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Importance Phosphorylated tau-217 (p-tau217) is now an established plasma biomarker for assessing amyloid-β pathology in individuals at risk of Alzheimer disease. However, its performance in identifying advanced neocortical neurofibrillary tangle burden remains suboptimal. Precise assessment of tau pathology is increasingly critical for the rational implementation of anti-amyloid therapies and developing anti-tau interventions. Improved biofluid biomarker-based tau staging could enhance patient stratification and optimize participant selection for clinical care and therapeutic trials. Objective To develop and validate a multiprotein plasma panel to improve identification of neocortical tau pathology beyond p-tau217 alone. Design, Setting, and Participants This multicenter cohort study included 2 independent observational cohorts, Swedish BioFINDER study and Translational Biomarkers in Aging and Dementia (TRIAD). Cross-sectional clinical data and blood samples were collected between 2017 and 2024. Participants included 560 individuals spanning the clinical spectrum from cognitively unimpaired to dementia. These data were analyzed from January 2025 to May 2026. Exposures Plasma concentrations of 125 proteins measured using Nucleic Linked Immuno-Sandwich Assay central nervous system panel. Main Outcome and Measure Advanced tau pathology defined as tau positron emission tomography (PET) uptake within Braak stage V and VI regions. Predictive performance of biomarker models was evaluated using area under the receiver operating characteristic curve (AUC). Results The study included 560 amyloid-positive participants (BioFINDER: n = 431; mean [SD] age, 73.6 [7.0] years; 212 female [49.2%] and 219 male [51.8%]; TRIAD: n = 129; mean [SD] age, 70.4 [8.3] years; 76 female [58.9%] and 53 male [41.1%]). Using multivariable logistic regression approaches, a 7-protein panel was found in BioFINDER to identify tau PET uptake within Braak stage V and VI regions. When compared with p-tau217 (AUC, 0.86-0.88; 95% CI, 0.82-0.94), this multiprotein panel was associated with improved identification in both discovery and validation cohorts (AUC, 0.92-0.94; 95% CI, 0.89-0.98; DeLong P < .001). This reduced the proportion of individuals classified within the intermediate-risk range (between paired sensitivity and specificity thresholds) in the validation cohort by 14.7% to 21.0%. Conclusions and Relevance This multicohort study demonstrated how including additional plasma proteins significantly enhanced the performance of p-tau217 in predicting advanced tau pathology among amyloid-positive individuals. This suggests a multiprotein approach may offer a viable and scalable alternative to tau PET staging in clinical or research settings.
ABSTRACT Pseudomonas aeruginosa (P.a) is a clinically important opportunistic pathogen capable of adapting and surviving a wide range of environments and stress conditions. A central regulator of this adaptability is the stringent response, mediated by the alarmones (p)ppGpp. Activation of the stringent response triggers a global physiological shift away from active metabolism toward stress management and cellular quiescence, a key transition to stationary phase. To date, few studies have investigated the protein-level processes under stringent response control. In this study, we performed shotgun proteomic profiling (LC-MS/MS) of a (p)ppGpp-null relA spoT double knockout mutant (ΔSR) and its isogenic PAO1 parent during late exponential and stationary phase planktonic growth in rich medium. In this first characterization of the stringent response proteome in P.a, we identified 146 differentially abundant proteins (DAP) in late exponential phase ΔSR cells, and 2.3-fold greater DAP (339) in stationary-phase cells. Functional characterization and system-level analysis of the differentially abundant stationary phase proteome highlighted the key role of (p)ppGpp in shutting down a wide range of metabolic processes while inducing adaptive processes such as responses to oxidative stress. Comparative RNA-seq analysis also uncovered incongruent protein and mRNA responses in the ΔSR relative to wild-type cells in several processes, including iron homeostasis and antioxidant defenses. Transcriptomic analysis of the ΔSR also revealed differential expression of numerous sRNAs, including PrrF1/2, raising the possibility that sRNAs may mediate certain stringent-response-dependent post-transcriptional control. Phenotypic validation of the ΔSR proteome confirmed multiple defects in antioxidant defenses and dysregulated pyoverdine biosynthesis. IMPORTANCE Pseudomonas aeruginosa is an important opportunistic human pathogen that causes difficult-to-treat infections and is highly adaptable to stressful environments. A key orchestrator of this adaptability is the stringent response, mediated by the signaling molecule (p)ppGpp. In this study, we characterized the extensive proteome remodeling in the (p)ppGpp-null relA spoT mutant during late exponential and stationary phase and provided the first protein-level analysis of the stringent response in P. aeruginosa. These data highlight the role of (p)ppGpp in shutting down broad metabolic functions and activating adaptive pathways, including stress-resistance responses, particularly during stationary phase. Using comparative proteomics and RNA-seq, we also find that several processes—such as iron regulation and oxidative stress responses—show mismatched RNA and protein changes, suggesting additional layers of post-transcriptional control, potentially involving small regulatory RNAs. Pseudomonas aeruginosa is an important opportunistic human pathogen that causes difficult-to-treat infections and is highly adaptable to stressful environments. A key orchestrator of this adaptability is the stringent response, mediated by the signaling molecule (p)ppGpp. In this study, we characterized the extensive proteome remodeling in the (p)ppGpp-null relA spoT mutant during late exponential and stationary phase and provided the first protein-level analysis of the stringent response in P. aeruginosa. These data highlight the role of (p)ppGpp in shutting down broad metabolic functions and activating adaptive pathways, including stress-resistance responses, particularly during stationary phase. Using comparative proteomics and RNA-seq, we also find that several processes—such as iron regulation and oxidative stress responses—show mismatched RNA and protein changes, suggesting additional layers of post-transcriptional control, potentially involving small regulatory RNAs.
Summary Background Reduced [18F]Fluorodeoxyglucose ([18F]FDG)-PET uptake is a core imaging feature of Alzheimer's disease (AD). While tau load correlates with this metabolic signature, it remains unclear whether the spatial extent of tauopathy (SEOT) more accurately explains brain glucose hypometabolic patterns. Here, we compared SEOT versus tau load to determine their ability to predict brain hypometabolic signatures in AD. Methods We performed a cross-sectional study of amyloid-β positive participants from ADNI (n = 150) and an atypical AD subset from the McGill University Research Centre for Studies in Ageing (MCSA; n = 44). Participants underwent [18F]AV1451 or [18F]MK6240 tau-PET and [18F]FDG-PET. Tau load was indexed with regional SUVR, and SEOT with the proportion of abnormal voxels. Linear regressions related temporal and whole-cortex tau-PET load or SEOT to [18F]FDG-PET. We also compared the accuracy of tau-PET metrics for identifying AD-like hypometabolism. Spearman correlations assessed SEOT/tau load-FDG associations at regional and network levels. Partial Least Squares (PLS) regression investigated whether distributed tau load and SEOT predicted [18F]FDG-PET signatures. Structural equation modelling and hierarchical linear models assessed associations between tau metrics and cognition dependent and independent of [18F]FDG-PET. Findings Whole-cortex SEOT best predicted decreased signal in the [18F]FDG-PET AD-meta-ROI. SEOT also performed better in classifying AD-related brain hypometabolism. Across regions and networks, SEOT performed similarly or better than tau load in predicting metabolic dysfunction. Voxelwise analyses suggested complementary predictive value of SEOT and tau load, each capturing slightly distinct spatial associations with [18F]FDG-PET. PLS demonstrated partially non-redundant contributions from tau load and SEOT. Cortical SEOT showed the strongest predictive value for cognition. Interpretation SEOT provides complementary, independent, and often stronger predictive value than tau load for brain metabolism, particularly for network-level dysfunction. SEOT may improve diagnostic characterisation and prediction of cognitive impairment beyond [18F]FDG-PET. Funding TRIAD is supported by the Weston Brain Institute, Canadian Institutes of Health Research, Canadian Consortium of Neurodegeneration and Aging, Brain Canada Foundation, the Fonds de Recherche du Québec – Santé, and the Colin J Adair Charitable Foundation. ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and the Canadian Institutes of Health Research.
The results suggest that co-morbid AD pathology is not a major contributor to early cognitive changes in this sample of PD patients without dementia.
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