CSF total tau as a proxy of synaptic degeneration.

Cerebrospinal fluid (CSF) total tau (t-tau) is considered a biomarker of neuronal degeneration alongside brain atrophy and fluid neurofilament light chain protein (NfL) in biomarker models of Alzheimer's disease (AD). However, previous studies show that CSF t-tau correlates strongly with synaptic dysfunction/degeneration biomarkers like neurogranin (Ng) and synaptosomal-associated protein 25 (SNAP25). Here, we compare the association between CSF t-tau and synaptic degeneration and axonal/neuronal degeneration biomarkers in cognitively unimpaired and impaired groups from two independent cohorts.

Simultaneous and synchronous characterization of blood and CSF flow dynamics using multiple Venc PC MRI.

Neurofluid dynamics are crucial for maintaining brain homeostasis and facilitating the clearance of brain metabolites through the coupling of arterial and venous blood with cerebrospinal fluid (CSF). Two-dimensional phase contrast (PC) magnetic resonance imaging (MRI) is frequently used to study neurofluids; however, separate examinations are typically required for assessing blood and CSF flow, which can confound analyses due to asynchronous physiological measurements. To enable simultaneous assessment of neurofluid dynamics, we describe and evaluate a 2D PC MRI approach in human participant experiments.

Lifestyle, genetic risk, plasma pTau217, and incident cognitive impairment in WRAP.

Introduction: Whether lifestyle-based dementia risk in midlife impacts risk of incident cognitive impairment (ICI) in the presence of apolipoprotein E (APOE) ε4 allele or plasma pTau217 remains unknown.

Methods: In initially cognitively unimpaired participants (N = 1088; baseline age, M(SD) = 57.8(6.

Polygenic Scores of Core-1 Alzheimer's Disease Biomarkers Predict Early Cognitive and Pathological Change.

Background: Core-1 biomarkers, such as amyloid PET, capture the earliest biological changes leading to Alzheimer's disease (AD). While is a major genetic factor, the contribution of other variants to Core-1 biomarkers remains unclear. The goal of this study is to determine whether genetic regulators of Core-1 biomarker levels predict AD pathology better than genetic regulators of clinical AD.

More fit KL-VS heterozygotes have more favorable AD-relevant biomarker profiles.

Introduction: Although hallmarked by β-amyloid plaques (Aβ) and neurofibrillary tangles (tau), Alzheimer's disease (AD) is a multifactorial disorder that involves neuroinflammation, neurodegeneration, and synaptic dysfunction. AD-associated biomolecular changes seem to be attenuated in carriers of the functionally advantageous variant of the gene (KL-VS). Independently, better cardiorespiratory fitness (CRF) is associated with better health outcomes related to AD pathology.

Fecal Short-Chain Fatty Acids Vary by Sex and Amyloid Status.

Introduction: Short-chain fatty acids (SCFAs), produced by gut microbes, influence Alzheimer's disease (AD) pathology in animals. Less is known about SCFAs and AD in humans. We profiled feces of adults along the AD continuum to investigate gut microbiome and SCFA associations with AD pathology and cognition.

Metabolic factors associated with plasma phosphorylated tau analytes used to detect Alzheimer's disease pathology.

Introduction: The interpretation of plasma phosphorylated tau (pTau) levels may be influenced by metabolic conditions, such as insulin resistance (IR), type 2 diabetes mellitus (T2DM), obesity, and kidney function. We examined the extent to which metabolic factors are associated with plasma pTau concentrations (pTau181, pTau217, pTau231) and the contribution of these factors on analytical outcomes.

Methods: We analyzed data from 287 participants using partial Spearman's rho, Mann Whitney U, ROC analysis, and linear mixed models.

Guided by the community: Insights on recruitment science from the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Project.

Introduction: Although Alzheimer's disease and related dementias (ADRDs) are disproportionately high in Black/African American (AA) individuals, this population is under-included in biomarker studies and clinical trials. This underrepresentation contributes to health disparities in treatment and disease outcomes. The Wisconsin Alzheimer's Disease Research Center (ADRC) and the Wisconsin Registry for Alzheimer's Prevention (WRAP) at the University of Wisconsin-Madison have been successfully conducting the African Americans Fighting Alzheimer's in Midlife (AA-FAIM) Project since 2016.

Validating remote cognitive tests in the Wisconsin Registry for Alzheimer's Prevention.

Introduction: Remote cognitive assessment addresses barriers to research participation for older participants, but continuity in longitudinal studies is a challenge. We examined whether scores from telephone-based assessments (T-COG) were valid and reliable estimates of in-person traditional neuropsychological findings.

Methods: Participants in the Wisconsin Registry for Alzheimer's Prevention (WRAP) who had completed in-person testing within the prior 12 months were invited to complete a follow-up T-COG visit.

A General Linear Mixed Effect Model to Infer Biomarker Correlations by Bridging Retrospectively Measured Data Across Multiple Studies.

A major challenge in biomedical research is that large sample sizes are necessary for sufficient statistical power to detect subtle but potentially important associations between biomarkers and clinical outcomes. Large sample sizes can be achieved by combining biomarker data from multiple studies, but because fluid biomarker platforms and imaging protocols often vary across studies, data from different studies must be bridged or harmonized. We conceptualize that, for a biomarker measured by different studies, a true and latent biomarker exists and underlies the different versions of the observed biomarker through a measurement error model.

Sex differences in cerebral pulsatility and damping: A 4D flow MRI study.

Cerebral pulsatility is a potential marker of cerebrovascular health, yet little is understood about sex differences in cerebral pulsatility with age, especially within different cerebral arteries. Additionally, cerebral damping can blunt cerebral pulsatility and might decline with age. Therefore, we aimed to identify sex differences in cerebral pulsatility and damping across the adult lifespan.

Revisiting Centiloids using AI.

The Centiloid scale is the standard for Amyloid PET quantification, widely used in research, clinical settings, and trial stratification. However, variability between tracers and scanners remains a challenge. This study introduces DeepSUVR, a deep learning method to correct Centiloid quantification, by penalising implausible longitudinal trajectories during training.

Tau PET positivity in individuals with and without cognitive impairment varies with age, amyloid-β status, APOE genotype and sex.

Tau positron emission tomography (PET) imaging allows in vivo detection of tau proteinopathy in Alzheimer's disease, which is associated with neurodegeneration and cognitive decline. Understanding how demographic, clinical and genetic factors relate to tau PET positivity will facilitate its use for clinical practice and research. Here we conducted an analysis of 42 cohorts worldwide (N = 12,048), including 7,394 cognitively unimpaired (CU) participants, 2,177 participants with mild cognitive impairment (MCI) and 2,477 participants with dementia.

Cardiorespiratory fitness modifies the relationship between arterial stiffness and cerebral blood flow independent of physical activity.

Introduction: Central arterial stiffness and cerebral blood flow (CBF) are inversely related. Poor cardiorespiratory fitness (CRF) and low physical activity (PA) are related to both higher arterial stiffness and lower CBF. The present study examined (i) whether CRF or PA moderate the relationship between arterial stiffness and CBF, and (ii) whether the intensity or the type of PA needs to be considered.

Use of preclinical Alzheimer's disease trajectories for clinical trial design.

Introduction: This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials.

Methods: PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power).

Depression modifies age-associated [C]PiB-PET amyloid burden in a cohort enriched with risk for Alzheimer's disease.

BackgroundDepression-especially late-life onset-is associated with age-related cognitive decline and may be a key risk factor for amyloid-β (Aβ) deposition in preclinical Alzheimer's disease (AD).ObjectiveThis study assesses whether depressive symptoms modify the relationship between age and Aβ burden in a cohort at-risk for AD.MethodsN = 238 cognitively unimpaired participants from the Wisconsin Alzheimer's Disease Research Center participated in Pittsburgh Compound-B positron emission tomography (C-PiB-PET), where distribution volume ratio scores were used to quantify Aβ burden in nine regions of interest (ROIs) susceptible to early Aβ burden.

Gut microbiome compositional and functional features associate with Alzheimer's disease pathology.

Background: The gut microbiome is a potentially modifiable risk factor for Alzheimer's disease (AD); however, understanding of its composition and function regarding AD pathology is limited.

Methods: Shallow-shotgun metagenomics was used to analyze the fecal microbiome of participants in the Wisconsin Microbiome in Alzheimer's Risk Study, leveraging clinical data and cerebrospinal fluid (CSF) biomarkers. Differential abundance and ordinary least squares regression analyses were performed to find differentially abundant gut microbiome features and their associations with CSF biomarkers of AD and related pathologies.

The impact of estimated cardiorespiratory fitness on Alzheimer's disease biomarkers and their relationships with cognitive decline.

Introduction: The accumulation of core Alzheimer's disease (AD) pathology contributes to cognitive decline. Cardiorespiratory fitness (CRF) influences AD pathological progression resulting in improvement or maintenance of cognitive function with age. CRF-related differences in accumulation rates or risk of reaching clinically relevant AD biomarker levels, and potentially interactive effects of core AD pathology and CRF on cognitive decline, remain largely unknown.

PET-measured amyloid beta accumulates at an accelerated rate in Down syndrome compared to neurotypical populations.

Introduction: Individuals with Down syndrome (DS) have a high prevalence of Alzheimer's disease (AD) and reveal an earlier age of amyloid beta (Aβ) onset compared to sporadic AD. Differences in amyloid accumulation rates between DS and sporadic AD populations have not been established.

Methods: Participants with ≥ 3 [C-11]PiB scans (spanning > 6 years) and transitioning to Aβ+ were included, resulting in 20 DS and 23 neurotypical (NT) participants.

Return of research results across the Alzheimer's Disease Research Centers network.

Introduction: The Consortium for Clarity in Alzheimer's Disease and Related Dementias Through Imaging (CLARiTI) Return of Results Core aims to develop tools and a framework for disclosing individual results at Alzheimer's Disease Research Centers (ADRCs). An understanding of current disclosure practices is necessary to generate this protocol.

Methods: All 37 ADRCs received a survey between January and April 2024; 36 provided valid responses.

White Matter Abnormalities and Cognition in Aging and Alzheimer Disease.

Importance: There has yet to be a large-scale study quantifying the association between white matter microstructure and cognitive performance and decline in aging and Alzheimer disease (AD).

Objective: To investigate the associations between tract-specific white matter microstructure and cognitive performance and decline in aging and AD-related cognitive impairment.

Design Setting And Participants: This prognostic study of aging and AD, a secondary data analysis of multisite cohort studies, acquired data from 9 cohorts between September 2002 and November 2022.

Gut bacterial metabolite imidazole propionate potentiates Alzheimer's disease pathology.

The gut microbiome modulates metabolic, immune, and neurological functions and has been implicated in Alzheimer's disease (AD), though the specific mechanisms remain poorly defined. The bacterial metabolite imidazole propionate (ImP) has been previously associated with several AD comorbidities, such as type 2 diabetes and cardiovascular disease. Here, we show that elevated plasma ImP levels are associated with lower cognitive scores and AD biomarkers in a cohort of >1,100 cognitively unimpaired individuals.

Sex-Specific Genetic Drivers of Memory, Executive Functioning, and Language Performance in Older Adults.

We previously identified sex-specific genetic loci associated with memory performance, a strong Alzheimer's disease (AD) endophenotype. Here, we expand on this work by conducting sex-specific, cross-ancestral, genome-wide meta-analyses of three cognitive domains (memory, executive functioning, and language) in 33,918 older adults (57% female; 41% cognitively impaired; mean age=73 years) from 10 aging and AD cohorts. All three domains were comparably heritable across sexes.

Sex-Specific Differential DNA Methylation in Mild Cognitive Impairment and Alzheimer's Disease.

Sex differences in late-onset Alzheimer's disease (AD) progression include accelerated decrements in cognitive status and greater amyloid and tau biomarker burdens in females. To identify sex-specific differentially methylated positions (DMPs) and genes in persons with mild cognitive impairment (MCI) and AD, we analyzed whole genome methylation sequencing on blood samples from participants with MCI (N=99, 52% female), AD (N=109, 43% female), and those cognitively unimpaired (CU; N=174, 52% female). Ninety-four percent of DMPs from MCI .

Genetic architecture of the limbic white matter microstructure in aging and Alzheimer's Disease.

Background: Limbic white matter (WM) abnormalities are prevalent in aging and Alzheimer's disease (AD), yet their underlying biological mechanisms remain unclear. This study aims to identify the genetic architecture of limbic WM microstructure in older adults by leveraging harmonized data from multiple cohorts, including those enriched for cognitively impaired individuals.

Methods: We analyzed diffusion MRI (dMRI) data from 2,614 non-Hispanic White older adults (mean age = 73.