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

INTRODUCTION: African-American (AA) individuals have a higher risk for late-onset Alzheimer's 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 Alzheimer's 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. METHODS: We performed a comprehensive analysis of genetically determined local and global ancestry in AAs with regard to LOAD status. RESULTS: Compared to controls, LOAD cases showed higher levels of African ancestry, both globally and at several LOAD relevant loci, which explained risk for AD beyond global differences. DISCUSSION: Exploratory post hoc analyses highlight regions with greatest differences in ancestry as potential candidate regions for future genetic analyses.

Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans.

IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 × 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE ϵ4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 × 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.

Health Disparities Research Curricula and Training Development: Recommendations From a National Institute of Neurological Disorders and Stroke Workgroup.

The national mandate to improve health equity in the United Sates is advancing. Racial and ethnic disparities in various aspects of health care have been clearly delineated, and sources of such disparities have been identified. However, implementing solution-focused interventions to eradicate such disparities, thereby achieving health equity in all US communities, has remained a daunting challenge, and no area more so, than with neurologic diseases. To assure success with bridging prominent disparities in neurologic outcomes, the pipeline of neurologic disparities researchers needs to be broadened, numbers of mid-career and senior disparities scientists sustained, partnerships with community stakeholders enhanced, incentivization of academic organizations pursued, education of all neurologic researchers conducted, and exemplary training of funding agency staff prioritized. To improve the current state of neurologic disparities, the National Institute of Neurological Disorders and Stroke assembled a working group of its advisory council. (2020-2022) to examine the state of health disparity training and research. Through consensus building, we present identified gaps and recommendations to the current state of underrepresented groups in medicine in health disparity research and its training and curricula in the United States.

Racial-ethnic disparities in stroke care: the American experience: a statement for healthcare professionals from the American Heart Association/American Stroke Association.

PURPOSE: Our goal is to describe the effect of race and ethnicity on stroke epidemiology, personal beliefs, access to care, response to treatment, and participation in clinical research. In addition, we seek to determine the state of knowledge on the main factors that may explain disparities in stroke care, with the goal of identifying gaps in knowledge to guide future research. The intended audience includes physicians, nurses, other healthcare professionals, and policy makers. METHODS: Members of the writing group were appointed by the American Heart Association Stroke Council Scientific Statement Oversight Committee and represent different areas of expertise in relation to racial-ethnic disparities in stroke care. The writing group reviewed the relevant literature, with an emphasis on reports published since 1972. The statement was approved by the writing group; the statement underwent peer review, then was approved by the American Heart Association Science Advisory and Coordinating Committee. RESULTS: There are limitations in the definitions of racial and ethnic categories currently in use. For the purpose of this statement, we used the racial categories defined by the US federal government: white, black or African American, Asian, American Indian/Alaskan Native, and Native Hawaiian/other Pacific Islander. There are 2 ethnic categories: people of Hispanic/Latino origin or not of Hispanic/Latino origin. There are differences in the distribution of the burden of risk factors, stroke incidence and prevalence, and stroke mortality among different racial and ethnic groups. In addition, there are disparities in stroke care between minority groups compared with whites. These disparities include lack of awareness of stroke symptoms and signs and lack of knowledge about the need for urgent treatment and the causal role of risk factors. There are also differences in attitudes, beliefs, and compliance among minorities compared with whites. Differences in socioeconomic status and insurance coverage, mistrust of the healthcare system, the relatively limited number of providers who are members of minority groups, and system limitations may contribute to disparities in access to or quality of care, which in turn might result in different rates of stroke morbidity and mortality. Cultural and language barriers probably also contribute to some of these disparities. Minorities use emergency medical services systems less, are often delayed in arriving at the emergency department, have longer waiting times in the emergency department, and are less likely to receive thrombolysis for acute ischemic stroke. Although unmeasured factors may play a role in these delays, the presence of bias in the delivery of care cannot be excluded. Minorities have equal access to rehabilitation services, although they experience longer stays and have poorer functional status than whites. Minorities are inadequately treated with both primary and secondary stroke prevention strategies compared with whites. Sparse data exist on racial-ethnic disparities in access to surgical care after intracerebral hemorrhage and subarachnoid hemorrhage. Participation of minorities in clinical research is limited. Barriers to participation in clinical research include beliefs, lack of trust, and limited awareness. Race is a contentious topic in biomedical research because race is not proven to be a surrogate for genetic constitution. CONCLUSIONS: There are limitations in the current definitions of race and ethnicity. Nevertheless, racial and ethnic disparities in stroke exist and include differences in the biological determinants of disease and disparities throughout the continuum of care, including access to and quality of care. Access to and participation in research is also limited among minority groups. Acknowledging the presence of disparities and understanding the factors that contribute to them are necessary first steps. More research is required to understand these differences and find solutions.

Patellofemoral joint loading during the forward and backward lunge.

OBJECTIVE: To examine patellofemoral joint (PFJ) loading in two lunge movements: Forward Lunge (FL) and Backward Lunge (BL). DESIGN: Repeated Measures. SETTING: University Biomechanics Laboratory. PARTICIPANTS: 20 asymptomatic females. MAIN OUTCOME MEASURES: Six trials of two lunge movements (FL and BL) to a depth of 75% of leg length were performed. 3-D motion capture and force platforms were used to collect data as input into a musculoskeletal model to determine quadriceps force, PFJ reaction force, PFJ stress, and knee flexion angle. RESULTS: Multivariate analysis indicated differences in PFJ loading variables and joint angles between the lunge movements (Forward vs. Backward) and phases (Down vs. Up). Quadriceps force, PFJ reaction force, and knee flexion angle were larger in the FL movement and Up phases. PFJ loading rate was greater in the FL movement along with a lower forward trunk tilt. CONCLUSION: The FL produced greater PFJ loading variables compared to the BL. Further research is needed to examine a population of individuals who have patellofemoral pain (PFP) to see if their symptoms may be reduced when using the BL.

Complex reproductive secretions occur in all extant gymnosperm lineages: a proteomic survey of gymnosperm pollination drops.

KEY MESSAGE: Complex protein-containing reproductive secretions are a conserved trait amongst all extant gymnosperms; the pollination drops of most groups include carbohydrate-modifying enzymes and defence proteins. Pollination drops are aqueous secretions that receive pollen and transport it to the ovule interior in gymnosperms (Coniferales, Cycadales, Ginkgoales, Gnetales). Proteins are well established as components of pollination drops in conifers (Coniferales) and Ephedra spp. (Gnetales), but it is unknown whether proteins are also present in the pollination drops of cycads (Cycadales), Ginkgo (Ginkgoales), Gnetum (Gnetales), or in the pollination drops produced by sterile ovules occurring on pollen plants in the Gnetales. We used liquid chromatography-tandem mass spectrometry followed by database-derived protein identification to conduct proteomic surveys of pollination drops collected from: Ceratozamia hildae, Zamia furfuracea and Cycas rumphii (Cycadales); Ginkgo biloba (Ginkgoales); Gnetum gnemon and Welwitschia mirabilis, including pollination drops from both microsporangiate and ovulate plants (Gnetales). We identified proteins in all samples: C. hildae (61), Z. furfuracea (40), C. rumphii (9), G. biloba (57), G. gnemon ovulate (17) and sterile ovules from microsporangiate plants (25) and W. mirabilis fertile ovules (1) and sterile ovules from microsporangiate plants (138). Proteins involved in defence and carbohydrate modification occurred in the drops of most groups, indicating conserved functions for proteins in pollination drops. Our study demonstrates that all extant gymnosperm groups produce complex reproductive secretions containing proteins, an ancient trait that likely contributed to the evolutionary success of seed plants.

Commentary on "Perspective on race and ethnicity in Alzheimer's disease research".

There are persistent disparities in Alzheimer's disease by race and ethnicity that are not well understood. The emphasis given to seeking a genetic basis for racial differences might be a distraction from the more relevant issue of identifying preventable causes of Alzheimer's disease. The majority of Alzheimer's disease cases are diagnosed as the late onset type and are unlikely to be inherited. Late onset Alzheimer's disease cases, therefore, more likely represent variations in gene expression than gene frequency. Although conceptual and methodologic problems have limited our understanding of this relationship, race-based studies provide important opportunities to understand the environmental factors associated with gene expression. Improving our understanding of the factors associated with race and ethnicity might help to clarify the epidemiology and course of Alzheimer's disease.

Safety and efficacy of donepezil in African Americans with mild-to-moderate Alzheimer's disease.

BACKGROUND: African Americans have a higher incidence and prevalence of Alzheimer's disease (AD) than whites but have been underrepresented in clinical trials, including studies of cholinesterase inhibitors. PURPOSE: The purpose of this 12-week, open-label study was to evaluate the efficacy and safety of donepezil in African Americans with mild-to-moderate AD. METHODS: Efficacy was assessed via the Mini-Mental State Examination (MMSE), Clinician's Interview-Based Impression of Change-Plus interview with the patient and caregiver (CIBIC-Plus) and Fuld Object Memory Evaluation (FOME), a measure that has been validated for use with elderly African Americans. RESULTS: Significant improvements were observed in cognition (MMSE), global function (CIBIC-Plus) and memory (all four subscales of the FOME). Donepezil was well tolerated; 51% of patients experienced adverse events, most commonly diarrhea (5.6%), hypertension (5.6%) and urinary tract infection (4.8%). CONCLUSIONS: These results suggest that donepezil is effective and safe in treating African Americans with mild-to-moderate AD, and support the value of FOME in assessing efficacy in AD trials in diverse populations.

Use of mobile devices and medication errors in acute care: a systematic review protocol.

REVIEW QUESTION/OBJECTIVE: The objective of this review is to synthesize the best available evidence on the effects of healthcare providers using mobile devices at any stage of medication provision on medication errors in acute care settings. Provision of medication includes prescribing, dispensing or administrating medicine in the acute care setting.

Association of Long Runs of Homozygosity With Alzheimer Disease Among African American Individuals.

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.

Depression as a risk factor for Alzheimer disease: the MIRAGE Study.

BACKGROUND: Depression symptoms may be associated with the development of Alzheimer disease (AD). OBJECTIVES: To evaluate the association between depression symptoms and risk of AD, and to explore the temporal aspects of this association. SETTING: Academic institutions with specialized memory clinics. DESIGN: Cross-sectional, family-based, case-control study with standardized self- and proxy questionnaires to collect information on depression symptoms and other risk factors. PARTICIPANTS: A total of 1953 subjects with AD and 2093 of their unaffected relatives enrolled in the Multi-institutional Research in Alzheimer's Genetic Epidemiology Study. MAIN OUTCOME MEASURES: Odds ratios (ORs) of AD were estimated with and without depression symptoms, adjusted for age, sex, education, history of head trauma, and apolipoprotein E status. RESULTS: There was a significant association between depression symptoms and AD (adjusted OR, 2.13; 95% confidence interval [CI], 1.71-2.67). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57; 95% CI, 2.87-7.31), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38; 95% CI, 1.03-1.85). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.71; 95% CI, 1.03-2.82). CONCLUSIONS: Depression symptoms before the onset of AD are associated with the development of AD, even in families where first depression symptoms occurred more than 25 years before the onset of AD. These data suggest that depression symptoms are a risk factor for later development of AD.

Association between apolipoprotein E genotype and Alzheimer disease in African American subjects.

BACKGROUND: The association between Alzheimer disease (AD) and genotypes at the apolipoprotein E (APOE) locus has been confirmed in numerous populations worldwide, but appears to be inconsistent in African American subjects. OBJECTIVE: To investigate the association between APOE genotypes and AD in elderly African American subjects. DESIGN: Clinic-based, multicenter case-control study and a family study. PARTICIPANTS: A total of 338 African American probands meeting criteria for probable or definite AD, 301 cognitively healthy, elderly unrelated control subjects (spouses and community volunteers), and 108 siblings of 88 AD probands. MAIN OUTCOME MEASURES: Odds of AD according to APOE genotype. RESULTS: Compared with individuals with the APOEepsilon3/epsilon3, the odds of having AD were significantly increased among those with 1 or more copies of the epsilon4 allele; the odds ratio (OR) for the epsilon3/epsilon4 genotype was 2.6 (95% confidence interval [CI], 1.8-3.7), and the OR for the epsilon4/epsilon4 genotype was 10.5 (95% CI, 5.1-21.8). These risks decreased substantially after 68 years of age. The risk for AD was lower among individuals with the epsilon2/epsilon3 genotype (OR, 0.41; 95% CI, 0.22-0.79). The patterns of association were similar in men and women. These results obtained from comparisons of unrelated AD patients and controls were bolstered by results of analysis of family data that showed preferential transmission of the epsilon4 allele to demented siblings (P<<.001) and of the epsilon2 allele to nondemented siblings (P=.005). CONCLUSIONS: The presence of 1 or 2 epsilon4 alleles is a determinant of AD risk in African American subjects. The age-related risk for decline associated with the epsilon4 allele and the apparent protective effect of the epsilon2 allele are similar to patterns observed in white subjects.

A comprehensive genetic association study of Alzheimer disease in African Americans.

OBJECTIVES: To evaluate the association of genetic variation with late-onset Alzheimer disease (AD) in African Americans, including genes implicated in recent genome-wide association studies of whites. DESIGN: We analyzed a genome-wide set of 2.5 million imputed markers to evaluate the genetic basis of AD in an African American population. SUBJECTS: Five hundred thirteen well-characterized African American AD cases and 496 cognitively normal African American control subjects. SETTING: Data were collected from multiple sites as part of the Multi-Institutional Research on Alzheimer Genetic Epidemiology (MIRAGE) Study and the Henry Ford Health System as part of the Genetic and Environmental Risk Factors for Alzheimer Disease Among African Americans (GenerAAtions) Study. RESULTS: Several significant single-nucleotide polymorphisms (SNPs) were observed in the region of the apolipoprotein E gene (APOE). After adjusting for the confounding effects of APOE genotype, one of these SNPs, rs6859 in PVRL2, remained significantly associated with AD (P = .0087). Association was also observed with SNPs in CLU, PICALM, BIN1, EPHA1, MS4A, ABCA7, and CD33, although the effect direction for some SNPs and the most significant SNPs differed from findings in data sets consisting of whites. Finally, using the African American genome-wide association study data set as a discovery sample, we obtained suggestive evidence of association with SNPs for several novel candidate genes. CONCLUSIONS: Some genes contribute to AD pathogenesis in both white and African American cohorts, although it is unclear whether the causal variants are the same. A larger African American sample will be needed to confirm novel gene associations, which may be population specific.

The art of sharing the diagnosis and management of Alzheimer's disease with patients and caregivers: recommendations of an expert consensus panel.

OBJECTIVE: To develop a set of recommendations for primary care physicians (PCPs) suggesting how best to communicate with patients, caregivers, and other family members regarding the diagnosis and management of Alzheimer's disease (AD). PARTICIPANTS: A national roundtable of 6 leading professionals involved in treating or advocating for patients with AD was convened on March 14, 2008. This roundtable included 4 leading academic physicians with diverse backgrounds (a geriatric psychiatrist, a neuropsychiatrist, a neurologist, and a geriatrician) from geographically diverse regions of the United States, who were invited on the basis of their national reputation in the field and experience working with minority populations with dementia; the executive director of a national AD advocacy organization; the executive director of a national advocacy organization for caregivers; and a medical correspondent with expertise in interviewing and small group leadership. EVIDENCE: Expert opinion supported by academic literature (search limited to PubMed, English language, 1996-2008, search terms: Alzheimer's disease, primary care, diagnosis, management, caregiver, family, patient-physician relationship). CONSENSUS PROCESS: Moderated dialogue aimed at generating consensus opinion; only statements endorsed by all authors were included in the final article. CONCLUSIONS: Diagnosis and management of AD by PCPs, utilizing specialist consultation as needed, may contribute to earlier diagnosis and treatment, improved doctor-patient and doctor-caregiver communication, increased attention to caregiver needs, and better clinical and quality-of-life outcomes for patients and caregivers. A set of expert panel recommendations describing practical strategies for achieving these goals was successfully developed.

Risk of dementia among white and African American relatives of patients with Alzheimer disease.

CONTEXT: Evidence exists that the incidence of Alzheimer disease (AD), as well as risk attributable to specific genetic factors such as apolipoprotein E (APOE) genotype, may vary considerably among ethnic groups. Family studies of probands with AD offer an opportunity to evaluate lifetime risk of dementia among relatives of these probands. OBJECTIVE: To compare lifetime dementia risk estimates among relatives of white and African American probands with probable or definite AD. DESIGN AND SETTING: Risk analysis using data collected by questionnaire and supplemental records between May 1991 and March 2001 at 17 medical centers contributing to the Multi-Institutional Research in Alzheimer's Genetic Epidemiology Study. PARTICIPANTS: A total of 17 639 first-degree biological relatives and 2474 spouses of 2339 white AD probands, and 2281 first-degree biological relatives and 257 spouses of 255 African American AD probands. MAIN OUTCOME MEASURES: Cumulative risk of dementia by age 85 years, stratified by ethnicity and sex of relatives and by APOE genotype of probands. RESULTS: Cumulative risk of dementia in first-degree biological relatives of African American AD probands by age 85 years was 43.7% (SE, 3.1%), and the corresponding risk in first-degree biological relatives of white AD probands was 26.9% (SE, 0.8%), yielding a relative risk (RR) of 1.6 (95% confidence interval [CI], 1.4-1.9; P<.001). The risk in spouses of African American AD probands of 18.5% (SE, 8.4%) was also higher than the risk in white spouses of 10.4% (SE, 1.7%) but did not reach statistical significance (RR, 1.8; 95% CI, 0.5-6.0; P =.34), likely due to the smaller sample size of African Americans. The proportional increase in risk of dementia among white first-degree biological relatives compared with white spouses of 2.6 (95% CI, 2.1-3.2) was similar to that of 2.4 (95% CI, 1.3-4.4) in African American first-degree biological relatives compared with African American spouses. Female first-degree biological relatives of probands had a higher risk of developing dementia than did their male counterparts, among whites (31.2% vs 20.4%; RR, 1.5; 95% CI, 1.3-1.7; P<.001) as well as among African Americans, although this was not significant among African Americans (46.7% vs 40.1%; RR, 1.2; 95% CI, 0.9-1.7, P =.30). The patterns of risk among first-degree biological relatives stratified by APOE genotype of the probands were similar in white families and African American families. CONCLUSION: First-degree relatives of African Americans with AD have a higher cumulative risk of dementia than do those of whites with AD. However, in this study, the additional risk of dementia conferred by being a first-degree relative, by being female, or by the probability of having an APOE epsilon4 allele appeared similar in African American and white families. These data provide estimates of dementia risk that can be used to offer counseling to family members of patients with AD.