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Challenging Assumptions About African American Participation in Alzheimer Disease Trials.

ABSTRACT: OBJECTIVE:The authors investigated potential effects of increased African American participation in Alzheimer disease (AD) and mild cognitive impairment (MCI) clinical trials by examining differences in comorbid conditions and treatment outcome affecting trial design. METHODS:Using a meta-database of 18 studies from the Alzheimer's Disease Cooperative Study and the Alzheimer's Disease Neuroimaging Initiative, a cohort of 5,164 subjects were included for whom there were baseline demographic data and information on comorbid disorders, grouped by organ system. Meta-analysis was used to compare prevalence of comorbidities, dropouts, and rates of change on the cognitive subscale of the Alzheimer's Disease Assessment Scale by race. Clinical trial scenarios similar to recent therapeutic trials were simulated to determine effects of increased African American participation on statistical power. RESULTS:Approximately 7% of AD, 4% of MCI, and 11% of normal participants were African American. African American subjects had higher prevalence of cardiovascular disorders (odds ratio: 2.10; 95% confidence interval [CI]: 1.71-2.57) and higher rate of dropouts (odds ratio: 1.60; 95% CI: 1.15-2.21) compared with whites but lower rates of other disorders. There were no significant differences in rate of progression (-0.862 points/year; 95% CI: -1.89 to 0.162) by race and little effect on power in simulated trials with sample sizes similar to current AD trial designs. CONCLUSION:Increasing African American participation in AD clinical trials will require adaptation of trial protocols to address comorbidities and dropouts. However, increased diversity is unlikely to negatively affect trial outcomes and should be encouraged to promote generalizability of trial results.

SUBMITTER: Kennedy RE

PROVIDER: S-EPMC5842064 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Challenging Assumptions About African American Participation in Alzheimer Disease Trials.

Kennedy Richard E RE Cutter Gary R GR Wang Guoqiao G Schneider Lon S LS

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 20170425 10

<h4>Objective</h4>The authors investigated potential effects of increased African American participation in Alzheimer disease (AD) and mild cognitive impairment (MCI) clinical trials by examining differences in comorbid conditions and treatment outcome affecting trial design.<h4>Methods</h4>Using a meta-database of 18 studies from the Alzheimer's Disease Cooperative Study and the Alzheimer's Disease Neuroimaging Initiative, a cohort of 5,164 subjects were included for whom there were baseline de ...[more]

PMID: 28554539

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Project description:IMPORTANCE:Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. OBJECTIVE:To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. DESIGN, SETTING, AND PARTICIPANTS:Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array: Alzheimer's Disease Genetics Consortium data set (871 cases and 1620 control individuals) and Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set (279 cases and 1367 control individuals). We then examined the entire data set using imputed genotypes from 1917 cases and 3858 control individuals. MAIN OUTCOMES AND MEASURES:The ROHs larger than 1 Mb, 2 Mb, or 3 Mb were investigated separately for global burden evaluation, consensus regions, and gene-based analyses. RESULTS:The African American cohort had a low degree of inbreeding (F?~?0.006). In the Alzheimer's Disease Genetics Consortium data set, we detected a significantly higher proportion of cases with ROHs greater than 2 Mb (P?=?.004) or greater than 3 Mb (P?=?.02), as well as a significant 114-kilobase consensus region on chr4q31.3 (empirical P value 2?=?.04; ROHs >2 Mb). In the Chicago Health and Aging Project-Indianapolis Ibadan Dementia Study data set, we identified a significant 202-kilobase consensus region on Chr15q24.1 (empirical P value 2?=?.02; ROHs >1 Mb) and a cluster of 13 significant genes on Chr3p21.31 (empirical P value 2?=?.03; ROHs >3 Mb). A total of 43 of 49 nominally significant genes common for both data sets also mapped to Chr3p21.31. Analyses of imputed SNP data from the entire data set confirmed the association of AD with global ROH measurements (12.38 ROHs?>1 Mb in cases vs 12.11 in controls; 2.986 Mb average size of ROHs?>2 Mb in cases vs 2.889 Mb in controls; and 22% of cases with ROHs?>3 Mb vs 19% of controls) and a gene-cluster on Chr3p21.31 (empirical P value 2?=?.006-.04; ROHs >3 Mb). Also, we detected a significant association between AD and CLDN17 (empirical P value 2?=?.01; ROHs >1 Mb), encoding a protein from the Claudin family, members of which were previously suggested as AD biomarkers. CONCLUSIONS AND RELEVANCE:To our knowledge, we discovered the first evidence of increased burden of ROHs among patients with AD from an outbred African American population, which could reflect either the cumulative effect of multiple ROHs to AD or the contribution of specific loci harboring recessive mutations and risk haplotypes in a subset of patients. Sequencing is required to uncover AD variants in these individuals.

Project description:The ApoE ?4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ?4, however, differs across populations, with populations of African ancestry showing lower ?4 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 ?4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ?4 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 ?4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.

Project description:Increased African-American research participation is critical to the applicability and generalizability of biomedical research, as population diversity continues to increase both domestically and abroad. Yet numerous studies document historical origins of mistrust, as well as other barriers that may contribute to resistance in the African-American community towards participation in biomedical research. However, a growing body of more recent scientific evidence suggests that African-Americans value research and are willing to participate when asked. In the present study, we set out to determine factors associated with research participation of African-American families in postmortem human brain tissue donation for neuropsychiatric disorders as compared with Caucasian families, from same-day medical examiner autopsy referrals. We retrospectively reviewed brain donation rates, as well as demographic and clinical factors associated with donation in 1,421 consecutive referrals to three medical examiner's offices from 2010-2015. Overall, 69.7% of all next-of-kin contacted agreed to brain donation. While Caucasian families consented to donate brain tissue at a significantly higher rate (74.1%) than African-American families (57.0%) (p<0.001), African-American brain donation rates were as high as 60.5% in referrals from Maryland. Neither African-American nor Caucasian donors differed significantly from non-donors on any demographic or clinical factors ascertained, including age, sex, diagnosis of the donor, or in the relationship of the next-of-kin being contacted (p>0.05). However, Caucasian donors were significantly older, had more years of education, were more likely to be referred for study due to a psychiatric diagnosis, more likely to have comorbid substance abuse, and more likely to have died via suicide, as compared with African-American donors (p<0.05). When African-American participants are identified and approached, African-American families as well as Caucasian families are indeed willing to donate brain tissue on the spot for neuropsychiatric research, which supports the belief that African-American attitudes towards biomedical research may be more favorable than previously thought.

Dataset Information

Challenging Assumptions About African American Participation in Alzheimer Disease Trials.

Publications

Challenging Assumptions About African American Participation in Alzheimer Disease Trials.

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