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Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10-8), PVRL2 (Score = 125.86, P = 1.64 × 10-9), TOMM40 (Score = - 18.58, P = 4.61 × 10-8), and APOE (Score = 75.12, P = 7.26 × 10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P

Background: Layperson cardiopulmonary resuscitation (CPR) and automated external defibrillator (AED) use are vital for improving survival rates after out-of-hospital cardiac arrest (OHCA), yet their application varies by community demographics. We evaluated the concerns and factors influencing willingness to perform CPR and use AEDs among laypersons in high-risk, low-resource communities. Methods: From April 2022 to March 2024, laypersons in Northern Manhattan's Community District 12 completed surveys assessing their attitudes toward CPR and AED use before attending Hands-Only CPR training. Fisher's Exact Test assessed differences in concerns and willingness to perform CPR and AED use across racial-ethnic groups and compared low-resource communities with high-resource groups consisting of non-clinical staff across eight ambulatory sites. Results: Among 669 participants from low-resource communities, 64% identified as Hispanic, 58% were under 40 years of age, and 67% were female. Significant knowledge gaps were identified: 62% had never learned CPR, and 77% were unfamiliar with AEDs. Top concerns about giving CPR included fear of incorrect performance (67%), causing harm (56%), and legal repercussions (53%). Willingness to perform CPR was most influenced by familiarity with the victim. The primary barrier to AED use was a lack of operational knowledge (66%). Non-Hispanic Black participants expressed significantly greater concerns than their Non-Hispanic White counterparts. Participants in high-resource settings (n = 309) showed higher training rates, albeit with similar apprehensions about CPR and AED use. Conclusions: Concerns regarding CPR and AED use stem from a lack of confidence and training, particularly predominant in certain racial-ethnic groups. Targeted, culturally sensitive community interventions could potentially address these barriers, enhance preparedness, and improve OHCA survival rates. [ABSTRACT FROM AUTHOR]

Introduction: Older individuals with a higher cardiovascular disease (CVD) burden have a higher risk for accelerated cognitive decline and dementia. Physical activity (PA) is an inexpensive and accessible preventive measure to CVD, cognitive impairment, and dementia. The current study examined (1) whether PA moderates the relationship between CVD burden and cognition and (2) whether the moderating effect of PA differs by race/ethnicity groups and by APOE-ɛ4 status. Methods: Our cross-sectional study included participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, community-based, longitudinal study on aging and dementia among individuals aged 65 years and older who reside in northern Manhattan. All participants underwent an interview and a neuropsychological assessment for global cognition, memory, language, visuospatial, and speed functioning. Results: In 2,122 older individuals without dementia, having a higher CVD burden was associated with worse cognitive scores for global, language, speed, and visuospatial cognitive functions. PA mitigated the relationship between CVD burden and visuospatial function. Furthermore, PA mitigated the association of CVD burden with global cognition, language, and visuospatial functions in APOE-ɛ4 carriers but not in non-carriers. Discussion/Conclusion: Our study suggests that PA may mitigate the negative association between CVD and cognition, especially in APOE-ɛ4 carriers. The moderating effect of PA did not differ by race/ethnicity. Introduction: Older individuals with a higher cardiovascular disease (CVD) burden have a higher risk for accelerated cognitive decline and dementia. Physical activity (PA) is an inexpensive and accessible preventive measure to CVD, cognitive impairment, and dementia. The current study examined (1) whether PA moderates the relationship between CVD burden and cognition and (2) whether the moderating effect of PA differs by race/ethnicity groups and by APOE-ɛ4 status. Methods: Our cross-sectional study included participants from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a multiethnic, community-based, longitudinal study on aging and dementia among individuals aged 65 years and older who reside in northern Manhattan. All participants underwent an interview and a neuropsychological assessment for global cognition, memory, language, visuospatial, and speed functioning. Results: In 2,122 older individuals without dementia, having a higher CVD burden was associated with worse cognitive scores for global, language, speed, and visuospatial cognitive functions. PA mitigated the relationship between CVD burden and visuospatial function. Furthermore, PA mitigated the association of CVD burden with global cognition, language, and visuospatial functions in APOE-ɛ4 carriers but not in non-carriers. Discussion/Conclusion: Our study suggests that PA may mitigate the negative association between CVD and cognition, especially in APOE-ɛ4 carriers. The moderating effect of PA did not differ by race/ethnicity. [ABSTRACT FROM AUTHOR]

Background: APOEε4 significantly increases the risk of developing Alzheimer's disease (AD). Cognitively healthy APOEε4‐carriers exist, suggesting potential protective mechanisms against APOEε4. We hypothesized that some APOEε4‐carriers may have genetic variations protecting them from developing APOEε4‐mediated AD pathology. We aim to identify these protective genetic variants. Methods: Whole genome sequencing (WGS) and cerebrospinal fluid (CSF) proteomics were performed from human cohorts to identify potential protective variants segregating exclusively among APOEε4 carriers. Bioinformatic analyses were performed to select candidate target genes. Immunohistochemistry on postmortem human brain tissues and mouse models expressing human APOE variants were performed along with in‐vivo functional studies in adult zebrafish AD model. Result: WGS analyses revealed 510 potential gene variants segregating exclusively among APOEε4 carriers, which included rare and loss‐of‐function (LOF) variants. Pathway analysis of these genes showed significant enrichment in extracellular matrix (ECM)‐related processes, suggesting protective effects of LOF in ECM proteins. This was further validated by CSF proteome profiling and subsequent analyses in APOEε4 carriers and non‐carriers. Fibronectin‐1 (FN1) and Collagen‐6A2 (COL6A2) were prioritized as candidate target genes for postmortem validation and in‐vivo functional studies. FN1 protein was increased in APOEε4 carriers resulting in thickened ECM at the basement membrane around the blood vessels, potentially impairing pathology‐induced responses such as clearance and immune system activity. This observation is validated in human brains, mouse models and zebrafish model; therefore, the pathological association of FN1 to AD is evolutionarily conserved. Supporting this hypothesis, in‐vivo functional study in zebrafish model with LOF mutations in fn1b revealed that fibronectin LOF enhanced gliovascular remodeling and microglial activation while reducing astrogliosis, suggesting that pathological accumulation of FN1 could impair toxic protein clearance, which is ameliorated with FN1 LOF. Conclusion: The vascular deposition of the ECM components FN1 and COL6A2 are increased in APOEε4 carriers. Rare variant in FN1 protect against APOEε4‐mediated pathogenesis in AD. We propose a new disease mechanisms and potential therapeutic intervention targets for vascular contribution to dementia to mitigate the risk of developing AD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Few rare variants have been identified in genetic loci from genome‐wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS: Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS: Eighty‐six rare missense or loss‐of‐function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E (APOE)‐휀4 was the only variant segregating. However, in 60.3% of families, APOE 휀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION: Although APOE 휀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. Highlights: Rare coding variants from GWAS loci segregate in familial Alzheimer's disease.Missense or loss of function variants were found segregating in nearly 7% of families.APOE‐휀4 was the only segregating variant in 29.7% in familial Alzheimer's disease.In Hispanic and non‐Hispanic families, different variants were found in segregating genes.No coding variants were found segregating in many Hispanic and non‐Hispanic families. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The Información de la Enfermedad de Alzheimer para Latinos (IDEAL) Study is a randomized clinical trial investigating the psychosocial, behavioral, and cognitive impacts of apolipoprotein E (APOE) genotype disclosure for late‐onset Alzheimer's disease (AD) among Latinos. METHODS: We used address‐based sampling to recruit English‐ and Spanish‐speaking Latinos aged 40–64 living in northern Manhattan for a community‐based Baseline Survey about their knowledge and opinions about AD. Participants eligible for the clinical trial were invited to complete an Introductory Session, including AD and genetics education and informed consent, before undergoing genotyping for APOE. Participants were then randomized to learn their risk of AD by age 85 (range: 21%–55%) based on either Latino ethnicity and family history alone, or the same factors and their APOE genotype. Risk information is provided in a semi‐structured genetic counseling session. Psychological impacts, health‐related behavioral changes, and cognitive performance are evaluated 6 weeks, 9 months, and 15 months later via surveys and qualitative interviews. To promote cultural competence, study materials were developed by a multidisciplinary team including bilingual and bicultural staff, Latinx content experts, and genetic counselors. RESULTS: We sent invitations to 91,433 households; 5542 (6.1%) responded, 2120 completed the Baseline Survey (78.5% online; 21.5% via computer‐assisted telephone interview), and 2087 were deemed eligible, yielding a response rate of 2.3%. Many participants expressed appreciation for the opportunity to contribute to AD research. We randomized 374 participants for the clinical trial. DISCUSSION: We describe the study design, recruitment and retention strategies, and interventions employed in the IDEAL Study. Our design provides a framework for future studies using rigorous mixed methods. Our findings may facilitate the development of culturally‐sensitive educational materials about AD and genetic testing, as well as genetic counseling protocols, to improve coping and adjustment in response to receiving risk information. Highlights: The Información de la Enfermedad de Alzheimer para Latinos (IDEAL) Study investigates apolipoprotein E (APOE) genotype disclosure among Latinos using mixed methods.We recruited adults 40–64 years of age without Alzheimer's disease (AD) for a community‐based survey and randomized trial.Trial participants receives AD risk estimates with or without APOE genotypes.Psychosocial, behavioral, and cognitive impacts are assessed over 15 months.Findings may inform AD educational materials and genetic counseling protocols. [ABSTRACT FROM AUTHOR]

BackgroundCommunity social and economic resources influence colorectal (CRC) screening decisions by physicians and patients. The aim of this study is to systematically assess the differences in screening recommendations of primary care physicians within two urban communities that are distinct in socioeconomic characteristics.MethodsTwo-hundred-sixty-four primary care community (i.e., not hospital-based) physicians were stratified by community. Using self-report questionnaires, we examined primary care physicians' CRC screening practices, knowledge of risk factors and perceived physician and patient barriers to screening, Physicians practicing in upper-socioeconomic status (SES) communities were compared with those of participants practicing in lower SES communities.ResultsPhysicians practicing in low-SES urban communities were significantly more likely to screen with fecal occult blood test than were physicians in upper-SES areas. Alternatively, upper-SES physicians were significantly more likely to recommend screening colonoscopy than were lower-SES physicians. The number of physicians (N=11) who screened for CRC using the double-contrast barium enema were few.ConclusionsCommunity-level SES influences physician cancer screening practices. Further understanding of these relationships may guide the development of interventions targeted to specific neighborhoods within urban areas.

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. The goal here was to identify genes that interact with CVRFs, incorporating stroke as an additional factor, on AD in multi‐ethnic cohorts. Method: We conducted a genome‐wide gene‐CVRF score interaction analysis for AD, in 7,939 AD patients and 9,631 controls from eight multi‐ethnic cohorts of non‐Hispanic Whites, African Americans, and Hispanics including ADNI, NACC, NOMAS, WHICAP, EFIGA, and ROSMAP. A CVRF score was created from the first principal component of history of clinical stroke, hypertension, diabetes, and heart disease, and measured BMI. Gene‐based interaction test was performed with the adaptive gene‐environment interaction test. Results were summarized using a meta‐analysis. We investigated the association of pathological AD, amyloid‐β, or brain infarcts with gene expression and protein expression from the frontal cortex in ROSMAP using a generalized linear model. Age, sex, and the first three principal components were adjusted in the models. Result: The interaction of CVRF score with FMNL2 on AD (p = 1.02E‐05) was identified and additional genes were identified to interact with CVRF score, including SLC22A14 (p = 1.44E‐06), AMMECR1L (p = 2.74E‐06), PRG3 (p = 2.76E‐06), CFAP99 (p = 5.22E‐06), ADPGK‐AS1 (p = 8.58E‐06) and BRINP1 (p = 6.29E‐06). ADPGK‐AS1 and FMNL2 gene expressions were associated with pathological AD (p = 0.004 and p = 0.0002). FMNL2 and BRINP1 gene expressions were higher in the brains of patients with brain infarcts (p = 0.025 and p = 0.006). BRINP1 protein expression was associated with pathological AD (p = 0.0002) and was higher in the brains of patients with brain infarcts (p = 0.022). Conclusion: We identified novel candidate genes that interact with CVRFs on AD in multi‐ethnic cohorts. Understanding the interplay between genes, CVRFs, and AD has the potential to reveal novel molecular targets for prevention and treatment for AD. [ABSTRACT FROM AUTHOR]

Background: Blood‐based biomarkers may aid in the diagnosis of Alzheimer's Disease (AD), but their contribution may be confounded by the presence of multiple chronic conditions and have not been well‐tested in community populations. In the current study, we aimed to determine whether blood‐based biomarkers can aid in refining a multi‐ethnic, urban clinically diagnosed AD community‐based cohort. Method: We included 546 individuals in the Washington Heights, Hamilton Heights, and Inwood Columbia Aging Project (WHICAP) study in this cross‐sectional study. Six biomarkers, including phosphorylated‐tau‐181 (P‐tau181), total (T‐tau), amyloid‐beta 40 and 42 (Aβ40, Aβ42), Glial Fibrillary Acid Protein (GFAP), and Neurofilament Light Chain (NfL) were measured using Quanterix SIMOA HD‐X platforms. The association between the biomarkers and AD or cognitive impairment was tested using logistic regression, adjusted for age, sex, ethnic group, and years of education. Individuals were subsequently characterized as 'biomarker positive' or 'biomarker negative' based on combined GFAP and P‐tau181/Aβ42 cut scores. Result: The mean age of individuals was 79.3 years (6.56) and 379 (69.4%) were women, 133 (24.48%), were Non‐Hispanic Black, 153 (28.0%) Non‐Hispanic White, and 248 (45.4%) were Hispanic. A clinical diagnosis of AD was made in 129 (25.49%) individuals. Low Aβ42 (OR = 0.18, [95% CI: 0.04 ‐ 0.92]), low Aβ42/Aβ40 (OR = 0.49, [95% CI: 0.228 ‐ 0.872), and high P‐tau181/Ab42 (OR = 5.494, [95% CI: 1.523 – 20.416]) were associated with a clinical diagnosis of AD suggesting a role as predictive biomarkers. However, the best combination, GFAP and P‐tau181/Aβ42 cut scores, yielded a sensitivity of 41% and specificity of 70.5% for clinically diagnosed AD. The concordance was 54.5% and the discordance was present in both directions. Low education, cardiovascular and other comorbidities might contribute to the discrepancy between biomarker positivity and clinical diagnosis. Conclusion: While GFAP and P‐tau181/Aβ42 levels are associated with AD pathology and can aid in the diagnosis of AD, the presence of multiple chronic conditions may lead to either false positives or negatives. Large multi‐ethnic community cohort studies are needed to further examine the utility of these biomarkers in aiding in the clinical diagnosis of AD. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) risk is markedly increased among APOE ε4/ε4 homozygotes. Previous studies of APOE genotype disclosure impact have included few ethnic minorities. This study addresses this gap by investigating the immediate impact of disclosing an APOE ε4/ε4 genotype in the Información de la Enfermedad de Alzheimer para Latinos (IDEAL) study, a Latino community‐based study. Methods: IDEAL participants attended semi‐structured genetic counseling sessions conducted via Zoom in Spanish or English by certified genetic counselors. Sessions included a PowerPoint presentation covering genetics, genotype results, risk estimates, and AD prevention methods. Risk estimates were based on data from the Washington Heights‐Inwood Columbia Aging Project, a longitudinal study conducted in the same communities. The estimate of risk to age 85 among ε4 homozygotes was 55%. We transcribed session recordings and conducted content analysis. Results: Eleven ε4/ε4 participants aged 41‐64 attended risk evaluation sessions (English 8, Spanish 3). Six had a family history of AD (first‐degree 1, distant 5). Nine were women and two men. Overall, participants did not show strong emotional reactions. Many expressed surprise, accompanied by thoughtful reflections on the connection between their AD risk and perceived memory problems or emotional well‐being. Participants generally appreciated the information provided during the genetic counseling sessions because it offered insights into the importance of AD risk awareness and prevention strategies. Conclusion: Latinos at high AD genetic risk showed limited immediate emotional response to risk disclosure and appreciated the information that was shared. Longitudinal analyses may provide further insight into the impacts of this disclosure. This study is supported by the National Institute on Aging (R01 AG062528) and registered in ClinicalTrials.gov (NCT04471779). Keywords: Alzheimer's disease, APOE ε4ε4, genetic counseling, Latinos, qualitative research, risk disclosure [ABSTRACT FROM AUTHOR]