Gentrification, gun violence, and disparities in access to care for shooting victims.

Background: Gentrification is associated with redistribution of shootings but impacts on access to care are unknown. We evaluate the association of gentrification with shooting rates, transport times, and survival in Boston.

Methods: Gentrification was defined using income, housing, and educational attainment from the 2010-2020 census.

Multi-modal comparison of molecular programs driving nurse cell death and clearance in Drosophila melanogaster oogenesis.

The death and clearance of nurse cells is a consequential milestone in Drosophila melanogaster oogenesis. In preparation for oviposition, the germline-derived nurse cells bequeath to the developing oocyte all their cytoplasmic contents and undergo programmed cell death. The death of the nurse cells is controlled non-autonomously and is precipitated by epithelial follicle cells of somatic origin acquiring a squamous morphology and acidifying the nurse cells externally.

Updated Geriatrics Competencies for Graduating Medical Students: Training Physicians to Provide Age-Friendly Care.

Purpose: Medical student education in geriatrics is a critical need for every doctor-in-training as the population ages, with fewer than 7,000 geriatricians, and older patients, who now approach 20% of the U.S. population, having unique health care needs.

Basic Science and Pathogenesis.

Background: Several viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method: Whole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer's Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome-wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source.

Basic Science and Pathogenesis.

Background: Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of the cell type-specific transcriptional profiles of tissue specimens. In this study, we compared gene expression in multiple brain cell types in brain tissue from Alzheimer disease (AD) cases with no or other co-existing pathologies including Lewy body disease (LBD) and vascular disease (VaD).

Method: We evaluated differential gene expression measured from single nucleus RNA sequencing (snRNAseq) data generated from the hippocampus region tissue donated by 11 BU ADRC participants with neuropathologically confirmed AD with or without a co-existing pathology (AD-only = 3, AD+VaD = 6, AD+LBD = 2).

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: We aim to investigate efficacies of Ras homolog (Rho)-associated kinases (ROCK) inhibitors on Alzheimer's disease (AD) pathological proteins in human induced pluripotent stem cell (iPSC)-differentiated human neurons and the P301S tau transgenic mouse model (PS19).

Method: Quantitative liquid chromatography-mass spectrometry (LC-MS/MS) and targeted ELISA were implemented to investigate the effect of treatment with fasudil or its derivatives on the human neurons and brains from PS19 mice. We explored the efficacy of these ROCK inhibitors in reducing tau phosphorylation, and the brain proteomic profiles after their administration in mice.

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: With a rapidly aging population, South Korea anticipates a surge in Alzheimer disease (AD). However, the genetic basis of AD in Koreans is not well understood.

Method: We sequenced the genomes of 3,540 Koreans (1,583 AD cases and 1,957 controls) older than age 60 and performed a genome-wide association study (GWAS) of AD using logistic regression models that included covariates for age, sex, five ancestry principal components, and an empirical genetic relationship matrix.

Basic Science and Pathogenesis.

Background: T-cell infiltration into the brain parenchyma is associated with hyperphosphorylated tau (p-tau) accumulation in neurodegenerative diseases. Chronic traumatic encephalopathy (CTE) is a progressive tauopathy caused by exposure to repetitive head impacts (RHI). CTE is defined by the perivascular accumulation of p-tau at the cortical sulcal depths and can be stratified into mild and severe pathological stages.

Basic Science and Pathogenesis.

Background: We previously discovered that Aβ accumulates in the cortical/supranuclear region of the lens in people with Alzheimer's Disease (AD) (Goldstein et al., 2003) and Down Syndrome (DS; (Moncaster et al., 2010).

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: Age is the largest risk factor for late-onset Alzheimer's Disease (LOAD). Although >80 genetic loci have been associated with LOAD, little is known about the age dependencies of these associations except the APOE region.

Method: We performed cross-ancestry and ancestry-specific genome-wide gene-age interaction and age-stratified association study using TOPMed-imputed genome-wide association study (GWAS) data from Alzheimer's Disease Genetics Consortium (ADGC) including 34,833 non-Hispanic Whites (NHW), 7,264 African Americans (AA), 3,232 East Asians (EA), and 2,024 Caribbean Hispanics (CH) aged 60 years and older.

Basic Science and Pathogenesis.

Background: "SuperAgers" are older adults (ages 80+) whose cognitive performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary aging are underexplored in large, racially diverse cohorts. Using eight cohorts, we investigated the frequency of APOE genotypes in SuperAgers compared to middle-aged and older adults.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) and AD-related dementias (ADRD) are modulated by gene-environment (GxE) interactions across the lifespan. Variants of specific genes increase AD risk and synergize with lifetime exposure to environmental toxicants ("exposome"), including neurotoxic metals (lead, Pb; cadmium, Cd) and metalloid (As). These metal/metalloid toxicants readily enter the body (e.

Basic Science and Pathogenesis.

Background: There is growing evidence that epigenetic age acceleration may predict late life cognitive decline and dementia, but it is unknown whether this is due to accelerated neurodegeneration or reduction in cognitive resilience. We examined the relationship between epigenetic clocks and domain specific neuropsychological (NP) factor scores, mild cognitive impairment (MCI), Alzheimer's Disease (AD), and all-cause dementia, before and after accounting for plasma total tau (t-tau), a marker of neurodegeneration.

Method: DNA methylation and plasma t-tau (Simoa assay; Quanterix) data from 2091 Framingham Heart Study Offspring cohort participants were generated from blood at the same Exam 8 visit (2005-2008).

Basic Science and Pathogenesis.

Background: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with repetitive head impact (RHI) although little is known about its molecular pathogenesis. Previous studies of single neurons showed that private somatic mutations increase both during normal aging and in neurodegenerative disorders, and show diverse mutational patterns.

Method: We applied two orthogonal single-nucleus whole-genome sequencing (snWGS) methods to neurons isolated from the prefrontal cortex of 15 individuals with CTE, and 4 individuals with RHI but no CTE diagnosis, and compared mutational rates and spectra with neurons from neurotypical controls and Alzheimer's disease (AD).

Basic Science and Pathogenesis.

Background: The Alzheimer's Disease Sequencing Project (ADSP) aims to identify genetic variation contributing to the development or protection of Alzheimer's disease (AD) in diverse ancestral populations. The latest ADSP whole genome sequencing (WGS) data release includes over 36,000 individuals from 37 datasets (NIAGADS NG00067.v11 ADSP R4).

Basic Science and Pathogenesis.

Background: Some subjects exhibit AD pathology but remain cognitively intact. This resilience has been associated with cell-type abundance changes, particularly in neurons. We investigated the molecular basis of cognitive resilience by deconvoluting bulk RNA sequencing (RNA-seq) data into multiple brain cell types derived from three brain regions.

Basic Science and Pathogenesis.

Background: Although the rate of Alzheimer's disease (AD) in African-ancestry (AA) Americans is higher than that of persons from European-ancestry (EA) populations, AA participants have been underrepresented in AD neuropathological studies.

Method: Utilizing the AD Research Centers (ADRC) infrastructure, we obtained AA donor pre-frontal cortex (PFC) tissue from brain repositories of 12 ADRC and generated bulk RNA sequencing (RNA-seq) data for 179 samples that met QC and inclusion criteria. Previously generated PFC RNAseq data were obtained for 28 additional AA donors from the Columbia University ADRC.

Basic Science and Pathogenesis.

Background: The molecular mechanisms underlying individuals with neuropathologically confirmed Alzheimer disease (AD) but who were cognitively healthy prior to death (i.e., cognitively resilient) remain largely unknown.

Basic Science and Pathogenesis.

Background: Despite the prevalence of Alzheimer's Disease in the aged human population and advancements in our understanding of the disease at the molecular level, we still lack a fundamental understanding of how cognitive dysfunction stems from alterations in cellular neuron dynamics and how it relates to the normal aging process. To address this gap in knowledge, we measured the breakdown of nervous system function with cellular resolution during normal aging and in an Alzheimer's Disease model.

Method: Employing comprehensive multi-neuron florescence microscopy in the nematode worm, C.

Clinical Manifestations.

Background: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer's disease (AD) cognitive continuum. An international working group known as the SCD-initiative recently proposed "SCD plus" features, including report of memory problems, recent SCD relative to conversion, SCD over age 60, and consistent SCD over time, that increase the risk for future objective cognitive decline. These have not been fully assessed in a large community-based setting.

Clinical Manifestations.

Background: The long-term neurological impact of the SARS-CoV-2 virus is unknown and it remains to be seen whether it would create a surge in cases of dementia and cognitive decline years later, which is already a global public health challenge. Our group has previously shown that participants cognitive functioning as measured via mobile-based assessments using smartphone-based cognitive tests did not differ based on their COVID status. The goal of the present study was to examine participants longitudinal cognitive performance with the hypothesis that participants with a previous COVID-19 diagnosis (COVID+) will have worse cognitive performance over time than those without COVID-19 (COVID-).