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Neuronal dysfunction and cognitive deterioration in Alzheimer's disease (AD) are likely caused by multiple pathophysiological factors. However, evidence in humans remains scarce, necessitating improved non-invasive techniques and integrative mechanistic models. Here, we introduce personalized brain activity models incorporating functional MRI, amyloid-β (Aβ) and tau-PET from AD-related participants ( N = 132 ) . Within the model assumptions, electrophysiological activity is mediated by toxic protein deposition. Our integrative 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). Furthermore, our results reproduce 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 phenotypes. Mechanistic brain activity models can further clarify intricate neurodegenerative processes and accelerate preventive/treatment interventions., Competing Interests: Competing interests HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, 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). KB has served as a consultant, at advisory boards, or at data monitoring committees for Acumen, ALZPath, BioArctic, Biogen, Eisai, Julius Clinical, Lilly, Novartis, Ono Pharma, 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. The other authors declare no competing interests.

Importance: Phosphorylated tau (pTau) is a specific blood biomarker for Alzheimer's disease (AD) pathology, with pTau217 considered to have the most utility. However, availability of pTau217 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 Single molecule array (Simoa) for plasma pTau217 (ALZpath) to detect AD pathology. To evaluate references ranges for abnormal Aβ across three selected cohorts., Design Setting Participants: Three single-centre observational cohorts were involved in the study: Translational Biomarkers in Aging and Dementia (TRIAD), Wisconsin Registry for Alzheimer's Prevention (WRAP), and Sant Pau Initiative on Neurodegeneration (SPIN). MRI, Aβ-PET, and tau-PET data were available for TRIAD and WRAP, while CSF biomarkers were additionally measured in a subset of TRIAD and SPIN. Plasma measurements of pTau181, pTau217 (ALZpath), pTau231, Aβ42/40, GFAP, and NfL, were available for all cohorts. Longitudinal blood biomarker data spanning 3 years for TRIAD and 8 years for WRAP were included., Exposures: MRI, Aβ-PET, tau-PET, CSF biomarkers (Aβ42/40 and pTau immunoassays) and plasma pTau217 (ALZpath Simoa)., Main Outcomes and Measures: The accuracy of plasma pTau217 for detecting abnormal amyloid and tau pathology. Longitudinal pTau217 change according to baseline pathology status., Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%]) were included in the study. High accuracy was observed in identifying elevated Aβ (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 significantly higher than other plasma biomarker combinations and comparable to CSF biomarkers. The detection of abnormal Aβ pathology using binary or three-range references yielded reproducible results. Longitudinally, plasma pTau217 showed an annual increase only in Aβ-positive individuals, with the highest increase observed in those with tau-positivity., Conclusions and Relevance: The ALZpath plasma pTau217 Simoa assay accurately identifies biological AD, comparable to CSF biomarkers, with reproducible cut-offs across cohorts. It detects longitudinal changes, including at the preclinical stage, and is the first widely available, accessible, and scalable blood test for pTau217 detection., Competing Interests: Conflicts of interest NJA has given lectures, produced educational materials, and participated in educational programs for Eli-Lily, BioArtic, Quanterix. DA reported receiving personal fees for advisory board services and/or speaker honoraria from Fujirebio-Europe, Roche, Nutricia, Krka Farmacéutica, Grifols S.A., Lilly, Zambon S.A.U. and Esteve, outside the submitted work. AL has served as a consultant or on advisory boards for Fujirebio-Europe, Roche, Biogen and Nutricia, outside the submitted work. JF reported receiving personal fees for service on the advisory boards, adjudication committees or speaker honoraria from AC Immune, Lilly, Lundbeck, Roche, Fujirebio and Biogen, outside the submitted work. DA, AL and JF report holding a patent for markers of synaptopathy in neurodegenerative disease (licensed to ADx, EPI8382175.0). SCJ has served at scientific advisory boards for Roche Diagnostics, ALZPath, Prothena and Merck in the last three years and has received research funding from Cerveau Technologies. KB has served as a consultant and at advisory boards for Acumen, ALZPath, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, 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 AC Immune, Biogen, Celdara Medical, 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. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Annexon, Apellis, Artery Therapeutics, AZTherapies, 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).

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).)

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.)

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 are key to unleashing Aβ effects in pathological tau phosphorylation. In a large study ( n =1,016) across three cohorts, we tested whether astrocyte reactivity modulates the association of Aβ with plasma tau phosphorylation in CU people. We found that Aβ pathology was associated with increased plasma phosphorylated tau levels only in individuals positive for astrocyte reactivity (Ast+). Cross-sectional and longitudinal tau-PET analysis revealed that tau tangles accumulated as a function of Aβ burden only in CU Ast+ individuals with a topographic distribution compatible with early AD. Our findings suggest that increased astrocyte reactivity is an important upstream event linking Aβ burden with initial tau pathology which might have implications for the biological definition of preclinical AD and for selecting individuals for early preventive clinical trials.

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).)

Background: Tau in Alzheimer's disease (AD) is assessed via cerebrospinal fluid (CSF) and Positron emission tomography (PET). Novel methods to detect phosphorylated tau (pTau) in blood have been recently developed. We aim to investigate agreement of tau status as determined by [ 18 F]MK6240 tau-PET, plasma pTau181 and pTau231., Methods: We assessed cognitively unimpaired young, cognitively unimpaired, mild cognitive impairment and AD individuals with [ 18 F]MK6240, plasma pTau181, pTau 231, [ 18 F]AZD4694 amyloid-PET and MRI. A subset underwent CSF assessment. We conducted ROC curves to obtain cut-off values for plasma pTau epitopes. Individuals were categorized as positive or negative in all biomarkers. We then compared the distribution among concordant and discordant groups in relation to diagnosis, Aβ status, APOEε4 status, [ 18 F]AZD4694 global SUVR, hippocampal volume and CSF pTau181., Findings: The threshold for positivity was 15.085 pg/mL for plasma pTau181 and 17.652 pg/mL for plasma pTau231. Most individuals had concordant statuses, however, 18% of plasma181/PET, 26% of plasma231/PET and 25% of the pTau231/pTau181 were discordant. Positivity to at least one biomarker was often accompanied by diagnosis of cognitive impairment, Aβ positivity, APOEε4 carriership, higher levels of [ 18 F]AZD4694 global SUVR, hippocampal atrophy and CSF pTau181., Interpretation: Plasma pTau181, pTau231 and [ 18 F]MK6240 seem to reflect different stages of tau progression. Plasma biomarkers can be useful in the context of diagnostic information and clinical trials, to evaluate the disease stage. Moreover, they seem to confidently evaluate tau-PET positivity., Funding: Moreover, this study was supported by Weston Brain Institute, Canadian Institute of Health Research and Fonds de Recherche du Québec., Competing Interests: Declaration of interests Nothing to disclose., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)