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CSF and PET biomarkers of amyloid β and tau accurately detect Alzheimer's disease pathology, but the invasiveness, high cost, and poor availability of these detection methods restrict their widespread use as clinical diagnostic tools. CSF tau phosphorylated at threonine 181 (p-tau181) is a highly specific biomarker for Alzheimer's disease pathology. We aimed to assess whether blood p-tau181 could be used as a biomarker for Alzheimer's disease and for prediction of cognitive decline and hippocampal atrophy. We developed and validated an ultrasensitive blood immunoassay for p-tau181. Assay performance was evaluated in four clinic-based prospective cohorts. The discovery cohort comprised patients with Alzheimer's disease and age-matched controls. Two validation cohorts (TRIAD and BioFINDER-2) included cognitively unimpaired older adults (mean age 63–69 years), participants with mild cognitive impairment (MCI), Alzheimer's disease, and frontotemporal dementia. In addition, TRIAD included healthy young adults (mean age 23 years) and BioFINDER-2 included patients with other neurodegenerative disorders. The primary care cohort, which recruited participants in Montreal, Canada, comprised control participants from the community without a diagnosis of a neurological condition and patients referred from primary care physicians of the Canadian National Health Service for specialist care. Concentrations of plasma p-tau181 were compared with established CSF and PET biomarkers and longitudinal measurements using Spearman correlation, area under the curve (AUC), and linear regression analyses. We studied 37 individuals in the discovery cohort, 226 in the first validation cohort (TRIAD), 763 in the second validation cohort (BioFINDER-2), and 105 in the primary care cohort (n=1131 individuals). In all cohorts, plasma p-tau181 showed gradual increases along the Alzheimer's disease continuum, from the lowest concentrations in amyloid β-negative young adults and cognitively unimpaired older adults, through higher concentrations in the amyloid β-positive cognitively unimpaired older adults and MCI groups, to the highest concentrations in the amyloid β-positive MCI and Alzheimer's disease groups (p<0·001, Alzheimer's disease vs all other groups). Plasma p-tau181 distinguished Alzheimer's disease dementia from amyloid β-negative young adults (AUC=99·40%) and cognitively unimpaired older adults (AUC=90·21–98·24% across cohorts), as well as other neurodegenerative disorders, including frontotemporal dementia (AUC=82·76–100% across cohorts), vascular dementia (AUC=92·13%), progressive supranuclear palsy or corticobasal syndrome (AUC=88·47%), and Parkinson's disease or multiple systems atrophy (AUC=81·90%). Plasma p-tau181 was associated with PET-measured cerebral tau (AUC=83·08–93·11% across cohorts) and amyloid β (AUC=76·14–88·09% across cohorts) pathologies, and 1-year cognitive decline (p=0·0015) and hippocampal atrophy (p=0·015). In the primary care cohort, plasma p-tau181 discriminated Alzheimer's disease from young adults (AUC=100%) and cognitively unimpaired older adults (AUC=84·44%), but not from MCI (AUC=55·00%). Blood p-tau181 can predict tau and amyloid β pathologies, differentiate Alzheimer's disease from other neurodegenerative disorders, and identify Alzheimer's disease across the clinical continuum. Blood p-tau181 could be used as a simple, accessible, and scalable test for screening and diagnosis of Alzheimer's disease. Alzheimer Drug Discovery Foundation, European Research Council, Swedish Research Council, Swedish Alzheimer Foundation, Swedish Dementia Foundation, Alzheimer Society Research Program.

Compelling experimental evidence suggests that microglial activation is involved in the spread of tau tangles over the neocortex in Alzheimer’s disease (AD). We tested the hypothesis that the spatial propagation of microglial activation and tau accumulation colocalize in a Braak-like pattern in the living human brain. We studied 130 individuals across the aging and AD clinical spectrum with positron emission tomography brain imaging for microglial activation ([ 11 C]PBR28), amyloid-β (Aβ) ([ 18 F]AZD4694) and tau ([ 18 F]MK-6240) pathologies. We further assessed microglial triggering receptor expressed on myeloid cells 2 ( TREM2 ) cerebrospinal fluid (CSF) concentrations and brain gene expression patterns. We found that [ 11 C]PBR28 correlated with CSF soluble TREM2 and showed regional distribution resembling TREM2 gene expression. Network analysis revealed that microglial activation and tau correlated hierarchically with each other following Braak-like stages. Regression analysis revealed that the longitudinal tau propagation pathways depended on the baseline microglia network rather than the tau network circuits. The co-occurrence of Aβ, tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between Aβ and activated microglia sets the pace for tau spread across Braak stages. Microglial activation and tau accumulation propagate together in patients with Alzheimer’s disease, suggesting an interaction that determines disease progression.

Background Mitochondrial electron transport chain abnormalities have been reported in postmortem pathological specimens of Alzheimer’s disease (AD). However, it remains unclear how amyloid and tau are associated with mitochondrial dysfunction in vivo. The purpose of this study is to assess the local relationships between mitochondrial dysfunction and AD pathophysiology in mild AD using the novel mitochondrial complex I PET imaging agent [ 18 F]BCPP-EF. Methods Thirty-two amyloid and tau positive mild stage AD dementia patients (mean age ± SD: 71.1 ± 8.3 years) underwent a series of PET measurements with [ 18 F]BCPP-EF mitochondrial function, [ 11 C]PBB3 for tau deposition, and [ 11 C] PiB for amyloid deposition. Age-matched normal control subjects were also recruited. Inter and intrasubject comparisons of levels of mitochondrial complex I activity, amyloid and tau deposition were performed. Results The [ 18 F]BCPP-EF uptake was significantly lower in the medial temporal area, highlighting the importance of the mitochondrial involvement in AD pathology. [ 11 C]PBB3 uptake was greater in the temporo-parietal regions in AD. Region of interest analysis in the Braak stage I-II region showed significant negative correlation between [ 18 F]BCPP-EF SUVR and [ 11 C]PBB3 BP ND (R = 0.2679, p  = 0.04), but not [ 11 C] PiB SUVR. Conclusions Our results indicated that mitochondrial complex I is closely associated with tau load evaluated by [ 11 C]PBB3, which might suffer in the presence of its off-target binding. The absence of association between mitochondrial complex I dysfunction with amyloid load suggests that mitochondrial dysfunction in the trans-entorhinal and entorhinal region is a reflection of neuronal injury occurring in the brain of mild AD.

Neurofilament light chain (NFL) measurement has been gaining strong support as a clinically useful neuronal injury biomarker for various neurodegenerative conditions. However, in Alzheimer’s disease (AD), its reflection on regional neuronal injury in the context of amyloid pathology remains unclear. This study included 83 cognitively normal (CN), 160 mild cognitive impairment (MCI), and 73 AD subjects who were further classified based on amyloid-beta (Aβ) status as positive or negative (Aβ+ vs Aβ−). In addition, 13 rats (5 wild type and 8 McGill-R-Thy1-APP transgenic (Tg)) were examined. In the clinical study, reduced precuneus/posterior cingulate cortex and hippocampal grey matter density were significantly associated with increased NFL concentrations in cerebrospinal fluid (CSF) or plasma in MCI Aβ+ and AD Aβ+. Moreover, AD Aβ+ showed a significant association between the reduced grey matter density in the AD-vulnerable regions and increased NFL concentrations in CSF or plasma. Congruently, Tg rats recapitulated and validated the association between CSF NFL and grey matter density in the parietotemporal cortex, entorhinal cortex, and hippocampus in the presence of amyloid pathology. In conclusion, reduced grey matter density and elevated NFL concentrations in CSF and plasma are associated in AD-vulnerable regions in the presence of amyloid positivity in the AD clinical spectrum and amyloid Tg rat model. These findings further support the NFL as a neuronal injury biomarker in the research framework of AD biomarker classification and for the evaluation of therapeutic efficacy in clinical trials.

The choroid plexus (CP), a critical structure for cerebrospinal fluid (CSF) production, has been increasingly recognized for its involvement in Alzheimer's disease (AD). Accurate segmentation of CP from magnetic resonance imaging (MRI) remains challenging due to its irregular shape, variable MR signal, and proximity to the lateral ventricles. This study aimed to develop and evaluate a region-informed Gaussian Mixture Model (One-GMM) for automatic CP segmentation using anatomical priors derived from FreeSurfer (FS) software and compare it with manual, FS, and one previous GMM-based (Two-GMM) methods. T1-weighted (T1w) and T2-fluid-attenuated inversion recovery (FLAIR) MRI scans were acquired from 38 participants [19 cognitively normal (CN)], 11 with mild cognitive impairment (MCI), and 8 with AD. Manual segmentations served as ground truth. A GMM was applied within an anatomically constrained region combining the lateral ventricles and CP derived from FS reconstruction. The segmentation accuracy was assessed using the dice similarity coefficient (DSC), the 95th percentile Hausdorff distance (HD95), and volume difference percentage (VD%). Results were compared with those from FS and one previous GMM method-based segmentations across diagnostic groups. The region-informed One-GMM achieved significantly higher accuracy compared to FS and Two-GMM, with a mean DSC of 0.82 ± 0.05 for One-GMM versus 0.24 ± 0.11 for FS (   <  0.001), and 0.66 ± 0.10 for Two-GMM (  < 0.001), lower HD95 (One-GMM: 6.06 ± 10.32 mm vs. FS: 26.21 ± 7.32 mm vs. Two-GMM: 10.58 ± 6.47 mm), and comparable volume difference (One-GMM: 20.97 ± 9.53% vs. FS: 24.32 ± 28.13% vs. Two-GMM: 24.27 ± 22.10,  = 0.87). Segmentation accuracy of our proposed method was consistent across all diagnostic groups. Clinical analysis showed that there is no diagnostic group difference in CP volume obtained from manual, FS, Two-GMM, and our proposed One-GMM methods. In the whole cohort, there are also no age and sex effects of CP volume with all methods. Restricting to the CN group, CP volume from both manual (  = 0.03), Two-GMM (  < 0.01) and the proposed One-GMM (  = 0.05), methods show an aging effect, but not for the FS segmented CP volume (  = 0.22). A region-informed One-GMM method significantly improved CP segmentation accuracy over FS, providing a practical and accessible tool for CP quantification in AD and other research studies. Within this small cohort, no diagnostic group difference in CP volume was observed. An aging effect of CP volume was found within the CN group.

Background To investigate the association of plasma pTau181, assessed with a new immunoassay, with neurodegeneration of white matter and gray matter cross-sectionally and longitudinally, in aging and Alzheimer’s disease. Methods Observational data was obtained from the Alzheimer’s Disease Neuroimaging Initiative, in which participants underwent plasma assessment and magnetic resonance imaging. Based on their clinical diagnosis, participants were classified as cognitively unimpaired and cognitively impaired. Linear regressions and linear mixed-effect models were used to test the cross-sectional and longitudinal associations between baseline plasma pTau181 and neurodegeneration using voxel-based morphometry. Results We observed a negative correlation at baseline between plasma pTau181 and gray matter volume in cognitively unimpaired individuals. In cognitively impaired individuals, we observed a negative association between plasma pTau181 and both gray and white matter volume. In longitudinal analyses conducted in the cognitively unimpaired group, plasma pTau181 was negatively correlated with gray matter volume, starting 36 months after baseline assessments. Finally, in cognitively impaired individuals, plasma pTau181 concentrations were negatively correlated with both gray and white matter volume as early as 12 months after baseline, and neurodegeneration increased in an incremental manner until 48 months. Conclusions Higher levels of plasma pTau181 correlate with neurodegeneration and predict further brain atrophy in aging and Alzheimer’s disease. Plasma pTau181 may be useful in predicting AD-related neurodegeneration, comparable to positron emission tomography or cerebrospinal fluid assessment with high specificity for AD neurodegeneration.

Background Mild behavioural impairment (MBI) is a neurobehavioural syndrome that represents an at-risk state for incident cognitive decline. No study to date has systematically investigated whole-brain within- and between- network functional connectivity (FC) disruptions in MBI and their effects on cognitive performance in dementia-free individuals. Hence, we sought to evaluate the whole-brain functional network phenotypes associated with MBI and its subdomains, and their relationships with amyloid and tau pathology in predicting future cognition and function in dementia-free older adults. Methods We studied 203 dementia-free individuals aged between 55 and 90 years (77 males) from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort with baseline functional MRI, amyloid-β [18 F]AZD4694 and tau [18 F]MK6240 PET imaging, and longitudinal neuropsychological assessments up to 32 months. Multivariate associations between MBI-Checklist (MBI-C) subdomain scores and whole-brain FC matrices were examined using partial least squares correlation. We then assessed how these MBI-related network phenotypes were associated with baseline and longitudinal changes in global cognition (via Montreal Cognitive Assessment (MoCA) scores) and functional performance (via clinical dementia rating (CDR) sum of boxes), and whether they interacted with baseline Alzheimer’s disease pathology (global amyloid uptake and tau temporal meta-region-of-interest uptake via PET) to influence future outcomes using linear regression models. Results We identified an MBI-related functional network phenotype characterized by greater MBI severity and widespread dysfunctions particularly in higher-order networks. Greater expression of this phenotype was associated with poorer baseline global cognition, as well as greater functional impairment at baseline and over time. Further, baseline global amyloid uptake, but not temporal tau uptake, moderated the effects of baseline MBI-related FC disruptions on longitudinal global cognition changes in dementia-free older adults. Specifically, individuals with higher amyloid burden and greater MBI-related FC disruptions showed accelerated cognitive decline over time. In contrast, the MBI-C total score did not show independent or interactive effects with amyloid and tau burden on longitudinal cognitive and functional outcomes. Conclusions Our findings demonstrated a global MBI-related functional network phenotype in dementia-free individuals that was associated with impaired cognition and function. Moreover, this phenotype interacts with amyloid burden to accelerate cognitive decline, underscoring its relevance in preclinical Alzheimer’s disease.

Neurofilament light chain (NfL) is a promising blood biomarker to detect neurodegeneration in Alzheimer's disease (AD) and other brain disorders. However, there are limited reports of how longitudinal NfL relates to imaging biomarkers. We herein investigated the relationship between blood NfL and brain metabolism in AD. Voxelwise regression models tested the cross-sectional association between [18F]fluorodeoxyglucose ([18F]FDG) and both plasma and cerebrospinal fluid NfL in cognitively impaired and unimpaired subjects. Linear mixed models were also used to test the longitudinal association between NfL and [18F]FDG in amyloid positive (Aβ+) and negative (Aβ−) subjects. Higher concentrations of plasma and cerebrospinal fluid NfL were associated with reduced [18F]FDG uptake in correspondent brain regions. In Aβ+ participants, NfL associates with hypometabolism in AD-vulnerable regions. Longitudinal changes in the association [18F]FDG-NfL were confined to cognitively impaired Aβ+ individuals. These findings indicate that plasma NfL is a proxy for neurodegeneration in AD-related regions in Aβ+ subjects. •Plasma and CSF neurofilament light show similar pattern of association with [18F]FDG.•In Aβ+ group, brain hypometabolism associates with NfL in Alzheimer's disease signature regions.•The association [18F]fluorodeoxyglucose-plasma NfL increases over 24 months in Aβ+ patients.

Background Neuropsychiatric symptoms (NPS) are frequent in aging and Alzheimer's disease (AD). Here we study the relationship between NPS and AD pathologies in vivo. Method Two hundred and twenty‐one individuals from the TRIAD cohort (143 cognitively unimpaired, 52 mild cognitive impairment, and 26 AD) underwent [18F]MK6240‐tau‐positron emission tomography (PET), [18F]AZD4694‐amyloid‐PET, magnetic resonance imaging, and neuropsychological evaluations. Spearman correlations and voxel‐based regression models evaluated the relationship between Neuropsychiatric Inventory Questionnaire (NPI‐Q) scores, and tau‐PET, amyloid‐PET, and voxel‐based morphometry. Results Fifty percent of individuals presented NPS; these correlated with tau, not amyloid beta or neurodegeneration. Associations between NPI‐Q score and tau‐PET were stronger in the parietal association area, superior frontal, temporal, and medial occipital lobes. NPI‐Q domains associated with distinct patterns of tau uptake. Conclusions NPS are predominantly related to tau in aging and dementia. Regions affected are part of the behavioral circuits, and vulnerable to early AD pathology. Domain‐specific analyses showed NPS are related to the AD pathophysiological processes in a symptom‐specific manner.

Recent studies suggest a framework where white-matter (WM) atrophy plays an important role in fronto-temporal dementia (FTD) pathophysiology. However, these studies often overlook the fact that WM tracts bridging different brain regions may have different vulnerabilities to the disease and the relative contribution of grey-matter (GM) atrophy to this WM model, resulting in a less comprehensive understanding of the relationship between clinical symptoms and pathology. Using a common factor analysis to extract a semantic and an executive factor, we aimed to test the relative contribution of WM and GM of specific tracts in predicting cognition in the Frontotemporal Lobar Degeneration Neuroimaging Initiative (FTLDNI). We found that semantic symptoms were mainly dependent on short-range WM fibre disruption, while damage to long-range WM fibres was preferentially associated to executive dysfunction with the GM contribution to cognition being predominant for local processing. These results support the importance of the disruption of specific WM tracts to the core cognitive symptoms associated with FTD. As large-scale WM tracts, which are particularly vulnerable to vascular disease, were highly associated with executive dysfunction, our findings highlight the importance of controlling for risk factors associated with deep WM disease, such as vascular risk factors, in patients with FTD in order not to potentiate underlying executive dysfunction.