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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 ([.sup.11C]PBR28), amyloid-[beta] (A[beta]) ([.sup.18F]AZD4694) and tau ([.sup.18F]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 [.sup.11C]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 A[beta], tau and microglia abnormalities was the strongest predictor of cognitive impairment in our study population. Our findings support a model where an interaction between A[beta] 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., Author(s): Tharick A. Pascoal [sup.1] [sup.2] [sup.3] [sup.4] , Andrea L. Benedet [sup.3] , Nicholas J. Ashton [sup.5] [sup.6] [sup.7] , Min Su Kang [sup.3] [sup.4] , Joseph Therriault [sup.3] [...]

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 [18F]AZD4694 and tau‐PET with [18F]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 [CI95%] = 0.89 [0.82, 0.96]) and NTA‐tau (AUC [CI95%] = 0.88 [0.91, 0.95]). Combining pTau‐217 and NTA‐tau resulted in the strongest agreement (Cohen's Kappa = 0.74, CI95% = 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. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized by the brain accumulation of amyloid-β and tau proteins. A growing body of literature suggests that epigenetic dysregulations play a role in the interplay of hallmark proteinopathies with neurodegeneration and cognitive impairment. Here, we aim to characterize an epigenetic dysregulation associated with the brain deposition of amyloid-β and tau proteins. Using positron emission tomography (PET) tracers selective for amyloid-β, tau, and class I histone deacetylase (HDAC I isoforms 1–3), we find that HDAC I levels are reduced in patients with AD. HDAC I PET reduction is associated with elevated amyloid-β PET and tau PET concentrations. Notably, HDAC I reduction mediates the deleterious effects of amyloid-β and tau on brain atrophy and cognitive impairment. HDAC I PET reduction is associated with 2-year longitudinal neurodegeneration and cognitive decline. We also find HDAC I reduction in the postmortem brain tissue of patients with AD and in a transgenic rat model expressing human amyloid-β plus tau pathology in the same brain regions identified in vivo using PET. These observations highlight HDAC I reduction as an element associated with AD pathophysiology. The link between amyloid and tau proteins with Alzheimer's disease progression remains unclear. Here, the authors propose HDACs I downregulation as an element linking the deleterious effects of brain proteinopathies with disease progression. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between the topography of amyloid‐β plaques, tau neurofibrillary tangles, and the overlap between the two, with cognitive dysfunction in individuals without dementia. Methods: We evaluated 154 individuals who were assessed with amyloid‐β PET with [18F]AZD4694, tau‐PET with [18F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid‐β PET with [18F]Florbetapir, tau‐PET with [18F]Flortaucipir, structural MRI, and neuropsychological testing. Using the VoxelStats toolbox, we conducted voxel‐wise linear regressions between amyloid‐PET, tau‐PET, and their interaction with cognitive function, correcting for age, sex, and years of education. Results: In both cohorts, we observed that tau‐PET standardized uptake value ratio in medial temporal lobes was associated with clinical dementia rating Sum of Boxes (CDR‐SoB) scores independently of local amyloid‐PET uptake (FWE corrected at p < 0.001). We also observed in both cohorts that in regions of the neocortex, associations between neocortical tau‐PET and clinical function were dependent on local amyloid‐PET (FWE corrected at p < 0.001). Interpretation: In medial temporal brain regions, characterized by the accumulation of tau pathology in the absence of amyloid‐β, tau had direct associations with cognitive dysfunction. In brain regions characterized by the accumulation of both amyloid‐β and tau pathologies such as the posterior cingulate and medial frontal cortices, tau's relationship with cognitive dysfunction was dependent on local amyloid‐β concentrations. Our results provide evidence that amyloid‐β in Alzheimer's disease influences cognition by potentiating the deleterious effects of tau pathology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Neurofilament light (NfL) is a marker of neuroaxonal injury, a prominent feature of Alzheimer's disease. It remains uncertain, however, how it relates to amyloid and tau pathology or neurodegeneration across the Alzheimer's disease continuum. The aim of this study was to investigate how plasma NfL relates to amyloid and tau PET and MRI measures of brain atrophy in participants with and without cognitive impairment. We retrospectively examined the association between plasma NfL and MRI measures of grey/white matter volumes in the Alzheimer's Disease Neuroimaging Initiative [ADNI: n = 1149; 382 cognitively unimpaired control subjects and 767 cognitively impaired participants (mild cognitive impairment n = 420, Alzheimer's disease dementia n = 347)]. Longitudinal plasma NfL was measured using single molecule array (Simoa) technology. Cross-sectional associations between plasma NfL and PET amyloid and tau measures were independently assessed in two cohorts: ADNI [n = 198; 110 cognitively unimpaired, 88 cognitively impaired (MCI n = 67, Alzheimer's disease dementia n = 21), data accessed October 2018]; and Translational Biomarkers in Aging and Dementia [TRIAD, n = 116; 74 cognitively unimpaired, 42 cognitively impaired (MCI n = 16, Alzheimer's disease dementia n = 26), data obtained November 2017 to January 2019]. Associations between plasma NfL and imaging-derived measures were examined voxel-wise using linear regression (cross-sectional) and linear mixed effect models (longitudinal). Cross-sectional analyses in both cohorts showed that plasma NfL was associated with PET findings in brain regions typically affected by Alzheimer's disease; associations were specific to amyloid PET in cognitively unimpaired and tau PET in cognitively impaired (P < 0.05). Longitudinal analyses showed that NfL levels were associated with grey/white matter volume loss; grey matter atrophy in cognitively unimpaired was specific to APOE ε4 carriers (P < 0.05). These findings suggest that plasma NfL increases in response to amyloid-related neuronal injury in preclinical stages of Alzheimer's disease, but is related to tau-mediated neurodegeneration in symptomatic patients. As such, plasma NfL may a useful measure to monitor effects in disease-modifying drug trials. [ABSTRACT FROM AUTHOR]

Background: Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau imaging agent [18F]MK-6240. Methods: In vitro properties of [18F]MK-6240 were estimated with autoradiography in postmortem brain tissues of 14 subjects (seven AD patients and seven age-matched controls). In vivo quantification of [18F]MK-6240 binding was performed in 16 subjects (four AD patients, three mild cognitive impairment patients, six healthy elderly individuals, and three healthy young individuals) who underwent 180-min dynamic scans; six subjects had arterial sampling for metabolite correction. Simplified approaches for [18F]MK-6240 quantification were validated using full kinetic modeling with metabolite-corrected arterial input function. All participants also underwent amyloid-PET and structural magnetic resonance imaging. Results: In vitro [18F]MK-6240 uptake was higher in AD patients than in age-matched controls in brain regions expected to contain tangles such as the hippocampus, whereas no difference was found in the cerebellar gray matter. In vivo, [18F]MK-6240 displayed favorable kinetics with rapid brain delivery and washout. The cerebellar gray matter had low binding across individuals, showing potential for use as a reference region. A reversible two-tissue compartment model well described the time–activity curves across individuals and brain regions. Distribution volume ratios using the plasma input and standardized uptake value ratios (SUVRs) calculated after the binding approached equilibrium (90 min) were correlated and higher in mild cognitive impairment or AD dementia patients than in controls. Reliability analysis revealed robust SUVRs calculated from 90 to 110 min, while earlier time points provided inaccurate estimates. Conclusions: This evaluation shows an [18F]MK-6240 distribution in concordance with postmortem studies and that simplified quantitative approaches such as the SUVR offer valid estimates of neurofibrillary tangle load 90 min post injection. [18F]MK-6240 is a promising tau tracer with the potential to be applied in the disease diagnosis and assessment of therapeutic interventions. [ABSTRACT FROM AUTHOR]

The article presents animal studies suggesting that the apolipoprotein E ε4 (APOEε4) allele as a culprit of early microglial activation in Alzheimer's disease (AD). It mentions the testing of the association between APOEε4 status and microglial activation in living individuals across the aging and AD spectrum.

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.)