Rosalyn Lang

Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians

Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimers disease (AD), we hypothesized that C9ORF72 expansions might contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological re-evaluation of identified C9ORF72 expansion carriers revealed 9 clinical and/or autopsy confirmed AD and 2 FTD final diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.

African American Participation in Health-Related Research Studies: Indicators for Effective Recruitment

OBJECTIVE To elucidate factors that influence African American willingness to participate in health-related research studies. METHODS The African American Alzheimer disease research study group at North Carolina A&T State University designed an in-person questionnaire and surveyed more than 700 African American adults on their willingness to participate in health-related research studies. The questionnaire was distributed and collected in a nonclinical setting during the years 2008 and 2009. This study was approved by the North Carolina A&T State University Institutional Review Board. RESULTS Of the 733 valid respondents, 16% had previously participated in a health-related research study. Of these, more than 90% were willing to participate again in future research studies. Of the 614 who had never participated in a research study, more than 70% expressed willingness to participate. The majority (75%) of experienced research study participants (RSP) were older than 40 years compared with 45% of non-research study participants. Experienced research participants were also twice as likely to have a college degree compared with non-research study participants. Seventy-three percent of non-research study participants were willing to participate in research studies in the future. The factors that were probable impediments to participation included lack of time and trust. Men with knowledge of the Tuskegee Syphilis Study were 50% less likely to be willing to participate compared with those who had not heard of Tuskegee Syphilis Study. CONCLUSIONS African Americans are willing to participate in health-related research studies. Several factors such as the appropriate incentives, community trust building, outreach, and community partnership creation are necessary for engaging minority participants. Incorporating factors that target African American enrollment in research design and implementation, such as increased training of minority health ambassadors and African American researchers and public health specialists, are needed to better engage minorities across generations, in research.

ABCA7 frameshift deletion associated with Alzheimer disease in African Americans

Objective: To identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD. Methods: Custom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families. Results: A 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42–3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12–2.44]), and joint analysis increased the significance (p = 1.414 × 10−5, OR = 1.81 [95% CI: 1.38–2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function. Conclusions: This common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

Global and local ancestry in African-Americans: Implications for Alzheimer's disease risk.

African‐American (AA) individuals have a higher risk for late‐onset Alzheimers disease (LOAD) than Americans of primarily European ancestry (EA). Recently, the largest genome‐wide association study in AAs to date confirmed that six of the Alzheimers disease (AD)‐related genetic variants originally discovered in EA cohorts are also risk variants in AA; however, the risk attributable to many of the loci (e.g., APOE, ABCA7) differed substantially from previous studies in EA. There likely are risk variants of higher frequency in AAs that have not been discovered.

Relationship Between Depressive Symptoms and Cognition in Older, Non-demented African Americans

Knowledge of the relationship between depressive symptoms and cognition in older adults has primarily come from studies of clinically depressed, functionally impaired or cognitively impaired individuals, and in predominately White samples. Limited minority representation in depression research exposes the need to examine these associations in more ethnic/racially diverse populations. We sought to examine the relationship between depressive symptoms and cognition in a sample of non-demented older African Americans recruited from surrounding U.S. cities of New York, Greensboro, Miami, and Nashville (N=944). Depressive symptoms were evaluated with the Geriatric Depression Scale (GDS). Cognition was evaluated with a comprehensive neuropsychological battery. Test scores were summarized into attention, executive function, memory, language, and processing speed composites. Controlling for age, education, reading level, and sex, African American older adults who endorsed more symptoms obtained significantly lower scores on measures of memory, language, processing speed, and executive functioning. Further investigation of the causal pathway underlying this association, as well as potential mediators of the relationship between depressive symptoms and cognitive test performance among older African Americans, such as cardiovascular and cerebrovascular disease, may offer potential avenues for intervention.

ABCA7 FRAMESHIFT DELETION ASSOCIATED WITH ALZHEIMER’S DISEASE IN AFRICAN AMERICANS

heimer’s Project (IGAP) using LD score regression and GenoSkyline tissue-specific functional annotations. We defined enrichment as the ratio between the percentage of heritability explained by variants in each annotated category and the percentage of variants covered by that category. We developed cell-type-specific annotations for all 23 immune cells in the Roadmap Epigenomics Project through integrative analysis of epigenomic marks from ChIP-seq data. We applied LD score regression to these annotations to identify relevant cell types whose functional regions are relatively enriched for LOAD genetic associations. Results: Variants located in blood-specific functional regions, which account for 8.4% of the variants in the IGAP data, could explain 81.6% of LOAD heritability (enrichment1⁄49.6; p-value1⁄49.6310). The signal enrichment for blood-specific elements was substantially stronger than the enrichment for brain-specific elements (p-value1⁄42.0310 ) and for other tissue types. On the cell level, we observed strong enrichment in many cells, including primary neutrophils from peripheral blood (p-value1⁄47.9310), primary hematopoietic stem cells from males or females mobilized with GCSF (p-values1⁄43.8310 and 4.2310), primary B cells from peripheral blood (p-value1⁄42.2310), and primary monocytes from peripheral blood (p-value1⁄44.4310). Analysis based on refined annotation categories further revealed that the enrichment in primary neutrophils could be explained by shared functional elements with hematopoietic stem cells. T cells showed weaker signal enrichment compared with other immune cells. Conclusions:Tissue-specific enrichment analyses of IGAP Stage I data identified strong signal enrichment in blood, suggesting a crucial role for the immune system in LOAD etiology. Our findings provide additional support to the notion that microglial biology may be critically relevant in LOAD etiology, and suggest a previously unsuspected role for neutrophils.

Trial Participation and Inclusion

Improving clinical research participation among diverse populations continues to be a challenge, despite governmental policy which mandates the inclusion of women and minorities in clinical studies. Underrepresentation of these groups contributes to a literature that fails to serve all populations with equal effectiveness and lessens opportunities to eliminate health disparities. The lack of inclusion of Blacks, Hispanics, Native Americans, Asians, and Pacific Islanders, along with women, contributes to a scientific literature that neglects the lives of many who it was intended to serve. Investing in historically disenfranchised populations in a manner that yields a better understanding of their communities, cultures, morals, attitudes, values, and beliefs will require a facilitated shift in perspective and behaviors of researchers and participants. The effectiveness of science will be impaired, and health disparities will continue to increase without intentional and strategic efforts to engage diverse communities in research and clinical trials. In this chapter, the authors address the significance of minority inclusion in research, outline unique challenges to recruitment and retention, and offer important concepts and methodologies that address these challenges.