Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations

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

Ancestry‐Specific eQTL Associations in AA/NHW Alzheimer Disease Cohorts

Background Although the genetic etiology of Alzheimer’s Disease (AD) has been shown to vary among ancestrally diverse populations, the influence of genetic variation on the transcriptome within these populations has not yet been extensively investigated. Multi‐ancestry AD datasets featuring both genetic information and gene expression measurements are needed to support expression quantitative trait loci (eQTl) studies in historically underrepresented populations. In this work, we have compared eQTL signals in case/control AD sample populations of both African American (AA) and non‐Hispanic white (NHW) ancestries. Method We analyzed cohorts of AA and NHW ancestries (Naa = 232, Nnhw = 241) with corresponding array‐based genotypes and RNA‐seq mRNA expression levels from whole blood, along with clinical AD diagnoses (Naa_case = 115, Naa_control = 117, Nnhw_case = 121, Nnhw_control = 120). Transcriptome‐wide eQTL associations between genetic variants and gene expression levels were assessed via regression across 17,638 gene units, adjusting for age, sex, experimental factors, and genetic principal components. This was repeated across all sample set combinations of ancestry‐AD pairings (ancestry = [aa, nhw, both] * AD = [case, control, both]). Result The number of significant (p‐value < 10e‐7) eQTL signals varied by ancestry, with the AA cohort showing 76,742 raw eQTL associations, the NHW cohort 19,734, and both ancestries combined 81,763. When further sub‐setting sample sets to AD cases only, 770 and 788 significant eQTL signals were observed for AA and NHW cohorts respectively, which impacted 135 (AA) and 130 (NHW) genes. Interestingly, these ancestry‐aware, case‐only eQTLs were remarkably distinct between the two ancestries, with only 71 (∼9.1%) of the eQTLs and only 19 (∼14.3%) of the impacted genes being shared by both ancestral cohorts. Of particular interest is the appearance of WWOX (a gene of wide neurological importance, and known AD risk loci), as differentially significant in the AA cohort (P = 8.07e‐7) as compared to the NHW cohort (P = 9.06e‐3). Conclusion We have observed differences in eQTL signals relative to AD diagnosis status between AA and NHW sample populations, which may indicate the presence of novel ancestry‐specific effects impacting the genetic etiology of AD through changes in gene expression

Perceptions of Brain donation and Medical Research Among African American Individuals: Implications for Recruitment and Retention into Alzheimer’s Research

Abstract Background African Americans (AAs) are twice as likely to have Alzheimer’s disease (AD) as their White counterparts; yet, this population is largely missing from brain donation research. According to the National Alzheimer’s Coordinating Center, merely 2% of brain donations are obtained from AAs. Medical mistrust among AAs has been well‐documented as a barrier to medical research participation. The purpose of this study was to expand our understanding of AA perceptions of medical research and brain donation. Method Using validated survey items, a 35‐item cross‐sectional survey was developed to understand attitudes and beliefs about medical research and brain donation among AAs. Surveys were administered via REDCap (Research Electronic Data Capture) and paper in Florida, New York, North Carolina and Ohio, United States from November 2021 to September 2022. Descriptive analysis of data on research participation and trust in medical research was conducted using SAS® software version 9.4. Result A total of 227 AAs participated in this study with about three‐quarters of participants being female. Approximately 90% of AAs reported being born in the US, and nearly half of the sample reported receiving some college education or higher. Only 10.6% of participants reported being very likely to donate their brain to research after death. Despite the low percentage of AAs willing to donate their brain to research, 77.1% had a positive view of medical research and 72.7% trusted researchers in general. In fact, participants perceived that it is “very important” to participate in medical research to help future generations (78.4%), to learn more about AD (66.5%), and receive medical information (56.8%). Conclusion Most AAs in this study reported strong trust in medical research and researchers. Medical mistrust may not be a significant barrier to participation in brain donation or AD research for AAs in this sample. Improved health literacy in AD research and brain donation procedures may facilitate engagement of AAs to participate in such research. Findings from this study will be used to inform the development of a culturally relevant health literacy program, with a focus on brain donation and AD research, to enhance opportunities for recruitment and retention of AAs

Outreach and recruitment of African Americans for Alzheimer’s disease studies during the COVID‐19 pandemic

Background Recruiting African Americans in AD studies remains a challenge, particularly during a pandemic, where major health disparities in this population are illuminated. The recruitment literature suggests myriad factors that contribute to the underrepresentation of AAs, including, but not limited to “mistrust” in researchers and their institutions. Maintaining a continuous presence in the AA community builds trust even when traditional outreach methods are not allowed. We continued to provide outreach and recruitment opportunities through COVID education and food for families as we educated them about AD, and opportunities for study participation. Method While our traditional outreach methods for recruiting AAs were interrupted, we continued to conduct AD outreach using virtual platforms, mobile phone calls, family conference calls and food distributions. We hosted nine webinars on COVID‐19 to maintain a presence in local and national AA communities and to remain connected to existing AD participants. We reached over 160,000 persons through webinars and social media. We established new relationship new faith leaders in the AA community who co‐hosted COVID‐19 webinars and also expressed interest in forming partnerships on AD education. In addition, we hosted food drives in AA communities that not only addressed food insecurity and COVID prevention, but also AD education and AD research opportunities. At the food drives we distributed bags with masks, hand sanitizers, AD brochures, booklets and study participation information. Result Between October and December of 2020, 64 AAs who attended food drives expressed interest in AD studies that required blood draws and cognitive testing. Fifteen enrolled in our genetic study, 15 requested additional follow‐up and 13 expressed interest in participating in more than one study. Conclusion Prior research suggests that recruiting AAs into AD studies requires continuous engagement. We used multiple strategies to maintain contact with the AA community and existing research participants, and successfully increased enrollment in the last quarter of the year. Maintaining consistent and continuous engagement facilitates trustworthiness with AAs and yields positive recruitment outcomes, even in a pandemic where traditional recruitment methods are limited

Attitudes and Perceptions about Brain Donation Among African Americans: Implications for Recruitment into Alzheimer’s Disease Research

The objective of this study was to investigate attitudes toward brain donation and perceptions of medical research that influence brain donation among African Americans. Cross-sectional surveys were administered to African American community members (n = 227). Findings indicate that only 27% of respondents were willing to donate their brain. As medical mistrust was not found to be a significant barrier to research participation, there may be opportunity to increase brain donation by providing information about Alzheimer’s disease and brain donation to potential donors and their families so that informed decisions about participating in research can be made

iPSC‐derived neurons and microglia with an African‐specific ABCA7 frameshift deletion have impaired function

Background The ATP‐binding cassette, sub‐family A (ABC1), member 7 (ABCA7) gene has been implicated as a risk factor in Alzheimer’s disease (AD) across populations. However, the risk effect of ABCA7 in African Americans (AAs) is stronger than in non‐Hispanic white (NHW) populations. We identified a 44 base pair deletion in AA significantly associated with disease (cases = 15.2%, controls = 9.74%, p = 1.414 × 10−5, Cukier, et al, 2016). The deleted allele is predicted to produce a frameshift mutation (p.Arg578Alafs), resulting in a truncated protein that may interfere with its normal functions, including APP processing and Aβ clearance. Method To further understand the mechanism by which the ABCA7 deletion may be acting, induced pluripotent stem cells (iPSC) lines were developed from the blood of two unrelated AA AD individuals heterozygous for the deletion, as well as age matched cognitively normal individuals. The iPSC lines were differentiated into cortical neurons and microglia, as both cell types endogenously express ABCA7. Result Each iPSC line generated was karyotyped and validated for pluripotency through immunocytochemical staining. RNA from the cases demonstrated that a stable RNA transcript is produced from the ABCA7 deletion allele. Preliminary results from iPSC‐derived neurons and microglia identified impaired functions in both cells types. Cortical neurons from patients produced higher levels of Aβ40 and Aβ42 compared to controls. In addition, while the patient‐derived microglia had normal rates of phagocytosis, they were impaired in the uptake and clearance of fibrillar Ab. Furthermore, when exposed to the proinflammatory stimulus lipopolysaccharide (LPS), the patient‐derived microglia had decreased cytokine responses. Conclusion This deletion in ABCA7 is an ethnic specific, pathogenic alteration in AD that may result in an increased production of toxic β‐amyloid production in neurons and a depressed ability to clear Ab and impaired responsiveness to proinflammatory signals in microglia

African ancestry APOE e4 non-carriers with higher educational attainment are resilient to Alzheimer disease pathology-specific blood biomarker pTau181

Cognitive and functional abilities in individuals with Alzheimer disease (AD) pathology (ADP) show greater than expected variability. While most individuals show substantial impairments in these abilities, a considerable number show little or no impairments. Factors contributing to this variability are not well understood. For instance, multiple studies have shown that higher levels of education are associated with reduced cognitive impairments among those with ADP. However, it remains unclear whether higher levels of education are associated with functional impairments among those with ADP. We studied 410 AA individuals with advanced levels of pTau181 (a biomarker for ADP; individuals as those having log 10 (pTau181) level greater than one standard deviation above the mean) to determine whether EA (categorized as low EA for individuals with ≤ 8 years of education and high EA for those with >8 years) promotes functional resilience and whether this effect varies between APOE ε4 carriers and non-carriers. We used the four non-memory components of the Clinical Dementia Rating (CDR) to create a composite score (CDR-FUNC) to evaluate functional difficulties (scored from 0=no impairment to 12=severe). We employed the non-parametric Mann-Whitney U test to assess the relationship between EA and CDR-FUNC in advanced levels of pTau181 individuals. The results showed that EA promotes resilience to functional problems in AA individuals with advanced levels of pTau181, such that individuals with high EA are more likely to have better functional ability compared to those with lower EA (W=730.5, p=0.0007). Additionally, we found that the effect of high EA on functional resilience was stronger in ε4 non-carriers compared to ε4 carriers (W=555.5, p=0.022). This study extends the role of cognitive reserve and EA to functional performance showing that cognitive reserve influences the association between ADP burden and functional difficulties. Interestingly, this protective effect seems less pronounced in carriers of the strong genetic risk allele ε4. The results highlight the intricate interplay of genetic and non-genetic factors in AD progression, suggesting a need for more personalized strategies to manage functional decline in AD

Education and its effect on risk and age at onset in Alzheimer disease (AD) in African Americans

Background Increased years of education have been previously associated with a decreased risk of developing Alzheimer disease (AD) with cognitive reserve suggested as the source of the protective effect in Non‐Hispanic Whites (NHW). African Americans (AA) are twice as likely to develop AD compared to NHW. We investigated the hypothesis that education was similarly correlated with risk of AD in the AA population. We also examined the relationship of education and age at onset (AAO) of AD in AA. Method Participants consisted of 132 AA AD cases and 428 AA cognitively intact (CI) individuals with known years of completed education, ascertained for a genetics study of AD. Education levels were stratified into three categories: 12 years. We used logistic regression to determine the effect of age, sex, education level and APOE4 status between cases versus controls. Additionally, using a linear model we examined the effect of education on AAO including sex and APOE4 status as covariates. Result Results showed that increasing years of education had a protective effect on AD risk. Initially including sex and age as covariates, both higher education categories were significant, with 9‐12 years (p = 0.02;OR = 0.461[0.23,0.9])) and >12 years (p = 1.30e0‐04;OR = 0.26[0.13,0.41]). Adding APOE4 dosage (0(Ref), 1,2 alleles) to the model (significant at p = 9.54e‐05; p = 5.27e‐07), the effect of education remained significant (p = 0.03;OR = 0.46[0.23,0.93]) and p = 4.84e‐05;OR = 0.22[0.10,0.46]) for 9‐12 and >12, respectively further supporting its role in AD risk. We examined the effect of education on AAO. Education (8‐12 years) trended in significance (p‐value = 0.07; β = ‐3.76[‐7.82,0.307]) with >12 years significant (p‐value = 1.63e‐04; β = ‐13.07,‐4.25]) supporting later AAO with higher education. The effect of APOE4 on AAO was not significant (p = 0.226). APOE4 added to the model as a covariate did not have a significant effect on AAO, however, education levels continued trending (8‐12; p = 0.07; β = ‐3.76[‐7.86,0.34]) and significant (>12; p = 3.71e‐04; β = ‐8.33[‐12.84,‐3.82]). Conclusion These data support the hypothesis that higher education results in a decreased risk of AD in AA regardless of APOE4 status. We also found a similar protective effect for a later AAO. Thus, the potential outcome of education on cognitive reserve appears across multiple racial backgrounds