Multimodal neuroimaging biomarkers and subtle cognitive decline in a population-based cohort without dementia.

Background: The relationship between subtle cognitive decline and Alzheimer's disease (AD) pathology as measured by biomarkers in settings outside of specialty memory clinics is not well characterized.

Objective: To investigate how subtle longitudinal cognitive decline relates to neuroimaging biomarkers in individuals drawn from a population-based study in an economically depressed, small-town area in southwestern Pennsylvania, USA.

Methods: A subset of participants without dementia (N = 115, age 76.

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.

A streamlined, resource-efficient immunoprecipitation-mass spectrometry method for quantifying plasma amyloid-β biomarkers in Alzheimer's disease.

High-performance, resource-efficient methods for plasma amyloid-β (Aβ) quantification in Alzheimer's disease are lacking; existing mass spectrometry-based assays are resource- and time-intensive. We developed a streamlined mass spectrometry method with a single immunoprecipitation step, an optimized buffer system, and ≤75% less antibody requirement. Analytical and clinical performances were compared with an in-house reproduced version of a well-known two-step assay.

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.

Associations of endogenous estrogens, plasma Alzheimer's disease biomarkers, and carrier status on regional brain volumes in postmenopausal women.

Background: Women carrying the allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and carrier status on regional brain volumes in a sample of late midlife postmenopausal women.

Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women ( = 171, mean age = 59.

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.

Effect of blood collection tube containing protease inhibitors on the pre-analytical stability of Alzheimer's disease plasma biomarkers.

The reliability of plasma biomarkers of Alzheimer's disease (AD) can be compromised by protease-induced degradation. This can limit the feasibility of conducting plasma biomarker studies in environments that lack the capacity for immediate processing and appropriate storage of blood samples. We hypothesized that blood collection tube supplementation with protease inhibitors can improve the stability of plasma biomarkers at room temperatures (RT).

Kinetic modeling of the monoamine oxidase-B radioligand [F]SMBT-1 in human brain with positron emission tomography.

This paper describes pharmacokinetic analyses of the monoamine-oxidase-B (MAO-B) radiotracer [F]()-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline ([F]SMBT-1) for positron emission tomography (PET) brain imaging. Brain MAO-B expression is widespread, predominantly within astrocytes. Reactive astrogliosis in response to neurodegenerative disease pathology is associated with MAO-B overexpression.

Voxel-wise hemispheric Amyloid Asymmetry and its association with cerebral metabolism and grey matter density in cognitively normal older adults.

Introduction: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by changes in beta amyloid (Aß) and tau as well as changes in cerebral glucose metabolism and gray matter volume. This has been categorized as three distinct stages of amyloid, tau, and neurodegeneration. Past studies have shown asymmetric Aβ accumulation and its association with asymmetric cerebral metabolism in preclinical AD.

Novel avenues of tau research.

Introduction: The pace of innovation has accelerated in virtually every area of tau research in just the past few years.

Methods: In February 2022, leading international tau experts convened to share selected highlights of this work during Tau 2022, the second international tau conference co-organized and co-sponsored by the Alzheimer's Association, CurePSP, and the Rainwater Charitable Foundation.

Results: Representing academia, industry, and the philanthropic sector, presenters joined more than 1700 registered attendees from 59 countries, spanning six continents, to share recent advances and exciting new directions in tau research.

Neuropsychiatric Symptoms and Microglial Activation in Patients with Alzheimer Disease.

Importance: Neuropsychiatric symptoms are commonly encountered and are highly debilitating in patients with Alzheimer disease. Understanding their underpinnings has implications for identifying biomarkers and treatment for these symptoms.

Objective: To evaluate whether glial markers are associated with neuropsychiatric symptoms in individuals across the Alzheimer disease continuum.

Cardiovascular Disease and Alzheimer's Disease: The Heart-Brain Axis.

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in aging adults across the United States. Prior studies indicate that the presence of atherosclerosis, the pathogenic basis of CVD, is linked with dementias. Alzheimer's disease (AD) and AD-related dementias are a major public health challenge in the United States.

Unhealthy white matter connectivity, cognition, and racialization in older adults.

Introduction: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non-Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology-affected regions and cognition.

Methods: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions.

Sex-dependent alterations in hippocampal connectivity are linked to cerebrovascular and amyloid pathologies in normal aging.

Introduction: Compared to males, females have an accelerated trajectory of cognitive decline in Alzheimer's disease (AD). The neurobiological factors underlying the more rapid cognitive decline in AD in females remain unclear. This study explored how sex-dependent alterations in hippocampal connectivity over 2 years are associated with cerebrovascular and amyloid pathologies in normal aging.

APOEε4 potentiates amyloid β effects on longitudinal tau pathology.

The mechanisms by which the apolipoprotein E ε4 (APOEε4) allele influences the pathophysiological progression of Alzheimer's disease (AD) are poorly understood. Here we tested the association of APOEε4 carriership and amyloid-β (Aβ) burden with longitudinal tau pathology. We longitudinally assessed 94 individuals across the aging and AD spectrum who underwent clinical assessments, APOE genotyping, magnetic resonance imaging, positron emission tomography (PET) for Aβ ([F]AZD4694) and tau ([F]MK-6240) at baseline, as well as a 2-year follow-up tau-PET scan.

Low thalamic activity during a digit-symbol substitution task is associated with symptoms of subjective cognitive decline.

Introduction: Subjective cognitive decline (SCD) may represent the earliest preclinical stage of Alzheimer's Disease (AD) for some older adults. However, the underlying neurobiology of SCD is not completely understood. Since executive function may be affected earlier than memory function in the progression of AD, we aimed to characterize SCD symptoms in terms of fMRI brain activity during the computerized digit-symbol substitution task (DSST), an executive function task.

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.

Functional Asymmetry During Working Memory and Its Association with Markers of Alzheimer's Disease in Cognitively Normal Older Adults.

Background: Amyloid-β (Aβ) deposits asymmetrically early in Alzheimer's disease (AD). This process is variable and has been associated with asymmetric hypometabolism.

Objective: We investigated whether neural asymmetry during working memory and executive function processing was associated with AD genetic risk and markers of AD as well as other brain neuropathology biomarkers, cognitive function, and cognitive reserve in cognitively normal older adults.

Plasma p-tau231 and p-tau217 inform on tau tangles aggregation in cognitively impaired individuals.

Introduction: Phosphorylated tau (p-tau) biomarkers have been recently proposed to represent brain amyloid-β (Aβ) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aβ and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI).

Methods: We assessed 138 CU and 87 CI with available plasma p-tau231, 217 , and 181, Aβ42/40, GFAP and Aβ- and tau-PET.

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.