it is critical to find biomarkers reflective of these brain changes associated with AD to identify this disease and monitor its prognosis and development. The increased plasma level of hyperphosphorylated tau 181 (p-tau181) has been recently considered a novel biomarker for the diagnosis of AD, preclinical AD, and mild cognitive impairment (MCI). In the current study, we examined the association of cerebrospinal fluid (CSF) and plasma levels of p-tau181 with structural brain changes in cortical thickness, cortical volume, surface area, and subcortical volume in MCI patients. In this cross-sectional study, we included the information of 461 MCI patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The results of voxel-wise partial correlation analyses showed a significant negative correlation between the increased levels of plasma p-tau181, CSF total tau, and CSF p-tau181 with structural changes in widespread brain regions. These results provide evidence for the use of plasma p-tau181 as a diagnostic marker for structural changes in the brain associated with the early stages of AD and neurodegeneration. [ABSTRACT FROM AUTHOR]

Purpose: Biomarkers used for predicting longitudinal cognitive change in Alzheimer's disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Patients and Methods: A total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer's Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline. Results: Baseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline. Conclusion: Our study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction. [ABSTRACT FROM AUTHOR]

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 (Aβ−) or presence (Aβ+) of brain amyloidosis. Results: Plasma GFAP, t‐tau, p‐tau181, and p‐tau231 concentrations were higher in Aβ+ CU compared with Aβ− CU cross‐sectionally. GFAP had the highest effect size and area under the curve (AUC) in differentiating between Aβ+ and Aβ− 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 Aβ+ CU and increased NFL in Aβ− 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. [ABSTRACT FROM AUTHOR]

New diagnostic methods have been developed for the early diagnosis of Alzheimer's disease (AD) with the primary purpose of intercepting the transition-phase (mild cognitive impairment, MCI) between normal aging and dementia. We aimed to explore whether the five-word test (FWT) and the mini-mental state examination (MMSE) are predictive for the early diagnosis of MCI due to AD (AD-MCI). We computed ROC analyses to evaluate the sensitivity and specificity of MMSE and FWT in predicting abnormal CSF (t-Tau, p-Tau181, Aβ1–42) and amyloid-PET biomarkers. AD-MCI patients showed lower MMSE and FWT scores (all p < 0.001) than non-AD-MCI. The best predictor of amyloid plaques' presence at amyloid-PET imaging was the encoding sub-score of the FWT (AUC = 0.84). Both FWT and MMSE had low/moderate accuracy for the detection of pathological CSF Aβ42, t-Tau and p-Tau181 values, with higher accuracy for the t-Tau/Aβ1–42 ratio. In conclusion, the FWT, as a single-domain cognitive screening test, seems to be prompt and moderately accurate tool for the identification of an underlying AD neuropathological process in patients with MCI, supporting the importance of associating biomarkers evaluation in the work-up of patients with dementing neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Abstract Background To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer’s disease (AD) pathology and predict clinical progression in a memory clinic setting. Methods Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression. Results Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1–42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1–42, and Aβ1–42/Aβ1–40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants. Conclusion Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment.

PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer’s disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort.Patients and MethodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer’s Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.

Introduction: Post-stroke cognitive impairment (PSCI) cannot be neglected because it drastically influences the daily life of patients and their families. However, there are no studies exploring the association between preclinical blood biomarkers of neurodegeneration including plasma amyloid-β (Aβ), tau, and brain-derived neurotrophic factor (BDNF) together with the risk of PSCI. This longitudinal study was to investigate whether these blood biomarkers with imaging markers of cerebral small vessel disease can improve the prediction for PSCI. In addition, we also explored the association between blood biomarkers with the trajectories of PSCI. Methods: Adult patients with first-ever acute ischemic stroke were recruited, and the cognitive and functional abilities of these patients were evaluated. Furthermore, blood biomarkers of neurodegeneration including plasma Aβ-40, Aβ-42, total tau, phosphorylated tau 181 (p-tau181), and BDNF levels and image markers of cerebral small vessel disease were measured. Each patient was followed up at 3 and 12 months at the outpatient department. Results: Of 136 patients, 40 and 50 patients developed PSCI at 3 and 12 months after stroke, respectively. In functional trajectories, 27 patients did not have PSCI at 3 months but did at 12 months. By contrast, the PSCI status of 17 patients at 3 months was reversed at 12 months. Patients with high-acute plasma p-tau181 had a significantly lower PSCI risk at 3 months (odds ratio [OR] = 0.62, 95% CI = 0.40–0.94, p = 0.0243) and 12 months (OR = 0.69, 95% CI = 0.47–0.99, p = 0.0443) after adjustment for covariates and image biomarkers. Discrimination and reclassification statistics indicated that the p-tau181 level can improve discrimination ability for PSCI at 3 and 12 months, respectively. In addition, the plasma p-tau181 level was the highest in subjects without PSCI followed by those with delayed-onset PSCI and early-onset PSCI with reversal, whereas the lowest plasma p-tau181 level was found among those with persistent PSCI, showing a significant trend test (p = 0.0081). Conclusion: Plasma p-tau181 is a potential biomarker for predicting early- and delayed-onset PSCI. Future studies should incorporate plasma p-tau181 as an indicator for timely cognitive intervention in the follow-up of patients with stroke. [ABSTRACT FROM AUTHOR]

Alzheimer's Disease (AD) is characterized by cognitive impairments that hinder daily activities and lead to personal and behavioral problems. Plasma hyperphosphorylated tau protein at threonine 181 (p-tau181) has recently emerged as a new sensitive tool for the diagnosis of AD patients. We herein investigated the association of plasma P-tau181 and white matter (WM) microstructural changes in AD. We obtained data from a large prospective cohort of elderly individuals participating in the Alzheimer's Disease Neuroimaging Initiative (ADNI), which included baseline measurements of plasma P-tau181 and imaging findings. A subset of 41 patients with AD, 119 patients with mild cognitive impairments (MCI), and 43 healthy controls (HC) was included in the study, all of whom had baseline blood P-tau181 levels and had also undergone Diffusion Tensor Imaging. The analysis revealed that the plasma level of P-tau181 has a positive correlation with changes in Mean Diffusivity (MD), Radial Diffusivity (RD), and Axial Diffusivity (AxD), but a negative with Fractional Anisotropy (FA) parameters in WM regions of all participants. There is also a significant association between WM microstructural changes in different regions and P-tau181 plasma measurements within each MCI, HC, and AD group. In conclusion, our findings clarified that plasma P-tau181 levels are associated with changes in WM integrity in AD. P-tau181 could improve the accuracy of diagnostic procedures and support the application of blood-based biomarkers to diagnose WM neurodegeneration. Longitudinal clinical studies are also needed to demonstrate the efficacy of the P-tau181 biomarker and predict its role in structural changes. [ABSTRACT FROM AUTHOR]

IntroductionPost-stroke cognitive impairment (PSCI) cannot be neglected because it drastically influences the daily life of patients and their families. However, there are no studies exploring the association between preclinical blood biomarkers of neurodegeneration including plasma amyloid-β (Aβ), tau, and brain-derived neurotrophic factor (BDNF) together with the risk of PSCI. This longitudinal study was to investigate whether these blood biomarkers with imaging markers of cerebral small vessel disease can improve the prediction for PSCI. In addition, we also explored the association between blood biomarkers with the trajectories of PSCI.MethodsAdult patients with first-ever acute ischemic stroke were recruited, and the cognitive and functional abilities of these patients were evaluated. Furthermore, blood biomarkers of neurodegeneration including plasma Aβ-40, Aβ-42, total tau, phosphorylated tau 181 (p-tau181), and BDNF levels and image markers of cerebral small vessel disease were measured. Each patient was followed up at 3 and 12 months at the outpatient department.ResultsOf 136 patients, 40 and 50 patients developed PSCI at 3 and 12 months after stroke, respectively. In functional trajectories, 27 patients did not have PSCI at 3 months but did at 12 months. By contrast, the PSCI status of 17 patients at 3 months was reversed at 12 months. Patients with high-acute plasma p-tau181 had a significantly lower PSCI risk at 3 months (odds ratio [OR] = 0.62, 95% CI = 0.40–0.94, p = 0.0243) and 12 months (OR = 0.69, 95% CI = 0.47–0.99, p = 0.0443) after adjustment for covariates and image biomarkers. Discrimination and reclassification statistics indicated that the p-tau181 level can improve discrimination ability for PSCI at 3 and 12 months, respectively. In addition, the plasma p-tau181 level was the highest in subjects without PSCI followed by those with delayed-onset PSCI and early-onset PSCI with reversal, whereas the lowest plasma p-tau181 level was found among those with persistent PSCI, showing a significant trend test (p = 0.0081).ConclusionPlasma p-tau181 is a potential biomarker for predicting early- and delayed-onset PSCI. Future studies should incorporate plasma p-tau181 as an indicator for timely cognitive intervention in the follow-up of patients with stroke.

Background: Plasma biomarker assays provide an opportunity to reassess whether Alzheimer's disease, Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB) plasma biomarkers are diagnostically useful., Objective: We hypothesized that immunomagnetic reduction (IMR) of plasma biomarkers could differentiate between patients with PDD and DLB and healthy patients when combined with established clinical testing measures., Methods: Plasma samples from 61 participants (12 PDD, 12 DLB, 37 controls) were analyzed using IMR to quantify amyloid-β 42 (Aβ 42 ), total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and α-synuclein (α-syn). Receiver operating characteristic curve (ROC) analysis was used to obtain sensitivity, specificity, and area under the ROC curve. Biomarker results were combined with clinical measures from the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment, and Hoehn-Yahr stage to optimize diagnostic test performance., Results: Participants with PDD had higher α-syn than those with DLB and healthy participants and were distinguishable by their biomarker products Aβ 42 ×p-tau181 and Aβ 42 ×α-syn. Patients with DLB had higher p-tau181 than those with PDD and healthy participants and were distinguishable by their concentrations of α-syn×p-tau181. Plasma α-syn plus UPDRS versus either test alone increased sensitivity, specificity, and AUC when healthy patients were compared with those with PDD and DLB. Combined clinical examination scores and plasma biomarker products demonstrated utility in differentiating PDD from DLB when p-tau181 was combined with UPDRS, α-syn was combined with UPDRS, and α-syn×p-tau181 was combined with UPDRS., Conclusions: In this pilot study, IMR plasma p-tau181 and α-syn may discriminate between PDD and DLB when used in conjunction with clinical testing., Competing Interests: Dr. Malaty declares no conflict of interest at the time this publication was written. Dr. Decourt declares no conflict of interest at the time this publication was written. Dr. Shill received research support from NIH, the Michael J. Fox Foundation for Parkinson’s Research, Transposon Therapeutics, Inc, Saccadous, Inc, the National Institute of Neurological Disorders and Stroke at NIH, Jazz Pharmaceuticals, Inc, Supernus Pharmaceuticals, Inc, The Parkinson’s Foundation, and Barrow Neurological Foundation, and also received consulting honoraria from AbbVie, Inc, and the Tremor Research Group. Dr. Sabbagh discloses ownership interest (stock or stock options) in uMETHOD, Athira Pharma, Inc, CervoMed, Inc, and Lighthouse Pharmaceuticals, Inc; consulting for Alzheon, Inc, Genentech (Roche Group), Prothena Corp, plc, Eisai Co, Ltd, Eli Lilly and Co, Cognito Therapeutics, Inc, and Anavex Life Sciences Corp. Dr. Sabbagh is an Editorial Board member of this journal, but was not involved in the peer-review process of this article nor had access to any information regarding its peer review. An overview of key findings from this study was previously presented in a poster titled “Assessment of Plasma Biomarkers by ImmunoMagnetic Reduction in Parkinson’s Disease Dementia and Dementia with Lewy Bodies” (P10.008) at the American Academy of Neurology meeting held on April 25-26, 2023, in Boston, MA., (© 2024 – The authors. Published by IOS Press.)

Objectives: We examine the clinical utility of plasma-based detection for Alzheimer's disease (AD) pathophysiology in older adults with mild cognitive impairment (MCI) and whether cognitive screening can inform when to use plasma-based AD tests., Methods: Seventy-four community-dwelling older adults with MCI had testing with plasma phosphorylated tau (p-tau) 217 and 181, positron emission tomography (PET) imaging for amyloid beta (Aβ), and cognitive assessment. Receiver operating characteristic (ROC) analysis was used to assess the diagnostic value of plasma p-tau., Results: Plasma p-tau217 distinguished MCI participants who had PET imaging evidence of Aβ accumulation from those without (AUC of 0.92, specificity of 0.96, and sensitivity of 0.90), outperforming plasma p-tau181 (AUC of 0.76, specificity of 0.87 and sensitivity of 0.59) for the same purpose. Of the 60 MCI participants that were amnestic, 22 were Aβ+. The 14 participants that were nonamnestic were all Aβ-., Conclusions: Our findings support the clinical use of plasma p-tau, particularly p-tau217, for patient detection of AD pathophysiology in older adults with amnestic MCI, but not in those who are nonamnestic., Competing Interests: DISCLOSURE In the past 5 years, Dr. Lopez was a consultant for Novo Nordisk, Lundbeck, Eisai, Grifols, and Biogen. All other authors report no conflicts with any product mentioned or concept discussed in this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Plasma biomarkers for Alzheimer's disease (AD) have broad potential as screening tools in primary care and disease-modifying trials. Detecting elevated amyloid-β (Aβ) pathology to support trial recruitment or initiating Aβ-targeting treatments would be of critical value. In this study, we aimed to examine the robustness of plasma biomarkers to detect elevated Aβ pathology at different stages of the AD continuum. Beyond determining the best biomarker—or biomarker combination—for detecting this outcome, we also simulated increases in inter-assay coefficient of variability (CV) to account for external factors not considered by intra-assay variability. With this, we aimed to determine whether plasma biomarkers would maintain their accuracy if applied in a setting which anticipates higher variability (i.e., clinical routine). Methods: We included 118 participants (cognitively unimpaired [CU, n = 50], cognitively impaired [CI, n = 68]) from the ADNI study with a full plasma biomarker profile (Aβ42/40, GFAP, p-tau181, NfL) and matched amyloid imaging. Initially, we investigated how simulated CV variations impacted single-biomarker discriminative performance of amyloid status. Then, we evaluated the predictive performance of models containing different biomarker combinations, based both on original and simulated measurements. Plasma Aβ42/40 was represented by both immunoprecipitation mass spectrometry (IP-MS) and single molecule array (Simoa) methods in separate analyses. Model selection was based on a decision tree which incorporated Akaike information criterion value, likelihood ratio tests between the best-fitting models and, finally, and Schwartz's Bayesian information criterion. Results: Increasing variation greatly impacted the performance of plasma Aβ42/40 in discriminating Aβ status. In contrast, the performance of plasma GFAP and p-tau181 remained stable with variations >20%. When biomarker models were compared, the models "AG" (Aβ42/40 + GFAP; AUC = 86.5), "A" (Aβ42/40; AUC = 82.3), and "AGP" (Aβ42/40 + GFAP + p-tau181; AUC = 93.5) were superior in determining Aβ burden in all participants, within-CU, and within-CI groups, respectively. In the robustness analyses, when repeating model selection based on simulated measurements, models including IP-MS Aβ42/40 were also most often selected. Simoa Aβ42/40 did not contribute to any selected model when used as an immunoanalytical alternative to IP-MS Aβ42/40. Conclusions: Plasma Aβ42/40, as quantified by IP-MS, shows high performance in determining Aβ positivity at all stages of the AD continuum, with GFAP and p-tau181 further contributing at CI stage. However, between-assay variations greatly impacted the performance of Aβ42/40 but not that of GFAP and p-tau181. Therefore, when dealing with between-assay CVs that exceed 5%, plasma GFAP and p-tau181 should be considered for a more robust determination of Aβ burden in CU and CI participants, respectively. [ABSTRACT FROM AUTHOR]

Background: The Apolipoprotein E (APOE) ɛ4 allele has been linked to increased tau phosphorylation and tangle formation. APOE ɛ4 carriers with elevated tau might be at the higher risk for Alzheimer's disease (AD) progression. Previous studies showed that tau pathology begins early in areas of the medial temporal lobe. Similarly, APOE ɛ4 carriers showed altered hippocampal functional integrity. However, it remains unknown whether the influence of elevated tau accumulation on hippocampal functional changes would be more pronounced for APOE ɛ4 carriers.Objective: We related ɛ4 carriage to levels of plasma phosphorylated tau (p-tau181) up to 15 years prior to AD onset. Furthermore, elevated p-tau181 was explored in relation to longitudinal changes in hippocampal function and connectivity.Methods: Plasma p-tau181 was analyzed in 142 clinically defined AD cases and 126 matched controls. The longitudinal analysis involved 87 non-demented individuals (from population-based study) with two waves of plasma samples and three waves of functional magnetic resonance imaging during rest and memory encoding.Results: Increased p-tau181 was observed for both ɛ4 carriers and non-carriers close to AD onset, but exclusively for ɛ4 carriers in the early preclinical groups (7- and 13-years pre-AD). In ɛ4 carriers, longitudinal p-tau181 increase was paralleled by elevated local hippocampal connectivity at rest and subsequent reduction of hippocampus encoding-related activity.Conclusion: Our findings support an association of APOE ɛ4 and p-tau181 with preclinical AD and hippocampus functioning. [ABSTRACT FROM AUTHOR]

Objectives: To assess plasma phosphorylated tau181 (p‐tau181) levels in Alzheimer's disease (AD), cognitively impaired non‐AD participants (CI non‐AD) and Control participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset that could potentially act as reference data for clinic diagnoses of AD. Methods: Data from 1558 participants (649 AD participants, 445 CI non‐AD participants and 464 controls) were examined, comparing p‐tau181 levels between Controls, AD and other dementias, stratified by age. Results: There were significant differences in plasma p‐tau181 values between Controls and those with AD at all ages up to 85 years. There were also significant differences between AD and CI non‐AD participants up to the age of 85 years. Conclusions: Plasma P‐tau181 may be a useful tool in the diagnosis of AD in those clinical settings where biomarkers have traditionally been less used. P‐tau181 may be less useful as an aid to diagnosis in the very oldest‐old. Further work is needed to establish the feasibility and utility of this biomarker within dementia diagnosis services not led by Neurologists, such as UK National Health Service Memory Services. Key points: In the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset there were significant differences in plasma p‐tau181 between controls and those with Alzheimer's disease (AD) across all included age ranges, although there was overlap in 95% confidence intervals in the highest age ranges.There were significant differences in plasma p‐tau181 between AD participants and cognitively impaired participants without AD pathology.P‐tau181 may be a useful tool to aid clinicians in the diagnosis of AD in situations where AD biomarkers have not been traditionally used. [ABSTRACT FROM AUTHOR]

Introduction: Blood‐based Alzheimer's disease (AD) biomarkers show promise, but pre‐analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [Aβ]42${\rm{A\beta }}]{_{42}}$, Aβ40${\rm{A}}{{{\beta}}_{40}}$, phosphorylatedtau[p−tau181${\rm{phosphorylated\;tau\;[p - ta}}{{\rm{u}}_{181}}$, total tau [t‐tau], neurofilament light chain [NfL], Aβ4240,${\rm{A}}{{{\beta}}_{\frac{{42}}{{40}}}},$ and p−tau181Aβ42$\frac{{{\rm{p - ta}}{{\rm{u}}_{181}}}}{{{\rm{A}}{{{\beta}}_{42}}}}$) in three collection tube types (ethylenediaminetetraacetic acid [EDTA] plasma, heparin plasma, serum). Methods: Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography‐positive and ‐negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis. Results: Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL (R2${{\rm{R}}^2}\;$= 0.94), adequate for amyloid (R2${{\rm{R}}^2}\;$= 0.40‐0.69), and weaker for t‐tau (R2${{\rm{R}}^2}\;$= 0.04‐0.42) and p−tau181${\rm{p - ta}}{{\rm{u}}_{181}}$ (R2${{\rm{R}}^2}\;$= 0.22‐0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTau181Aβ42$\frac{{{\rm{pTa}}{{\rm{u}}_{181}}}}{{{\rm{A}}{\beta _{42}}}}$ (d$d\;$= 1.29). Discussion: AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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-β 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-β 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-β PET standardized uptake value ratio, was shown to be earlier than standard thresholds of amyloid-β PET positivity and the increase of plasma p-tau181. Furthermore, plasma p-tau231 was significantly increased in amyloid-β 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-β deposition, prior to the threshold for amyloid-β 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-β positivity or apparent entorhinal tau deposition. [ABSTRACT FROM AUTHOR]

Background: To assess the performance of plasma neurofilament light (NfL) and phosphorylated tau 181 (p-tau181) to inform about cerebral Alzheimer's disease (AD) pathology and predict clinical progression in a memory clinic setting. Methods: Plasma NfL and p-tau181, along with established cerebrospinal fluid (CSF) biomarkers of AD pathology, were measured in participants with normal cognition (CN) and memory clinic patients with cognitive impairment (mild cognitive impairment and dementia, CI). Clinical and neuropsychological assessments were performed at inclusion and follow-up visits at 18 and 36 months. Multivariate analysis assessed associations of plasma NfL and p-tau181 levels with AD, single CSF biomarkers, hippocampal volume, and clinical measures of disease progression. Results: Plasma NfL levels were higher in CN participants with an AD CSF profile (defined by a CSF p-tau181/Aβ1–42 > 0.0779) as compared with CN non-AD, while p-tau181 plasma levels were higher in CI patients with AD. Plasma NfL levels correlated with CSF tau and p-tau181 in CN, and with CSF tau in CI patients. Plasma p-tau181 correlated with CSF p-tau181 in CN and with CSF tau, p-tau181, Aβ1–42, and Aβ1–42/Aβ1–40 in CI participants. Compared with a reference model, adding plasma p-tau181 improved the prediction of AD in CI patients while adding NfL did not. Adding p-tau181, but not NfL levels, to a reference model improved prediction of cognitive decline in CI participants. Conclusion: Plasma NfL indicates neurodegeneration while plasma p-tau181 levels can serve as a biomarker of cerebral AD pathology and cognitive decline. Their predictive performance depends on the presence of cognitive impairment. [ABSTRACT FROM AUTHOR]

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 (Aβ) co-pathology. N-terminal p-tau181 and p-tau231 in Aβ-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., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)