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Background and Purpose: This study was undertaken to compare the performance of plasma p-tau181 with that of [ 18 F]fluorodeoxyglucose (FDG) positron emission tomography (PET) in the identification of early biological Alzheimer disease (AD)., Methods: We included 533 cognitively impaired participants from the Alzheimer's Disease Neuroimaging Initiative. Participants underwent PET scans, biofluid collection, and cognitive tests. Receiver operating characteristic analyses were used to determine the diagnostic accuracy of plasma p-tau181 and [ 18 F]FDG-PET using clinical diagnosis and core AD biomarkers ([ 18 F]florbetapir-PET and cerebrospinal fluid [CSF] p-tau181) as reference standards. Differences in the diagnostic accuracy between plasma p-tau181 and [ 18 F]FDG-PET were determined by bootstrap-based tests. Correlations of [ 18 F]FDG-PET and plasma p-tau181 with CSF p-tau181, amyloid β (Aβ) PET, and cognitive performance were evaluated to compare associations between measurements., Results: We observed that both plasma p-tau181 and [ 18 F]FDG-PET identified individuals with positive AD biomarkers in CSF or on Aβ-PET. In the MCI group, plasma p-tau181 outperformed [ 18 F]FDG-PET in identifying AD measured by CSF (p = 0.0007) and by Aβ-PET (p = 0.001). We also observed that both plasma p-tau181 and [ 18 F]FDG-PET metabolism were associated with core AD biomarkers. However, [ 18 F]FDG-PET uptake was more closely associated with cognitive outcomes (Montreal Cognitive Assessment, Mini-Mental State Examination, Clinical Dementia Rating Sum of Boxes, and logical memory delayed recall, p < 0.001) than plasma p-tau181., Conclusions: Overall, although both plasma p-tau181 and [ 18 F]FDG-PET were associated with core AD biomarkers, plasma p-tau181 outperformed [ 18 F]FDG-PET in identifying individuals with early AD pathophysiology. Taken together, our study suggests that plasma p-tau181 may aid in detecting individuals with underlying early AD., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Recently approved anti-amyloid immunotherapies for Alzheimer's disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing., Competing Interests: Competing interests J.T. has served as a consultant for the Neurotorium educational platform, outside of the scope of the submitted work. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics and Wave; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen and Roche; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program (outside submitted work). O.H. has acquired research support (for the institution) from ADx, AVID Radiopharmaceuticals, Biogen, Eli Lilly, Eisai, Fujirebio, GE Healthcare, Pfizer and Roche. In the past 2 years, he has received consultancy/speaker fees from AC Immune, Amylyx, Alzpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens. R.C.P. has consulted for Roche, Genentech, Eli Lilly, Eisai and Nestle, all outside the scope of the current work. M.S.-C. has served as a consultant and at advisory boards for Roche Diagnostics International Ltd and Grifols S.L.; has given lectures in symposia sponsored by Roche Diagnostics, S.L.U and Roche Farma, S.A.; and was granted with a project funded by Roche Diagnostics International Ltd; payments were made to the institution (BBRC). A.P.P. has served at advisory boards for Schwabe Farma Iberica. D.A. participated in advisory boards from Fujirebio-Europe, Roche Diagnostics, Grifols S.A. and Lilly, and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. D.A. declares a filed patent application (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). S. Johnson has served at scientific advisory boards or as a consultant for ALZpath, Prothena, Roche Diagnostics, and Enigma. M.M.M. has served as a consultant and at advisory boards for Biogen, Eisai, Lilly, Merck, Roche, and Siemens Healthineers. P.R.-N. has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. A.A.-S. has participated in advisory boards for Roche Diagnostics, Fujirebio Diagnostics and Siemens Healthineers. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Background: Blood-based disease staging across the Alzheimer's disease (AD) continuum holds the promise to identify individuals that profit from disease-modifying therapies. We set out to identify Braak V + (Braak V and/or VI) tau PET-positive individuals within amyloid-β (Aβ)-positive individuals using plasma biomarkers., Methods: In this cross-sectional study, we assessed 289 individuals from the TRIAD cohort and 306 individuals from the WRAP study across the AD continuum. The participants were evaluated by amyloid-PET with [ 18 F]AZD4694 or [ 11 C]PiB and tau-PET with [ 18 F]MK6240 and measured plasma levels included total tau, phospho-tau isoforms (pTau) pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers using different analytic platforms to predict Braak V + positivity in Aβ+ individuals., Findings: Highest associations with Braak V + tau positivity in Aβ+ individuals were found for plasma pTau-217+ Janssen (AUC [CI 95% ] = 0.97 [0.94, 1.0]) and ALZpath pTau-217 (AUC [CI 95% ] = 0.93 [0.86, 1.0]) in TRIAD. Plasma ALZpath pTau-217 separated Braak V + tau PET-positive individuals in the WRAP longitudinal study (AUC [CI 95% ] = 0.97 [0.94, 1.0])., Interpretation: Thus, we demonstrate that using adjusted cut-offs, plasma pTau-217 identifies individuals with later Braak stage tau accumulation which will be helpful to stratify patients for treatments and clinical studies., Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR) [MOP-11-51-31; RFN 152985, 159815, 162303], Canadian Consortium of Neurodegeneration and Aging (CCNA; MOP-11-51-31 -team 1), the Alzheimer's Association [NIRG-12-92090, NIRP-12-259245], Brain Canada Foundation (CFI Project 34874; 33397), the Fonds de Recherche du Québec-Santé (FRQS; Chercheur Boursier, 2020-VICO-279314). P.R-N and SG are members of the CIHR-CCNA Canadian Consortium of Neurodegeneration in Aging. Colin J. Adair Charitable Foundation., Competing Interests: Declaration of interests H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.B. has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for Biogen, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. H.C.K and G.T.B receive salary and stock from Janssen R&D. All other authors declare no conflicts of interest. E.M.J. served on DSMB for the NIA study K01 AG073587. S.G. received consulting fees as a member of the scientific advisory boards in Abbvie, Alzheon, AmyriAD, Eisai, Enigma/Meilleur, Lilly, Okutsa, Novo Nordisk, TauRx, honoraria for educational videos from Lundbeck, reimbursement for AD/PD 2024 travel expenses by TauRx. S.G. is board member at the Sharon and Robert Francis Foundation, Toronto, Canada, and the Canadian Conference on Dementia (CCD). S.C.J. received payment for consulting Enigma Biomedical and consulted ALZpath without payment. T.J.B. received funding from NIH/NIA (R01AG080766), personal honoraria from the NIH, Intermountain Healthcare, reimbursements for travel by University College London, Alzheimer's Association, and NIH. J.T. served as a Consultant for the Neurotorium Educational platform and for Alzheon. P.V. received consulting fees from Eisai, Novo Nordisk, honoraria from Astra, support for travelling by Lilly, and participated on DMSB for the IntelGenxCorp. Y.T.W. has written an educational article for the Neurotorium Educational platform. P.R.N. received consulting fees from Novo Nordisk, Eisai, and honoraria for an academic talk from Novo Nordisk., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Objectives: Updates in Alzheimer disease (AD) diagnostic guidelines by the National Institute on Aging-Alzheimer's Association (NIA-AA) and the International Working Group (IWG) over the past 11 years may affect clinical diagnoses. We assessed how these guidelines affect clinical AD diagnosis in a cohort of cognitively unimpaired (CU) and cognitively impaired (CI) individuals., Methods: We applied clinical and biomarker data in algorithms to classify individuals from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort according to the following diagnostic guidelines for AD: 2011 NIA-AA, 2016 IWG-2, 2018 NIA-AA, and 2021 IWG-3, assigning the following generic diagnostic labels: (1) not AD (nAD), (2) increased risk of developing AD (irAD), and (3) AD. Diagnostic labels were compared according to their frequency, convergence across guidelines, biomarker profiles, and prognostic value. We also evaluated the diagnostic discordance among the criteria., Results: A total of 1,195 individuals (mean age 73.2 ± 7.2 years, mean education 16.1 ± 2.7, 44.0% female) presented different repartitions of diagnostic labels according to the 2011 NIA-AA (nAD = 37.8%, irAD = 23.0%, AD = 39.2%), 2016 IWG-2 (nAD = 37.7%, irAD = 28.7%, AD = 33.6%), 2018 NIA-AA (nAD = 40.7%, irAD = 9.3%, AD = 50.0%), and 2021 IWG-3 (nAD = 51.2%, irAD = 8.4%, AD = 48.3%) frameworks. Discordant diagnoses across all guidelines were found in 512 participants (42.8%) (138 [91.4%] occurring in only β-amyloid [CU 65.4%, CI 34.6%] and 191 [78.6%] in only tau-positive [CU 71.7%, CI 28.3%] individuals). Differences in predicting cognitive impairment between nAD and irAD groups were observed with the 2011 NIA-AA (hazard ratio [HR] 2.21, 95% CI 1.34-3.65, p = 0.002), 2016 IWG-2 (HR 2.81, 95% CI 1.59-4.96, p < 0.000), and 2021 IWG-3 (HR 3.61, 95% CI 2.09-6.23, p < 0.000), but not with 2018 NIA-AA (HR 1.69, 95% CI 0.87-3.28, p = 0.115)., Discussion: Over 42% of the studied population presented discordant diagnoses when using the different examined AD criteria, mostly in individuals with a single positive biomarker. Except for 2018 NIA-AA, all guidelines identified asymptomatic individuals at risk of cognitive impairment. Our findings highlight important differences between the guidelines, emphasizing the necessity for updated criteria with enhanced staging metrics, considering clinical, research, therapeutic, and trial design aspects.

Background: Females represent approximately 70% of the Alzheimer's disease (AD) cases and the literature has proposed a connection between the decreased estrogen levels during menopause and an increased AD risk. Previous investigations have predominantly focused on assessing how hormone therapy (HT) affects the likelihood of AD development and cognitive deterioration. However, as the research framework has shifted toward a biomarker-defined AD and alterations in specific biomarkers could take place years before cognitive decline becomes discernible, it is crucial to examine how HT influences AD biomarkers. The main goal of this study was to evaluate the impact of HT on AD biomarker-informed pathophysiology in both cognitively unimpaired (CU) and cognitively impaired (CI) post-menopausal females across the aging and AD spectrum., Methods: This cross-sectional study included post-menopausal females without HT history (HT-) and with HT (HT+) at the time of PET imaging assessment from two cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, and the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent magnetic resonance imaging (MRI), positron emission tomography (PET) and biofluid collection. Voxel-based t-tests were performed to assess the differences in amyloid-β (Aβ) and tau neurofibrillary tangles (NFTs) loads between HT- and HT + females. Linear regression models with interaction terms were also conducted to examine the interactive effects of HT and Aβ-PET on regional tau-PET., Results: HT + females demonstrated significantly lower tau-PET standardized uptake value ratio (SUVR) in Braak I-II ROIs (P < 0.05, Hedges' g = 0.73), Braak III-IV ROIs (P < 0.0001, Hedges' g = 0.74) and Braak V-VI ROIs (P < 0.0001, Hedges' g = 0.69) compared to HT- females. HT + females also showed significantly lower CSF p-tau 181 (P < 0.001) and plasma p-tau 181 (P < 0.0001) concentrations. Additionally, results from multivariate linear regression models indicated that HT interacts with cortical Aβ and is associated with lower regional NFT load., Conclusions: Overall, findings from this observational study suggest that HT is associated with lower tau neuroimaging and fluid biomarkers in postmenopausal females. Due to the close link between tau and cognition, this study highlights the need for large randomized controlled trials designed to systemically study the influences of HT on AD biomarkers and disease progression., (© 2024. The Author(s).)

Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, mechanistic evidence in humans remains scarce, requiring improved non-invasive techniques and integrative models. We introduce personalized AD computational models built on whole-brain Wilson-Cowan oscillators and incorporating resting-state functional MRI, amyloid-β (Aβ) and tau-PET from 132 individuals in the AD spectrum to evaluate the direct impact of toxic protein deposition on neuronal activity. This subject-specific approach uncovers key patho-mechanistic interactions, including synergistic Aβ and tau effects on cognitive impairment and neuronal excitability increases with disease progression. The data-derived neuronal excitability values strongly predict clinically relevant AD plasma biomarker concentrations (p-tau217, p-tau231, p-tau181, GFAP) and grey matter atrophy obtained through voxel-based morphometry. Furthermore, reconstructed EEG proxy quantities show the hallmark AD electrophysiological alterations (theta band activity enhancement and alpha reductions) which occur with Aβ-positivity and after limbic tau involvement. Microglial activation influences on neuronal activity are less definitive, potentially due to neuroimaging limitations in mapping neuroprotective vs detrimental activation phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions., (© 2024. The Author(s).)

Females are disproportionately affected by dementia due to Alzheimer's disease. Despite a similar amyloid-β (Aβ) load, a higher load of neurofibrillary tangles (NFTs) is seen in females than males. Previous literature has proposed that Aβ and phosphorylated-tau (p-tau) synergism accelerates tau tangle formation, yet the effect of biological sex in this process has been overlooked. In this observational study, we examined longitudinal neuroimaging data from the TRIAD and ADNI cohorts from Canada and USA, respectively. We assessed 457 participants across the clinical spectrum of Alzheimer's disease. All participants underwent baseline multimodal imaging assessment, including MRI and PET, with radioligands targeting Aβ plaques and tau tangles, respectively. CSF data were also collected. Follow-up imaging assessments were conducted at 1- and 2-year intervals for the TRIAD cohort and 1-, 2- and 4-year intervals for the ADNI cohort. The upstream pathological events contributing to faster tau progression in females were investigated-specifically, whether the contribution of Aβ and p-tau synergism to accelerated tau tangle formation is modulated by biological sex. We hypothesized that cortical Aβ predisposes tau phosphorylation and tangle accumulation in a sex-specific manner. Findings revealed that Aβ-positive females presented higher CSF p-tau181 concentrations compared with Aβ-positive males in both the TRIAD (P = 0.04, Cohen's d = 0.51) and ADNI (P = 0.027, Cohen's d = 0.41) cohorts. In addition, Aβ-positive females presented faster NFT accumulation compared with their male counterparts (TRIAD: P = 0.026, Cohen's d = 0.52; ADNI: P = 0.049, Cohen's d = 1.14). Finally, the triple interaction between female sex, Aβ and CSF p-tau181 was revealed as a significant predictor of accelerated tau accumulation at the 2-year follow-up visit (Braak I: P = 0.0067, t = 2.81; Braak III: P = 0.017, t = 2.45; Braak IV: P = 0.002, t = 3.17; Braak V: P = 0.006, t = 2.88; Braak VI: P = 0.0049, t = 2.93). Overall, we report sex-specific modulation of cortical Aβ in tau phosphorylation, consequently facilitating faster NFT progression in female individuals over time. This presents important clinical implications and suggests that early intervention that targets Aβ plaques and tau phosphorylation may be a promising therapeutic strategy in females to prevent the further accumulation and spread of tau aggregates., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Understanding whether vascular risk factors (VRFs) synergistically potentiate Alzheimer's disease (AD) progression is important in the context of emerging treatments for preclinical AD. In a group of 503 cognitively unimpaired individuals, we tested whether VRF burden interacts with AD pathophysiology to accelerate neurodegeneration and cognitive decline. Baseline VRF burden was calculated considering medical data and AD pathophysiology was assessed based on cerebrospinal fluid (CSF) amyloid-β 1-42 (Aβ 1-42 ) and tau phosphorylated at threonine 181 (p-tau 181 ). Neurodegeneration was assessed with plasma neurofilament light (NfL) and global cognition with the modified version of the Preclinical Alzheimer's Cognitive Composite. The mean (SD) age of participants was 72.9 (6.1) years, and 220 (43.7%) were men. Linear mixed-effects models revealed that an elevated VRF burden synergistically interacted with AD pathophysiology to drive longitudinal plasma NfL increase and cognitive decline. Additionally, VRF burden was not associated with CSF Aβ 1-42 or p-tau 181 changes over time. Our results suggest that VRF burden and AD pathophysiology are independent processes; however, they synergistically lead to neurodegeneration and cognitive deterioration. In preclinical stages, the combination of therapies targeting VRFs and AD pathophysiology might potentiate treatment outcomes., Competing Interests: Competing interests NJA has given lectures in symposia sponsored by Lilly and Quanterix. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, reMYND, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this paper. SOM reports receiving speaker fees from Medtronic, Novartis, Novo Nordisk, Pfizer, Bayer and advisory board fees from Boehringer Ingelheim. PR-N has served on scientific advisory boards and/or as a consultant for Eisai, Novo Nordisk and Roche. ERZ serves on the scientific advisory board of Next Innovative Therapeutics. All other authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Blood-based biomarkers of Alzheimer's disease (AD) have become increasingly important as scalable tools for diagnosis and determining clinical trial eligibility. P-tau217 is the most promising due to its excellent sensitivity and specificity for AD-related pathological changes., Methods: We compared the performance of two commercially available plasma p-tau217 assays (ALZpath p-tau217 and Janssen p-tau217+) in 294 individuals cross-sectionally. Correlations with amyloid PET and tau PET were assessed, and Receiver Operating Characteristic (ROC) analyses evaluated both p-tau217 assays for identifying AD pathology., Findings: Both plasma p-tau217 assays were strongly associated with amyloid and tau PET. Furthermore, both plasma p-tau217 assays identified individuals with AD vs other neurodegenerative diseases (ALZpath AUC = 0.95; Janssen AUC = 0.96). Additionally, plasma p-tau217 concentrations rose with AD severity and their annual changes correlated with tau PET annual change., Interpretation: Both p-tau217 assays had excellent diagnostic performance for AD. Our study supports the future clinical use of commercially-available assays for p-tau217., Funding: This research is supported by the Weston Brain Institute, Canadian Institutes of Health Research (CIHR), Canadian Consortium on Neurodegeneration in Aging, the Alzheimer's Association, Brain Canada Foundation, the Fonds de Recherche du Québec - Santé and the Colin J. Adair Charitable Foundation., Competing Interests: Declaration of interests Joseph Therriault has received consulting fees from the Neurotorium educational platform, outside of the scope of this work. Nicholas J. Ashton has served as consultant for Quanterix and has given lectures in symposia sponsored by Lilly, Quanterix and Biogen. Gallen Triana-Baltzer and Hartmuth Kolb are employees of, and have stocks from, Janssen R&D, who pays their travel-related expenses. They have been also granted and filled patent applications (US20190271710A1 and JAB7064USPSP2). Andreas Jeromin is an employee of, and has stocks from, Alzpath Inc. Pedro Rosa-Neto has served at scientific advisory boards and/or as a consultant for Roche, Novo Nordisk, Eisai, and Cerveau radiopharmaceuticals. Henrik Zetterberg has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeuthics, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). Kaj Blennow has served as a consultant, at advisory boards, or at data monitoring committees for Acumen, Abcam, ALZpath, AriBio, Axon, BioArctic, Biogen, Eisai, JOMDD/Shimadzu, Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. All other authors report no disclosures., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Disease staging, whereby the spatial extent and load of brain pathology are used to estimate the severity of Alzheimer disease (AD), is pivotal to the gold-standard neuropathological diagnosis of AD. Current in vivo diagnostic frameworks for AD are based on abnormal concentrations of amyloid-β and tau in the cerebrospinal fluid or on PET scans, and breakthroughs in molecular imaging have opened up the possibility of in vivo staging of AD. Focusing on the key principles of disease staging shared across several areas of medicine, this Review highlights the potential for in vivo staging of AD to transform our understanding of preclinical AD, refine enrolment criteria for trials of disease-modifying therapies and aid clinical decision-making in the era of anti-amyloid therapeutics. We provide a state-of-the-art review of recent biomarker-based AD staging systems and highlight their contributions to the understanding of the natural history of AD. Furthermore, we outline hypothetical frameworks to stage AD severity using more accessible fluid biomarkers. In addition, by applying amyloid PET-based staging to recently published anti-amyloid therapeutic trials, we highlight how biomarker-based disease staging frameworks could illustrate the numerous pathological changes that have already taken place in individuals with mildly symptomatic AD. Finally, we discuss challenges related to the validation and standardization of disease staging and provide a forward-looking perspective on potential clinical applications., (© 2024. Springer Nature Limited.)

Blood-based biomarkers for screening may guide tau positrion emissition tomography (PET) scan referrals to optimize prognostic evaluation in Alzheimer's disease. Plasma Aβ42/Aβ40, pTau181, pTau217, pTau231, NfL, and GFAP were measured along with tau-PET in memory clinic patients with subjective cognitive decline, mild cognitive impairment or dementia, in the Swedish BioFINDER-2 study (n = 548) and in the TRIAD study (n = 179). For each plasma biomarker, cutoffs were determined for 90%, 95%, or 97.5% sensitivity to detect tau-PET-positivity. We calculated the percentage of patients below the cutoffs (who would not undergo tau-PET; "saved scans") and the tau-PET-positivity rate among participants above the cutoffs (who would undergo tau-PET; "positive predictive value"). Generally, plasma pTau217 performed best. At the 95% sensitivity cutoff in both cohorts, pTau217 resulted in avoiding nearly half tau-PET scans, with a tau-PET-positivity rate among those who would be referred for a scan around 70%. And although tau-PET was strongly associated with subsequent cognitive decline, in BioFINDER-2 it predicted cognitive decline only among individuals above the referral cutoff on plasma pTau217, supporting that this workflow could reduce prognostically uninformative tau-PET scans. In conclusion, plasma pTau217 may guide selection of patients for tau-PET, when accurate prognostic information is of clinical value., (© 2024. The Author(s).)

Importance: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests., Objective: To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid β (Aβ) and longitudinal change across 3 selected cohorts., Design, Setting, and Participants: This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023., Exposures: Magnetic resonance imaging, Aβ positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aβ42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay)., Main Outcomes and Measures: Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status., Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aβ (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aβ pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau positivity., Conclusions and Relevance: This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.

Background: Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer's disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore, there remains a need for a biomarker capable of specifically tracking insoluble tau accumulation in brain., Methods: NTA is a novel ultrasensitive assay targeting N-terminal containing tau fragments (NTA-tau) in cerebrospinal fluid (CSF) and plasma, which is elevated in AD. Using two well-characterized research cohorts (BioFINDER-2, n = 1,294, and BioFINDER-1, n = 932), we investigated the association between plasma NTA-tau levels and disease progression in AD, including tau accumulation, brain atrophy and cognitive decline., Results: We demonstrate that plasma NTA-tau increases across the AD continuum¸ especially during late stages, and displays a moderate-to-strong association with tau-PET (β = 0.54, p < 0.001) in Aβ-positive participants, while weak with Aβ-PET (β = 0.28, p < 0.001). Unlike plasma p-tau181, GFAP, NfL and t-tau, tau pathology determined with tau-PET is the most prominent contributor to NTA-tau variance (52.5% of total R 2 ), while having very low contribution from Aβ pathology measured with CSF Aβ42/40 (4.3%). High baseline NTA-tau levels are predictive of tau-PET accumulation (R 2  = 0.27), steeper atrophy (R 2  ≥ 0.18) and steeper cognitive decline (R 2  ≥ 0.27) in participants within the AD continuum. Plasma NTA-tau levels significantly increase over time in Aβ positive cognitively unimpaired (β std  = 0.16) and impaired (β std  = 0.18) at baseline compared to their Aβ negative counterparts. Finally, longitudinal increases in plasma NTA-tau levels were associated with steeper longitudinal decreases in cortical thickness (R 2  = 0.21) and cognition (R 2  = 0.20)., Conclusion: Our results indicate that plasma NTA-tau levels increase across the AD continuum, especially during mid-to-late AD stages, and it is closely associated with in vivo tau tangle deposition in AD and its downstream effects. Moreover, this novel biomarker has potential as a cost-effective and easily accessible tool for monitoring disease progression and cognitive decline in clinical settings, and as an outcome measure in clinical trials which also need to assess the downstream effects of successful Aβ removal., (© 2024. The Author(s).)

Introduction: We set out to identify tau PET-positive (A+T+) individuals among amyloid-beta (Aβ) positive participants using plasma biomarkers., Methods: In this cross-sectional study we assessed 234 participants across the AD continuum who were evaluated by amyloid PET with [ 18 F]AZD4694 and tau-PET with [ 18 F]MK6240 and measured plasma levels of total tau, pTau-181, pTau-217, pTau-231, and N-terminal tau (NTA-tau). We evaluated the performances of plasma biomarkers to predict tau positivity in Aβ+ individuals., Results: Highest associations with tau positivity in Aβ+ individuals were found for plasma pTau-217 (AUC [CI 95% ] = 0.89 [0.82, 0.96]) and NTA-tau (AUC [CI 95% ] = 0.88 [0.91, 0.95]). Combining pTau-217 and NTA-tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI 95%  = 0.57/0.90, sensitivity = 92%, specificity = 81%) with PET for classifying tau positivity., Discussion: The potential for identifying tau accumulation in later Braak stages will be useful for patient stratification and prognostication in treatment trials and in clinical practice., Highlights: We found that in a cohort without pre-selection pTau-181, pTau-217, and NTA-tau showed the highest association with tau PET positivity. We found that in Aβ+ individuals pTau-217 and NTA-tau showed the highest association with tau PET positivity. Combining pTau-217 and NTA-tau resulted in the strongest agreement with the tau PET-based classification., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Blood biomarkers have proven useful in Alzheimer's disease (AD) research. However, little is known about their biological variation (BV), which improves the interpretation of individual-level data., Methods: We measured plasma amyloid beta (Aβ42, Aβ40), phosphorylated tau (p-tau181, p-tau217, p-tau231), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in plasma samples collected weekly over 10 weeks from 20 participants aged 40 to 60 years from the European Biological Variation Study. We estimated within- (CV I ) and between-subject (CV G ) BV, analytical variation, and reference change values (RCV)., Results: Biomarkers presented considerable variability in CV I and CV G . Aβ42/Aβ40 had the lowest CV I (≈ 3%) and p-tau181 the highest (≈ 16%), while others ranged from 6% to 10%. Most RCVs ranged from 20% to 30% (decrease) and 25% to 40% (increase)., Discussion: BV estimates for AD plasma biomarkers can potentially refine their clinical and research interpretation. RCVs might be useful for detecting significant changes between serial measurements when monitoring early disease progression or interventions. Highlights Plasma amyloid beta (Aβ42/Aβ40) presents the lowest between- and within-subject biological variation, but also changes the least in Alzheimer's disease (AD) patients versus controls. Plasma phosphorylated tau variants significantly vary in their within-subject biological variation, but their substantial fold-changes in AD likely limits the impact of their variability. Plasma neurofilament light chain and glial fibrillary acidic protein demonstrate high between-subject variation, the impact of which will depend on clinical context. Reference change values can potentially be useful in monitoring early disease progression and the safety/efficacy of interventions on an individual level. Serial sampling revealed that unexpectedly high values in heathy individuals can be observed, which urges caution when interpreting AD plasma biomarkers based on a single test result., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau 181 , p-tau 217 and p-tau 231 with established immunoassay techniques., Methods: We measured p-tau 181 , p-tau 217 and p-tau 231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland-Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau 181 , p-tau 217 and p-tau 231 . P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity., Results: Mass spectrometry and immunoassays of p-tau 217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau 181 and p-tau 231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays., Conclusions: Our results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification., (© 2023. The Author(s).)

Post-mortem staging of Alzheimer's disease (AD) neurofibrillary pathology is commonly performed by immunohistochemistry using AT8 antibody for phosphorylated tau (p-tau) at positions 202/205. Thus, quantification of p-tau205 and p-tau202 in cerebrospinal fluid (CSF) should be more reflective of neurofibrillary tangles in AD than other p-tau epitopes. We developed two novel Simoa immunoassays for CSF p-tau205 and p-tau202 and measured these phosphorylations in three independent cohorts encompassing the AD continuum, non-AD cases and cognitively unimpaired participants: a discovery cohort (n = 47), an unselected clinical cohort (n = 212) and a research cohort well-characterized by fluid and imaging biomarkers (n = 262). CSF p-tau205 increased progressively across the AD continuum, while CSF p-tau202 was increased only in AD and amyloid (Aβ) and tau pathology positive (A+T+) cases (P < 0.01). In A+ cases, CSF p-tau205 and p-tau202 showed stronger associations with tau-PET (r Sp205  = 0.67, r Sp202  = 0.45) than Aβ-PET (r Sp205  = 0.40, r Sp202  = 0.09). CSF p-tau205 increased gradually across tau-PET Braak stages (P < 0.01), whereas p-tau202 only increased in Braak V-VI (P < 0.0001). Both showed stronger regional associations with tau-PET than with Aβ-PET, and CSF p-tau205 was significantly associated with Braak V-VI tau-PET regions. When assessing the contribution of Aβ and tau pathologies (indexed by PET) to CSF p-tau205 and p-tau202 variance, tau pathology was found to be the most prominent contributor in both cases (CSF p-tau205: R 2  = 69.7%; CSF p-tau202: R 2  = 85.6%) Both biomarkers associated with brain atrophy measurements globally (r Sp205  = - 0.36, r Sp202  = - 0.33) and regionally, and correlated with cognition (r Sp205  = - 0.38/- 0.40, r Sp202  = - 0.20/- 0.29). In conclusion, we report the first high-throughput CSF p-tau205 immunoassay for the in vivo quantification of tau pathology in AD, and a potentially cost-effective alternative to tau-PET in clinical settings and clinical trials., (© 2024. The Author(s).)

Introduction: Fluid biomarkers capable of specifically tracking tau tangle pathology in vivo are greatly needed., Methods: We measured cerebrospinal fluid (CSF) and plasma concentrations of N-terminal tau fragments (NTA-tau), using a novel immunoassay (NTA) in the TRIAD cohort, consisting of 272 individuals assessed with amyloid beta (Aβ) positron emission tomography (PET), tau PET, magnetic resonance imaging (MRI) and cognitive assessments., Results: CSF and plasma NTA-tau concentrations were specifically increased in cognitively impaired Aβ-positive groups. CSF and plasma NTA-tau concentrations displayed stronger correlations with tau PET than with Aβ PET and MRI, both in global uptake and at the voxel level. Regression models demonstrated that both CSF and plasma NTA-tau are preferentially associated with tau pathology. Moreover, plasma NTA-tau was associated with longitudinal tau PET accumulation across the aging and Alzheimer's disease (AD) spectrum., Discussion: NTA-tau is a biomarker closely associated with in vivo tau deposition in the AD continuum and has potential as a tau tangle biomarker in clinical settings and trials., Highlights: An assay for detecting N-terminal tau fragments (NTA-tau) in plasma and CSF was evaluated. NTA-tau is more closely associated with tau PET than amyloid PET or neurodegeneration. NTA-tau can successfully track in vivo tau deposition across the AD continuum. Plasma NTA-tau increased over time only in cognitively impaired amyloid-β positive individuals., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears., Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages., Results: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss., Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation., (© 2023. The Author(s).)

Importance: Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms., Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum., Design, Setting, and Participants: This cross-sectional study was conducted from January to June 2023, leveraging data from the Translational Biomarkers in Aging and Dementia cohort at McGill University, Canada. Recruitment was based on referrals of individuals from the community or from outpatient clinics. Exclusion criteria included active substance abuse, major surgery, recent head trauma, safety contraindications for positron emission tomography (PET) or magnetic resonance imaging, being currently enrolled in other studies, and having inadequately treated systemic conditions., Main Outcomes and Measures: All individuals underwent assessment for neuropsychiatric symptoms (Neuropsychiatry Inventory Questionnaire [NPI-Q]), and imaging for microglial activation ([11C]PBR28 PET), amyloid-β ([18F]AZD4694 PET), and tau tangles ([18F]MK6240 PET)., Results: Of the 109 participants, 72 (66%) were women and 37 (34%) were men; the median age was 71.8 years (range, 38.0-86.5 years). Overall, 70 had no cognitive impairment and 39 had cognitive impairment (25 mild; 14 Alzheimer disease dementia). Amyloid-β PET positivity was present in 21 cognitively unimpaired individuals (30%) and in 31 cognitively impaired individuals (79%). The NPI-Q severity score was associated with microglial activation in the frontal, temporal, and parietal cortices (β = 7.37; 95% CI, 1.34-13.41; P = .01). A leave-one-out approach revealed that irritability was the NPI-Q domain most closely associated with the presence of brain microglial activation (β = 6.86; 95% CI, 1.77-11.95; P = .008). Furthermore, we found that microglia-associated irritability was associated with study partner burden measured by NPI-Q distress score (β = 5.72; 95% CI, 0.33-11.10; P = .03)., Conclusions and Relevance: In this cross-sectional study of 109 individuals across the AD continuum, microglial activation was associated with and a potential biomarker of neuropsychiatric symptoms in Alzheimer disease. Moreover, our findings suggest that the combination of amyloid-β- and microglia-targeted therapies could have an impact on relieving these symptoms.

Introduction: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed., Methods: We assessed the diagnostic performance of p-tau 181 , p-tau 217 , and p-tau 231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid-PET and tau-PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid-PET and tau-PET positivity., Results: Plasma p-tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p-tau. Plasma p-tau 181 (AUC = 76%) and p-tau 231 (AUC = 82%) assessments performed inferior to CSF p-tau 181 (AUC = 87%) and p-tau 231 (AUC = 95%) for amyloid-PET positivity. However, plasma p-tau 217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid-PET positivity., Discussion: Plasma and CSF p-tau 217 had equivalent diagnostic performance for biomarker-defined AD. Our results suggest that plasma p-tau 217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD., Highlights: p-tau 217 in plasma performed equivalent to p-tau 217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p-tau 217 is not offset by lower accuracy. p-tau biomarkers in plasma had lower mean fold-changes between amyloid-PET negative and positive groups than p-tau biomarkers in CSF. CSF p-tau biomarkers had greater effect sizes than plasma p-tau biomarkers when differentiating between amyloid-PET positive and negative groups. Plasma p-tau 181 and plasma p-tau 231 performed worse than p-tau 181 and p-tau 231 in CSF for AD diagnosis., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan. We found that APOEε4 carriership potentiates Aβ effects on longitudinal tau accumulation over 2 years. The APOEε4-potentiated Aβ effects on tau-PET burden were mediated by longitudinal plasma phosphorylated tau at threonine 217 (p-tau217 + ) increase. This longitudinal tau accumulation as measured by PET was accompanied by brain atrophy and clinical decline. Our results suggest that the APOEε4 allele plays a key role in Aβ downstream effects on the aggregation of phosphorylated tau in the living human brain., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-β (Aβ) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aβ and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI)., Methods: We assessed 138 CU and 87 CI with available plasma p-tau231, 217 + , and 181, Aβ42/40, GFAP and Aβ- and tau-PET., Results: In CU, only plasma p-tau231 and p-tau217 + significantly improved the performance of the demographics in detecting Aβ-PET positivity, while no plasma biomarker provided additional information to identify tau-PET positivity. In CI, p-tau217 + and GFAP significantly contributed to demographics to identify both Aβ-PET and tau-PET positivity, while p-tau231 only provided additional information to identify tau-PET positivity., Discussion: Our results support plasma p-tau231 and p-tau217 + as state markers of early Aβ deposition, but in later disease stages they inform on tau tangle accumulation., Highlights: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex). Plasma p-tau231 and p-tau217 + contribute to demographic information to identify brain Aβ pathology in preclinical AD. In CI individuals, plasma p-tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p-tau217 + and GFAP inform on both Aβ deposition and tau pathology., (© 2023 the Alzheimer's Association.)

Introduction: Amyloid-β (Aβ) and tau can be quantified in blood. However, biological factors can influence the levels of brain-derived proteins in the blood. The blood-brain barrier (BBB) regulates protein transport between cerebrospinal fluid (CSF) and blood. BBB altered permeability might affect the relationship between brain and blood biomarkers., Methods: We assessed 224 participants in research (TRIAD, n = 96) and clinical (BIODEGMAR, n = 128) cohorts with plasma and CSF/positron emission tomography Aβ, p-tau, and albumin measures., Results: Plasma Aβ 42/40 better identified CSF Aβ 42/40 and Aβ-PET positivity in individuals with high BBB permeability. An interaction between plasma Aβ 42/40 and BBB permeability on CSF Aβ 42/40 was observed. Voxel-wise models estimated that the association of positron emission tomography (PET), with plasma Aβ was most affected by BBB permeability in AD-related brain regions. BBB permeability did not significantly impact the relationship between brain and plasma p-tau levels., Discussion: These findings suggest that BBB integrity may influence the performance of plasma Aβ, but not p-tau, biomarkers in research and clinical settings., Highlights: BBB permeability affects the association between brain and plasma Aβ levels. BBB integrity does not affect the association between brain and plasma p-tau levels. Plasma Aβ was most affected by BBB permeability in AD-related brain regions. BBB permeability increases with age but not according to cognitive status., (© 2023 the Alzheimer's Association.)

Cost-effective strategies for identifying amyloid-β (Aβ) positivity in patients with cognitive impairment are urgently needed with recent approvals of anti-Aβ immunotherapies for Alzheimer's disease (AD). Blood biomarkers can accurately detect AD pathology, but it is unclear whether their incorporation into a full diagnostic workflow can reduce the number of confirmatory cerebrospinal fluid (CSF) or positron emission tomography (PET) tests needed while accurately classifying patients. We evaluated a two-step workflow for determining Aβ-PET status in patients with mild cognitive impairment (MCI) from two independent memory clinic-based cohorts (n = 348). A blood-based model including plasma tau protein 217 (p-tau217), age and APOE ε4 status was developed in BioFINDER-1 (area under the curve (AUC) = 89.3%) and validated in BioFINDER-2 (AUC = 94.3%). In step 1, the blood-based model was used to stratify the patients into low, intermediate or high risk of Aβ-PET positivity. In step 2, we assumed referral only of intermediate-risk patients to CSF Aβ42/Aβ40 testing, whereas step 1 alone determined Aβ-status for low- and high-risk groups. Depending on whether lenient, moderate or stringent thresholds were used in step 1, the two-step workflow overall accuracy for detecting Aβ-PET status was 88.2%, 90.5% and 92.0%, respectively, while reducing the number of necessary CSF tests by 85.9%, 72.7% and 61.2%, respectively. In secondary analyses, an adapted version of the BioFINDER-1 model led to successful validation of the two-step workflow with a different plasma p-tau217 immunoassay in patients with cognitive impairment from the TRIAD cohort (n = 84). In conclusion, using a plasma p-tau217-based model for risk stratification of patients with MCI can substantially reduce the need for confirmatory testing while accurately classifying patients, offering a cost-effective strategy to detect AD in memory clinic settings., (© 2023. The Author(s).)

Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β 42 , phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans., Competing Interests: E.R.Z. is a member of the scientific advisory board of Next Innovative Therapeutics (Nintx) and co-founder and member of the scientific advisory board of Masima. The other authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objective: To test the utility of longitudinal changes in plasma phosphorylated tau 181 (p-tau181) and neurofilament light chain (NfL) as surrogate markers for clinical trials targeting cognitively unimpaired (CU) populations., Methods: We estimated the sample size needed to test a 25% drug effect with 80% of power at a 0.05 level on reducing changes in plasma markers in CU participants from Alzheimer's Disease Neuroimaging Initiative database., Results: We included 257 CU individuals (45.5% males; mean age = 73 [6] years; 32% β-amyloid [Aβ] positive). Changes in plasma NfL were associated with age, whereas changes in plasma p-tau181 with progression to amnestic mild cognitive impairment. Clinical trials using p-tau181 and NfL would require 85% and 63% smaller sample sizes, respectively, for a 24-month than a 12-month follow-up. A population enrichment strategy using intermediate levels of Aβ PET (Centiloid 20-40) further reduced the sample size of the 24-month clinical trial using p-tau181 (73%) and NfL (59%) as a surrogate., Discussion: Plasma p-tau181/NfL can potentially be used to monitor large-scale population interventions in CU individuals. The enrollment of CU with intermediate Aβ levels constitutes the alternative with the largest effect size and most cost-effective for trials testing drug effect on changes in plasma p-tau181 and NfL., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

An unresolved question for the understanding of Alzheimer's disease (AD) pathophysiology is why a significant percentage of amyloid-β (Aβ)-positive cognitively unimpaired (CU) individuals do not develop detectable downstream tau pathology and, consequently, clinical deterioration. In vitro evidence suggests that reactive astrocytes unleash Aβ effects in pathological tau phosphorylation. Here, in a biomarker study across three cohorts (n = 1,016), we tested whether astrocyte reactivity modulates the association of Aβ with tau phosphorylation in CU individuals. We found that Aβ was associated with increased plasma phosphorylated tau only in individuals positive for astrocyte reactivity (Ast + ). Cross-sectional and longitudinal tau-positron emission tomography analyses revealed an AD-like pattern of tau tangle accumulation as a function of Aβ only in CU Ast + individuals. Our findings suggest astrocyte reactivity as an important upstream event linking Aβ with initial tau pathology, which may have implications for the biological definition of preclinical AD and for selecting CU individuals for clinical trials., (© 2023. The Author(s).)

Blood phosphorylated tau (p-tau) biomarkers, at differing sites, demonstrate high accuracy to detect Alzheimer's disease (AD). However, knowledge on the optimal marker for disease identification across the AD continuum and the link to pathology is limited. This is partly due to heterogeneity in analytical methods. In this study, we employed an immunoprecipitation mass spectrometry method to simultaneously quantify six phosphorylated (p-tau181, p-tau199, p-tau202, p-tau205, p-tau217 and p-tau231) and two non-phosphorylated plasma tau peptides in a total of 214 participants from the Paris Lariboisière and Translational Biomarkers of Aging and Dementia cohorts. Our results indicate that p-tau217, p-tau231 and p-tau205 are the plasma tau forms that best reflect AD-related brain changes, although with distinct emergences along the disease course and correlations with AD features-amyloid and tau. These findings support the differential association of blood p-tau variants with AD pathology, and our method offers a potential tool for disease staging in clinical trials., (© 2023. The Author(s).)

Introduction: In Alzheimer's disease clinical research, glial fibrillary acidic protein (GFAP) released/leaked into the cerebrospinal fluid and blood is widely measured and perceived as a biomarker of reactive astrogliosis. However, it was demonstrated that GFAP levels differ in individuals presenting with amyloid-β (Aβ) or tau pathologies. The molecular underpinnings behind this specificity are little explored. Here we investigated biomarker and transcriptomic associations of hippocampal GFAP-positive astrocytes with Aβ and tau pathologies in humans and mouse models., Methods: We studied 90 individuals with plasma GFAP, Aβ- and Tau-PET to investigate the association between biomarkers. Then, transcriptomic analysis in hippocampal GFAP-positive astrocytes isolated from mouse models presenting Aβ (PS2APP) or tau (P301S) pathologies was conducted to explore differentially expressed genes (DEGs), Gene Ontology terms, and protein-protein interaction networks associated with each phenotype., Results: In humans, we found that plasma GFAP associates with Aβ but not tau pathology. Unveiling the unique nature of hippocampal GFAP-positive astrocytic responses to Aβ or tau pathologies, mouse transcriptomics showed scarce overlap of DEGs between the Aβ. and tau mouse models. While Aβ GFAP-positive astrocytes were overrepresented with DEGs associated with proteostasis and exocytosis-related processes, tau hippocampal GFAP-positive astrocytes presented greater abnormalities in functions related to DNA/RNA processing and cytoskeleton dynamics., Conclusion: Our results offer insights into Aβ- and tau-driven specific signatures in hippocampal GFAP-positive astrocytes. Characterizing how different underlying pathologies distinctly influence astrocyte responses is critical for the biological interpretation of astrocyte biomarkers and suggests the need to develop context-specific astrocyte targets to study AD., Funding: This study was supported by Instituto Serrapilheira, Alzheimer's Association, CAPES, CNPq and FAPERGS., Competing Interests: Declaration of Competing Interest ERZ serves in the scientific advisory board of Next Innovative Therapeutics (Nintx). HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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.)

Animal studies suggest that the apolipoprotein E ε4 ( APOE ε4) allele is a culprit of early microglial activation in Alzheimer's disease (AD). Here, we tested the association between APOE ε4 status and microglial activation in living individuals across the aging and AD spectrum. We studied 118 individuals with positron emission tomography for amyloid-β (Aβ; [ 18 F]AZD4694), tau ([ 18 F]MK6240), and microglial activation ([ 11 C]PBR28). We found that APOE ε4 carriers presented increased microglial activation relative to noncarriers in early Braak stage regions within the medial temporal cortex accounting for Aβ and tau deposition. Furthermore, microglial activation mediated the Aβ-independent effects of APOE ε4 on tau accumulation, which was further associated with neurodegeneration and clinical impairment. The physiological distribution of APOE mRNA expression predicted the patterns of APOE ε4-related microglial activation in our population, suggesting that APOE gene expression may regulate the local vulnerability to neuroinflammation. Our results support that the APOE ε4 genotype exerts Aβ-independent effects on AD pathogenesis by activating microglia in brain regions associated with early tau deposition.

Importance: Blood phosphorylated tau (p-tau) and amyloid-β peptides (Aβ) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known., Objective: To evaluate whether the levels and trajectories of blood p-tau, Aβ42, and Aβ40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest., Design, Setting, and Participants: This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aβ42, and Aβ40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest., Exposures: Serum p-tau, Aβ42, and Aβ40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators., Main Outcomes and Measures: Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death)., Results: This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aβ42 and Aβ40 concentrations increased over time in most patients but were only weakly associated with neurological outcome., Conclusions and Relevance: In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aβ peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Background: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome., Methods: We performed a three-centre study of adults with Down syndrome, autosomal dominant Alzheimer's disease and euploid individuals enrolled in Hospital Sant Pau, Barcelona (Spain), Hospital Clinic, Barcelona (Spain) and Ludwig-Maximilians-Universität, Munich (Germany). Cerebrospinal fluid (CSF) and plasma GFAP concentrations were quantified using Simoa. A subset of participants had PET 18 F-fluorodeoxyglucose, amyloid tracers and MRI measurements., Findings: This study included 997 individuals, 585 participants with Down syndrome, 61 Familial Alzheimer's disease mutation carriers and 351 euploid individuals along the Alzheimer's disease continuum, recruited between November 2008 and May 2022. Participants with Down syndrome were clinically classified at baseline as asymptomatic, prodromal Alzheimer's disease and Alzheimer's disease dementia. Plasma GFAP levels were significantly increased in prodromal and Alzheimer's disease dementia compared to asymptomatic individuals and increased in parallel to CSF Aβ changes, ten years prior to amyloid PET positivity. Plasma GFAP presented the highest diagnostic performance to discriminate symptomatic from asymptomatic groups (AUC = 0.93, 95% CI 0.9-0.95) and its concentrations were significantly higher in progressors vs non-progressors (p < 0.001), showing an increase of 19.8% (11.8-33.0) per year in participants with dementia. Finally, plasma GFAP levels were highly correlated with cortical thinning and brain amyloid pathology., Interpretation: Our findings support the utility of plasma GFAP as a biomarker of Alzheimer's disease in adults with Down syndrome, with possible applications in clinical practice and clinical trials., Funding: AC Immune, La Caixa Foundation, Instituto de Salud Carlos III, National Institute on Aging, Wellcome Trust, Jérôme Lejeune Foundation, Medical Research Council, Alzheimer's Association, National Institute for Health Research, EU Joint Programme-Neurodegenerative Disease Research, Alzheimer's Society, Deutsche Forschungsgemeinschaft, Stiftung für die Erforschung von Verhaltens, Fundación Tatiana Pérez de Guzmán el Bueno & European Union's Horizon 2020 und Umwelteinflüssen auf die menschliche Gesundheit., Competing Interests: Declaration of interests JF has served as a consultant for Novartis and Lundbeck, has received honoraria for lectures from Roche, Novo Nordisk, Laboratorios Carnot, Nestle, Esteve and Biogen and served at advisory boards for AC Immune, Alzheon, Zambon and Lundbeck. DA participated in advisory boards from Fujirebio-Europe and Roche Diagnostics and received speaker honoraria from Fujirebio-Europe, Roche Diagnostics, Nutricia, Krka Farmacéutica S.L., Zambon S.A.U. and Esteve Pharmaceuticals S.A. JF, DA and ALL declare a filed patent sapplication (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). NJA has given lectures in sponsored symposia by Roche and Eli Lily. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, BioArctic, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Ono Pharma, Pharmatrophix, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. AL has served at scientific advisory boards from Fujirebio-Europe, Nutricia, Roche-Genentech, Biogen, Grifols and Roche Diagnostics and has filed a patent application of synaptic markers in neurodegenerative diseases (WO2019175379 A1 Markers of synaptopathy in neurodegenerative disease). HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Annexon, Artery Therapeutics, AZTherapies, CogRx, Denali, Eisai, Nervgen, Novo Nordisk, Pinteon Therapeutics, Red Abbey Labs, Passage Bio, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, Biogen, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work)., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

6-(fluoro- 18 F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([ 18 F]MK6240) tau PET tracer quantifies the brain tau neurofibrillary tangle load in Alzheimer disease. The aims of our study were to test the stability of common reference region estimates in the cerebellum over time and across diagnoses and evaluate the effects of age-related and off-target retention on the longitudinal quantification of [ 18 F]MK6240 in target regions. Methods: We assessed reference, target, age-related, and off-target regions in 125 individuals across the aging and Alzheimer disease spectrum with longitudinal [ 18 F]MK6240 SUVs and SUV ratios (SUVRs) (mean ± SD, 2.25 ± 0.40 y of follow-up). We obtained SUVR from meninges, exhibiting frequent off-target retention with [ 18 F]MK6240. Additionally, we compared tracer uptake between 37 cognitively unimpaired young (CUY) (mean age, 23.41 ± 3.33 y) and 27 cognitively unimpaired older (CU) adults (amyloid-β-negative and tau-negative, 58.50 ± 9.01 y) to identify possible nonvisually apparent, age-related signal. Two-tailed t testing and Pearson correlation testing were used to determine the difference between groups and associations between changes in region uptake, respectively. Results: Inferior cerebellar gray matter SUV did not differ on the basis of diagnosis and amyloid-β status, cross-sectionally and over time. [ 18 F]MK6240 uptake significantly differed between CUY and CU adults in the putamen or pallidum (affecting ∼75% of the region) and in the Braak II region (affecting ∼35%). Changes in meningeal and putamen or pallidum SUVRs did not significantly differ from zero, nor did they vary across diagnostic groups. We did not observe significant correlations between longitudinal changes in age-related or meningeal off-target retention and changes in target regions, whereas changes in all target regions were strongly correlated. Conclusion: Inferior cerebellar gray matter was similar across diagnostic groups cross-sectionally and stable over time and thus was deemed a suitable reference region for quantification. Despite not being visually perceptible, [ 18 F]MK6240 has age-related retention in subcortical regions, at a much lower magnitude but topographically colocalized with significant off-target signal of the first-generation tau tracers. The lack of correlation between changes in age-related or meningeal and target retention suggests little influence of possible off-target signals on longitudinal tracer quantification. Nevertheless, the age-related retention in the Braak II region needs to be further investigated. Future postmortem studies should elucidate the source of the newly reported age-related [ 18 F]MK6240 signal, and in vivo studies should further explore its impact on tracer quantification., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Importance: The recent proliferation of phosphorylated tau (p-tau) biomarkers has raised questions about their preferential association with the hallmark pathologies of Alzheimer disease (AD): amyloid-β plaques and tau neurofibrillary tangles., Objective: To determine whether cerebrospinal fluid (CSF) and plasma p-tau biomarkers preferentially reflect cerebral β-amyloidosis or neurofibrillary tangle aggregation measured with positron emission tomography (PET)., Design, Setting, and Participants: This was a cross-sectional study of 2 observational cohorts: the Translational Biomarkers in Aging and Dementia (TRIAD) study, with data collected between October 2017 and August 2021, and the Alzheimer's Disease Neuroimaging Initiative (ADNI), with data collected between September 2015 and November 2019. TRIAD was a single-center study, and ADNI was a multicenter study. Two independent subsamples were derived from TRIAD. The first TRIAD subsample comprised individuals assessed with CSF p-tau (p-tau181, p-tau217, p-tau231, p-tau235), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. The second TRIAD subsample included individuals assessed with plasma p-tau (p-tau181, p-tau217, p-tau231), [18F]AZD4694 amyloid PET, and [18F]MK6240 tau PET. An independent cohort from ADNI comprised individuals assessed with CSF p-tau181, [18F]florbetapir PET, and [18F]flortaucipir PET. Participants were included based on the availability of p-tau and PET biomarker assessments collected within 9 months of each other. Exclusion criteria were a history of head trauma or magnetic resonance imaging/PET safety contraindications. No participants who met eligibility criteria were excluded., Exposures: Amyloid PET, tau PET, and CSF and plasma assessments of p-tau measured with single molecule array (Simoa) assay or enzyme-linked immunosorbent assay., Main Outcomes and Measures: Associations between p-tau biomarkers with amyloid PET and tau PET., Results: A total of 609 participants (mean [SD] age, 66.9 [13.6] years; 347 female [57%]; 262 male [43%]) were included in the study. For all 4 phosphorylation sites assessed in CSF, p-tau was significantly more closely associated with amyloid-PET values than tau-PET values (p-tau181 difference, 13%; 95% CI, 3%-22%; P = .006; p-tau217 difference, 11%; 95% CI, 3%-20%; P = .003; p-tau231 difference, 15%; 95% CI, 5%-22%; P < .001; p-tau235 difference, 9%; 95% CI, 1%-19%; P = .02) . These results were replicated with plasma p-tau181 (difference, 11%; 95% CI, 1%-22%; P = .02), p-tau217 (difference, 9%; 95% CI, 1%-19%; P = .02), p-tau231 (difference, 13%; 95% CI, 3%-24%; P = .009), and CSF p-tau181 (difference, 9%; 95% CI, 1%-21%; P = .02) in independent cohorts., Conclusions and Relevance: Results of this cross-sectional study of 2 observational cohorts suggest that the p-tau abnormality as an early event in AD pathogenesis was associated with amyloid-β accumulation and highlights the need for careful interpretation of p-tau biomarkers in the context of the amyloid/tau/neurodegeneration, or A/T/(N), framework.

Background: Alterations in the endocannabinoid system (ES) have been described in Alzheimer's disease (AD) pathophysiology. In the past years, multiple ES biomarkers have been developed, promising to advance our understanding of ES changes in AD. Discussion: ES biomarkers, including positron emission tomography with cannabinoid receptors tracers and biofluid-based endocannabinoids, are associated with AD disease progression and pathological features. Conclusion: Although not specific enough for AD diagnosis, ES biomarkers hold promise for prognosis, drug-target engagement, and a better understanding of the disease. Here, we summarize currently available ES biomarker findings and discuss their potential applications in the AD research field.

Introduction: The optimal combination of amyloid-β/tau/neurodegeneration (A/T/N) biomarker profiles for the diagnosis of Alzheimer's disease (AD) dementia is unclear., Methods: We examined the discriminative accuracy of A/T/N combinations assessed with neuroimaging biomarkers for the differentiation of AD from cognitively unimpaired (CU) elderly and non-AD neurodegenerative diseases in the TRIAD, BioFINDER-1 and BioFINDER-2 cohorts (total n  = 832) using area under the receiver operating characteristic curves (AUC)., Results: For the diagnosis of AD dementia (vs. CU elderly), T biomarkers performed as well as the complete A/T/N system (AUC range: 0.90-0.99). A and T biomarkers in isolation performed as well as the complete A/T/N system in differentiating AD dementia from non-AD neurodegenerative diseases (AUC range; A biomarker: 0.84-1; T biomarker: 0.83-1)., Discussion: In diagnostic settings, the use of A or T neuroimaging biomarkers alone can reduce patient burden and medical costs compared with using their combination, without significantly compromising accuracy., Competing Interests: O.H. 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/speaker fees from Alzpath, Biogen, Cerveau and Roche. S.G. has served as a scientific advisor to Cerveau Technologies, Inc. A.L. is a scientific advisor to Cerveau Technologies, Inc. T.A.P., J.T., M.C., F.L., C.T., O.S., S.P., E.S., P.C.L.F., J.P.‐F.S., R.S., A.L.B. and P.‐R.N. declare no competing interests. Author disclosures are available in the supporting information., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background and Objectives: To test the associations between the presynaptic growth-associated protein 43 (GAP-43), quantified in CSF, and biomarkers of Alzheimer disease (AD) pathophysiology, cross-sectionally and longitudinally., Methods: In this retrospective study, GAP-43 was measured in participants from the AD Neuroimaging Initiative (ADNI) cohort using an in-house ELISA method, and levels were compared between groups, both cross-sectionally and longitudinally. Linear regression models tested the associations between biomarkers of AD (amyloid beta [Aβ] and tau pathologies, neurodegeneration, and cognition) adjusted by age, sex, and diagnosis. Linear mixed-effect models evaluated how baseline GAP-43 predicts brain hypometabolism, atrophy, and cognitive decline over time. Cox proportional hazard regression models tested how GAP-43 levels and Aβ status, at baseline, increased the risk of progression to AD dementia over time., Results: This study included 786 participants from the ADNI cohort, which were further classified in cognitively unimpaired (CU) Aβ-negative (n CU- = 197); CU Aβ-positive (n CU+ = 55), mild cognitively impaired (MCI) Aβ-negative (n MCI- = 228), MCI Aβ-positive (n MCI+ = 193), and AD dementia Aβ-positive (n AD = 113). CSF GAP-43 levels were increased in Aβ-positive compared with Aβ-negative participants, independent of the cognitive status. In Aβ-positive participants, high baseline GAP-43 levels led to worse brain metabolic decline ( p = 0.01), worse brain atrophy ( p = 8.8 × 10 -27 ), and worse MMSE scores ( p = 0.03) over time, as compared with those with low GAP-43 levels. Similarly, Aβ-positive participants with high baseline GAP-43 had the highest risk to convert to AD dementia (hazard ratio [HR = 8.56, 95% CI 4.94-14.80, p = 1.5 × 10 -14 ]). Despite the significant association with Aβ pathology (η 2 Aβ PET = 0.09, P Aβ PET < 0.001), CSF total tau (tTau) and phosphorylated tau (pTau) had a larger effect size on GAP43 than Aβ PET (η 2 pTau-181 = 0.53, P pTau-181 < 0.001; η 2 tTau = 0.59, P tTau < 0.001)., Discussion: High baseline levels of CSF GAP-43 are associated with progression in Aβ-positive individuals, with a more aggressive neurodegenerative process, faster rate of cognitive decline, and increased risk of converting to dementia., (© 2022 American Academy of Neurology.)

Introduction: Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer's disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms., Methods: In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aβ+], 10 Aβ+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aβ- individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [ 18 F]-AZD4694 and [ 18 F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay., Results: CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ-, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders (P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [ 18 F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181., Conclusion: The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease., (© 2022. The Author(s).)

Background: Alzheimer's disease is characterized by an abnormal increase of phosphorylated tau (pTau) species in the CSF. It has been suggested that emergence of different pTau forms may parallel disease progression. Therefore, targeting multiple specific pTau forms may allow for a deeper understanding of disease evolution and underlying pathophysiology. Current immunoassays measure pTau epitopes separately and may capture phosphorylated tau fragments of different length depending on the non-pTau antibody used in the assay sandwich pair, which bias the measurement., Methods: We developed the first antibody-free mass spectrometric method to simultaneously measure multiple phosphorylated epitopes in CSF tau: pT181, pS199, pS202, pT205, pT217, pT231, and pS396. The method was first evaluated in biochemically defined Alzheimer's disease and control CSF samples (n = 38). All seven pTau epitopes clearly separated Alzheimer's disease from non-AD (p < 0.001, AUC = 0.84-0.98). We proceeded with clinical validation of the method in the TRIAD (n = 165) and BioFINDER-2 cohorts (n = 563), consisting of patients across the full Alzheimer's disease continuum, including also young controls (< 40 years), as well as patients with frontotemporal dementia and other neurodegenerative disorders., Results: Increased levels of all phosphorylated epitopes were found in Alzheimer's disease dementia and Aβ positron emission tomography-positive patients with mild cognitive impairment compared with Aβ-negative controls. For Alzheimer's disease dementia compared with Aβ-negative controls, the best biomarker performance was observed for pT231 (TRIAD: AUC = 98.73%, fold change = 7.64; BioFINDER-2: AUC = 91.89%, fold change = 10.65), pT217 (TRIAD: AUC = 99.71%, fold change = 6.33; BioFINDER-2: AUC = 98.12%, fold change = 8.83) and pT205 (TRIAD: AUC = 99.07%, fold change = 5.34; BioFINDER-2: AUC = 93.51%, fold change = 3.92). These phospho-epitopes also discriminated between Aβ-positive and Aβ-negative cognitively unimpaired individuals: pT217 (TRIAD: AUC = 83.26, fold change = 2.39; BioFINDER-2: AUC = 91.05%, fold change = 3.29), pT231 (TRIAD: AUC = 86.25, fold change = 3.80; BioFINDER-2: AUC = 78.69%, fold change = 3.65) and pT205 (TRIAD: AUC = 71.58, fold change = 1.51; BioFINDER-2: AUC = 71.11%, fold change = 1.70)., Conclusions: While an increase was found for all pTau species examined, the highest fold change in Alzheimer's disease was found for pT231, pT217 and pT205. Simultaneous antibody-free measurement of pTau epitopes by mass spectrometry avoids possible bias caused by differences in antibody affinity for modified or processed forms of tau, provides insights into tau pathophysiology and may facilitate clinical trials on tau-based drug candidates., (© 2022. The Author(s).)

Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein (GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression., (© 2022. The Author(s).)

Purpose: Glial activation is one of the earliest mechanisms to be altered in Alzheimer's disease (AD). Glial fibrillary acidic protein (GFAP) relates to reactive astrogliosis and can be measured in both cerebrospinal fluid (CSF) and blood. Plasma GFAP has been suggested to become altered earlier in AD than its CSF counterpart. Although astrocytes consume approximately half of the glucose-derived energy in the brain, the relationship between reactive astrogliosis and cerebral glucose metabolism is poorly understood. Here, we aimed to investigate the association between fluorodeoxyglucose ([ 18 F]FDG) uptake and reactive astrogliosis, by means of GFAP quantified in both plasma and CSF for the same participants., Methods: We included 314 cognitively unimpaired participants from the ALFA + cohort, 112 of whom were amyloid-β (Aβ) positive. Associations between GFAP markers and [ 18 F]FDG uptake were studied. We also investigated whether these associations were modified by Aβ and tau status (AT stages)., Results: Plasma GFAP was positively associated with glucose consumption in the whole brain, while CSF GFAP associations with [ 18 F]FDG uptake were only observed in specific smaller areas like temporal pole and superior temporal lobe. These associations persisted when accounting for biomarkers of Aβ pathology but became negative in Aβ-positive and tau-positive participants (A + T +) in similar areas of AD-related hypometabolism., Conclusions: Higher astrocytic reactivity, probably in response to early AD pathological changes, is related to higher glucose consumption. With the onset of tau pathology, the observed uncoupling between astrocytic biomarkers and glucose consumption might be indicative of a failure to sustain the higher energetic demands required by reactive astrocytes., (© 2022. The Author(s).)