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This study used admixture mapping to prioritize the genetic regions associated with Alzheimer's disease (AD) in African American (AA) individuals, followed by ancestry-aware regression analysis to fine-map the prioritized regions.We analyzed 10,271 individuals from 17 different AA datasets. We performed admixture mapping and meta-analyzed the results. We then used regression analysis, adjusting for local ancestry main effects and interactions with genotype, to refine the regions identified from admixture mapping. Finally, we leveraged in silico annotation and differential gene expression data to prioritize AD-related variants and genes.Admixture mapping identified two genome-wide significant loci on chromosomes 17p13.2 (p = 2.2 × 10Our ancestry-aware regression approach showed that AA individuals have a lower risk of AD if they inherited African ancestry admixture block at the 17p13.2 locus.We identified two genome-wide significant admixture mapping signals: on chromosomes 17p13.2 and 18q21.33, which are novel in African American (AA) populations. Our ancestry-aware regression approach showed that AA individuals have a lower risk of Alzheimer's disease (AD) if they inherited African ancestry admixture block at the 17p13.2 locus. We found that the overall proportion of African ancestry does not differ between the cases and controls that suggest African genetic ancestry alone is not likely to explain the AD prevalence difference between AA and non-Hispanic White populations.

Introduction: Black and Hispanic Americans have higher rates for dementia than other racial/ethnic groups. Perceived discrimination has many adverse health effects and may contribute to racial disparities in dementia risk. Our objective was to assess the association between lifetime experiences of discrimination and incident dementia. Methods: We included data for 6509 participants, 45-84 years of age at baseline (2000-2002) enrolled in the Multi-Ethnic Study of Atherosclerosis (MESA). We assessed lifetime experiences of discrimination at baseline in six domains related to: hiring; promotion; police; education; housing; and from neighbors. Incidence of dementia was determined from International Classification of Diseases codes and medication inventory. We used Cox proportional hazards to estimate hazard ratios (HR) for incident dementia over 17 years after accounting for cohort attrition and sociodemographic, clinical, and behavioral factors. We assessed effect modification of the association by race/ethnicity. Results: Of the sample, 42% reported experiencing discrimination in their lifetime. We observed 466 incident cases of dementia and lifetime discrimination was associated with incident dementia (Wald χ 2 p=0.03). Individuals reporting lifetime discrimination in ≥2 domains (compared to none) had greater risk for dementia (HR: 1.40; 95%: 1.08, 1.82) after adjustment for sociodemographic, clinical, and behavioral risk factors ( Table ). Associations did not differ by race/ethnicity (p-interaction >0.1). Conclusion: Our findings demonstrate an association between discrimination and incident dementia and provide justification to advance research on the association of discrimination with race-disparities in dementia risk.

Most Alzheimer’s disease (AD)-associated genetic variants do not change protein coding sequence and thus likely exert their effects through regulatory mechanisms. RNA editing, the post-transcriptional modification of RNA bases, is a regulatory feature that is altered in AD patients that differs across ancestral backgrounds. Editing QTLs (edQTLs) are DNA variants that influence the level of RNA editing at a specific site. To study the relationship of DNA variants genome-wide, and particularly in AD-associated loci, with RNA editing, we performed edQTL analyses in self-reported individuals of African American (AF) or White (EU) race with corresponding global genetic ancestry averaging 82.2% African ancestry (AF) and 96.8% European global ancestry (EU) in the two groups, respectively. We used whole-genome genotyping array and RNA sequencing data from peripheral blood of 216 AD cases and 212 age-matched, cognitively intact controls. We identified 2144 edQTLs in AF and 3579 in EU, of which 1236 were found in both groups. Among these, edQTLs in linkage disequilibrium (r2 > 0.5) with AD-associated genetic variants in the SORL1, SPI1 and HLA-DRB1 loci were associated with sites that were differentially edited between AD cases and controls. While there is some shared RNA editing regulatory architecture, most edQTLs had distinct effects on the rate of RNA editing in different ancestral populations suggesting a complex architecture of RNA editing regulation. Altered RNA editing may be one possible mechanism for the functional effect of AD-associated variants and may contribute to observed differences in the genetic etiology of AD between ancestries.

This paper presents a brief historical look at education for young African American men from the post-Civil War era to the present. It explores reasons why education for this group has become a less favorable aspiration than when education became available to them. Changing role models are strong factors that negatively influence school participation and excellence. Suggestions for ways to instill resilience in young African American men to excel academically are offered, as well as areas for further study

The Washington University School of Medicine Knight Alzheimer Disease Research Center's "African American Participation in Alzheimer Disease Research: Effective Strategies" Workshop convened to address a major limitation of the ongoing scientific progress regarding Alzheimer's disease and related dementias (ADRD): participants in most ADRD research programs overwhelmingly have been limited to non-Hispanic white persons, thus precluding knowledge as to how ADRD may be represented in non-white individuals. Factors that may contribute to successful recruitment and retention of African Americans into ADRD research were discussed and organized into actionable next steps as described within this report.

BACKGROUND: The ApoE e4 allele is a well-known risk factor for Alzheimer’s disease (AD). Previous research argues that higher education helps to preserve cognition in older adults with AD pathology because of its key role in cognitive reserve and resilience. OBJECTIVE: To test if higher educational level buffers the effect of ApoE e4 on cognition among older non-Hispanic Blacks. METHODS: Participants were 849 non-demented older non-Hispanic Blacks (38.3% ApoE e4+), who underwent a comprehensive neuropsychological evaluation. Multiple linear regression models tested the relationship between ApoE e4 status and twelve cognitive measures with education (up to high school and beyond high school) as a moderator. RESULTS: Education buffered the effects of the ApoE e4 allele, such that there was no impact of ApoE e4 status on word-list memory retention and working memory among participants with more than a high school degree. This pattern was not observed for ten other cognitive measures of verbal and visual episodic memory, semantic memory, executive function, and processing speed—although a similar trend was observed for switching ability in executive functioning. The buffering effect of education was stronger among women than men. CONCLUSION: Our findings suggest that genetic effects on late-life cognition may be modified by environmental factors such as educational attainment. These results are consistent with the framework of cognitive reserve such that engaging in cognitively enriching activities and acquiring skills and knowledge with more years of education may increase the capacity to maintain cognitive function despite high genetic risk for impairment.

Objective Here, we re-examine TOMM40-523′ as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E (APOE) ε4 haplotypes. Methods The TOMM40-523′ size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε3 and APOE ε4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size. Results The TOMM40-523′ length did not modify risk for LOAD in APOE ε4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523′ was associated with a significantly reduced risk for LOAD in EUR APOE ε3 haplotypes. Conclusions Adjustment for LGA confirms that TOMM40-523′ cannot explain the strong differential risk for LOAD between APOE ε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the TOMM40-523′ repeat is associated with decreased risk for LOAD in carriers of homozygous APOE ε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE ε3 allele haplotype.

Objective We evaluated the effects of menstrual types inclusive of PMS on reports of chronic pain intensity and psychopathology in twenty-eight women (mean age 38.93 ± 13.51) with Sickle Cell disease (SCD). Methods Using the Menstrual Symptoms Questionnaire, we compared women with PMS to those with less distressing spasmodic cycle types. Results Thirty-four percent of the sample used oral contraception; there were no significant effects of birth control use on reports of pain. Women with PMS characterized the sensory (p = .04) and affective (p = .04) experiences of their SCD-related chronic pain, including their current pain intensity (p = .03), as significantly greater than women with primary spasmodic menstrual type. Further, there was a trend towards significance for women with PMS to report greater levels of overall pain intensity (p = .07) and average pain intensity over the past month (p = .08). Conclusions The authors interpret these results to suggest that there may be a complex interaction of neurohormonal, biological, and psychological factors associated with PMS that influence manifestation and experience of chronic pain in patients with SCD.

This chapter highlights the creation of a STEM Center of Excellence for Active Learning (SCEAL) at North Carolina Agricultural and Technical State University. The overarching goal of the STEM Center is to transform pedagogy and institutional teaching and learning in order to significantly increase the production of high-achieving students who will pursue careers and increase diversity in the STEM workforce. Some of the STEM Center’s efforts to reach its goals included supporting active learning classroom and course redesign efforts along with providing professional development workshops and opportunities to garner funding to cultivate student success projects through the development of an Innovation Ventures Fund. Outcomes from this Center have led to several publications and external grant funding awards to continue implementation, assessment, and refinement of active learning innovations and interventions for STEM student success for years to come.

The transformation of undergraduate science and math education will require broad-based faculty motivation to integrate innovative evidence-based pedagogies into classroom practice and advance scholarship in teaching and learning. Currently, the traditional lecture approach remains the dominant model in these disciplines. While research suggests that high-impact practices and active learning pedagogies may improve the success of students from historically underrepresented groups (HUGs), faculty must be motivated to invest their time and effort to do this work. Consequently, three strands of motivation theory (motivation, self-determination, and self-efficacy) may provide a framework for exploring faculty adoption and advancement of potentially transformative practices. Herein, motivation theory can support our investigation of the personal and institutional dynamics that promote and/or hinder faculty integration of high-impact and evidence-based pedagogical innovations into classroom practice. The study reported in this chapter uses quantitative methods to explore faculty engagement in scholarly teaching and other innovative educational practices that purport to increase success of HUGs in the STEM fields at a land-grant doctoral research university in the southeastern region of the USA. The university has a historical mission of educating HUGs and a designation of HBCU (Historically Black Colleges and Universities). One primary research question guides this effort: “To what extent do HBCU STEM faculty feel motivated to engage in high-impact, evidence-based pedagogies?” This work is important in the broader STEM education community for understanding how to foster faculty engagement in transforming the paradigm of instruction in the college classroom with a focus on student success.

Importance Compared with non-Hispanic White individuals, African American individuals from the same community are approximately twice as likely to develop Alzheimer disease. Despite this disparity, the largest Alzheimer disease genome-wide association studies to date have been conducted in non-Hispanic White individuals. In the largest association analyses of Alzheimer disease in African American individuals,ABCA7,TREM2, and an intergenic locus at 5q35 were previously implicated. Objective To identify additional risk loci in African American individuals by increasing the sample size and using the African Genome Resource panel. Design, Setting, and Participants This genome-wide association meta-analysis used case-control and family-based data sets from the Alzheimer Disease Genetics Consortium. There were multiple recruitment sites throughout the United States that included individuals with Alzheimer disease and controls of African American ancestry. Analysis began October 2018 and ended September 2019. Main Outcomes and Measures Diagnosis of Alzheimer disease. Results A total of 2784 individuals with Alzheimer disease (1944 female [69.8%]) and 5222 controls (3743 female [71.7%]) were analyzed (mean [SD] age at last evaluation, 74.2 [13.6] years). Associations with 4 novel common loci centered near the intracellular glycoprotein trafficking geneEDEM1(3p26;P = 8.9 × 10−7), near the immune response geneALCAM(3q13;P = 9.3 × 10−7), withinGPC6(13q31;P = 4.1 × 10−7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and withinVRK3(19q13.33;P = 3.5 × 10−7), a gene involved in glutamate neurotoxicity, were identified. In addition, several loci associated with rare variants, including a genome-wide significant intergenic locus nearIGF1Rat 15q26 (P = 1.7 × 10−9) and 6 additional loci with suggestive significance (P ≤ 5 × 10−7) such asAPI5 at 11p12 (P = 8.8 × 10−8) andRBFOX1at 16p13 (P = 5.4 × 10−7) were identified. Gene expression data from brain tissue demonstrate association ofALCAM, ARAP1, GPC6, andRBFOX1with brain β-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, onlyAPOE,ABCA7,TREM2,BIN1,CD2AP,FERMT2, andWWOXwere implicated at a nominal significance level or stronger in African American individuals. Pathway analyses strongly support the notion that immunity, lipid processing, and intracellular trafficking pathways underlying Alzheimer disease in African American individuals overlap with those observed in non-Hispanic White individuals. A new pathway emerging from these analyses is the kidney system, suggesting a novel mechanism for Alzheimer disease that needs further exploration. Conclusions and Relevance While the major pathways involved in Alzheimer disease etiology in African American individuals are similar to those in non-Hispanic White individuals, the disease-associated loci within these pathways differ.

ObjectiveHere, we re-examineTOMM40-523′ as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) inApolipoprotein E(APOE) ε4 haplotypes.MethodsTheTOMM40-523′ size was determined by fragment analysis and whole genome sequencing in homozygousAPOE ε3 andAPOE ε4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size.ResultsTheTOMM40-523′ length did not modify risk for LOAD inAPOE ε4haplotypes with EUR or AF LGA. Increasing length ofTOMM40-523′ was associated with a significantly reduced risk for LOAD in EURAPOEε3 haplotypes.ConclusionsAdjustment for LGA confirms thatTOMM40-523′ cannot explain the strong differential risk for LOAD betweenAPOEε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of theTOMM40-523′repeat is associated with decreased risk for LOAD in carriers of homozygousAPOEε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGAAPOEε3 allele haplotype.

Little is known about the post-transcriptional mechanisms that modulate the genetic effects in the molecular pathways underlying Alzheimer disease (AD), and even less is known about how these changes might differ across diverse populations. RNA editing, the process that alters individual bases of RNA, may contribute to AD pathogenesis due to its roles in neuronal development and immune regulation. Here, we pursued one of the first transcriptome-wide RNA editing studies in AD by examining RNA sequencing data from individuals of both African-American (AA) and non-Hispanic White (NHW) ethnicities. Whole transcriptome RNA sequencing and RNA editing analysis were performed on peripheral blood specimens from 216 AD cases (105 AA, 111 NHW) and 212 gender matched controls (105 AA, 107 NHW). 449 positions in 254 genes and 723 positions in 371 genes were differentially edited in AA and NHW, respectively. While most differentially edited sites localized to different genes in AA and NHW populations, these events converged on the same pathways across both ethnicities, especially endocytic and inflammatory response pathways. Furthermore, these differentially edited sites were preferentially predicted to disrupt miRNA binding and induce nonsynonymous coding changes in genes previously associated with AD in molecular studies, including PAFAH1B2 and HNRNPA1. These findings suggest RNA editing is an important post-transcriptional regulatory program in AD pathogenesis.

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome (“global” ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles (“local” ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors., Author summary The strongest risk gene identified for late-onset Alzheimer disease is ApoE. However, the risk for Alzheimer disease due to ApoE is not consistent across populations. For example, individuals with African ancestry experience less risk from ApoE ε4 than individuals of European or Asian ancestry. The cause of the difference in risk effect is currently unknown. This has led us to ask: What is/are the factor(s) contributing to the risk effect variation of ApoE across the populations? We hypothesized two possibilities for the variability of ApoE risk: 1) ethnic-related environmental factors that vary across populations, such as diet and lifestyle activities, or 2) a population-specific genetic difference in the ApoE gene, or in its surrounding region. We tested our hypothesis using populations with more than one genetic ancestral background, specifically African Americans and Puerto Ricans. Our study showed that the risk of Alzheimer disease is lower for individuals who inherited the genomic region surrounding the ApoE gene from an African ancestor than it is for risk allele carriers who inherited the region from a European ancestor. These findings suggest that protective genetic variant(s) most likely lie(s) within the genetic region surrounding the ApoE gene on the African ancestral background.