Comparison of tau‐PET tracers for in vivo Braak staging: the HEAD Study.

Background: Tau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.

Exploring the effects of using multiple different cerebellar reference regions to improve tau‐PET harmonization ‐ The HEAD Study.

Background: Tau‐PET tracers have been used to diagnose and stage Alzheimer’s disease. However, different tau tracers present distinct patterns of binding throughout the brain, challenging the harmonization of their results. We hypothesize that the choice of a reference region can impact the harmonization of the tau‐PET standardized uptake value ratio (SUVR).

Universal tau PET scale (Uniτ) – The HEAD Study.

Background: The HEAD study aims to collect a large dataset of multiple tau‐PET tracers to provide robust anchor values for tau‐PET harmonization. Here, we tested the hypothesis that anchoring two tau tracer uptake values using head‐to‐head measurements has the potential to generate an accurate universal tau‐PET scale, named Uniτ(tau).

Methods: We assessed 200 individuals across the aging and AD spectrum (Training: HEAD data freeze 2.

APOEε4 drives microglial activation in the medial temporal cortex in individuals across the AD spectrum.

Background: Microglial activation is an early phenomenon in Alzheimer’s disease (AD) that may occur prior to and independently of amyloid‐β (Aβ) aggregation. Compelling experimental evidence suggests that the apolipoprotein E ε4 (ε4) allele may be a culprit of early microglial activation in AD. However, it is unclear whether the ε4 genotype is associated with microglial reactivity in the living human brain.

Associations between plasma biomarkers and brain amyloid and tau pathologies in a population‐based cohort without evidence of cognitive impairment.

Background: Plasma biomarkers have been widely evaluated as surrogate markers for brain Alzheimer’s disease (AD) pathology. However, studies in diverse populations with lower socioeconomic status (SES) are limited. We evaluated associations between different plasma biomarkers and brain amyloid beta (Aβ) and tau positron emission tomography (PET) in a longitudinal cohort of cognitively normal participants from a medically‐ and economically‐underserved Rust Belt region of Western Pennsylvania, USA.

Utility of plasma p‐tau217 as a secondary outcome for clinical trials across AD continuum.

Background: Blood‐based biomarkers offer a cost‐effective and simple alternative for clinical use in the context of Alzheimer's disease (AD). It has already been shown that plasma phosphorylated tau at threonine 217 (p‐tau217) is associated with amyloid (Aβ), neurofibrillary tau tangles, and cognitive decline. Longitudinal studies confirmed its ability to track AD progression.

Clinical use of tau PET in Aβ PET positive individuals: a case series.

Background: Identifying individuals’ levels of tau PET pathology could prove to be beneficial in clinical settings, given that emerging therapies aimed reducing Aβ seem to be most effective in these individuals. Here, we present the cases of four patients who visited the memory clinic at the University of Pittsburgh Medical Center between June and December 2023 and underwent both Aβ and tau‐PET scans.

Method: These individuals had standard clinical and cognitive outcomes, typical blood tests order in patients with memory impairment, MRI, and, as part of the HEAD study, PET PIB Aβ and two tau PET tracers (MK6240 and Flortaucipir).

Direct comparisons of the associations between the tau PET tracers [F]Flortaucipir and [F]MK6240 with tests of general cognitive performance ‐ The HEAD study.

Background: Tau PET tracers are employed to measure the accumulation of tau in vivo in the brain. Each tau tracer possesses unique characteristics, including binding affinity, sensitivity, and specificity to tau aggregates. This study leverages the HEAD study dataset, which is currently performing baseline tau PET tracers and conducting multiple clinical and cognitive assessments.

Alzheimer's disease staging with [F]MK6240 and [F]Flortaucipir ‐ the HEAD study.

Background: Utilizing PET amyloid‐beta (Aβ) and tau for staging Alzheimer’s Disease (AD) has demonstrated potential in identifying individuals with varying degrees of disease severity, applicable to both clinical trials and practice. However, the diverse binding characteristics of tau tracers pose challenges to the application of this staging across different ligands. In this study, we evaluate a novel staging framework proposed by the AA working group, employing Aβ PET and either [F]MK6240 or [F]Flortaucipir in individuals participating in a head‐to‐head study of tau PET tracers.

Impact of anchoring cutoff point of tau positivity on CU young or older adults using Flortaucipir and MK‐6240 – Head Study.

Background: Tau PET provides continuous measurements of tau tangle pathology in the human brain. However, establishing cutoffs is crucial for selecting individuals for treatment in clinical trials or practice. In the absence of postmortem data, PET cutoffs must be established using statistical methods based on what is considered normal tracer uptake.

Exploring the utility of Plasma GFAP as a secondary endpoint in Alzheimer's disease Clinical trials to monitor disease progression.

Background: Recent anti‐amyloid clinical trials have incorporated plasma glial fibrillary acidic protein (GFAP) as an exploratory endpoint, reporting a notable decrease in plasma GFAP levels over time. Additionally, plasma GFAP has been associated with Aβ pathology and cognitive decline in individuals with cognitive impairment, making it a robust biomarker of neuroinflammation for Alzheimer’s disease (AD). Here, we tested the utility of changes in plasma GFAP as a secondary endpoint in AD clinical trials focusing on cognitively impaired (CI) individuals.

Creating Universal Tau PET Scale (Uniτ) Parametric Images – The HEAD Study.

Background: The HEAD study focuses on collecting an extensive dataset from various tau‐PET tracers, aiming to establish robust anchor values, which are essential for harmonizing tau‐PET measurements. Here, we aim to showcase the capability of converting 3D tau‐PET images into a common scale using the Universal Tau‐PET Scale, Uniτ (tau), and to use these 3D images to subsequently obtain ROIs as needed.

Methods: We assessed 185 individuals across the aging and AD spectrum from the HEAD study, with [F]Flortaucipir and [F]MK‐6240 tau‐PET tracers.

Technical and clinical validation of a novel plasma p‐tau217 assay: evaluation in real world population‐based and racially‐diverse cohorts.

Background: Plasma phospho‐tau217 (p‐tau217) is a promising blood‐based biomarkers for Alzheimer's disease (AD). However, the accessibility of pTau217 tests for both research and clinical applications has been constrained. Previous studies focused on highly‐phenotyped cohorts that differ substantially from the wider population.

Microglial activation impacts amyloid‐β effects on reactive astrogliosis.

Background: Glial reactivity is a key phenomenon in Alzheimer’s disease (AD) and is closely associated with amyloid‐β (Aβ) pathology. Although compelling experimental data suggest that microglial activation modulates reactive astrogliosis, it remains to be elucidated whether microglial activation influences the association of Aβ pathology with reactive astrogliosis in the living AD human brain. Here, we tested the association of microglial activation and Aβ pathology with reactive astrogliosis in individuals across the aging and AD clinical spectrum.

Feasibility of using plasma p‐tau217 as a surrogate for brain Aβ PET in the community.

Background: Plasma p‐tau217 is probably the best‐performing blood biomarker to detect brain amyloid‐beta (Aβ) accumulation. However, previous studies were mostly performed in highly selected cohorts. Thus, it is unclear if it can be used independently of confirmatory neuroimaging tests to identify individuals with abnormal brain Ab load in the wider population where positron emission tomography (PET) may be unavailable.

Plasma GFAP use for population enrichment of clinical trials in preclinical Alzheimer’s disease.

Background: We showed that plasma GFAP (a proxy of astrocyte reactivity) abnormality is key to unleashing Aβ effects on tau phosphorylation in preclinical AD. This suggests that selecting cognitively unimpaired(CU) individuals with both high Aβ and plasma GFAP could offer an early time window in the disease, but with an increased risk of developing tau pathology. Here, we tested the utility of plasma GFAP for population enrichment in clinical trials focusing on CU individuals.

Multi‐analyte measurement of blood biomarkers for Alzheimer's disease: enabling concurrent analysis of affected pathophysiological processes.

Background: Alzheimer’s disease (AD) is a multifaceted condition associated with various brain pathologies, necessitating diverse biomarkers for precise prognosis, diagnosis, clinical management, and therapeutic development/evaluation. The integration of multiple biomarkers into a single test can enhance efficiency, reduce analytical errors, and save on specimen volume. Alamar Biosciences recently introduced the NULISAseq CNS disease panel, a multiplex NUcleic acid‐linked Immuno‐Sandwich Assay (NULISA) targeting ∼120 analytes.

Astrocyte reactivity associates with tau phosphorylation and neurodegeneration before detectable amyloid‐β pathology.

Background: Aβ plaques are the first detectable signs of AD pathology. Our group recently demonstrated that the astrocyte activation marker, glial fibrillary acidic protein (GFAP), has a pivotal role in the association between Aβ burden and tau phosphorylation. However, the role of astrocyte activation in individuals that do not present detectable Aβ pathology using biomarkers is still underexplored.

Performance of an AI‐based prediction model versus stratified thresholds using plasma biomarkers for biological staging of AD.

Background: The potential clinical utility of plasma biomarkers for biological staging of AD demands definition and validation of cutoff values. Plasma ptau‐217 and GFAP have accurately predicted core pathological changes such as tau aggregation and amyloid (Aβ) deposition, being proposed as complementary biomarkers. Thus, we aim to test a staging framework with plasma GFAP and ptau‐217 using cuttof values to predict Aβ/Tau PET stages and compare its performance with an artificial intelligence (AI) prediction model.

Confounding factors to Alzheimer`s disease plasma biomarkers in patients from a memory‐clinic cohort.

Background: Blood‐based biomarkers for Alzheimer’s disease (AD) are increasingly prevalent and accessible beyond research environments. Consequently, it is crucial to determine whether confounding factors, particularly highly prevalent comorbidities, influence the levels of these blood biomarkers, thereby refining their clinical interpretation. In this study, we examined the impact of comorbidities on plasma AD biomarker levels within a memory‐clinic cohort.

CU PET Aβ and Tau Positive Individuals Show Impairment in MoCA Delayed Recall.

Background: Identification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer’s disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out‐patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) ‐ a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances.

Voxel‐wise comparison of [F]MK6240 and [F]Flortaucipir for the diagnosis of individuals across the Alzheimer’s disease spectrum – the HEAD study.

Background: In vivo studies using the tau PET tracers have shown high performance for the diagnosis of Alzheimer’s disease dementia and patterns of tracer uptake that resemble those observed in post‐mortem studies. However, tau tracers present distinct patterns of binding that might influence their performance in detecting AD pathology. In a head‐to‐head study, we investigated the performance of [F]MK6240 and [F]Flortaucipir for the diagnosis of AD.

Head‐to‐head comparison of four different plasma p‐tau217 assays to detect brain amyloid pathology and cognitive decline in diverse population‐based cohorts.

Background: Plasma p‐tau217 is a highly promising biomarker for detecting Alzheimer’s disease (AD) pathology. However, it is unclear how p‐tau217 assays from different sources perform compared to one another. Moreover, studies in diverse cohorts and population‐based settings are limited.

Blood transcriptomics of preclinical Alzheimer’s Disease patients.

Background: Blood transcriptomic differences have been described in patients with Alzheimer’s disease (AD). However, blood transcriptomic core molecular programs in cognitively unimpaired (CU) individuals positive to biomarkers of Amyloid and Tau pathology, defined as preclinical AD, remains to be explored. Therefore, we aimed to establish blood molecular core programs in preclinical AD.

Comparison of tau‐PET tracers for in vivo Braak staging: the HEAD Study.

Background: Tau‐PET tracers allow for in vivo Braak staging of individuals in the Alzheimer’s disease (AD) continuum. The impact of tracers’ characteristics for Braak staging using tau‐PET remains unclear. Therefore, we performed a head‐to‐head comparison of Braak staging using first‐ and second‐generation tau‐PET tracers.