Plasma amyloid, tau, and neurodegeneration biomarker profiles predict Alzheimer's disease pathology and clinical progression in older adults without dementia
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ABSTRACT:
SUBMITTER: Shen X
PROVIDER: S-EPMC7513626 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
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Project description:ImportanceA National Institute on Aging and Alzheimer's Association workgroup proposed a research framework for Alzheimer disease in which biomarker classification of research participants is labeled AT(N) for amyloid, tau, and neurodegeneration biomarkers.ObjectiveTo determine the associations between AT(N) biomarker profiles and memory decline in a population-based cohort of individuals without dementia age 60 years or older, and to determine whether biomarkers provide incremental prognostic value beyond more readily available clinical and genetic information.Design, setting, and participantsPopulation-based cohort study of cognitive aging in Olmsted County, Minnesota, that included 480 nondemented Mayo Clinic Study of Aging participants who had a clinical evaluation and amyloid positron emission tomography (PET) (A), tau PET (T), and magnetic resonance imaging (MRI) cortical thickness (N) measures between April 16, 2015, and November 1, 2017, and at least 1 clinical evaluation follow-up by November 12, 2018.ExposuresAge, sex, education, cardiovascular and metabolic conditions score, APOE genotype, and AT(N) biomarker profiles. Each of A, T, or (N) can be abnormal (+) or normal (-), resulting in 8 AT(N) profiles.Main outcomes and measuresPrimary outcome was a composite memory score measured longitudinally at 15-month intervals. Analyses measured the associations between predictor variables and the memory score, and whether AT(N) biomarker profiles significantly improved prediction of memory z score rates of change beyond a model with clinical and genetic variables only.ResultsParticipants were followed up for a median of 4.8 years (interquartile range [IQR], 3.8-5.1) and 44% were women (211/480). Median (IQR) ages ranged from 67 years (65-73) in the A-T-(N)- group to 83 years (76-87) in the A+T+(N)+ group. Of the participants, 92% (441/480) were cognitively unimpaired but the A+T+(N)+ group had the largest proportion of mild cognitive impairment (30%). AT(N) biomarkers improved the prediction of memory performance over a clinical model from an R2 of 0.26 to 0.31 (P?<?.001). Memory declined fastest in the A+T+(N)+, A+T+(N)-, and A+T-(N)+ groups compared with the other 5 AT(N) groups (P?=?.002). Estimated rates of decline in the 3 fastest declining groups were -0.13 (95% CI, -0.17 to -0.09), -0.10 (95% CI, -0.16 to -0.05), and -0.10 (95% CI, -0.13 to -0.06) z score units per year, respectively, for an 85-year-old APOE ?4 noncarrier.Conclusions and relevanceAmong older persons without baseline dementia followed for a median of 4.8 years, a prediction model that included amyloid PET, tau PET, and MRI cortical thickness resulted in a small but statistically significant improvement in predicting memory decline over a model with more readily available clinical and genetic variables. The clinical importance of this difference is uncertain.
| S-EPMC6582267 | biostudies-literature
Project description:Brain autopsy and biomarker studies indicate that the pathology of Alzheimer's disease (AD) is initiated at least 10-20 years before clinical symptoms. This provides a window of opportunity to initiate preventive treatment. However, this emphasizes the necessity for biomarkers that identify individuals at risk for developing AD later in life. In this cross-sectional study, originating from three epidemiologic studies in Sweden (n=1428), the objective was to examine whether amyloid pathology, as determined by low cerebrospinal fluid (CSF) concentration of the 42 amino acid form of β-amyloid (Aβ42), is associated with biomarker evidence of other pathological changes in cognitively healthy elderly. A total of 129 patients were included and CSF levels of Aβ42, total tau, tau phosphorylated at threonine 181 (p-tau), neurogranin, VILIP-1, VEGF, FABP3, Aβ40, neurofilament light, MBP, orexin A, BDNF and YKL-40 were measured. Among these healthy elderly, 35.6% (N=46) had CSF Aβ42 levels below 530 pg ml-1. These individuals displayed significantly higher CSF concentrations of t-tau (P<0.001), p-tau (181) (P<0.001), neurogranin (P=0.009) and FABP3 (P=0.044) compared with amyloid-negative individuals. Our study indicates that there is a subpopulation among healthy older individuals who have amyloid pathology along with signs of ongoing neuronal and synaptic degeneration, as well as tangle pathology. Previous studies have demonstrated that increase in CSF tau and p-tau is a specific sign of AD progression that occurs downstream of the deposition of Aβ. On the basis of this, our data suggest that these subjects are at risk for developing AD. We also confirm the association between APOE ɛ4 and amyloid pathology in healthy older individuals.
| S-EPMC5545720 | biostudies-literature
Project description:Staging amyloid-beta (Aβ) pathophysiology according to the intensity of neurodegeneration could identify individuals at risk for cognitive decline in Alzheimer's disease (AD). In blood, phosphorylated tau (p-tau) associates with Aβ pathophysiology but an AD-type neurodegeneration biomarker has been lacking. In this multicenter study (n = 1076), we show that brain-derived tau (BD-tau) in blood increases according to concomitant Aβ ("A") and neurodegeneration ("N") abnormalities (determined using cerebrospinal fluid biomarkers); We used blood-based A/N biomarkers to profile the participants in this study; individuals with blood-based p-tau+/BD-tau+ profiles had the fastest cognitive decline and atrophy rates, irrespective of the baseline cognitive status. Furthermore, BD-tau showed no or much weaker correlations with age, renal function, other comorbidities/risk factors and self-identified race/ethnicity, compared with other blood biomarkers. Here we show that blood-based BD-tau is a biomarker for identifying Aβ-positive individuals at risk of short-term cognitive decline and atrophy, with implications for clinical trials and implementation of anti-Aβ therapies.
| S-EPMC10995141 | biostudies-literature
Project description:PurposeBiomarkers used for predicting longitudinal cognitive change in Alzheimer's disease (AD) continuum are still elusive. Tau pathology, neuroinflammation, and neurodegeneration are the leading candidate predictors. We aimed to determine these three aspects of biomarkers in cerebrospinal fluid (CSF) and plasma to predict longitudinal cognition status using Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort.Patients and methodsA total of 430 subjects including, 96 cognitive normal (CN) with amyloid β (Aβ)-negative, 54 CN with Aβ-positive, 195 mild cognitive impairment (MCI) with Aβ-positive, and 85 AD with amyloid-positive (Aβ-positive are identified by CSF Aβ42/Aβ40 < 0.138). Aβ burden was evaluated by CSF and plasma Aβ42/Aβ40 ratio; tau pathology was evaluated by CSF and plasma phosphorylated-tau (p-tau181); microglial activation was measured by CSF soluble TREM2 (sTREM2) and progranulin (PGRN); neurodegeneration was measured by CSF and plasma t-tau and structural magnetic resonance imaging (MRI); cognition was examined annually over the subsequent 8 years using the Alzheimer's Disease Assessment Scale Cognition 13-item scale (ADAS13) and Mini-Mental State Exam (MMSE). Linear mixed-effects models (LME) were applied to assess the correlation between biomarkers and longitudinal cognition decline, as well as their effect size on the prediction of longitudinal cognitive decline.ResultsBaseline CSF Aβ42/Aβ40 ratio was decreased in MCI and AD compared to CN, while CSF p-tau181 and t-tau increased. Baseline CSF sTREM2 and PGRN did not show any differences in MCI and AD compared to CN. Baseline brain volumes (including the hippocampal, entorhinal, middle temporal lobe, and whole-brain) decreased in MCI and AD groups. For the longitudinal study, there were significant interaction effects of CSF p-tau181 × time, plasma p-tau181 × time, CSF sTREM2 × time, and brain volumes × time, indicating CSF, and plasma p-tau181, CSF sTREM2, and brain volumes could predict longitudinal cognition deterioration rate. CSF sTREM2, CSF, and plasma p-tau181 had similar medium prediction effects, while brain volumes showed stronger effects in predicting cognition decline.ConclusionOur study reported that baseline CSF sTREM2, CSF, and plasma p-tau181, as well as structural MRI, could predict longitudinal cognitive decline in subjects with positive AD pathology. Plasma p-tau181 can be used as a relatively noninvasive reliable biomarker for AD longitudinal cognition decline prediction.
| S-EPMC9280990 | biostudies-literature
Project description:Electroencephalography signatures of amyloid-β, tau and neurodegenerative pathologies would aid in screening for, tracking progression of, and critically, understanding the pathogenesis of dementia. We hypothesized that slowing of the alpha peak frequency, as a signature of hyperpolarization-activated cyclic nucleotide gated 'pacemaker' channel activity, would correlate with amyloid and tau pathology burden measured by amyloid (Pittsburgh Compound B) and tau (MK-6240) positron emission tomography or CSF biomarkers. We also hypothesized that EEG power would be associated with neurodegeneration (CSF neurofilament light and hippocampal volume). Wakeful high-density EEG data were collected from 53 subjects. Both amyloid-β and tau pathology were associated with slowing in the alpha peak frequency [Pittsburgh Compound B (+) vs. Pittsburgh Compound B (-) subjects, P = 0.039 and MK-6240 (+) vs. MK-6240 (-) subjects, P = 0.019]. Furthermore, slowing in the peak alpha frequency correlated with CSF Aβ42/40 ratio (r 2 = 0.270; P = 0.003), phosphoTau (pTau181, r 2 = 0.290; P = 0.001) and pTau181/Aβ42 (r 2 = 0.343; P < 0.001). Alpha peak frequency was not associated with neurodegeneration. Higher CSF neurofilament light was associated with lower total EEG power (r 2 = 0.136; P = 0.018), theta power (r 2 = 0.148; P = 0.014) and beta power (r 2 = 0.216; P = 0.002); the latter was also associated with normalized hippocampal volume (r 2 = 0.196; P = 0.002). Amyloid-tau and neurodegenerative pathologies are associated with distinct electrophysiological signatures that may be useful as mechanistic tools and diagnostic/treatment effect biomarkers in clinical trials.
| S-EPMC7475697 | biostudies-literature
Project description:Mild cognitive impairment (MCI) can be an early manifestation of Alzheimer's disease (AD) pathology, other pathologic entities [e.g., cerebrovascular disease, Lewy body disease, LATE (limbic-predominant age-related TDP-43 encephalopathy)], or mixed pathologies, with concomitant AD- and non-AD pathology being particularly common, albeit difficult to identify, in living MCI patients. The National Institute on Aging and Alzheimer's Association (NIA-AA) A/T/(N) [β-Amyloid/Tau/(Neurodegeneration)] AD research framework, which classifies research participants according to three binary biomarkers [β-amyloid (A+/A-), tau (T+/T-), and neurodegeneration (N+/N-)], provides an indirect means of identifying such cases. Individuals with A+T-(N+) MCI are thought to have both AD pathologic change, given the presence of β-amyloid, and non-AD pathophysiology, given neurodegeneration without tau, because in typical AD it is tau accumulation that is most tightly linked to neuronal injury and cognitive decline. Thus, in A+T-(N+) MCI (hereafter referred to as "mismatch MCI" for the tau-neurodegeneration mismatch), non-AD pathology is hypothesized to drive neurodegeneration and symptoms, because β-amyloid, in the absence of tau, likely reflects a preclinical stage of AD. We compared a group of individuals with mismatch MCI to groups with A+T+(N+) MCI (or "prodromal AD") and A-T-(N+) MCI (or "neurodegeneration-only MCI") on cross-sectional and longitudinal cognition and neuroimaging characteristics. β-amyloid and tau status were determined by CSF assays, while neurodegeneration status was based on hippocampal volume on MRI. Overall, mismatch MCI was less "AD-like" than prodromal AD and generally, with some exceptions, more closely resembled the neurodegeneration-only group. At baseline, mismatch MCI had less episodic memory loss compared to prodromal AD. Longitudinally, mismatch MCI declined more slowly than prodromal AD across all included cognitive domains, while mismatch MCI and neurodegeneration-only MCI declined at comparable rates. Prodromal AD had smaller baseline posterior hippocampal volume than mismatch MCI, and whole brain analyses demonstrated cortical thinning that was widespread in prodromal AD but largely restricted to the medial temporal lobes (MTLs) for the mismatch and neurodegeneration-only MCI groups. Longitudinally, mismatch MCI had slower rates of volume loss than prodromal AD throughout the MTLs. Differences in cross-sectional and longitudinal cognitive and neuroimaging measures between mismatch MCI and prodromal AD may reflect disparate underlying pathologic processes, with the mismatch group potentially being driven by non-AD pathologies on a background of largely preclinical AD. These findings suggest that β-amyloid status alone in MCI may not reveal the underlying driver of symptoms with important implications for enrollment in clinical trials and prognosis.
| S-EPMC8207301 | biostudies-literature
Project description:Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer's disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer's disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer's disease (n = 5) or probable Alzheimer's disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged-although less spatially extended-when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer's disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.
| S-EPMC5841139 | biostudies-literature
Project description:BackgroundTREM2 is a transmembrane receptor that is predominantly expressed by microglia in the central nervous system. Rare variants in the TREM2 gene increase the risk for late-onset Alzheimer's disease (AD). Soluble TREM2 (sTREM2) resulting from shedding of the TREM2 ectodomain can be detected in the cerebrospinal fluid (CSF) and is a surrogate measure of TREM2-mediated microglia function. CSF sTREM2 has been previously reported to increase at different clinical stages of AD, however, alterations in relation to Amyloid ?-peptide (A?) deposition or additional pathological processes in the amyloid cascade (such as tau pathology or neurodegeneration) remain unclear. In the current cross-sectional study, we employed the biomarker-based classification framework recently proposed by the NIA-AA consensus guidelines, in combination with clinical staging, in order to examine the CSF sTREM2 alterations at early asymptomatic and symptomatic stages of AD.MethodsA cross-sectional study of 1027 participants of the Alzheimer's Disease Imaging Initiative (ADNI) cohort, including 43 subjects carrying TREM2 rare genetic variants, was conducted to measure CSF sTREM2 using a previously validated enzyme-linked immunosorbent assay (ELISA). ADNI participants were classified following the A/T/N framework, which we implemented based on the CSF levels of A?1-42 (A), phosphorylated tau (T) and total tau as a marker of neurodegeneration (N), at different clinical stages defined by the clinical dementia rating (CDR) score.ResultsCSF sTREM2 differed between TREM2 variants, whereas the p.R47H variant had higher CSF sTREM2, p.L211P had lower CSF sTREM2 than non-carriers. We found that CSF sTREM2 increased in early symptomatic stages of late-onset AD but, unexpectedly, we observed decreased CSF sTREM2 levels at the earliest asymptomatic phase when only abnormal A? pathology (A+) but no tau pathology or neurodegeneration (TN-), is present.ConclusionsA? pathology (A) and tau pathology/neurodegeneration (TN) have differing associations with CSF sTREM2. While tau-related neurodegeneration is associated with an increase in CSF sTREM2, A? pathology in the absence of downstream tau-related neurodegeneration is associated with a decrease in CSF sTREM2.
| S-EPMC6327425 | biostudies-literature
Project description:ObjectiveTo 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.MethodsWe evaluated 154 individuals who were assessed with amyloid-β PET with [18 F]AZD4694, tau-PET with [18 F]MK6240, structural MRI, and neuropsychological testing. We also evaluated an independent cohort of 240 individuals who were assessed with amyloid-β PET with [18 F]Florbetapir, tau-PET with [18 F]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.ResultsIn 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).InterpretationIn 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.
| S-EPMC8528464 | biostudies-literature
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.
| S-EPMC8665586 | biostudies-literature