Loneliness and biomarkers of Alzheimer's disease, axonal damage, and astrogliosis: A coordinated analysis of two longitudinal cohorts.

Objectives: Loneliness is associated with an elevated risk of dementia. There is mixed evidence from imaging studies on whether loneliness is associated with neuropathology in dementia-free adults. This study tests whether loneliness is associated with plasma neurobiomarkers of amyloid (Aβ42/Aβ40), phosphorylated tau 181 (pTau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) and imaging measures of amyloid and tau.

Sex differences in the trajectories of plasma biomarkers, brain atrophy, and cognitive decline relative to amyloid onset.

Introduction: The factors that influence the progression of Alzheimer's disease (AD) after individuals become amyloid-positive are poorly understood. This study examines how sex influences the longitudinal trajectories of plasma AD and neurodegenerative biomarkers in the years following a person's estimated onset of amyloid-β.

Methods: Linear mixed-effects modeling investigated overall and sex-specific longitudinal trajectories of plasma biomarkers, brain volumes, and cognition relative to the estimated age of amyloid onset in a cohort of 78 amyloid-positive Baltimore Longitudinal Study of Aging (BLSA) participants (n = 45 male; follow-up time: 6.

The Alzheimer's Association Global Biomarker Standardization Consortium (GBSC) plasma phospho-tau Round Robin study.

Background: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer's disease (AD) pathology. Multiple p-tau biomarkers on several analytical platforms are poised for clinical use. The Alzheimer's Association Global Biomarker Standardisation Consortium plasma phospho-tau Round Robin study engaged assay developers in a blinded case-control study on plasma p-tau, aiming to learn which assays provide the largest fold-changes in AD compared to non-AD, have the strongest relationship between plasma and cerebrospinal fluid (CSF), and show the most consistent relationships between methods (commutability) in measuring both patient samples and candidate reference materials (CRM).

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression.

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-β (Aβ) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aβ accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aβ progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aβ-positive status in the Atherosclerosis Risk in Communities (ARIC) study.

Cerebrospinal fluid p-tau181, 217, and 231 in definite Creutzfeldt-Jakob disease with and without concomitant pathologies.

Introduction: The established cerebrospinal fluid (CSF) phosphorylated tau181 (p-tau181) may not reliably reflect concomitant Alzheimer's disease (AD) and primary age-related tauopathy (PART) found in Creutzfeldt-Jakob disease (CJD) at autopsy.

Methods: We investigated CSF N-terminal p-tau181, p-tau217, and p-tau231 with in-house Simoa assays in definite CJD (n = 29), AD dementia (n = 75), mild cognitive impairment (MCI) due to AD (n = 65), and subjective cognitive decline (SCD, n = 28). Post-mortem examination performed in patients with CJD 1.

Plasma brain-derived tau is an amyloid-associated neurodegeneration biomarker in Alzheimer's disease.

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.

Plasma p-tau212 antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217.

Novel ultrasensitive immunoassay for the selective quantification of tau oligomers and related soluble aggregates.

Introduction: Tau aggregation into paired helical filaments and neurofibrillary tangles is characteristic of Alzheimer's disease (AD) and related disorders. However, biochemical assays for the quantification of soluble, earlier-stage tau aggregates are lacking. We describe an immunoassay that is selective for tau oligomers and related soluble aggregates over monomers.

Longitudinal progression of blood biomarkers reveals a key role of astrocyte reactivity in preclinical Alzheimer's disease.

Defining the progression of blood biomarkers of Alzheimer's disease (AD) is essential for targeting treatments in patients most likely to benefit from early intervention. We delineated the temporal ordering of blood biomarkers a decade prior to the onset of AD symptoms in participants in the Baltimore Longitudinal Study of Aging. We show that increased astrocyte reactivity, assessed by elevated glial fibrillary acidic protein (GFAP) levels is an early event in the progression of blood biomarker changes in preclinical AD.

Plasma p-tau212: antemortem diagnostic performance and prediction of autopsy verification of Alzheimer's disease neuropathology.

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer's disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217.

A novel ultrasensitive assay for plasma p-tau217: Performance in individuals with subjective cognitive decline and early Alzheimer's disease.

Introduction: Detection of Alzheimer's disease (AD) pathophysiology among individuals with mild cognitive changes and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma phosphorylated tau 217 (p-tau217) is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited.

A novel ultrasensitive assay for plasma p-tau217: performance in individuals with subjective cognitive decline and early Alzheimer's disease.

Introduction: Detection of Alzheimer's disease (AD) pathophysiology among cognitively unimpaired individuals and those experiencing subjective cognitive decline (SCD) remains challenging. Plasma p-tau217 is one of the most promising of the emerging biomarkers for AD. However, accessible methods are limited.

Association of Serum Brain-Derived Tau With Clinical Outcome and Longitudinal Change in Patients With Severe Traumatic Brain Injury.

Importance: Blood-based measurements of total tau (T-tau) are commonly used to examine neuronal injury in patients with traumatic brain injury (TBI), but current assays do not differentiate between brain-derived tau (BD-tau) and tau produced in peripheral tissues. A novel assay for BD-tau has recently been reported that selectively quantifies nonphosphorylated tau of central nervous system origin in blood samples.

Objectives: To examine the association of serum BD-tau with clinical outcomes in patients with severe TBI (sTBI) and its longitudinal changes over 1 year.

Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease.

Introduction: Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset.

Methods: We measured longitudinal changes in plasma amyloid-beta (Aβ) ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression.

Results: Aβ ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up.

Preanalytical stability of plasma/serum brain-derived tau.

Introduction: We investigated the effects of matrix type and reagent batch changes on diagnostic performances and longitudinal trajectories of brain-derived tau (BD-tau).

Methods: We evaluated (i) Cohort 1: paired EDTA plasma and serum from Alzheimer biomarker-positive older adults versus controls (n = 26); and (ii) Cohort 2: n = 79 acute ischemic stroke patients with 265 longitudinal samples across four time points.

Results: In Cohort 1, plasma and serum BD-tau were strongly correlated (rho = 0.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

Introduction: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies.

Methods: We examined the temporal order of changes in plasma amyloid-β ratio ( ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( , ) relative to C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.

Plasma and cerebrospinal fluid glial fibrillary acidic protein levels in adults with Down syndrome: a longitudinal cohort study.

Background: The diagnosis of symptomatic Alzheimer's disease is a clinical challenge in adults with Down syndrome. Blood biomarkers would be of particular clinical importance in this population. The astrocytic Glial Fibrillary Acidic Protein (GFAP) is a marker of astrogliosis associated with amyloid pathology, but its longitudinal changes, association with other biomarkers and cognitive performance have not been studied in individuals with Down syndrome.

Plasma phospho-tau in Alzheimer's disease: towards diagnostic and therapeutic trial applications.

As the leading cause of dementia, Alzheimer's disease (AD) is a major burden on affected individuals, their families and caregivers, and healthcare systems. Although AD can be identified and diagnosed by cerebrospinal fluid or neuroimaging biomarkers that concord with neuropathological evidence and clinical symptoms, challenges regarding practicality and accessibility hinder their widespread availability and implementation. Consequently, many people with suspected cognitive impairment due to AD do not receive a biomarker-supported diagnosis.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

Introduction: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies.

Methods: We examined the temporal order of changes in plasma amyloid-β ratio (Aβ /Aβ ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios (p-tau181/Aβ , p-tau231/Aβ ) relative to C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.

Brain-derived tau: a novel blood-based biomarker for Alzheimer's disease-type neurodegeneration.

Blood-based biomarkers for amyloid beta and phosphorylated tau show good diagnostic accuracies and agreements with their corresponding CSF and neuroimaging biomarkers in the amyloid/tau/neurodegeneration [A/T/(N)] framework for Alzheimer's disease. However, the blood-based neurodegeneration marker neurofilament light is not specific to Alzheimer's disease while total-tau shows lack of correlation with CSF total-tau. Recent studies suggest that blood total-tau originates principally from peripheral, non-brain sources.

Diagnostic value of serum versus plasma phospho-tau for Alzheimer's disease.

Background: Blood phosphorylated tau (p-tau) forms are promising Alzheimer's disease (AD) biomarkers, but validation in matrices other than ethylenediaminetetraacetic acid (EDTA) plasma is limited. Firstly, we assessed the diagnostic potential of p-tau231 and p-tau181 in paired plasma and serum samples. Secondly, we compared serum and cerebrospinal fluid (CSF) samples from biomarker-positive AD and biomarker-negative control participants.