Age and sex are associated with Alzheimer's disease neuropathology in Down syndrome.

Introduction: This study investigates the association of age and biological sex with Alzheimer's disease (AD) neuropathology in Down syndrome (DS).

Methods: We examined the frontal/occipital cortex in people with DS (n = 14/13, 1-39 years), DS with AD (DSAD) neuropathology (n = 18/19, 42-61 years), late-onset AD (n = 15/16, 72-96 years), and age-matched controls (n = 50/47)(n = 156). The area occupied by AT8 and 6E10 immunolabeling, representing tangle and plaque loads, respectively, was used for segmented linear regression analyses.

Pittsburgh plasma p-tau217: Classification accuracies for autosomal dominant and sporadic Alzheimer's disease in the community.

Introduction: Most available phosphorylated tau (p-tau)217 immunoassays have similar performance. It is unclear if this is due to the use of the same antibody (the "ALZpath antibody"). We established and evaluated a novel p-tau217 assay that uses an alternative antibody and benchmarked the results against ALZpath-p-tau217.

Impact of racialization on neuroimaging and plasma biomarkers of Alzheimer's disease.

Introduction: Given the predominance of imaging and plasma biomarkers in Alzheimer's disease observational studies and clinical trials, it is critical to understand the differences between these biomarkers across racialized groups.

Methods: A total of 260 older adults without dementia racialized as Black and/or African American (AA) and non-Hispanic white (NHW), ranging in age from 50 to 90 years (68.8 ± 9.

Pittsburgh plasma p-tau217: classification accuracies for autosomal dominant and sporadic Alzheimer's disease in the community.

Introduction: Most available p-tau217 immunoassays have similar performances. It is unclear if this is due to the use of the same antibody (the "ALZpath antibody"). We established and evaluated a novel p-tau217 assay that employs an alternative antibody, and benchmarked the results against ALZpath-p-tau217.

Structure-Activity Relationships and Evaluation of 2-(Heteroaryl-cycloalkyl)-1-indoles as Tauopathy Positron Emission Tomography Radiotracers.

Structure-activity relationship studies were performed on a library of synthesized compounds based on previously identified tau ligands. The top 13 new compounds had values in the range of 5-14 nM in Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) post-mortem brain tissues. One of the more promising new compounds ([H]) bound with high affinity in AD, PSP, and CBD tissues ('s = 1-1.

Correlating hippocampal and amygdala volumes with neuropathological burden in Down syndrome and Alzheimer's disease and related neurodegenerative pathologies using 7T postmortem MRI.

Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), is common in elderly brains and often seen in conjunction with Alzheimer's disease neuropathologic change (ADNC). LATE-NC typically begins in the amygdala and spreads to the hippocampus and neocortex. Whether it contributes to hippocampal and amygdala atrophy in Down syndrome (DS) remains unexplored.

F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy.

Background: Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo F-MK-6240 tau PET study in former American football players.

Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer's disease.

Patients with Alzheimer's disease (AD) with little or no quantifiable insoluble brain tau neurofibrillary tangle (NFT) pathology demonstrate stronger clinical benefits of therapies than those with advanced NFTs. The formation of NFTs can be prevented by targeting the intermediate soluble tau assemblies (STAs). However, biochemical understanding and biomarkers of STAs are lacking.

A neuropathology case report of a woman with Down syndrome who remained cognitively stable: Implications for resilience to neuropathology.

Introduction: Aging adults with Down syndrome (DS) accumulate Alzheimer's disease (AD) neuropathology, including amyloid beta plaques and neurofibrillary tangles, by age 40.

Methods: We present findings from an individual with DS who remained cognitively stable despite AD neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition.

Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.

Background: Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced.

Implementation and Assessment of Tau Thresholds in Non-Demented Individuals as Predictors of Cognitive Decline in Tau Imaging Studies.

Background: Tau accumulation in Alzheimer's disease is associated with short term clinical progression and faster rates of cognitive decline in individuals with high amyloid-β deposition. Defining an optimal threshold of tau accumulation predictive of cognitive decline remains a challenge.

Objective: We tested the ability of regional tau PET sensitivity and specificity thresholds to predict longitudinal cognitive decline.

Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.

Background: Blood-based biomarkers are gaining grounds for Alzheimer's disease (AD) detection. However, two key obstacles need to be addressed: the lack of methods for multi-analyte assessments and the need for markers of neuroinflammation, vascular, and synaptic dysfunction. Here, we evaluated a novel multi-analyte biomarker platform, NULISAseq CNS disease panel, a multiplex NUcleic acid-linked Immuno-Sandwich Assay (NULISA) targeting ~120 analytes, including classical AD biomarkers and key proteins defining various disease hallmarks.

Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting.

Alzheimer's disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms.

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.

Application of robust regression in translational neuroscience studies with non-Gaussian outcome data.

Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer's disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables are often highly skewed and fail to meet the assumption of normality. Applying linear regression analyses to highly skewed datasets can generate imprecise results, which lead to erroneous estimates derived from statistical models.

Association Between β-Amyloid Accumulation and Incident Dementia in Individuals 80 Years or Older Without Dementia.

Background And Objectives: While the highest prevalence of dementia occurs in individuals older than 80 years, most imaging studies focused on younger populations. The rates of β-amyloid (Aβ) accumulation and the effect of Alzheimer disease (AD) pathology on progression to dementia in this age group remain unexplored. In this study, we examined the relationship between changes in Aβ deposition over time and incident dementia in nondemented individuals followed during a period of 11 years.

Biostatistical Estimation of Tau Threshold Hallmarks (BETTH) Algorithm for Human Tau PET Imaging Studies.

A methodology for determining tau PET thresholds is needed to confidently detect early tau deposition. We compared multiple threshold-determining methods in participants who underwent either F-flortaucipir or F-MK-6240 PET scans. F-flortaucipir ( = 798) and F-MK-6240 ( = 216) scans were processed and sampled to obtain regional SUV ratios.

Astrocyte reactivity influences amyloid-β effects on tau pathology in preclinical Alzheimer's disease.

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.

Vesicular Glutamate Transporter Changes in the Cortical Default Mode Network During the Clinical and Pathological Progression of Alzheimer's Disease.

Background: Altered glutamatergic neurotransmission may contribute to impaired default mode network (DMN) function in Alzheimer's disease (AD). Among the DMN hub regions, frontal cortex (FC) was suggested to undergo a glutamatergic plasticity response in prodromal AD, while the status of glutamatergic synapses in the precuneus (PreC) during clinical-neuropathological AD progression is not known.

Objective: To quantify vesicular glutamate transporter VGluT1- and VGluT2-containing synaptic terminals in PreC and FC across clinical stages of AD.

Plasma Glial Fibrillary Acidic Protein Is Associated with 18F-SMBT-1 PET: Two Putative Astrocyte Reactivity Biomarkers for Alzheimer's Disease.

Background: Astrocyte reactivity is an early event along the Alzheimer's disease (AD) continuum. Plasma glial fibrillary acidic protein (GFAP), posited to reflect astrocyte reactivity, is elevated across the AD continuum from preclinical to dementia stages. Monoamine oxidase-B (MAO-B) is also elevated in reactive astrocytes observed using 18F-SMBT-1 PET in AD.

The flutemetamol analogue cyano-flutemetamol detects myocardial AL and ATTR amyloid deposits: a post-mortem histofluorescence analysis.

Background: [F]flutemetamol is a PET radioligand used to image brain amyloid, but its detection of myocardial amyloid is not well-characterized. This histological study characterized binding of fluorescently labeled flutemetamol (cyano-flutemetamol) to amyloid deposits in myocardium.

Methods: Myocardial tissue was obtained post-mortem from 29 subjects with cardiac amyloidosis including transthyretin wild-type (ATTRwt), hereditary/variant transthyretin (ATTRv) and immunoglobulin light-chain (AL) types, and from 10 cardiac amyloid-free controls.

Assessing Reactive Astrogliosis with F-SMBT-1 Across the Alzheimer Disease Spectrum.

A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). F-()-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (F-SMBT-1) is a novel F PET tracer highly selective for MAO-B. We characterized the clinical performance of F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis.

Chronic effects of blast injury on the microvasculature in a transgenic mouse model of Alzheimer's disease related Aβ amyloidosis.

Background: Altered cerebrovascular function and accumulation of amyloid-β (Aβ) after traumatic brain injury (TBI) can contribute to chronic neuropathology and increase the risk for Alzheimer's disease (AD). TBI due to a blast-induced shock wave (bTBI) adversely affects the neurovascular unit (NVU) during the acute period after injury. However, the chronic effects of bTBI and Aβ on cellular components of the NVU and capillary network are not well understood.

11C-PiB PET can underestimate brain amyloid-β burden when cotton wool plaques are numerous.

Individuals with familial Alzheimer's disease due to PSEN1 mutations develop high cortical fibrillar amyloid-β load but often have lower cortical 11C-Pittsburgh compound B (PiB) retention than Individuals with sporadic Alzheimer's disease. We hypothesized this is influenced by limited interactions of Pittsburgh compound B with cotton wool plaques, an amyloid-β plaque type common in familial Alzheimer's disease but rare in sporadic Alzheimer's disease. Histological sections of frontal and temporal cortex, caudate nucleus and cerebellum were obtained from 14 cases with sporadic Alzheimer's disease, 12 cases with familial Alzheimer's disease due to PSEN1 mutations, two relatives of a PSEN1 mutation carrier but without genotype information and three non-Alzheimer's disease cases.