Plasma Tau Research Articles

Amyloid β-protein and beyond: the path forward in Alzheimer's disease.

Basic research on the biological mechanism of Alzheimer's disease has focused for decades on the age-related aggregation of the amyloid β-protein and its apparent downstream effects on microglia, astrocytes and neurons, including the posttranslational modification of the tau protein that seems necessary for symptom expression. Here, we discuss the highly challenging process of developing disease-modifying therapies and highlight several key areas of current research that are progressing in exciting directions. We conclude that further deep molecular analyses of the disease, including the mechanisms of β-amyloidosis, will enable more effective clinical trials and ultimately achieve the progress that our patients so deserve.

Nanoparticle-based immunomagnetic assay of plasma biomarkers for differentiating dementia and prodromal states of Alzheimer's disease – A cross-validation study

Blood-based biomarker assays of plasma β-amyloid (Aβ) and tau have the advantages of cost-effective and less invasive for the diagnosis of Alzheimer's disease (AD). We used two independent cohorts to cross-validate the clinical use of the nanoparticle-based immunomagnetic assay of plasma biomarkers to assist in the differential diagnosis of early AD. There were in total 160 subjects in the derivation cohort, and 242 in the validation cohort both containing controls, mild cognitive impairment due to AD and AD dementia diagnosed according to the 2011 NIA-AA guidelines. The cutoff value for plasma Aβ1–42 (16.4 pg/ml) performed the best in differentiating between controls and patients with prodromal or clinical AD, with 92.5% for positive percent agreement (PPA), negative percent agreement (NPA), and overall rate of agreement (ORA). Aβ1–42 × tau (642.58) was useful for separating patients with dementia and prodromal states of AD, with 84.9% PPA, 78.8% NPA and 83% ORA.

Plasma tau, neurofilament light chain and amyloid-β levels and risk of dementia; a population-based cohort study.

CSF biomarkers, including total-tau, neurofilament light chain (NfL) and amyloid-β, are increasingly being used to define and stage Alzheimer's disease. These biomarkers can be measured more quickly and less invasively in plasma and may provide important information for early diagnosis of Alzheimer's disease. We used stored plasma samples and clinical data obtained from 4444 non-demented participants in the Rotterdam study at baseline (between 2002 and 2005) and during follow-up until January 2016. Plasma concentrations of total-tau, NfL, amyloid-β40 and amyloid-β42 were measured using the Simoa NF-light® and N3PA assays. Associations between biomarker plasma levels and incident all-cause and Alzheimer's disease dementia during follow-up were assessed using Cox proportional-hazard regression models adjusted for age, sex, education, cardiovascular risk factors and APOE ε4 status. Moreover, biomarker plasma levels and rates of change over time of participants who developed Alzheimer's disease dementia during follow-up were compared with age and sex-matched dementia-free control subjects. During up to 14 years follow-up, 549 participants developed dementia, including 374 cases with Alzheimer's disease dementia. A log2 higher baseline amyloid-β42 plasma level was associated with a lower risk of developing all-cause or Alzheimer's disease dementia, adjusted hazard ratio (HR) 0.61 [95% confidence interval (CI), 0.47-0.78; P < 0.0001] and 0.59 (95% CI, 0.43-0.79; P = 0.0006), respectively. Conversely, a log2 higher baseline plasma NfL level was associated with a higher risk of all-cause dementia [adjusted HR 1.59 (95% CI, 1.38-1.83); P < 0.0001] or Alzheimer's disease [adjusted HR 1.50 (95% CI, 1.26-1.78); P < 0.0001]. Combining the lowest quartile group of amyloid-β42 with the highest of NfL resulted in a stronger association with all-cause dementia [adjusted HR 9.5 (95% CI, 2.3-40.4); P < 0.002] and with Alzheimer's disease [adjusted HR 15.7 (95% CI, 2.1-117.4); P < 0.0001], compared to the highest quartile group of amyloid-β42 and lowest of NfL. Total-tau and amyloid-β40 levels were not associated with all-cause or Alzheimer's disease dementia risk. Trajectory analyses of biomarkers revealed that mean NfL plasma levels increased 3.4 times faster in participants who developed Alzheimer's disease compared to those who remained dementia-free (P < 0.0001), plasma values for cases diverged from controls 9.6 years before Alzheimer's disease diagnosis. Amyloid-β42 levels began to decrease in Alzheimer's disease cases a few years before diagnosis, although the decline did not reach significance compared to dementia-free participants. In conclusion, our study shows that low amyloid-β42 and high NfL plasma levels are each independently and in combination strongly associated with risk of all-cause and Alzheimer's disease dementia. These data indicate that plasma NfL and amyloid-β42 levels can be used to assess the risk of developing dementia in a non-demented population. Plasma NfL levels, although not specific, may also be useful in monitoring progression of Alzheimer's disease dementia.

Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration.

With the potential development of new disease-modifying Alzheimer’s Disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals who are experiencing symptoms of cognitive or behavioral decline should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved CSF or amyloid β-PET diagnostic tests. We examined whether plasma phosphorylated tau at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy confirmed AD and Frontotemporal Lobar Degeneration (FTLD). Plasma pTau181 concentrations were increased by 3.5 fold in AD compared to controls and differentiated AD from both clinically diagnosed (Receiver Operating Characteristic Area Under the Curve [AUC]=0.894) and autopsy confirmed FTLD (AUC=0.878). Plasma pTau181 identified amyloid β-PET positive individuals regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-Flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.

Changes in Plasma Amyloid and Tau in a Longitudinal Study of Normal Aging, Mild Cognitive Impairment, and Alzheimer’s Disease

Background: Changes in cerebrospinal fluid, neuroimaging, and cognitive functions have been used as diagnostic biomarkers of Alzheimer’s disease (AD). This study aimed to investigate the temporal trajectories of plasma biomarkers in subjects with mild cognitive impairment (MCI) and patients with AD relative to healthy controls (HCs). Methods: In this longitudinal study, 82 participants (31 HCs, 33 MCI patients, and 18 AD patients) were enrolled. After 3 years, 7 HCs had transitioned to MCI and 10 subjects with MCI had converted to AD. We analyzed plasma amyloid beta (Aβ) and tau proteins at baseline and annually to correlate with biochemical data and neuropsychological scores. Results: Longitudinal data analysis showed an evolution of Aβ-related biomarkers over time within patients, whereas tau-related biomarkers differed primarily across diagnostic classifications. An initial steady increase in Aβ42 in the MCI stage was followed by a decrease just prior to clinical AD onset. Hyperphosphorylated tau protein levels correlated with cognitive decline in the MCI stage, but not in the AD stage. Conclusion: Plasma Aβ and tau levels change in a dynamic, nonlinear, nonparallel manner over the AD continuum. Changes in plasma Aβ concentration are time-dependent, whereas changes in hyperphosphorylated tau protein levels paralleled the clinical progression of MCI. It remains to be clarified whether diagnostic efficiency can be improved by combining multiple plasma markers or combining plasma markers with other diagnostic biomarkers.

Plasma tau protein and Aβ42 level as markers of cognitive impairment in patients with Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with a characteristic clinical picture. Apart from classical movement disorders, a significant role is also played by non-motor symptoms, in particular cognitive impairments, which have a significant impact on the quality of life of the patients. Tau protein and amyloid beta are well-known non-specific biomarkers in Alzheimer's disease (AD). The study assessed the practical value of determining tau protein and amyloid beta (Aβ42) in the blood serum of patients with PD and their relationship with cognitive impairments, radiographic image and the used dose of L-DOPA. The neuropsychological assessment was carried for 64 patients with PD. The levels of amyloid beta 1-42 (Aβ42) and tau proteins in serum were also measured. The Aβ42 level in the serum was statistically higher in patients with longer duration of the disease (p < 0.05) and those who were taking a higher dose of L-DOPA (p < 0.05). The average level of tau protein in the serum was slightly lower in the study groups than in the control group and showed no statistical significance. No correlation was found between the levels of tau protein and Aβ42 and the results of neuropsychological tests. Tau protein correlated with hippocampal atrophy (p < 0.05). Serum levels of Aβ42 and tau protein in PD may be a useful marker for the assessment of cognitive impairments. The role of L-DOPA in the process of dementia in PD remains unclear.

A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer's Disease by Peptidome Technology.

Background:Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer’s disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1 - 42 are not yet well established.Objective:We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology.Methods:With only 1.5μl of serum, we examined a new target plate “BLOTCHIP®” plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n = 100), MCI (n = 60), and AD (n = 99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains.Results:Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p < 0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains.Conclusion:The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

Plasma levels of Interleukin 18 but not amyloid-β or Tau are elevated in female depressive patients

BackgroundDepression is associated with inflammation and Alzheimer's disease (AD). However, detailed molecular mechanisms linking mood, neuroinflammation and AD remain unclear. Although changes in peripheral inflammatory factors such as Interleukin 18 (IL18), and AD-associated amyloid-β (Aβ) peptides have been linked to depression, a solid relationship between these factors in depressive disorder has yet to be established. This study aims to further determine whether plasma IL18, Aβ40, Aβ42, and the AD-associated tangle component Tau, as well as IL18 single nucleotide polymorphisms (SNPs) may be biomarkers for depression. MethodsWe measured plasma IL18, Aβ40, Aβ42, and Tau in 64 depressive patients and 75 healthy controls, and characterized genotypes of three IL18 SNPs (rs187238, rs1946518 and rs1946519) in these subjects. Comparisons between depressive patients and controls were carried out in males, in females or in combination. Regression analyses were conducted to examine the correlation between these parameters. ResultsWe found that none of the plasma levels of IL18, Aβ40, Aβ42, and Tau, the ratio of Aβ42/Aβ40, and the genotypes of IL18 SNPs were significantly different between combined depressive patients and combined healthy controls, or between male depressive patients and male controls. However, IL18 levels were less in females than in males in healthy people and were significantly increased in female depressive patients compared to female controls. Moreover, IL18 and standardized IL18 were correlated with standardized Aβ42/Aβ40 ratio and standardized Tau in depressive patients. ConclusionsPlasma IL18 may be a potential biomarker for depression in women.

Immune system stimulation increases the irreversible loss of cysteine to taurine, but not sulfate, in starter pigs.

An isotope tracer study was conducted to evaluate the effects of immune system stimulation (ISS) on the irreversible loss of cysteine (Cys) to taurine (Tau) and sulfate (SO4), as well as glutathione (GSH) synthesis, during the fed state in pigs. We previously have reported that ISS increases plasma Cys flux and the GSH synthesis rate at the tissue and whole-body levels in growing pigs. Thus, the current article presents the data on the irreversible loss of Cys during ISS in pigs. Ten gilts (BW: 7.0 ± 0.12 kg) were feed restricted a sulfur amino acids (SAA) limiting diet and injected twice with either saline (n = 4) or increasing amounts of E. coli lipopolysaccharide (n = 6). The day after the second injection, a 5-h primed continuous intravenous infusion of 35S-Cys was conducted. ISS reduced plasma Cys and total SAA concentrations (16% and 21%, respectively; P < 0.05). However, ISS had no effect on the plasma concentrations of Tau and SO4, nor did it affect the appearance of 35S in plasma Tau, plasma SO4, urinary Tau, or urinary SO4 (P > 0.19). On a whole-body basis and including urinary excretion, ISS increased the appearance of 35S in Tau by 67% (P < 0.05), but tended to decrease the appearance of 35S in SO4 by 22% (P < 0.09). Overall, the current findings indicate that during ISS, decreased plasma SAA concentrations and increased plasma Cys flux are attributed in part to increased rates of Cys conversion to Tau, but not Cys catabolism to SO4. Thus, increased utilization of Cys for the synthesis of immune system metabolites, such as GSH and Tau, is likely the main contributor to increased Cys flux during ISS in pigs. In addition, the irreversible loss of Cys during ISS is small and has a minimal impact on the daily SAA requirements of starter pigs.

Tau Is Elevated in Pediatric Patients on Extracorporeal Membrane Oxygenation.

Neurologic injury is a known and feared complication of extracorporeal membrane oxygenation (ECMO). Neurologic biomarkers may have a role in assisting in early identification of such. Axonal biomarker tau has not been investigated in the pediatric ECMO population. The objective of this study is to evaluate plasma levels of tau in pediatric patients supported with ECMO. Eighteen patients requiring ECMO support in a quaternary pediatric intensive care unit at a university-affiliated children's hospital from October 2015 to February 2017 were enrolled. Patients undergoing extracorporeal cardiopulmonary resuscitation or recent history of bypass were excluded. Plasma tau was measured using enzyme-linked immunosorbent assay. Neuroimaging was reviewed for acute neurologic injury, and tau levels were analyzed to assess for correlation. Tau was significantly higher in ECMO patients than in control subjects. Sixty-one percent of subjects had evidence of acute brain injury on neuroimaging, but tau level did not correlate with injury. Subjects with multifocal injury all experienced infarction and had significantly higher tau levels on ECMO day 3 than patients with isolated injury. In addition, peak tau levels of neuro-injured subjects were compared with controls and noninjured ECMO subjects using receiver operating curve analysis. This study demonstrates preliminary evidence of axonal injury in pediatric ECMO patients.

Plasma amyloid, tau, and neurodegeneration biomarker profiles predict Alzheimer's disease pathology and clinical progression in older adults without dementia.

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.

Composite Scores of Plasma Tau and β-Amyloids Correlate with Dementia in Down Syndrome.

Dementia frequently occurs in Down syndrome (DS) patients, and early intervention is important in its management. We have previously demonstrated a positive correlation of plasma β-amyloid Aβ42 levels and negative correlations of Aβ40 and tau levels with dementia in DS. In this study, we examined more cases and constructed composite scores with both tau and amyloids to correlate with dementia in DS. Plasma Aβ42, Aβ40, and tau proteins were measured by an immunomagnetic reduction assay in DS patients. Data were randomly and repeatedly split into training and validating sets, and logistic regression was applied to calculate the area under the curve (AUC) for each biomarker. A total of 73 DS patients (among them, 23 had neurodegeneration) and 77 controls were recruited. In DS patients without dementia, plasma Aβ40 and tau levels were highly elevated, but Aβ42 levels were lower than those of the healthy controls. DS patients with dementia, compared with DS patients with no dementia, had a large decline in Aβ40 and tau but a rise in Aβ42. For biomarker scores correlating with dementia, Aβ40 revealed an AUC of 0.912; the composite score of Aβ40 × tau revealed an AUC of 0.953; and a combined composite score of 0.1 for Aβ40 × Tau +0.9 Tau × Aβ40/Aβ42 achieved the highest AUC of 0.965. Therefore, composite biomarker scores including both plasma tau and β-amyloid levels correlate with dementia in DS better than using individual biomarker scores. The pattern of tau decline and Aβ42 rise in DS patients with dementia are also different from previous findings in Alzheimer's disease.

Plasma tau correlates with basal forebrain atrophy rates in people at risk for Alzheimer disease.

To investigate whether baseline concentrations of plasma total tau (t-tau) and neurofilament light (NfL) chain proteins are associated with annual percent change (APC) of the basal forebrain cholinergic system (BFCS) in cognitively intact older adults at risk for Alzheimer disease (AD). This was a large-scale study of 276 cognitively intact older adults from the monocentric INSIGHT-preAD (Investigation of Alzheimer's Predictors in Subjective Memory Complainers) cohort. Participants underwent baseline assessment of plasma t-tau and NfL concentrations as well as baseline and 24-month follow-up MRI scans. Linear models with and without influential observations (calculated using the Cook distance) were carried out to investigate the effect of plasma NfL and t-tau concentrations, and their interaction effect with β-amyloid status and APOE genotype, on the APC of the whole BFCS and its anterior (Ch1/2) and posterior (Ch4) subdivisions separately. Higher plasma t-tau concentrations at baseline were associated with higher BFCS rate of atrophy (model without influencers: n = 251, F value = 4.6815; p value = 0.031). Subregional analyses showed similar results for both the APC of the Ch1/2 (model without influencers: n = 256, F value = 3.9535, p corrected = 0.047) and Ch4 BFCS sectors (model without influencers: n = 253, F value = 4.9090, p corrected = 0.047). Baseline NfL, β-amyloid load, and APOE ε4 carrier status did not affect APC of the BFCS. Increased concentrations of baseline plasma t-tau may predict in vivo structural BFCS atrophy progression in older adults at risk for AD, independently of β-amyloid status and APOE genotype.

Combined use of CSF NfL and CSF TDP-43 improves diagnostic performance in ALS.

ObjectiveTo determine the diagnostic and prognostic significance of neurofilament light chain (NfL), TAR DNA‐binding protein 43 (TDP‐43), and total tau (t‐tau) in cerebrospinal fluid (CSF) and plasma of patients with amyotrophic lateral sclerosis (ALS) and to investigate whether the combined use of those biomarker candidates can improve their diagnostic performance.MethodsThis was a single–center, prospective, longitudinal study. CSF and plasma samples were collected at the time of enrollment from a discovery cohort of 29 patients with ALS and 29 age–matched controls without neurodegenerative disease. In a validation cohort, there were 46 patients with ALS, and 46 control (not age‐matched) patients with motor weakness resulting from neuromuscular diseases. NfL, TDP‐43, and t‐tau levels in CSF and plasma were measured using ultrasensitive single molecule assay (Simoa) technology.ResultsThe following findings were reproducibly observed among the discovery and validation cohorts: increased levels of CSF NfL, plasma NfL, and CSF TDP‐43 in ALS compared with control groups; shorter survival associated with higher levels of CSF and plasma NfL. When the CSF NfL and CSF TDP‐43 levels were combined, the areas under the ROC curves (AUC) were slightly improved relative to AUCs for each biomarker alone.InterpretationCSF and plasma NfL may not only serve as diagnostic biomarkers but also provide a measure of disease progression. CSF TDP‐43 is also useful as a diagnostic biomarker of ALS, but has no prognostic value. The combined use of CSF NfL and CSF TDP‐43 may be a useful biomarker for the diagnosis of ALS.

Elevated Plasma Tau Predicts Stroke Risk Over and Above Other Factors

Elevated Plasma Tau Predicts Stroke Risk Over and Above Other Factors

Plasma Neurofilament Light Chain Levels Are Associated With Cortical Hypometabolism in Alzheimer Disease Signature Regions.

Neurofilament light chain (NFL) has been recently introduced as a biomarker of early dementia. 18-Fluorodeoxyglucose positron emission tomography (18F-FDG-PET) is a proxy for regional hypometabolism in Alzheimer disease (AD). Globally normalized 18F-FDG-PET values and levels of NFL and tau were obtained from 149 patients with mild cognitive impairment (MCI) from the baseline cohort of the Alzheimer's Disease Neuroimaging Initiative database. We adopted a stepwise partial correlation model using plasma NFL, plasma tau, CSF NFL, and regional cerebral metabolic rate of glucose (CMRGlc) as main variables, and age, sex, and Alzheimer's Disease Rating Scale (ADAS) as covariates. Significant regions were entered into a stepwise multiple regression analysis to investigate the independent correlation of each biomarker to baseline regional CMRGlc and its progression in patients with MCI. Higher baseline CSF NFL levels correlated with hypometabolism in bilateral precuneal and posterior cingulate cortex. After correction for age, sex, and ADAS score, plasma NFL levels correlated with hypometabolism in bilateral parahippocampal and middle temporal gyri. Cortical hypometabolism in bilateral parahippocampal gyri and right fusiform and middle temporal gyri was independently predicted by higher baseline plasma NFL levels in a multiple regression model. Plasma NFL promises to be an early biomarker of cortical hypometabolism in MCI and for MCI progression to AD.

Plasma Amyloid Beta and Tau Levels Are Predictors of Post-stroke Cognitive Impairment: A Longitudinal Study.

Objectives: Post-stroke cognitive impairment (PSCI) is a common disease that may occur within 3 months after a stroke or even later. However, the mechanism of PSCI development is unclear. The present study investigated whether the levels of plasma amyloid beta-42 (Aβ42) and tau are associated with the onset of PSCI.Methods: Fifty-five patients admitted within 7 days of acute ischemic stroke were enrolled and followed up for 1 year. Montreal Cognitive Assessment (MoCA) was administered at 3 months and 1 year, and plasma Aβ42 and tau levels were determined using an ultrasensitive immunoassay (immunomagnetic reduction) within 7 days of the stroke event and 3 months later.Results: In this study, 13 of 55 patients developed PSCI (MoCA score <23) at 3 months. Seven patients with PSCI at 3 months recovered to a cognitively normal state at 1 year, whereas seven cognitively normal patients developed PSCI at 1 year. The patients with PSCI at 1 year had a higher incidence of cognitive function deterioration between 3 months and 1 year compared with those without PSCI at 1 year. Plasma Aβ42 and tau levels at 3 months were lower in the patients with PSCI at 1 year than in those without PSCI (Aβ42: 15.1 vs. 17.2 pg/mL, P = 0.013; tau: 16.7 vs. 19.9 pg/mL, P = 0.018). Low education levels and pre-existing white matter disease were the most significant predictors of PSCI at 3 months, and poor cognitive performance at 3 months and low plasma Aβ42 and tau levels at 3 months were the most significant predictors of PSCI at 1 year.Conclusion: The pathogenesis of PSCI is complex and changes with time. Ischemia-induced Aβ42/tau pathology might be involved in PSCI development.

Plasma amyloid and tau as dementia biomarkers in Down syndrome: Systematic review and meta-analyses.

Individuals with Down syndrome (DS) are at high risk of developing Alzheimer's disease (AD). Discovering reliable biomarkers which could facilitate early AD diagnosis and be used to predict/monitor disease course would be extremely valuable. To examine if analytes in blood related to amyloid plaques may constitute such biomarkers, we conducted meta‐analyses of studies comparing plasma amyloid beta (Aβ) levels between DS individuals and controls, and between DS individuals with and without dementia. PubMed, Embase, and Google Scholar were searched for studies investigating the relationship between Aβ plasma concentrations and dementia in DS and 10 studies collectively comprising >1,600 adults, including >1,400 individuals with DS, were included. RevMan 5.3 was used to perform meta‐analyses. Meta‐analyses showed higher plasma Aβ40 (SMD = 1.79, 95% CI [1.14, 2.44], Z = 5.40, p < .00001) and plasma Aβ42 levels (SMD = 1.41, 95% CI [1.15, 1.68], Z = 10.46, p < .00001) in DS individuals than controls, and revealed that DS individuals with dementia had higher plasma Aβ40 levels (SMD = 0.23, 95% CI [0.05, 0.41], Z = 2.54, p = .01) and lower Aβ42/Aβ40 ratios (SMD = −0.33, 95% CI [−0.63, −0.03], Z = 2.15, p = .03) than DS individuals without dementia. Our results indicate that plasma Aβ40 levels may constitute a promising biomarker for predicting dementia status in individuals with DS. Further investigations using new ultra‐sensitive assays are required to obtain more reliable results and to investigate to what extent these results may be generalizable beyond the DS population.

GENOME-WIDE ASSOCIATION STUDY OF PLASMA TAU LEVELS USING HRC IMPUTATIONS IN THE FRAMINGHAM STUDY

GENOME-WIDE ASSOCIATION STUDY OF PLASMA TAU LEVELS USING HRC IMPUTATIONS IN THE FRAMINGHAM STUDY

Plasma tau complements CSF tau and P-tau in the diagnosis of Alzheimer's disease

IntroductionPlasma tau may be an accessible biomarker for Alzheimer's disease (AD), but the correlation between plasma and cerebrospinal fluid (CSF) tau and the value of combining plasma tau with CSF tau and phospho-tau (P-tau) are still unclear. MethodsPlasma-tau, CSF-tau, and P-tau were measured in 97 subjects, including elderly cognitively normal controls (n = 68) and patients with AD (n = 29) recruited at the NYU Center for Brain Health, with comprehensive neuropsychological and magnetic resonance imaging evaluations. ResultsPlasma tau was higher in patients with AD than cognitively normal controls (P < .001, area under the receiver operating characteristic curve = 0.79) similarly to CSF tau and CSF P-tau and was negatively correlated with cognition in AD. Plasma and CSF tau measures were poorly correlated. Adding plasma tau to CSF tau or CSF P-tau significantly increased the areas under the receiver operating characteristic curve from 0.80 and 0.82 to 0.87 and 0.88, respectively. DiscussionPlasma tau is higher in AD independently from CSF-tau. Importantly, adding plasma tau to CSF tau or P-tau improves diagnostic accuracy, suggesting that plasma tau may represent a useful biomarker for AD, especially when added to CSF tau measures.