Plasma GFAP is an early marker of amyloid-β but not tau pathology in Alzheimer's disease.
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ABSTRACT: Although recent clinical trials targeting amyloid-β in Alzheimer's disease have shown promising results, there is increasing evidence suggesting that understanding alternative disease pathways that interact with amyloid-β metabolism and amyloid pathology might be important to halt the clinical deterioration. In particular, there is evidence supporting a critical role of astroglial activation and astrocytosis in Alzheimer's disease. However, so far, no studies have assessed whether astrocytosis is independently related to either amyloid-β or tau pathology in vivo. To address this question, we determined the levels of the astrocytic marker GFAP in plasma and CSF of 217 amyloid-β-negative cognitively unimpaired individuals, 71 amyloid-β-positive cognitively unimpaired individuals, 78 amyloid-β-positive cognitively impaired individuals, 63 amyloid-β-negative cognitively impaired individuals and 75 patients with a non-Alzheimer's disease neurodegenerative disorder from the Swedish BioFINDER-2 study. Participants underwent longitudinal amyloid-β (18F-flutemetamol) and tau (18F-RO948) PET as well as cognitive testing. We found that plasma GFAP concentration was significantly increased in all amyloid-β-positive groups compared with participants without amyloid-β pathology (P < 0.01). In addition, there were significant associations between plasma GFAP with higher amyloid-β-PET signal in all amyloid-β-positive groups, but also in cognitively normal individuals with normal amyloid-β values (P < 0.001), which remained significant after controlling for tau-PET signal. Furthermore, plasma GFAP could predict amyloid-β-PET positivity with an area under the curve of 0.76, which was greater than the performance achieved by CSF GFAP (0.69) and other glial markers (CSF YKL-40: 0.64, soluble TREM2: 0.71). Although correlations were also observed between tau-PET and plasma GFAP, these were no longer significant after controlling for amyloid-β-PET. In contrast to plasma GFAP, CSF GFAP concentration was significantly increased in non-Alzheimer's disease patients compared to other groups (P < 0.05) and correlated with amyloid-β-PET only in amyloid-β-positive cognitively impaired individuals (P = 0.005). Finally, plasma GFAP was associated with both longitudinal amyloid-β-PET and cognitive decline, and mediated the effect of amyloid-β-PET on tau-PET burden, suggesting that astrocytosis secondary to amyloid-β aggregation might promote tau accumulation. Altogether, these findings indicate that plasma GFAP is an early marker associated with brain amyloid-β pathology but not tau aggregation, even in cognitively normal individuals with a normal amyloid-β status. This suggests that plasma GFAP should be incorporated in current hypothetical models of Alzheimer's disease pathogenesis and be used as a non-invasive and accessible tool to detect early astrocytosis secondary to amyloid-β pathology.
Project description:The amyloid cascade hypothesis proposes that amyloid beta (Abeta) pathology precedes and induces tau pathology, but the neuropathological connection between these two lesions has not been demonstrated. We examined the regional distribution and co-localization of Abeta and phosphorylated tau (p-tau) in synaptic terminals of Alzheimer's disease brains. To quantitatively examine large populations of individual synaptic terminals, flow cytometry was used to analyze synaptosomes prepared from cryopreserved Alzheimer's disease tissue. An average 68.4% of synaptic terminals in the Alzheimer's disease cohort (n = 11) were positive for Abeta, and 32.3% were positive for p-tau; Abeta and p-tau fluorescence was lowest in cerebellum. In contrast to synaptic p-tau, which was highest in the entorhinal cortex and hippocampus (P = 0.004), synaptic Abeta fluorescence was significantly lower in the entorhinal cortex and hippocampus relative to neocortical regions (P = 0.0003). Synaptic Abeta and p-tau fluorescence was significantly correlated (r = 0.683, P < 0.004), and dual-labeling experiments demonstrated that 24.1% of Abeta-positive terminals were also positive for p-tau, with the highest fraction of dual labeling (39.3%) in the earliest affected region, the entorhinal cortex. Western blotting experiments show a significant correlation between synaptic Abeta levels measured by flow cytometry and oligomeric Abeta species (P < 0.0001). These results showing overlapping Abeta and tau pathology are consistent with a model in which both synaptic loss and dysfunction are linked to a synaptic amyloid cascade within the synaptic compartment.
Project description: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.
Project description:IntroductionWe examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline.MethodsCerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aβ), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aβ (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years.ResultsCSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline.DiscussionCSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.
Project description:IntroductionAlzheimer-type neuropil threads (NTs) and neurofibrillary tangles (NFTs) are comprised of either 4 repeat (4R)-tau, 3 repeat (3R)-tau, or a mixture of both. In the hippocampus, the number of NFTs, and the proportion of 3R tau progressively increases. If this preferential accumulation of 3R tau also occurs in the brainstem, it may be fundamentally related to progression of Alzheimer pathology.MethodsMidbrain and pontine sections of brainstems from 23 cases (Braak-NFT stages I/II: 8, III/IV: 8, and V/VI: 7) were double immunofluorolabeled for 4R and 3R tau. High-resolution (0.645 μm/pixel), in-focus snapshots were tiled to cover entire brain sections using a virtual slide system. Each lesion was classified by size (NT < 200 μm2 < NFT) and staining profile (3R/4R). In addition, the localization and quantity of amyloid β (Aβ) deposits were examined in adjacent sections for comparison with tau.ResultsThe data sets obtained from approximately 286 gigabytes of image files consisted of 847,763 NTs and 7859 NFTs. The proportion of 3R tau-positive NTs and NFTs in the midbrain, and 3R tau-positive NTs in the pons gradually increased with advancing NFT stages, while the proportion of 3R tau-positive NFTs in the pons was already elevated at early stages. Aβ deposits were absent at NFT stages I/II, and when present at later stages, their regional distribution was different from that of tau. These observations suggest that a progressive increase in the proportion of 3R tau occurs independently of Aβ deposits.ConclusionsThis is the first quantitative analysis of NFTs and NTs in the human brainstem. We demonstrate that the proportion of 3R tau in the brainstem neurofibrillary changes increases with disease progression. Because this phenomenon is shared between the brainstem and the hippocampus, this increase may be fundamental to the pathogenesis of Alzheimer disease.
Project description:Accumulation of damaged mitochondria is a hallmark of aging and age-related neurodegeneration, including Alzheimer's disease (AD). The molecular mechanisms of impaired mitochondrial homeostasis in AD are being investigated. Here we provide evidence that mitophagy is impaired in the hippocampus of AD patients, in induced pluripotent stem cell-derived human AD neurons, and in animal AD models. In both amyloid-β (Aβ) and tau Caenorhabditis elegans models of AD, mitophagy stimulation (through NAD+ supplementation, urolithin A, and actinonin) reverses memory impairment through PINK-1 (PTEN-induced kinase-1)-, PDR-1 (Parkinson's disease-related-1; parkin)-, or DCT-1 (DAF-16/FOXO-controlled germline-tumor affecting-1)-dependent pathways. Mitophagy diminishes insoluble Aβ1-42 and Aβ1-40 and prevents cognitive impairment in an APP/PS1 mouse model through microglial phagocytosis of extracellular Aβ plaques and suppression of neuroinflammation. Mitophagy enhancement abolishes AD-related tau hyperphosphorylation in human neuronal cells and reverses memory impairment in transgenic tau nematodes and mice. Our findings suggest that impaired removal of defective mitochondria is a pivotal event in AD pathogenesis and that mitophagy represents a potential therapeutic intervention.
Project description:Amyloid-β (Aβ) and tau proteins accumulate within distinct neuronal systems in Alzheimer's disease (AD). Although it is not clear why certain brain regions are more vulnerable to Aβ and tau pathologies than others, gene expression may play a role. We study the association between brain-wide gene expression profiles and regional vulnerability to Aβ (gene-to-Aβ associations) and tau (gene-to-tau associations) pathologies by leveraging two large independent AD cohorts. We identify AD susceptibility genes and gene modules in a gene co-expression network with expression profiles specifically related to regional vulnerability to Aβ and tau pathologies in AD. In addition, we identify distinct biochemical pathways associated with the gene-to-Aβ and the gene-to-tau associations. These findings may explain the discordance between regional Aβ and tau pathologies. Finally, we propose an analytic framework, linking the identified gene-to-pathology associations to cognitive dysfunction in AD at the individual level, suggesting potential clinical implication of the gene-to-pathology associations.
Project description:Changes in soluble amyloid-beta (Aβ) levels in cerebrospinal fluid (CSF) are detectable at early preclinical stages of Alzheimer's disease (AD). However, whether Aβ levels can predict downstream AD pathological features in cognitively unimpaired (CU) individuals remains unclear. With this in mind, we aimed at investigating whether a combination of soluble Aβ isoforms can predict tau pathology (T+) and neurodegeneration (N+) positivity. We used CSF measurements of three soluble Aβ peptides (Aβ1-38, Aβ1-40 and Aβ1-42) in CU individuals (n = 318) as input features in machine learning (ML) models aiming at predicting T+ and N+. Input data was used for building 2046 tuned predictive ML models with a nested cross-validation technique. Additionally, proteomics data was employed to investigate the functional enrichment of biological processes altered in T+ and N+ individuals. Our findings indicate that Aβ isoforms can predict T+ and N+ with an area under the curve (AUC) of 0.929 and 0.936, respectively. Additionally, proteomics analysis identified 17 differentially expressed proteins (DEPs) in individuals wrongly classified by our ML model. More specifically, enrichment analysis of gene ontology biological processes revealed an upregulation in myelinization and glucose metabolism-related processes in CU individuals wrongly predicted as T+. A significant enrichment of DEPs in pathways including biosynthesis of amino acids, glycolysis/gluconeogenesis, carbon metabolism, cell adhesion molecules and prion disease was also observed. Our results demonstrate that, by applying a refined ML analysis, a combination of Aβ isoforms can predict T+ and N+ with a high AUC. CSF proteomics analysis highlighted a promising group of proteins that can be further explored for improving T+ and N+ prediction.
Project description:Recent studies show that fibrinogen plays a role in the pathogenesis of Alzheimer's disease (AD), which may be crucial to neurovascular damage and cognitive impairment. However, there are few clinical studies on the relationship between fibrinogen and AD. 59 11C-PiB-PET diagnosed AD patients and 76 age- and gender-matched cognitively normal controls were included to analyze the correlation between plasma β-amyloid (Aβ) and tau levels with fibrinogen levels. 35 AD patients and 76 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation between CSF Aβ and tau levels with fibrinogen levels. In AD patients, plasma fibrinogen levels were positively correlated with plasma Aβ40 and Aβ42 levels, and negatively correlated with CSF Aβ42 levels. Besides, fibrinogen levels were positively correlated with CSF total tau (t-tau), and phosphorylated tau-181 (p-tau) levels and positively correlated with the indicators of Aβ deposition in the brain, such as t-tau/Aβ42, p-tau/Aβ42 levels. In normal people, fibrinogen levels lack correlation with Aβ and tau levels in plasma and CSF. This study suggests that plasma fibrinogen levels are positively correlated with Aβ levels in the plasma and brain in AD patients. Fibrinogen may be involved in the pathogenesis of AD.
Project description:BackgroundHyperactivity of the classical axis of the renin-angiotensin system (RAS), mediated by angiotensin II (Ang II) activation of the angiotensin II type 1 receptor (AT1R), is implicated in the pathogenesis of Alzheimer's disease (AD). Angiotensin-converting enzyme-2 (ACE-2) degrades Ang II to angiotensin 1-7 (Ang (1-7)) and counter-regulates the classical axis of RAS. We have investigated the expression and distribution of ACE-2 in post-mortem human brain tissue in relation to AD pathology and classical RAS axis activity.MethodsWe measured ACE-2 activity by fluorogenic peptide substrate assay in mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59) for which we have previous data on ACE-1 activity, amyloid β (Aβ) level and tau pathology, as well as known ACE1 (rs1799752) indel polymorphism, apolipoprotein E (APOE) genotype, and cerebral amyloid angiopathy severity scores.ResultsACE-2 activity was significantly reduced in AD compared with age-matched controls (P < 0.0001) and correlated inversely with levels of Aβ (r = -0.267, P < 0.001) and phosphorylated tau (p-tau) pathology (r = -0.327, P < 0.01). ACE-2 was reduced in individuals possessing an APOE ε4 allele (P < 0.05) and was associated with ACE1 indel polymorphism (P < 0.05), with lower ACE-2 activity in individuals homozygous for the ACE1 insertion AD risk allele. ACE-2 activity correlated inversely with ACE-1 activity (r = -0.453, P < 0.0001), and the ratio of ACE-1 to ACE-2 was significantly elevated in AD (P < 0.0001). Finally, we show that the ratio of Ang II to Ang (1-7) (a proxy measure of ACE-2 activity indicating conversion of Ang II to Ang (1-7)) is reduced in AD.ConclusionsTogether, our findings indicate that ACE-2 activity is reduced in AD and is an important regulator of the central classical ACE-1/Ang II/AT1R axis of RAS, and also that dysregulation of this pathway likely plays a significant role in the pathogenesis of AD.
Project description:IntroductionPlasma markers have been reported to be associated with brain amyloid burden, tau pathology, or neurodegeneration. We aimed to evaluate whether plasma biomarker profiles could predict Alzheimer's disease (AD) pathology and clinical progression in older adults without dementia.MethodsCross-sectional and longitudinal data of participants enrolled in this study were from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Plasma amyloid beta (Aβ)1-42/Aβ1-40 ratio was selected as the marker for amyloid pathology, p-tau181 for tau pathology, and neurofilament light for neurodegeneration. Cut-offs for these plasma markers were calculated with well-established positron emission tomography and structural imaging biomarkers as reference. Older adults without dementia were categorized into eight groups at baseline by plasma amyloid/tau/neurodegeneration (A/T/N) cut-offs. Clinical progression was analyzed using linear mixed-effects models and Cox proportional hazard models.ResultsA total of 183 participants (97 cognitively normal [CN] subjects and 86 patients with mild cognitive impairment [MCI]; mean age 72.6 years, and 48.1% men) were included. Participants with A+ had significantly higher proportions of apolipoprotein E (APOE) gene ɛ4 carriers than those with A-. Brain atrophy was observed in all groups of CN, whereas cognition decline was obvious in the A+T+N+ group. Compared to A-T-N-, MCI patients with A+T+N+ had faster cognition worsening and faster brain atrophy. In the whole cohort, A+T+N+ and A+T+N- participants were at higher risk of clinical progression.DiscussionPlasma A/T/N biomarker profiles may predict AD pathology and clinical progression, indicating a potential role for plasma biomarkers in clinical trials. More research is warranted to develop a robust plasma AD framework.