Sex-stratified genome-wide meta-analysis identifies novel loci for cognitive decline in older adults.

Introduction: Many complex traits and diseases show sex-specific biases in clinical presentation and prevalence.

Methods: To understand sex-specific genetic architecture of cognitive decline across five cognitive domains (attention, memory, executive function, language, and visuospatial function) and global cognitive function, we performed sex-stratified genome-wide meta-analysis in 3021 older adults aged ≥ 65 years (female = 1545, male = 1476) from three prospective cohorts. Gene-based and gene-set enrichment analyses were conducted for each cognitive trait.

Association of mid-life cardiovascular risk with biomarkers of Alzheimer's disease, neurodegeneration, and white matter hyperintensities: Heart SCORE brain study.

Background: Atherosclerotic cardiovascular disease (ASCVD) risk factors in mid-life are associated with cognitive decline and late-life dementia. However, the role of these risk factors in Alzheimer's disease (AD) pathology remains elusive.

Objective: We investigated the association of mid-life 10-year ASCVD risk with late-life amyloid, tau, neurodegeneration [AT(N)] measures and white matter hyperintensities (WMHs).

Whole-genome sequencing reveals the impact of lipid pathway and APOE genotype on brain amyloidosis.

Amyloid-PET imaging tracks the accumulation of amyloid beta (Aβ) deposits in the brain. Amyloid plaques accumulation may begin 10 to 20 years before the individual experiences clinical symptoms associated with Alzheimer's diseases (ad). Recent large-scale genome-wide association studies reported common risk factors associated with brain amyloidosis, suggesting that this endophenotype is driven by genetic variants.

Long-term Cognitive Trajectories in Older Adults After Surgery: A Population-based Cohort Study.

Introduction: Postoperative cognitive decline (POCD) is a common, but often unrecognized condition after surgery. We evaluate postsurgical cognitive changes in a longitudinal population-based study.

Methods: The study cohort comprises an age-stratified population-based random sample of individuals aged 65+ years from a small-town region of the United States.

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.

Examining Brain Structures and Cognitive Functions in Patients with Recovered COVID-19 Infection: A Multicenter Study Using 7T MRI.

Importance: Emerging evidence suggests that severe acute respiratory syndrome, COVID-19, negatively impacts brain health, with clinical magnetic resonance imaging (MRI) showing a wide range of neurologic manifestations but no consistent pattern. Compared with 3 Tesla (3T) MRI, 7 Tesla (7T) MRI can detect more subtle injuries, including hippocampal subfield volume differences and additional standard biomarkers such as white matter lesions. 7T MRI could help with the interpretation of the various persistent post-acute and distal onset sequelae of COVID-19 infection.

Social determinants of health and mild cognitive impairment in a diverse community sample.

Background: The associations between community-wide social determinants of health and mild cognitive impairment (MCI) among individuals warrant investigation.

Methods: Among 2830 dementia-free individuals aged 65+ years in a community-based US study, we examined cross-sectional associations of MCI (Clinical Dementia Rating = 0.5) with the following potential social determinants of health: at the census tract or block group level obtained from public sources: neighborhood disadvantage (Area Deprivation Index, ADI), air pollution with fine particulate matter (PM), greenspace, Walkability Index, ambulatory healthcare availability per square mile, homicide rate; and at the individual participant level, birth/schooling in a southern US state.

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.

Validating the Fluctuating Mental Status Evaluation in Neurocritically Ill Patients With Acute Stroke.

Objectives: Neurocritically ill patients are at high risk for developing delirium, which can worsen the long-term outcomes of this vulnerable population. However, existing delirium assessment tools do not account for neurologic deficits that often interfere with conventional testing and are therefore unreliable in neurocritically ill patients. We aimed to determine the accuracy and predictive validity of the Fluctuating Mental Status Evaluation (FMSE), a novel delirium screening tool developed specifically for neurocritically ill patients.

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.

Association of plasma biomarkers of Alzheimer's disease and related disorders with cognition and cognitive decline: The MYHAT population-based study.

Introduction: Plasma biomarkers of Alzheimer's disease and related dementias predict global cognitive performance and decline over time; it remains unclear how they associate with changes in different dementia syndromes affecting distinct cognitive domains.

Methods: In a prospective study with repeated assessments of a randomly selected population-based cohort (n = 787, median age 73), we evaluated performance and decline in different cognitive domains over up to 8 years in relation to plasma concentrations of amyloid beta 42/40 (Aβ42/40) ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP).

Results: Cross-sectionally, memory showed the strongest associations with p-tau181, and attention, executive, and visuospatial functions with NfL.

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.

Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and β-amyloid (Aβ) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aβ or tau PET overall, stratified by racialized group, and with a racialized group interaction.

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.

Longitudinal Cognitive Decline in Alzheimer Disease Prevention Trials: A Test of Time.

The landscape of clinical trials for Alzheimer disease (AD) has undergone significant evolution in the past decade, most notably by the inclusion of individuals at progressively earlier stages of the disease. Recent approvals by the Food and Drug Administration have predominantly centered around individuals with prodromal and mild AD, signaling a shift toward early intervention. Despite the result of some recent trials, there is optimism and hope that treating individuals at preclinical stages could have even greater effects.

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.

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.

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.

Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk.

The APOE 2/3/4 polymorphism is the greatest genetic risk factor for Alzheimer's disease (AD). This polymorphism is also associated with variation in plasma ApoE level; while APOE*4 lowers, APOE*2 increases ApoE level. Lower plasma ApoE level has also been suggested to be a risk factor for incident dementia.

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.

Social Isolation and Loneliness in a Population Study of Cognitive Impairment: The MYHAT Study.

In this study, we examined associations of social isolation and loneliness with cognitive impairment among older adults from a Rust Belt region in Southwest Pennsylvania. We used data from the population-based Monongahela-Youghiogheny Healthy Aging Team (MYHAT) study. We found that (a) 11 items combined into two reliable composites of social isolation and loneliness; (b) unique to this study, providing unpaid help to others was an indicator of reduced social isolation; (c) social isolation and loneliness were positively associated with cognitive impairment; and (d) these associations were appreciably attenuated by general health and physical functional status and depressive symptoms, respectively.