Extended genome-wide association study employing the African Genome Resources Panel identifies novel susceptibility loci for Alzheimer's Disease in individuals of African ancestry.

INTRODUCTION: Despite a two-fold increased risk, individuals of African ancestry have been significantly underrepresented in Alzheimer's Disease (AD) genomics efforts. METHODS: GWAS of 2,903 AD cases and 6,265 cognitive controls of African ancestry. Within-dataset results were meta-analyzed, followed by gene-based and pathway analyses, and analysis of RNAseq and whole-genome sequencing data. RESULTS: A novel AD risk locus was identified in MPDZ on chromosome 9p23 (rs141610415, MAF=.002, P =3.68×10 -9 ). Two additional novel common and nine novel rare loci approached genome-wide significance at P <9×10 -7 . Comparison of association and LD patterns between datasets with higher and lower degrees of African ancestry showed differential association patterns at chr12q23.2 ( ASCL1 ), suggesting that the association is modulated by regional origin of local African ancestry. DISCUSSION: Increased sample sizes and sample sets from Africa covering as much African genetic diversity as possible will be critical to identify additional disease-associated loci and improve deconvolution of local genetic ancestry effects.

Use of Antihypertensives, Blood Pressure, and Estimated Risk of Dementia in Late Life: An Individual Participant Data Meta-Analysis.

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Screening and Assessment for Alzheimer's Disease in the Days of Biological Biomarkers.

The 1980s saw an upsurge of research in Alzheimer's disease (AD). The necessity of standardized assessment batteries became apparent, leading to the development of standardized instruments, such as the CERAD, the CAMDEX, the CSI 'D', and later the TOOLBOX. The advent of new biological markers has led to speculation in the research community about the necessity for these instruments. As the association of biomarkers with subsequent clinical dementia remains unclear, assessment batteries are still necessary, especially with growing evidence that prodromal symptoms of AD may not be cognitive decline but emotional or behavioral symptoms. Inclusion of ethnic minority groups is also essential.

A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry.

African descent populations have a lower Alzheimer disease risk from ApoE ε4 compared to other populations. Ancestry analysis showed that the difference in risk between African and European populations lies in the ancestral genomic background surrounding the ApoE locus (local ancestry). Identifying the mechanism(s) of this protection could lead to greater insight into the etiology of Alzheimer disease and more personalized therapeutic intervention. Our objective is to follow up the local ancestry finding and identify the genetic variants that drive this risk difference and result in a lower risk for developing Alzheimer disease in African ancestry populations. We performed association analyses using a logistic regression model with the ApoE ε4 allele as an interaction term and adjusted for genome-wide ancestry, age, and sex. Discovery analysis included imputed SNP data of 1,850 Alzheimer disease and 4,331 cognitively intact African American individuals. We performed replication analyses on 63 whole genome sequenced Alzheimer disease and 648 cognitively intact Ibadan individuals. Additionally, we reproduced results using whole-genome sequencing of 273 Alzheimer disease and 275 cognitively intact admixed Puerto Rican individuals. A further comparison was done with SNP imputation from an additional 8,463 Alzheimer disease and 11,365 cognitively intact non-Hispanic White individuals. We identified a significant interaction between the ApoE ε4 allele and the SNP rs10423769_A allele, (ß = -0.54,SE = 0.12,p-value = 7.50x10-6) in the discovery data set, and replicated this finding in Ibadan (ß = -1.32,SE = 0.52,p-value = 1.15x10-2) and Puerto Rican (ß = -1.27,SE = 0.64,p-value = 4.91x10-2) individuals. The non-Hispanic Whites analyses showed an interaction trending in the "protective" direction but failing to pass a 0.05 significance threshold (ß = -1.51,SE = 0.84,p-value = 7.26x10-2). The presence of the rs10423769_A allele reduces the odds ratio for Alzheimer disease risk from 7.2 for ApoE ε4/ε4 carriers lacking the A allele to 2.1 for ApoE ε4/ε4 carriers with at least one A allele. This locus is located approximately 2 mB upstream of the ApoE locus, in a large cluster of pregnancy specific beta-1 glycoproteins on chromosome 19 and lies within a long noncoding RNA, ENSG00000282943. This study identified a new African-ancestry specific locus that reduces the risk effect of ApoE ε4 for developing Alzheimer disease. The mechanism of the interaction with ApoEε4 is not known but suggests a novel mechanism for reducing the risk for ε4 carriers opening the possibility for potential ancestry-specific therapeutic intervention.

Novel Alzheimer Disease Risk Loci and Pathways in African American Individuals Using the African Genome Resources Panel: A Meta-analysis.

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 gene EDEM1 (3p26; P = 8.9 × 10-7), near the immune response gene ALCAM (3q13; P = 9.3 × 10-7), within GPC6 (13q31; P = 4.1 × 10-7), a gene critical for recruitment of glutamatergic receptors to the neuronal membrane, and within VRK3 (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 near IGF1R at 15q26 (P = 1.7 × 10-9) and 6 additional loci with suggestive significance (P ≤ 5 × 10-7) such as API5 at 11p12 (P = 8.8 × 10-8) and RBFOX1 at 16p13 (P = 5.4 × 10-7) were identified. Gene expression data from brain tissue demonstrate association of ALCAM, ARAP1, GPC6, and RBFOX1 with brain ß-amyloid load. Of 25 known loci associated with Alzheimer disease in non-Hispanic White individuals, only APOE, ABCA7, TREM2, BIN1, CD2AP, FERMT2, and WWOX were 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.

Perspective on the "African American participation in Alzheimer disease research: Effective strategies" workshop, 2018.

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.

Understanding the healthcare experiences and needs of African immigrants in the United States: a scoping review.

BACKGROUND: Africans immigrants in the United States are the least-studied immigrant group, despite the research and policy efforts to address health disparities within immigrant communities. Although their healthcare experiences and needs are unique, they are often included in the "black" category, along with other phenotypically-similar groups. This process makes utilizing research data to make critical healthcare decisions specifically targeting African immigrants, difficult. The purpose of this Scoping Review was to examine extant information about African immigrant health in the U.S., in order to develop lines of inquiry using the identified knowledge-gaps. METHODS: Literature published in the English language between 1980 and 2016 were reviewed in five stages: (1) identification of the question and (b) relevant studies, (c) screening, (d) data extraction and synthesis, and (e) results. Databases used included EBSCO, ProQuest, PubMed, and Google Scholar (hand-search). The articles were reviewed according to title and abstract, and studies deemed relevant were reviewed as full-text articles. Data was extracted from the selected articles using the inductive approach, which was based on the comprehensive reading and interpretive analysis of the organically emerging themes. Finally, the results from the selected articles were presented in a narrative format. RESULTS: Culture, religion, and spirituality were identified as intertwined key contributors to the healthcare experiences of African immigrants. In addition, lack of culturally-competent healthcare, distrust, and complexity, of the U.S. health system, and the exorbitant cost of care, were identified as major healthcare access barriers. CONCLUSION: Knowledge about African immigrant health in the U.S. is scarce, with available literature mainly focusing on databases, which make it difficult to identify African immigrants. To our knowledge, this is the first Scoping Review pertaining to the healthcare experiences and needs of African immigrants in the U.S.

Incidence of Dementia and Alzheimer Disease Over Time: A Meta-Analysis.

BACKGROUND/OBJECTIVES: Population-based incidence estimates of dementia and Alzheimer disease (AD) provide important information for public health policy and resource allocation. We conducted a meta-analysis of published studies that reported age-specific incidence rates of dementia and AD to determine whether dementia and AD incidence rates are changing over time. DESIGN: PubMed and MEDLINE were searched for publications through June 30, 2017, using key words "dementia", "Alzheimer", and "incidence." Inclusion criteria for the meta-analysis are: (1) population-based studies using personal interviews and direct examinations of the study subjects, (2) standardized clinical diagnosis criteria, (3) reporting age-specific incidence rates, (4) published in English, and (5) sample size of 500 or greater and length of follow-up of 2 years or greater. Mixed-effects models were used to determine the association between birth year and incidence rates. MEASUREMENTS: Age-specific dementia/AD incidence rates and their standard errors reported in each study. RESULTS: Thirty-eight articles with 53 cohorts on dementia incidence and 31 articles with 35 cohorts on AD incidence met the inclusion criteria. There were significant associations between later birth years and decreased dementia incidence rates in all three age groups (65-74, 75-84, and 85 years and older). There were no significant associations between birth year and AD incident rates in any of the three age groups. In particular, AD incidence rates reported from Western countries stayed steady in all age groups, while studies in non-Western countries showed significantly increased AD incidence rates for the 65 to 74 years age group (odds ratio = 2.78; P = .04), but a nonsignificant association for the 75 to 84 or 85 years and older groups. CONCLUSION: Dementia incidence declined over the past four decades, but AD incidence did not decline. Further research, especially from non-Western countries, is needed to elucidate the mechanism underlying the trends in dementia and AD incidence over time.

Exploration of Perceived Psychosocial Benefits of Senior Companion Program Participation Among Urban-Dwelling, Low-Income Older Adult Women Volunteers.

BACKGROUND: As the older adult population increases, it is imperative to increase older adults' opportunities for social involvement, thus maintaining their important roles and contributions to society. While there are known health-related benefits of volunteerism among older adults, a dearth of information exists on the perceived benefits of volunteerism among low-income and ethnic minority older adults. PURPOSE: To understand the perceived psychosocial benefits of volunteering in the Senior Companion Program and to present findings of focus groups conducted with urban-dwelling, low-income older adult women volunteers. DESIGN AND METHODS: Inductive content analysis and the Dedoose qualitative data analysis software were used for analyzing data obtained from 59 older adult women Senior Companions who participated in nine focus groups. RESULTS: Content analyses of the focus group transcripts identified four major themes: (1) Reducing social isolation; (2) Improving quality of life; (3) Finding purpose and meaning; and (4) Increasing understanding of aging. The majority of our participants (81%) were African American women, with a mean age of 70 years. Approximately 83.1% had completed high school and 62.7% lived below the poverty line. DISCUSSION AND IMPLICATIONS: Findings provided data rich in descriptions of positive psychosocial outcomes, finding meaning and purpose, and a better understanding of aging in urban-dwelling, low-income older women volunteers. The findings also provide support for the need for policies and programs that promote civic engagement in this population.

Changes of glucose levels precede dementia in African-Americans with diabetes but not in Caucasians.

INTRODUCTION: Changes in glucose levels may represent a powerful metabolic indicator of dementia in African-Americans with diabetes. It is unclear whether these changes also occur in Caucasians. METHODS: A secondary data analysis using electronic medical records from 5228 African-Americans and Caucasians aged ≥65 years was carried out. Mixed effects models with repeated serum glucose measurements were used to compare changes in glucose levels between African-Americans and Caucasian patients with and without incident dementia. RESULTS: African-Americans and Caucasians with diabetes had significantly different changes in glucose levels by dementia status (P < .0001). African-Americans experienced a significant decline in glucose levels before the dementia diagnosis (estimated glucose decline 1.3421 mg/dL per year, P < .0001) than those who did not develop dementia. Caucasians with and without dementia showed stable glucose levels over time (P = .3071). DISCUSSION: Significant changes in glucose levels precede dementia in African-American patients with diabetes but not in Caucasians.

The Association of Early Life Factors and Declining Incidence Rates of Dementia in an Elderly Population of African Americans.

Objectives: To explore the possible association of childhood residence, education levels, and occupation with declining incidence rates of dementia in 2 cohorts of elderly African Americans. Methods: African Americans residing in Indianapolis without dementia were enrolled in 1992 and 2001 and evaluated every 2-3 years. The cohorts consist of 1,440 participants in 1992 and 1,835 participants in 2001 aged 70 years and older. Cox proportional hazard regression models were used to compare cohort differences in dementia and Alzheimer's disease (AD) risk. Results: The 2001 cohort had significantly decreased risk of both incident dementia and AD (hazard ratio [HR]: 0.62/0.57 for dementia/AD). Years of education was associated with decreased risk of dementia (HR = 0.93; p = .0011). A significant interaction (p = .0477) between education and childhood rural residence was found for the risk of AD that higher education level is significantly associated with reduced AD risk (HR = 0.87) in participants with childhood rural residence, but no association in those with urban upbringing. The cohort difference for dementia rates were attenuated by adjusting for the 3 risk factors but remained significant (HR = 0.75; p = .04). Discussion: These results emphasize the importance of early life factors including rural residence and education for the risk for dementia later in life.

Antihypertensive Medication and Dementia Risk in Older Adult African Americans with Hypertension: A Prospective Cohort Study.

BACKGROUND: African Americans are especially at risk of hypertension and dementia. Antihypertensive medications reduce the risk of cardiovascular events, but may also reduce the risk of dementia. OBJECTIVE: To assess the longitudinal effects of antihypertensive medications and blood pressure on the onset of incident dementia in a cohort of African Americans. DESIGN: Prospective cohort. PARTICIPANTS: 1236 community-dwelling patients from an inner-city public health care system, aged 65 years and older, with a history of hypertension but no history of dementia, and who had at least three primary care visits and a prescription filled for any medication. MAIN MEASURES: Blood pressure was the average of three seated measurements. Dementia was diagnosed using a two-stage design, with a screening evaluation every 2 to 3 years followed by a comprehensive in-home clinical evaluation for those with a positive screen. Laboratory, inpatient and outpatient encounter data, coded diagnoses and procedures, and medication records were derived from a health information exchange. KEY RESULTS: Of the 1236 hypertensive participants without dementia at baseline, 114 (9%) developed incident dementia during follow-up. Individuals prescribed any antihypertensive medication (n = 816) were found to have a significantly reduced risk of dementia (HR = 0.57, 95% CI 0.37-0.88, p = 0.0114) compared to untreated hypertensive participants (n = 420). When this analysis was repeated including a variable indicating suboptimally treated blood pressure (> 140 mmHg systolic or >90 mmHg diastolic), the effect of antihypertensive medication was no longer statistically significant (HR = 0.65, 95% CI 0.32-1.30, p = 0.2217). CONCLUSIONS: Control of blood pressure in older adult African American patients with hypertension is a key intervention for preventing dementia, with similar benefits from most of the commonly available antihypertensive medications.

Population Neuroscience: Dementia Epidemiology Serving Precision Medicine and Population Health.

Over recent decades, epidemiology has made significant contributions to our understanding of dementia, translating scientific discoveries into population health. Here, we propose reframing dementia epidemiology as "population neuroscience," blending techniques and models from contemporary neuroscience with those of epidemiology and biostatistics. On the basis of emerging evidence and newer paradigms and methods, population neuroscience will minimize the bias typical of traditional clinical research, identify the relatively homogenous subgroups that comprise the general population, and investigate broader and denser phenotypes of dementia and cognitive impairment. Long-term follow-up of sufficiently large study cohorts will allow the identification of cohort effects and critical windows of exposure. Molecular epidemiology and omics will allow us to unravel the key distinctions within and among subgroups and better understand individuals' risk profiles. Interventional epidemiology will allow us to identify the different subgroups that respond to different treatment/prevention strategies. These strategies will inform precision medicine. In addition, insights into interactions between disease biology, personal and environmental factors, and social determinants of health will allow us to measure and track disease in communities and improve population health. By placing neuroscience within a real-world context, population neuroscience can fulfill its potential to serve both precision medicine and population health.

Categorizing Health Outcomes and Efficacy of mHealth Apps for Persons With Cognitive Impairment: A Systematic Review.

BACKGROUND: Use of mobile health (mHealth) apps is growing at an exponential rate in the United States and around the world. Mild cognitive impairment (MCI), Alzheimer disease, and related dementias are a global health problem. Numerous mHealth interventions exist for this population, yet the effect of these interventions on health has not been systematically described. OBJECTIVE: The aim of this study is to catalog the types of health outcomes used to measure effectiveness of mHealth interventions and assess which mHealth interventions have been shown to improve the health of persons with MCI, Alzheimer disease, and dementia. METHODS: We searched 13 databases, including Ovid MEDLINE, PubMed, EMBASE, the full Cochrane Library, CINAHL, PsycINFO, Ei Compendex, IEEE Xplore, Applied Science & Technology Source, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar from inception through May 2017 for mHealth studies involving persons with cognitive impairment that were evaluated using at least one quantitative health outcome. Proceedings of the Annual ACM Conferences on Human Factors in Computing Systems, the ACM User Interface Software and Technology Symposium, and the IEEE International Symposium on Wearable Computers were searched in the ACM Digital Library from 2012 to 2016. A hand search of JMIR Publications journals was also completed in July 2017. RESULTS: After removal of duplicates, our initial search returned 3955 records. Of these articles, 24 met final inclusion criteria as studies involving mHealth interventions that measured at least one quantitative health outcome for persons with MCI, Alzheimer disease, and dementia. Common quantitative health outcomes included cognition, function, mood, and quality of life. We found that 21.2% (101/476) of the fully reviewed articles were excluded because of a lack of health outcomes. The health outcomes selected were observed to be inconsistent between studies. For those studies with quantitative health outcomes, more than half (58%) reported postintervention improvements in outcomes. CONCLUSIONS: Results showed that many mHealth app interventions targeting those with cognitive impairment lack quantitative health outcomes as a part of their evaluation process and that there is a lack of consensus as to which outcomes to use. The majority of mHealth app interventions that incorporated health outcomes into their evaluation noted improvements in the health of persons with MCI, Alzheimer disease, and dementia. However, these studies were of low quality, leading to a grade C level of evidence. Clarification of the benefits of mHealth interventions for people with cognitive impairment requires more randomized controlled trials, larger numbers of participants, and trial designs that minimize bias. TRIAL REGISTRATION: PROSPERO Registration: PROSPERO 2016:CRD42016033846; http://www.crd.york.ac.uk/PROSPERO/ display_record.asp?ID=CRD42016033846 (Archived by WebCite at http://www.webcitation.org/6sjjwnv1M).

The changing prevalence and incidence of dementia over time - current evidence.

Dementia is an increasing focus for policymakers, civil organizations and multidisciplinary researchers. The most recent descriptive epidemiological research into dementia is enabling investigation into how the prevalence and incidence are changing over time. To establish clear trends, such comparisons need to be founded on population-based studies that use similar diagnostic and research methods consistently over time. This narrative Review synthesizes the findings from 14 studies that investigated trends in dementia prevalence (nine studies) and incidence (five studies) from Sweden, Spain, the UK, the Netherlands, France, the USA, Japan and Nigeria. Besides the Japanese study, these studies indicate stable or declining prevalence and incidence of dementia, and some provide evidence of sex-specific changes. No single risk or protective factor has been identified that fully explains the observed trends, but major societal changes and improvements in living conditions, education and healthcare might have favourably influenced physical, mental and cognitive health throughout an individual's life course, and could be responsible for a reduced risk of dementia in later life. Analytical epidemiological approaches combined with translational neuroscientific research could provide a unique opportunity to explore the neuropathology that underlies changing occurrence of dementia in the general population.

Adherence and Tolerability of Alzheimer's Disease Medications: A Pragmatic Randomized Trial.

BACKGROUND/OBJECTIVES: Post-marketing comparative trials describe medication use patterns in diverse, real-world populations. Our objective was to determine if differences in rates of adherence and tolerability exist among new users to acetylcholinesterase inhibitors (AChEI's). DESIGN: Pragmatic randomized, open label comparative trial of AChEI's currently available in the United States. SETTING: Four memory care practices within four healthcare systems in the greater Indianapolis area. PARTICIPANTS: Eligibility criteria included older adults with a diagnosis of possible or probable Alzheimer's disease (AD) who were initiating treatment with an AChEI. Participants were required to have a caregiver to complete assessments, access to a telephone, and be able to understand English. Exclusion criteria consisted of a prior severe adverse event from AChEIs. INTERVENTION: Participants were randomized to one of three AChEIs in a 1:1:1 ratio and followed for 18 weeks. MEASUREMENTS: Caregiver-reported adherence, defined as taking or not taking study medication, and caregiver-reported adverse events, defined as the presence of an adverse event. RESULTS: 196 participants were included with 74.0% female, 30.6% African Americans, and 72.9% who completed at least twelfth grade. Discontinuation rates after 18 weeks were 38.8% for donepezil, 53.0% for galantamine, and 58.7% for rivastigmine (P = .063) in the intent to treat analysis. Adverse events and cost explained 73.1% and 25.4% of discontinuation. No participants discontinued donepezil due to cost. Adverse events were reported by 81.2% of all participants; no between-group differences in total adverse events were statistically significant. CONCLUSIONS: This pragmatic comparative trial showed high rates of adverse events and cost-related non-adherence with AChEIs. Interventions improving adherence and persistence to AChEIs may improve AD management. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01362686 (https://clinicaltrials.gov/ct2/show/NCT01362686).