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Introduction: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes., Methods: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes., Results: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes., Discussion: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes., Highlights: Plasma p-tau217 measures most accurately classified amyloid and tau status. Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status. Plasma p-tau217 measures had higher correlations with cortical thickness than NfL. Correlations of plasma biomarkers with dementia symptoms were relatively low., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Objective: We compared the accuracy of amyloid and [ 18 F]Flortaucipir (FTP) tau positron emission tomography (PET) visual reads for distinguishing patients with mild cognitive impairment (MCI) or dementia with fluid biomarker support of Alzheimer's disease (AD)., Methods: Participants with FTP-PET, amyloid-PET, and diagnosis of dementia-AD (n = 102), MCI-AD (n = 41), non-AD diseases (n = 76), and controls (n = 20) were included. AD status was determined independent of PET by cerebrospinal fluid or plasma biomarkers. The mean age was 66.9 years, and 44.8% were women. Three readers interpreted scans blindly and independently. Amyloid-PET was classified as positive/negative using tracer-specific criteria. FTP-PET was classified as positive with medial temporal lobe (MTL) binding as the minimum uptake indicating AD tau (tau-MTL+), positive with posterolateral temporal or extratemporal cortical binding in an AD-like pattern (tau-CTX+), or negative. The majority of scan interpretations were used to calculate diagnostic accuracy of visual reads in detecting MCI/dementia with fluid biomarker support for AD (MCI/dementia-AD)., Results: Sensitivity of amyloid-PET for MCI/dementia-AD was 95.8% (95% confidence interval 91.1-98.4%), which was comparable to tau-CTX+ 92.3% (86.7-96.1%, p = 0.67) and tau-MTL+ 97.2% (93.0-99.2%, p = 0.27). Specificity of amyloid-PET for biomarker-negative healthy and disease controls was 84.4% (75.5-91.0%), which was like tau-CTX+ 88.5% (80.4-94.1%, p = 0.34), and trended toward being higher than tau-MTL+ 75.0% (65.1-83.3%, p = 0.08). Tau-CTX+ had higher specificity than tau-MTL+ (p = 0.0002), but sensitivity was lower (p = 0.02), driven by decreased sensitivity for MCI-AD (80.5% [65.1-91.2] vs. 95.1% [83.5-99.4], p = 0.03)., Interpretation: Amyloid- and tau-PET visual reads have similar sensitivity/specificity for detecting AD in cognitively impaired patients. Visual tau-PET interpretations requiring cortical binding outside MTL increase specificity, but lower sensitivity for MCI-AD. ANN NEUROL 2024;96:476-487., (© 2024 American Neurological Association.)

Introduction: Direct comparisons of the main blood phosphorylated tau immunoassays in memory clinic populations are needed to understand possible differences., Methods: In the BIODEGMAR study, 197 participants presenting with cognitive complaints were classified into an Alzheimer's disease (AD) or a non-AD cerebrospinal fluid (CSF) profile group, according to their amyloid beta 42/ phosphorylated tau (Aβ42/p-tau) ratio. We performed a head-to-head comparison of nine plasma and nine CSF tau immunoassays and determined their accuracy to discriminate abnormal CSF Aβ42/p-tau ratio., Results: All studied plasma tau biomarkers were significantly higher in the AD CSF profile group compared to the non-AD CSF profile group and significantly discriminated abnormal CSF Aβ42/p-tau ratio. For plasma p-tau biomarkers, the higher discrimination accuracy was shown by Janssen p-tau217 (r = 0.76; area under the curve [AUC] = 0.96), ADx p-tau181 (r = 0.73; AUC = 0.94), and Lilly p-tau217 (r = 0.73; AUC = 0.94)., Discussion: Several plasma p-tau biomarkers can be used in a specialized memory clinic as a stand-alone biomarker to detect biologically-defined AD., Highlights: Patients with an Alzheimer's disease cerebrospinal fluid (AD CSF) profile have higher plasma phosphorylated tau (p-tau) levels than the non-AD CSF profile group. All plasma p-tau biomarkers significantly discriminate patients with an AD CSF profile from the non-AD CSF profile group. Janssen p-tau217, ADx p-tau181, and Lilly p-tau217 in plasma show the highest accuracy to detect biologically defined AD. Janssen p-tau217, ADx p-tau181, Lilly p-tau217, Lilly p-tau181, and UGot p-tau231 in plasma show performances that are comparable to their CSF counterparts., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited., Objective: To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity., Design, Setting, and Participants: In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023., Main Outcomes and Measures: Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests., Exposures: Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index., Results: This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD., Conclusions and Relevance: In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Introduction: The prognostic utility of cerebrospinal fluid (CSF) phosphorylated tau 217 (p-tau217) and p-tau181 is not understood., Methods: Analyses included 753 Mayo Clinic Study on Aging participants (median age = 71.6; 57% male). CSF amyloid beta (Aβ)42 and p-tau181 were measured with Elecsys immunoassays. CSF p-tau181 and p-tau217 were also measured with Meso Scale Discovery (MSD). We used Cox proportional hazards models for risk of mild cognitive impairment (MCI) and linear mixed models for risk of global and domain-specific cognitive decline and cortical thickness. Analyses were stratified by elevated brain amyloid based on CSF Aβ42 or amyloid positron emission tomography for those with imaging., Results: CSF p-tau217 was superior to p-tau181 for the diagnosis of Alzheimer's disease (AD) pathology. CSF MSD p-tau181 and p-tau217 were associated with risk of MCI among amyloid-positive individuals. Differences between CSF p-tau measures predicting cortical thickness were subtle., Discussion: There are subtle differences for CSF p-tau217 and p-tau181 as prognostic AD markers., (© 2021 the Alzheimer's Association.)

Recent studies highlight phosphorylated tau (p-tau) at threonine tau 217 (p-tau217) as a new promising plasma biomarker for pathological changes implicated in Alzheimer's disease (AD), but the specific brain pathological events related to the alteration in p-tau217 plasma levels are still largely unknown. Using immunostaining techniques of postmortem AD brain tissue, we show that p-tau217 is found in neurofibrillary tangles (NFTs) and neuropil threads that are also positive for p-tau181, 202, 202/205, 231, and 369/404. The p-tau217, but not the other five p-tau variants, was also prominently seen in vesicles structure positive for markers of granulovacuolar degeneration bodies and multi-vesicular bodies. Further, individuals with a high likelihood of AD showed significantly higher p-tau217 area fraction in 4 different brain areas (entorhinal cortex, inferior temporal gyrus, and superior frontal gyrus) compared to those with Primary age related tauopathy or other non-AD tauopathies. The p-tau217 area fraction correlated strongly with total amyloid-beta (Aβ) and NFT brain load when the whole group was analyzed. Finally, the mean p-tau217 area fraction correlated significantly with p-tau217 concentrations in antemortem collected plasma specifically in individuals with amyloid plaques and not in those without amyloid plaques. These studies highlight differences in cellular localization of different p-tau variants and suggest that plasma levels of p-tau217 reflect an accumulation of p-tau217 in presence of Aβ plaque load., (© 2021. The Author(s).)

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., (© 2021. The Author(s).)

Background and Objectives: Phosphorylated tau (p-tau) in CSF is considered an important biomarker in Alzheimer disease (AD) and has been incorporated in recent diagnostic criteria. Several variants exist, including p-tau at threonines 181 (p-tau181), 217 (p-tau217), and 231 (p-tau231). However, no studies have compared their diagnostic performance or association to β-amyloid (Aβ) and tau-PET. Understanding which p-tau variant to use remains an important yet answered question. We aimed to compare the diagnostic accuracy of p-tau181, p-tau217, and p-tau231 in CSF for AD and their association with Aβ and tau-PET., Methods: A total of 629 participants in the Swedish BioFINDER-2 study were included (cognitively unimpaired, n = 334; Aβ-positive mild cognitive impairment, n = 84; AD dementia, n = 119; and non-AD disorders, n = 92). In addition to p-tau181 and p-tau217 measured using assays with the same detector antibodies from Eli Lilly (p-tau181 Lilly , p-tau217 Lilly ) and p-tau231, we also included p-tau181 measurements from 2 commonly used assays (Innotest and Elecsys)., Results: Although all p-tau variants increased across the AD continuum, p-tau217 Lilly showed the greatest dynamic range (13-fold increase vs 1.9-5.4-fold increase for other p-tau variants for AD dementia vs non-AD). P-Tau217 Lilly showed stronger correlations with Aβ- and tau-PET ( p < 0.0001). P-Tau217 Lilly exhibited higher accuracy than other p-tau variants for separating AD dementia from non-AD (area under the curve [AUC], 0.98 vs 0.88 [ p < 0.0001] - 0.96 [ p < 0.05]) and for identifying Aβ-PET (AUC, 0.86 vs 0.74 [ p < 0.0001] and 0.83 [ p < 0.001]) and tau-PET positivity (AUC, 0.94 vs 0.80-0.92, p < 0.0001). Finally, p-Tau181 Lilly generally performed better than the other p-tau181 assays (e.g., AD dementia vs non-AD, AUC, 0.96 vs 0.88 [p-tau181 Innotest ] and 0.89 [p-tau181 Elecsys ]; p < 0.0001)., Discussion: CSF p-tau217 Lilly seems to be more useful than other included p-tau assays in the workup of AD. Varied results across p-tau181 assays highlights the importance of anti-tau antibodies for biomarker performance., Classification of Evidence: This study provides Class II evidence that p-tau217 provides higher diagnostic accuracy for diagnosis of AD dementia than p-tau181 or p-tau231., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes., Methods: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test., Findings: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; p diff =0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; p diff =0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; p diff =0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; p diff =0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; p diff <0·0001, n=230)., Interpretation: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology., Funding: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association., Competing Interests: Declaration of interests JLD and NKP are employees of Eli Lilly and Company, which is exploring commercial development opportunities for p-tau assays. JLD is listed as an inventor on a patent related to reagents used in the p-tau assays. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen, and is a cofounder of Brain Biomarker Solutions (BBS) in Gothenburg AB, which is a part of the GU Ventures Incubator Program. OH has acquired research support (for the institution) from AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, GE Healthcare, Pfizer, and Roche. In the past 2 years, he has received consultancy or speaker fees from AC Immune, Alzpath, Biogen, Cerveau, and Roche. KB served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Roche Diagnostics, and Siemens Healthineers, and is a cofounder of BBS in Gothenburg AB, outside the submitted work. LTG receives research support from Avid Radiopharmaceuticals and Eli Lilly. She has received consulting fees from the Simon Foundation and Cura Sen, and serves as associate editor for Frontiers in Aging Neurosciences, Frontiers in Dementia, and the Journal of Alzheimer Disease. HR has received research support from Biogen Pharmaceuticals, has consulting agreements with Wave Neuroscience and Ionis Pharmaceuticals, and receives research support from US National Institutes of Health (NIH). BFB receives research support from NIH, the Mangurian Foundation, and the Little Family Foundation. He is on the Scientific Advisory Board for the Tau Consortium, and has received grant support for clinical trials from Biogen, Alector, and EIP Pharma. GDR receives research support from NIH, Alzheimer's Association, American College of Radiology, Rainwater Charitable Foundation, Avid Radiopharmaceuticals, Eli Lilly, GE Healthcare, and Life Molecular Imaging. He has served as a consultant for Eisai, Merck, Axon Neurosciences, and Johnson & Johnson, and has received speaking honoraria from GE Healthcare. He serves as Associate Editor for JAMA Neurology. JCR is a site principal investigator for clinical trials supported by Eli Lilly and receives support from NIH. ALB receives research support from the NIH, the Rainwater Charitable Foundation, the Association for Frontotemporal Degeneration, Bluefield Project to Cure Frontotemporal Dementia, the Alzheimer's Drug Discovery Foundation, and the Alzheimer's Association. He has served as a consultant for Alector, AGTC, Arkuda, Arvinas, AZTherapies, GSK, Oligomerix, Ono, Regeneron, Roche, Samumed, Stealth, Third Rock, Transposon, and Wave, and received research support from Biogen, Eisai, and Regeneron. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Cerebrospinal fluid phosphorylated tau (p-tau) 181, p-tau217, and p-tau231 are associated with neuropathological outcomes, but a comparison of these p-tau isoforms in blood samples is needed., Objective: To conduct a head-to-head comparison of plasma p-tau181 and p-tau231 measured on the single-molecule array (Simoa) platform and p-tau181 and p-tau217 measured on the Meso Scale Discovery (MSD) platform on amyloid and tau positron emission tomography (PET) measures, neurodegeneration, vascular pathology, and cognitive outcomes., Design, Setting, and Participants: This study included data from the Mayo Clinic Study on Aging collected from March 1, 2015, to September 30, 2017, and analyzed between December 15, 2020, and May 17, 2021. Associations between the 4 plasma p-tau measures and dichotomous amyloid PET, metaregion of interest tau PET, and entorhinal cortex tau PET were analyzed using logistic regression models; the predictive accuracy was summarized using area under the receiver operating characteristic curve (AUROC) statistic. Of 1329 participants without dementia and with p-tau181 and p-tau217 on MSD, 200 participants with plasma p-tau181 and p-tau231 on Simoa and magnetic resonance imaging and amyloid and tau PET data at the same study visit were eligible., Main Outcomes and Measures: Primary outcomes included amyloid (greater than 1.48 standardized uptake value ratio) and tau PET, white matter hyperintensities, white matter microstructural integrity (fractional anisotropy genu of corpus callosum and hippocampal cingulum bundle), and cognition., Results: Of 200 included participants, 101 (50.5%) were male, and the median (interquartile range [IQR]) age was 79.5 (71.1-84.1) years. A total of 177 were cognitively unimpaired (CU) and 23 had mild cognitive impairment. Compared with amyloid-negative CU participants, among amyloid-positive CU participants, the median (IQR) Simoa p-tau181 measure was 49% higher (2.58 [2.00-3.72] vs 1.73 [1.45-2.13] pg/mL), MSD p-tau181 measure was 53% higher (1.22 [0.91-1.56] vs 0.80 [0.66-0.97] pg/mL), MSD p-tau217 measure was 77% higher (0.23 [0.17-0.34] vs 0.13 [0.09-0.18] pg/mL), and Simoa p-tau231 measure was 49% higher (20.21 [15.60-25.41] vs 14.27 [11.27-18.10] pg/mL). There were no differences between the p-tau species for amyloid PET and tau PET metaregions of interest. However, among CU participants, both MSD p-tau181 and MSD p-tau217 more accurately predicted abnormal entorhinal cortex tau PET than Simoa p-tau181 (MSD p-tau181: AUROC, 0.80 vs 0.70; P = .046; MSD p-tau217: AUROC, 0.81 vs 0.70; P = .04). MSD p-tau181 and p-tau217 and Simoa p-tau181, but not p-tau231, were associated with greater white matter hyperintensity volume and lower white matter microstructural integrity., Conclusions and Relevance: In this largely presymptomatic population, these results suggest subtle differences across plasma p-tau species and platforms for the prediction of amyloid and tau PET and magnetic resonance imaging measures of cerebrovascular and Alzheimer-related pathology.

Introduction: Blood-based Alzheimer's disease (AD) biomarkers provide opportunities for community studies and across ethnic groups. We investigated blood biomarker concentrations in the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multi-ethnic community study of aging and dementia., Methods: We measured plasma amyloid beta (Aβ)40, Aβ42, total tau (t-tau), phosphorylated tau (p-tau)181, and p-tau217, and neurofilament light chain (NfL) in 113 autopsied participants (29% with high AD neuropathological changes) and in 300 clinically evaluated individuals (42% with clinical AD). Receiver operating characteristics were used to evaluate each biomarker. We also investigated biomarkers as predictors of incident clinical AD., Results: P-tau181, p-tau217, and NfL concentrations were elevated in pathologically and clinically diagnosed AD. Decreased Aβ42/Aβ40 ratio and increased p-tau217 and p-tau181 were associated with subsequent AD diagnosis., Discussion: Blood-based AD biomarker concentrations are associated with pathological and clinical diagnoses and can predict future development of clinical AD, providing evidence that they can be incorporated into multi-ethnic, community-based studies., (© 2021 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

A combination of plasma phospho-tau (P-tau) and other accessible biomarkers might provide accurate prediction about the risk of developing Alzheimer's disease (AD) dementia. We examined this in participants with subjective cognitive decline and mild cognitive impairment from the BioFINDER (n = 340) and Alzheimer's Disease Neuroimaging Initiative (ADNI) (n = 543) studies. Plasma P-tau, plasma Aβ42/Aβ40, plasma neurofilament light, APOE genotype, brief cognitive tests and an AD-specific magnetic resonance imaging measure were examined using progression to AD as outcome. Within 4 years, plasma P-tau217 predicted AD accurately (area under the curve (AUC) = 0.83) in BioFINDER. Combining plasma P-tau217, memory, executive function and APOE produced higher accuracy (AUC = 0.91, P < 0.001). In ADNI, this model had similar AUC (0.90) using plasma P-tau181 instead of P-tau217. The model was implemented online for prediction of the individual probability of progressing to AD. Within 2 and 6 years, similar models had AUCs of 0.90-0.91 in both cohorts. Using cerebrospinal fluid P-tau, Aβ42/Aβ40 and neurofilament light instead of plasma biomarkers did not improve the accuracy significantly. The clinical predictions by memory clinic physicians had significantly lower accuracy (4-year AUC = 0.71). In summary, plasma P-tau, in combination with brief cognitive tests and APOE genotyping, might greatly improve the diagnostic prediction of AD and facilitate recruitment for AD trials.

Importance: There is an urgent need for inexpensive and minimally invasive blood biomarkers for Alzheimer disease (AD) that could be used to detect early disease changes., Objective: To assess how early in the course of AD plasma levels of tau phosphorylated at threonine 217 (P-tau217) start to change compared with levels of established cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers of AD pathology., Design, Setting, and Participants: This cohort study included cognitively healthy control individuals (n = 225) and participants with subjective cognitive decline (n = 89) or mild cognitive impairment (n = 176) from the BioFINDER-2 study. Participants were enrolled at 2 different hospitals in Sweden from January 2017 to October 2019. All study participants underwent plasma P-tau217 assessments and tau- and amyloid-β (Aβ)-PET imaging. A subcohort of 111 participants had 2 or 3 tau-PET scans., Main Outcomes and Measures: Changes in plasma P-tau217 levels in preclinical and prodromal AD compared with changes in CSF P-tau217 and PET measures., Results: Of 490 participants, 251 were women (51.2%) and the mean (SD) age was 65.9 (13.1) years. Plasma P-tau217 levels were increased in cognitively unimpaired participants with abnormal Aβ-PET but normal tau-PET in the entorhinal cortex (Aβ-PET+/ tau-PET- group vs Aβ-PET-/ tau-PET- group: median, 2.2 pg/mL [interquartile range (IQR), 1.5-2.9 pg/mL] vs 0.7 pg/mL [IQR, 0.3-1.4 pg/mL]). Most cognitively unimpaired participants who were discordant for plasma P-tau217 and tau-PET were positive for plasma P-tau217 and negative for tau-PET (P-tau217+/tau-PET-: 36 [94.7%]; P-tau217-/tau-PET+: 2 [5.3%]). Event-based modeling of cross-sectional data predicted that in cognitively unimpaired participants and in those with mild cognitive impairment, both plasma and CSF P-tau217 would change before the tau-PET signal in the entorhinal cortex, followed by more widespread cortical tau-PET changes. When testing the association with global Aβ load in nonlinear spline models, both plasma and CSF P-tau217 were increased at lower Aβ-PET values compared with tau-PET measures. Among participants with normal baseline tau-PET, the rates of longitudinal increase in tau-PET in the entorhinal cortex were higher in those with abnormal plasma P-tau217 at baseline (median standardized uptake value ratio, 0.029 [IQR, -0.006 to 0.041] vs -0.001 [IQR, -0.021 to 0.020]; Mann-Whitney U, P = .02)., Conclusions and Relevance: In this cohort study, plasma P-tau217 levels were increased during the early preclinical stages of AD when insoluble tau aggregates were not yet detectable by tau-PET. Plasma P-tau217 may hold promise as a biomarker for early AD brain pathology.

Plasma levels of tau phosphorylated at threonine-217 (p-tau217) is a candidate tool to monitor Alzheimer's disease. We studied 150 cognitively unimpaired participants and 100 patients with mild cognitive impairment in the Swedish BioFINDER study. P-tau217 was measured repeatedly for up to 6 years (median three samples per person, median time from first to last sample, 4.3 years). Preclinical (amyloid-β-positive cognitively unimpaired, n = 62) and prodromal (amyloid-β-positive mild cognitive impairment, n = 49) Alzheimer's disease had accelerated p-tau217 compared to amyloid-β-negative cognitively unimpaired (β  =  0.56, P < 0.001, using linear mixed effects models) and amyloid-β-negative mild cognitive impairment patients (β  =  0.67, P < 0.001), respectively. Mild cognitive impairment patients who later converted to Alzheimer's disease dementia (n = 40) had accelerated p-tau217 compared to other mild cognitive impairment patients (β  =  0.79, P < 0.001). P-tau217 did not change in amyloid-β-negative participants, or in patients with mild cognitive impairment who did not convert to Alzheimer's disease dementia. For 80% power, 109 participants per arm were required to observe a slope reduction in amyloid-β-positive cognitively unimpaired (71 participants per arm in amyloid-β-positive mild cognitive impairment). Longitudinal increases in p-tau217 correlated with longitudinal worsening of cognition and brain atrophy. In summary, plasma p-tau217 increases during early Alzheimer's disease and can be used to monitor disease progression., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Importance: There are limitations in current diagnostic testing approaches for Alzheimer disease (AD)., Objective: To examine plasma tau phosphorylated at threonine 217 (P-tau217) as a diagnostic biomarker for AD., Design, Setting, and Participants: Three cross-sectional cohorts: an Arizona-based neuropathology cohort (cohort 1), including 34 participants with AD and 47 without AD (dates of enrollment, May 2007-January 2019); the Swedish BioFINDER-2 cohort (cohort 2), including cognitively unimpaired participants (n = 301) and clinically diagnosed patients with mild cognitive impairment (MCI) (n = 178), AD dementia (n = 121), and other neurodegenerative diseases (n = 99) (April 2017-September 2019); and a Colombian autosomal-dominant AD kindred (cohort 3), including 365 PSEN1 E280A mutation carriers and 257 mutation noncarriers (December 2013-February 2017)., Exposures: Plasma P-tau217., Main Outcomes and Measures: Primary outcome was the discriminative accuracy of plasma P-tau217 for AD (clinical or neuropathological diagnosis). Secondary outcome was the association with tau pathology (determined using neuropathology or positron emission tomography [PET])., Results: Mean age was 83.5 (SD, 8.5) years in cohort 1, 69.1 (SD, 10.3) years in cohort 2, and 35.8 (SD, 10.7) years in cohort 3; 38% were women in cohort 1, 51% in cohort 2, and 57% in cohort 3. In cohort 1, antemortem plasma P-tau217 differentiated neuropathologically defined AD from non-AD (area under the curve [AUC], 0.89 [95% CI, 0.81-0.97]) with significantly higher accuracy than plasma P-tau181 and neurofilament light chain (NfL) (AUC range, 0.50-0.72; P < .05). The discriminative accuracy of plasma P-tau217 in cohort 2 for clinical AD dementia vs other neurodegenerative diseases (AUC, 0.96 [95% CI, 0.93-0.98]) was significantly higher than plasma P-tau181, plasma NfL, and MRI measures (AUC range, 0.50-0.81; P < .001) but not significantly different compared with cerebrospinal fluid (CSF) P-tau217, CSF P-tau181, and tau-PET (AUC range, 0.90-0.99; P > .15). In cohort 3, plasma P-tau217 levels were significantly greater among PSEN1 mutation carriers, compared with noncarriers, from approximately 25 years and older, which is 20 years prior to estimated onset of MCI among mutation carriers. Plasma P-tau217 levels correlated with tau tangles in participants with (Spearman ρ = 0.64; P < .001), but not without (Spearman ρ = 0.15; P = .33), β-amyloid plaques in cohort 1. In cohort 2, plasma P-tau217 discriminated abnormal vs normal tau-PET scans (AUC, 0.93 [95% CI, 0.91-0.96]) with significantly higher accuracy than plasma P-tau181, plasma NfL, CSF P-tau181, CSF Aβ42:Aβ40 ratio, and MRI measures (AUC range, 0.67-0.90; P < .05), but its performance was not significantly different compared with CSF P-tau217 (AUC, 0.96; P = .22)., Conclusions and Relevance: Among 1402 participants from 3 selected cohorts, plasma P-tau217 discriminated AD from other neurodegenerative diseases, with significantly higher accuracy than established plasma- and MRI-based biomarkers, and its performance was not significantly different from key CSF- or PET-based measures. Further research is needed to optimize the assay, validate the findings in unselected and diverse populations, and determine its potential role in clinical care.

Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer's disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate the performance of CSF p-tau217 as a biomarker of AD in comparison to p-tau181. In the Swedish BioFINDER cohort (n = 194), p-tau217 shows stronger correlations with the tau positron emission tomography (PET) tracer [ 18 F]flortaucipir, and more accurately identifies individuals with abnormally increased [ 18 F]flortaucipir retention. Furthermore, longitudinal increases in p-tau217 are higher compared to p-tau181 and better correlate with [ 18 F]flortaucipir uptake. P-tau217 correlates better than p-tau181 with CSF and PET measures of neocortical amyloid-β burden and more accurately distinguishes AD dementia from non-AD neurodegenerative disorders. Higher correlations between p-tau217 and [ 18 F]flortaucipir are corroborated in an independent EXPEDITION3 trial cohort (n = 32). The main results are validated using a different p-tau217 immunoassay. These findings suggest that p-tau217 might be more useful than p-tau181 in the diagnostic work up of AD.

Plasma phosphorylated tau181 (P-tau181) might be increased in Alzheimer's disease (AD), but its usefulness for differential diagnosis and prognosis is unclear. We studied plasma P-tau181 in three cohorts, with a total of 589 individuals, including cognitively unimpaired participants and patients with mild cognitive impairment (MCI), AD dementia and non-AD neurodegenerative diseases. Plasma P-tau181 was increased in preclinical AD and further increased at the MCI and dementia stages. It correlated with CSF P-tau181 and predicted positive Tau positron emission tomography (PET) scans (area under the curve (AUC) = 0.87-0.91 for different brain regions). Plasma P-tau181 differentiated AD dementia from non-AD neurodegenerative diseases with an accuracy similar to that of Tau PET and CSF P-tau181 (AUC = 0.94-0.98), and detected AD neuropathology in an autopsy-confirmed cohort. High plasma P-tau181 was associated with subsequent development of AD dementia in cognitively unimpaired and MCI subjects. In conclusion, plasma P-tau181 is a noninvasive diagnostic and prognostic biomarker of AD, which may be useful in clinical practice and trials.

With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18 F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Background: Activation of microglia, the resident immune cells of the central nervous system, is a prominent pathological hallmark of Alzheimer's disease (AD). However, the gene expression changes underlying microglia activation in response to tau pathology remain elusive. Furthermore, it is not clear how murine gene expression changes relate to human gene expression networks., Methods: Microglia cells were isolated from rTg4510 tau transgenic mice and gene expression was profiled using RNA sequencing. Four age groups of mice (2-, 4-, 6-, and 8-months) were analyzed to capture longitudinal gene expression changes that correspond to varying levels of pathology, from minimal tau accumulation to massive neuronal loss. Statistical and system biology approaches were used to analyze the genes and pathways that underlie microglia activation. Differentially expressed genes were compared to human brain co-expression networks., Results: Statistical analysis of RNAseq data indicated that more than 4000 genes were differentially expressed in rTg4510 microglia compared to wild type microglia, with the majority of gene expression changes occurring between 2- and 4-months of age. These genes belong to four major clusters based on their temporal expression pattern. Genes involved in innate immunity were continuously up-regulated, whereas genes involved in the glutamatergic synapse were down-regulated. Up-regulated innate inflammatory pathways included NF-κB signaling, cytokine-cytokine receptor interaction, lysosome, oxidative phosphorylation, and phagosome. NF-κB and cytokine signaling were among the earliest pathways activated, likely driven by the RELA, STAT1 and STAT6 transcription factors. The expression of many AD associated genes such as APOE and TREM2 was also altered in rTg4510 microglia cells. Differentially expressed genes in rTg4510 microglia were enriched in human neurodegenerative disease associated pathways, including Alzheimer's, Parkinson's, and Huntington's diseases, and highly overlapped with the microglia and endothelial modules of human brain transcriptional co-expression networks., Conclusion: This study revealed temporal transcriptome alterations in microglia cells in response to pathological tau perturbation and provides insight into the molecular changes underlying microglia activation during tau mediated neurodegeneration.

Introduction: We examined and compared plasma phospho-tau181 (pTau181) and total tau: (1) across the Alzheimer's disease (AD) clinical spectrum; (2) in relation to brain amyloid β (Aβ) positron emission tomography (PET), tau PET, and cortical thickness; and (3) as a screening tool for elevated brain Aβ., Methods: Participants included 172 cognitively unimpaired, 57 mild cognitively impaired, and 40 AD dementia patients with concurrent Aβ PET (Pittsburgh compound B), tau PET (AV1451), magnetic resonance imaging, plasma total tau, and pTau181., Results: Plasma total tau and pTau181 levels were higher in AD dementia patients than those in cognitively unimpaired. Plasma pTau181 was more strongly associated with both Aβ and tau PET. Plasma pTau181 was a more sensitive and specific predictor of elevated brain Aβ than total tau and was as good as, or better than, the combination of age and apolipoprotein E (APOE)., Discussion: Plasma pTau181 may have utility as a biomarker of AD pathophysiology and as a noninvasive screener for elevated brain Aβ., (Copyright © 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Importance: The utility of plasma total tau level as a prognostic marker for cognitive decline and dementia is not well understood., Objectives: To determine (1) the association between plasma total tau level, cognitive decline, and risk of mild cognitive impairment (MCI) and dementia; (2) whether this association differs by the presence of elevated brain amyloid β (Aβ); and (3) whether plasma total tau level is associated with cognitive decline over a short interval of 15 months., Design, Setting, and Participants: The present analyses included 458 participants who were enrolled in a population-based cohort study between October 2008 and June 2013. All included participants had available plasma total tau levels, Aβ positron emission tomography imaging, and a complete neuropsychological examine at the same visit, as well as at least 1 follow-up visit., Exposures: Concentration of plasma total tau., Main Outcomes and Measures: Risk of MCI and dementia; global and domain-specific cognitive decline., Results: Of the 458 participants, 287 (62.7%) were men; mean (SD) age was 80.6 (5.6) years. Among cognitively normal (CN) participants oversampled for elevated brain Aβ, both the middle (hazard ratio [HR], 2.43; 95% CI, 1.25-4.72) and highest (HR, 2.02; 95% CI, 1.01-4.06) tertiles of plasma total tau level, compared with the lowest, were associated with an increased risk of MCI. Among participants with MCI, higher plasma total tau levels were not significantly associated with risk of dementia (all-cause dementia or Alzheimer disease). Among all participants, higher levels of plasma total tau, examined as a continuous variable, were associated with significant (P < .05) declines in global cognition, memory, attention, and visuospatial ability over a median follow-up of 3.0 years (range, 1.1-4.9 years). In additional analyses restricting the follow-up to 15 months, plasma total tau did not predict decline among CN participants. However, among participants with MCI, higher plasma total tau levels were associated with greater decline in both visuospatial ability (regression coefficient [b] = -0.50 [0.15], P < .001) and global cognition (b = -0.27 [0.10], P = .009) at 15 months. Adjusting for elevated brain Aβ did not attenuate any association. There was no interaction between plasma total tau level and brain Aβ for prognosis with any outcome., Conclusions and Relevance: These results suggest that elevated plasma total tau levels are associated with cognitive decline, but the results differ based on cognitive status and the duration of follow-up. The association between plasma total tau levels and cognition is independent of elevated brain Aβ.

Introduction: Tau protein levels in plasma may be a marker of neuronal damage. We examined associations between plasma tau levels and Alzheimer's disease (AD)-related magnetic resonance imaging (MRI) and positron emission tomography (PET) neuroimaging measures among nondemented individuals., Methods: Participants included 378 cognitively normal (CN) and 161 mild cognitive impairment (MCI) individuals enrolled in the Mayo Clinic Study of Aging with concurrent neuropsychological measures and amyloid PET, fluorodeoxyglucose PET, and MRI. Baseline plasma tau levels were measured using the Quanterix Simoa-HD1 tau assay., Results: Plasma tau levels were higher in MCI compared with CN (4.34 vs. 4.14 pg/mL, P = .078). In regression models adjusted for age, gender, education, and APOE, higher plasma tau was associated with worse memory performance (b = -0.30, P = .02) and abnormal cortical thickness in an AD signature region (odds ratio = 1.80, P = .018)., Discussion: Plasma tau is associated with cortical thickness and memory performance. Longitudinal studies will better elucidate the associations between plasma tau, neurodegeneration, and cognition., (Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

The microtubule-associated protein tau plays a critical role in the pathogenesis of Alzheimer's disease and several related disorders. In the disease tau aggregates into paired helical and straight filaments, which can form higher order neurofibrillary tangles in neurons and this pathology is associated with progressive neuronal loss and cognitive decline. Tau is a cytoplasmic protein and is thought to be released only from degenerating cells. In contrast, here we provide evidence that tau is constitutively secreted at a low level. We directly show tau release in cell culture model systems. In inducible transfected cell lines we observe that a small proportion of full-length tau is released from intact cells in a time dependent manner. We show that this tau is released by an unconventional secretion process, as the release is temperature dependent but not blocked by inhibitors of the conventional secretory pathway. We characterize the released tau as full length, not vesicle associated and containing Phospho-Tau (181P) proportional to its intracellular concentration. We demonstrate that tau secretion and its suppression by low temperature also occurs in human neurons differentiated from induced pluripotent stem cells. The constitutive tau secretion that we propose provides the most parsimonious explanation for the observed presence of tau in the CSF of healthy animals and human beings. If previously postulated pathogenic extracellular tau intermediates are released by this route, low level constitutive tau secretion could play a role in the spread of tau pathology in Alzheimer's disease and other human tauopathies., (Copyright © 2012 Elsevier Inc. All rights reserved.)