Exposure to School Racial Segregation and Late-Life Cognitive Outcomes.

Importance: Disparities in cognition, including dementia occurrence, persist between non-Hispanic Black (hereinafter, Black) and non-Hispanic White (hereinafter, White) older adults, and are possibly influenced by early educational differences stemming from structural racism. However, the association between school racial segregation and later-life cognition remains underexplored.

Objective: To investigate the association between childhood contextual exposure to school racial segregation and cognitive outcomes in later life.

Multi-institutional development and testing of attention-enhanced deep learning segmentation of thyroid nodules on ultrasound.

Purpose: Thyroid nodules are common, and ultrasound-based risk stratification using ACR's TIRADS classification is a key step in predicting nodule pathology. Determining thyroid nodule contours is necessary for the calculation of TIRADS scores and can also be used in the development of machine learning nodule diagnosis systems. This paper presents the development, validation, and multi-institutional independent testing of a machine learning system for the automatic segmentation of thyroid nodules on ultrasound.

Health state utilities associated with invasive pneumococcal disease, pneumonia, and recurrent acute otitis media in young children.

Purpose: Cost-utility analyses examining the value of new vaccines for pneumococcal disease will require health state utilities as inputs. Existing utilities for pneumococcal infections in young children are limited. The purpose of this study was to estimate health state utilities associated with pneumococcal infections in young children.

The economic burden of diabetes in spinal fusion surgery: a systematic review and meta-analysis.

Purpose: This study aimed at comparing the costs of spinal fusion surgery between patients with and without diabetes.

Methods: Following PRISMA guidelines, a systematic search of four databases was conducted. A meta-analysis was performed on comparative studies examining diabetic versus non-diabetic adults undergoing cervical/lumbar fusion in terms of cost.

Basic Science and Pathogenesis.

Background: The recent approval of two anti-amyloid antibodies, Aducanamab and Lecanamab, have set the stage for the next generation of anti-amyloid treatments. Despite the capability of these treatments to lower Aβ brain levels, there is thus far limited clinical efficacy on cognitive outcomes. Because eligibility for treatment includes individuals with MCI or mild dementia, that often harbor mixed pathologies, the cognitive impact of other brain pathologies may be important.

Basic Science and Pathogenesis.

Background: The transfer of mitochondrial DNA into the nuclear genomes of eukaryotes (Numts) has been linked to lifespan in non-human species and recently demonstrated to occur in rare instances from one human generation to the next.

Method: Here we investigated numtogenesis dynamics in humans in two ways. First, we quantified Numts in 1,187 post-mortem brain and blood samples from different individuals.

Basic Science and Pathogenesis.

Background: MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, but we have limited insight into their role in age-related cerebral pathologies. Here, we investigated the association between miRNAs and nine age-related cerebral pathologies in participants of the ROS/MAP cohorts.

Method: MiRNA sequencing was performed on samples from the dorsolateral prefrontal cortex of 617 brain donors from participants of the ROS/MAP cohorts.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) has both genetic and environmental risk factors. Gene-environment interaction may help explain some missing heritability. There is strong evidence for cigarette smoking as a risk factor for AD.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with few therapies to treat, mitigate or prevent its onset. Understanding of this disease is predominantly based on research in non-Hispanic Whites (NHW) although AD disproportionately affects African Americans (AA) and Latin Americans (LA), underrepresented in AD research. To address this knowledge gap, the Accelerating Medicine Partnership for Alzheimer's Disease (AMP-AD) Diversity Working Group was launched to generate multi-omics data from post-mortem brain tissue from donors of predominantly AA and LA descent.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is highly comorbid with Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), and the combined AD+LATE-NC is more common than either pathology alone. However, the topographic relationship between tau and TDP-43 in AD+LATE-NC remains unclear.

Method: We analyzed the data from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) participants.

Basic Science and Pathogenesis.

Background: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).

Basic Science and Pathogenesis.

Background: To identify discrete and continuous cell type signatures in brain tissue from donors with minimal cognitive decline despite harboring substantial proteinopathies associated with Alzheimer's Disease and Alzheimer's Disease-related dementias.

Method: Three large-scale single-nucleus RNA-seq studies on Alzheimer's Disease post-mortem human tissue were re-annotated and integrated to identify cell type composition associations with cognitive resilience to various neuropathologies. Cell type signatures were defined in two ways: using an integrated clustering approach and using a continuous factor-based analysis.

Basic Science and Pathogenesis.

Background: Women are disproportionately affected by Alzheimer's disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI-escaping genes provide a promising avenue of discovery for biological pathways driving sex-specific AD risk.

Basic Science and Pathogenesis.

Background: As high as 50% of Alzheimer's disease (AD) patients experience "sundowning", which refers to an increased severity of neuropsychiatric symptoms (NPS), including agitation, confusion, and anxiety, selectively in the evening. Although sundowning significantly influences the decision to institutionalize patients, few preclinical models of this phenomenon exist and the underlying neural mechanisms are unknown. Here, we establish a model of sundowning by phenotyping the sleep-wake cycle and anxiety and exploratory behavior at different times of day in an AD mouse model.

Basic Science and Pathogenesis.

Background: Hemoglobin A1C (A1C) is a measure of long-term glycemic control. In a previous study using a single measure of A1C, we showed that it is related to postmortem cerebrovascular pathology. Here, we use annually collected A1C data to study the relationship of A1C average and variability over time with neuropathology in a large number of older adults with and without diabetes.

Basic Science and Pathogenesis.

Background: A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer's disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD.

Method: We integrated multi-modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi-regional single nucleus (n = 48) RNA sequencing.

Basic Science and Pathogenesis.

Background: Aging is a time-dependent deterioration of physiological functions that occurs in both humans and animals. Within the brain, aging cells gradually become dysfunctional through a complex interplay of intrinsic and extrinsic factors, ultimately leading to behavioral deficits and enhanced risk of neurodegenerative diseases such as Alzheimer's disease (AD). The characteristics of normal aging are distinct from those associated with age-related diseases and it is important to understand the processes that contribute to this pathological divergence.

Basic Science and Pathogenesis.

Background: Recent advances in Alzheimer's disease (AD) therapeutics involve immunization against amyloid-β (Aβ). Post-mortem brain analysis from the first active Aβ immunotherapy trial indicated clearance of Aβ in some AD patients. Yet, the mechanisms regulating Aβ clearance following immunization remain unknown.

Basic Science and Pathogenesis.

Background: Cellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer's disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so-called "senescence-associated secretory phenotype" (SASP) characterized by increased secretion of pro-inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.

Method: In this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive neuronal loss and the accumulation of misfolded proteins such as amyloid-β and tau. While neuroinflammation, mediated by microglia and brain-resident macrophages, plays a pivotal role in AD pathogenesis, the intricate interactions among age, genes, and other risk factors remain elusive. Somatic mutations, known to accumulate with age, instigate clonal expansion across diverse cell types, impacting both cancer and non-cancerous conditions.

Basic Science and Pathogenesis.

Background: Cardio and cerebrovascular risk factors (CVRFs) increase the risk of cerebrovascular disease and clinical Alzheimer's Disease (AD), and over 70% of the patients with AD coincident cerebrovascular pathology. We previously found that FMNL2 interacts with a burden score of hypertension, diabetes, heart disease, and body mass index (BMI) by altering the normal astroglial-vascular mechanisms that underly amyloid clearance. Stroke, defined by history of a clinical stroke or brain imaging, is a moderately robust risk factor for AD and dementia.

Basic Science and Pathogenesis.

Background: Annotation of target genes of non-coding GWAS loci remains a challenge since 1) regulatory elements identified by GWAS can be metabases away from its actual target, 2) one regulatory element can target multiple genes, and 3) multiple regulatory elements can target one gene. AD GWAS in populations with different ancestries have identified different loci, suggesting ancestry-specific genetic risks. To understand the connection between associated loci (potential regulatory elements) and their target genes, we conducted Hi-C analysis in frontal cortex of African American (AA) and Non-Hispanic Whites (NHW) AD patients to map chromatin loops, which often represent enhancer-promoter (EP) interactions.

Basic Science and Pathogenesis.

Background: Angiotensin-converting enzyme (ACE) is a validated risk locus for developing late-onset Alzheimer's disease (LOAD). ACE1 controls blood pressure through the renin-angiotensin system (RAS), but it is also present and acts locally in the brain. Hypertension is associated with an increased risk for developing AD, and people taking select RAS-targeting therapeutics have reduced incidence of AD.