Development of a Mobile-First Registry to Recruit Healthy Volunteers and Members of Underrepresented Communities for Alzheimer's Disease Prevention Studies.

BACKGROUND: Web-based participant recruitment registries can be useful tools for accelerating enrollment into studies, but existing Alzheimer's disease (AD)-focused recruitment registries have had limited success enrolling individuals from underrepresented racial and ethnic groups. Designing these registries to meet the needs of individuals from these communities, including designing mobile-first, may facilitate improvement in the enrollment of underrepresented groups. OBJECTIVES: Evaluate the usability of a prototype mobile-first participant recruitment registry for AD prevention studies; assess users' perceptions of and willingness to sign up for the registry. DESIGN AND SETTING: Quantitative usability testing and an online survey; online setting. PARTICIPANTS: We recruited 1,358 adults ages 45-75 who self-reported not having a diagnosis of mild cognitive impairment, AD, or other forms of dementia (Study 1: n=589, Study 2: n=769). Black/African American and Hispanic/Latino participants were specifically recruited, including those with lower health literacy. METHODS AND MEASUREMENTS: Study 1 measures the prototype's usability through observed task success rates, task completion times, and responses to the System Usability Scale. Study 2 uses an online survey to collect data on perceptions of and willingness to sign up for the mobile-first registry. RESULTS: Study 1 findings show the prototype mobile-first recruitment registry website demonstrates high usability and is equally usable for Black / African American, Hispanic/Latino, and White user groups. Survey results from Study 2 indicate that users from underrepresented communities understand the registry's purpose and content and express willingness to sign up for the registry on a mobile device. CONCLUSIONS: Designing mobile-first participant recruitment registries based on feedback from underrepresented communities may result in more sign-ups by individuals from minoritized communities.

Understanding Barriers and Facilitators to Signing Up for a Mobile-Responsive Registry to Recruit Healthy Volunteers and Members of Underrepresented Communities for Alzheimer's Disease Prevention Studies.

BACKGROUND: Alzheimer's disease (AD) disproportionately affects Black/African American and Hispanic/Latino adults, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings. OBJECTIVES: This study explores barriers and facilitators to signing up for an AD participant recruitment registry website intended to optimize recruitment of these adults. The registry is geared toward recruitment on smartphones and tablets (mobile devices), as research suggests that mobile-first approaches may be more successful within these populations. DESIGN: In 2020, we conducted four focus groups (n = 39) and an online survey (n = 1010) with Black/African American and Hispanic/Latino adults. The survey also included Whites as a comparison group. SETTING: Focus groups were in-person at research facilities in New Orleans, Louisiana, and Los Angeles, California. The online survey was distributed by a survey panel company to participants nationwide. PARTICIPANTS: Black/African American (n = 360), Hispanic/Latino (n = 359), or White (n = 330) individuals, 45-75 years old, who self-reported not having mild cognitive impairment (MCI), dementia, or AD. MEASUREMENTS: Barriers and facilitators explored in the focus groups and survey were related to health and AD (e.g., AD-related concerns and past participation/willingness to participate in health or AD studies); current use of mobile devices (e.g., comfort using devices and receptivity to the AD recruitment registry); and participant characteristics and beliefs (e.g., demographics, health literacy level, and trust in government and the scientific community). RESULTS: The focus groups and survey revealed similar findings. Participants commonly use mobile devices to go online and perform health-related activities. They were aware of AD, expressed concerns with developing it, and were willing to participate in AD-related studies (motivated by personal connection to AD, altruism, and compensation). When presented with the AD recruitment registry, most provided positive feedback (e.g., easy to use and informative) and shared an interest in joining. Barriers to joining the registry with a mobile device included complex or multistep enrollment processes, beliefs that studies are primarily for those with a specific disease, and confusion about how studies can prevent AD among those low-risk for AD. The focus groups also revealed that Black/African American participants expressed more hesitation than Hispanic/Latinos in joining the registry due to greater distrust in the government and scientific community. CONCLUSIONS: Recruiting more Black/African American and Hispanic/Latino participants into AD studies is vitally important. This mixed methods study suggests that adults in these underrepresented groups are motivated to prevent AD and willing to sign up for an AD participant recruitment registry using mobile devices. Most barriers to joining a registry can be addressed through slight modifications to the registry's design and functionality and by adding content. These findings can help enhance the appeal of joining AD recruitment registries to ultimately enroll more diverse, representative groups of participants and increase the generalizability of AD study findings.

Outreach, Screening, and Randomization of APOE ε4 Carriers into an Alzheimer's Prevention Trial: A global Perspective from the API Generation Program.

BACKGROUND: Alzheimer's disease (AD) prevention trials require a large outreach and screening funnel to identify cognitively unimpaired adults who meet the study's inclusion criteria, such as certain clinical or demographic criteria, genetic risk factors, and/or biomarker evidence of the disease. OBJECTIVES: Describe tactics and strategies to identify and enroll cognitively unimpaired adults with one (heterozygotes [HT]) or two (homozygotes [HM]) copies of the APOE ε4 allele, a genetic risk factor for dementia due to AD, into the Alzheimer's Prevention Initiative (API) Generation Program, the largest and only prevention trials for late onset AD using this enrichment technique. DESIGN AND SETTING: The Generation Program was comprised of two global, randomized, double-blind, placebo-controlled, parallel group adaptive design with variable treatment duration clinical trials. Generation Study 1 randomized participants into one of two cohorts: Cohort 1 which evaluated CAD106 vs. placebo or Cohort 2 which evaluated umibecestat vs placebo. Generation Study 2 randomized participants into two doses of umibecestat vs. placebo. The Generation Program was terminated early in 2019, while enrollment was still occurring. PARTICIPANTS: Both Generation Study 1 and Generation Study 2 enrolled cognitively unimpaired APOE ε4 HMs aged 60-75; Generation Study 2 also enrolled APOE ε4 HTs ages 60-75 with elevated brain amyloid. METHODS AND MEASUREMENTS: Describe results of the centralized and localized outreach, recruitment, screening strategies and tactics as well as characteristics of sites successful at enrolling genetically eligible participants, with a particular focus on APOE ε4 HMs given the 2-3% prevalence of this genotype. RESULTS: At the time the trial program was terminated, 35,333 individuals had consented to the optional prescreening ICF1a/ICFA and provided a sample of DNA for APOE genotyping, 1,138 APOE ε4 HMs consented to screening for Generation Study 1 (ICF1b), and 1,626 APOE ε4 carriers were randomized into either Generation Study 1 or Generation Study 2. Genetic testing registries, partnerships with genetic testing/counseling companies, and the optional prescreening ICF1a/ICFA were the most successful strategies for identifying genetically eligible participants for screening. CONCLUSIONS: It is feasible to recruit, screen and randomize cognitively unimpaired APOE ε4 carriers, particularly APOE ε4 HMs for a global AD prevention trial. The Generation Program was on track to complete enrollment by end of 2019. Factors that were key to this success included: working with sites to develop customizable outreach, recruitment, and screening programs specific to their site needs, providing forums for sites to exchange best practices, and developing partnerships between the sponsor team and trial sites.

The Alzheimer's Prevention Registry: A Large Internet-Based Participant Recruitment Registry to Accelerate Referrals to Alzheimer's-Focused Studies.

BACKGROUND: Recruitment for Alzheimer's disease (AD)-focused studies, particularly prevention studies, is challenging due to the public's lack of awareness about study opportunities coupled with studies' inclusion and exclusion criteria, resulting in a high screen fail rate. OBJECTIVES: To develop an internet-based participant recruitment registry for efficiently and effectively raising awareness about AD-focused study opportunities and connecting potentially eligible volunteers to studies in their communities. METHODS: Individuals age 18 and older are eligible to join the Alzheimer's Prevention Registry (APR). Individuals provide first and last name, year of birth, country, and zip/postal code to join the APR; for questions regarding race, ethnicity, sex, family history of AD or other dementia, and diagnosis of cognitive impairment, individuals have the option to select "prefer not to answer." The APR website maintains a list of recruiting studies and contacts members who have opted in by email when new studies are available for enrollment. RESULTS: As of December 1, 2019, 346,661 individuals had joined the APR. Members had a mean age of 63.3 (SD 11.7) years and were predominately women (75%). 94% were cognitively unimpaired, 50% reported a family history of AD or other dementia, and of those who provided race, 76% were white. 39% joined the APR as a result of a paid social media advertisement. To date, the APR helped recruit for 82 studies. CONCLUSIONS: The APR is a large, internet-based participant recruitment registry designed to raise awareness about AD prevention research and connect members with enrolling studies in their communities. It has demonstrated the ability to recruit and engage a large number of highly motivated members and assist researchers in meeting their recruitment goals. Future publications will report on the effectiveness of APR for accelerating recruitment and enrollment into AD-focused studies.

Assessment of Clinical Meaningfulness of Endpoints in the Generation Program by the Insights to Model Alzheimer's Progression in Real Life (iMAP) Study.

We are launching the Insights to Model Alzheimer's Progression in Real Life study in parallel with the Alzheimer Prevention Initiative Generation Program. This is a 5-year, multinational, prospective, longitudinal, non-interventional cohort study that will collect data across the spectrum of Alzheimer's disease. The primary objective is to assess the ability of the Alzheimer's Prevention Initiative Cognitive Composite Test Score and Repeatable Battery for the Assessment of Neuropsychological Status to predict clinically meaningful outcomes such as diagnosis of mild cognitive impairment or dementia due to Alzheimer's disease, and change in Clinical Dementia Rating - Global Score. This study is the first large-scale, prospective effort to establish the clinical meaningfulness of cognitive test scores that track longitudinal decline in preclinical Alzheimer's disease. This study is also expected to contribute to our understanding of the relationships among outcomes in different stages of Alzheimer's disease as well as models of individual trajectories during the course of the disease.

The Value of Pre-Screening in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease Trial.

The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) trial evaluates the anti-amyloid-ß antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed pre-screening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.

The Alzheimer's Prevention Initiative Generation Program: Evaluating CNP520 Efficacy in the Prevention of Alzheimer's Disease.

Alzheimer's disease pathology begins decades before the onset of clinical symptoms. This provides an opportunity for interventional clinical trials to potentially delay or prevent the onset of cognitive impairment or dementia. CNP520 (a beta-site-amyloid precursor protein-cleaving enzyme inhibitor) is in clinical development for the treatment of preclinical Alzheimer's disease under the Alzheimer's Prevention Initiative Generation Program. The Alzheimer's Prevention Initiative is a public-private partnership intended to accelerate the evaluation of Alzheimer's disease prevention therapies. The Generation Program comprises two pivotal phase II/III studies with similar designs to assess the efficacy and safety of investigational treatments in a cognitively unimpaired population at increased risk for developing Alzheimer's disease based on age and apolipoprotein E (APOE) genotype (i.e., presence of the APOE ε4 allele). The program has been designed to maximize benefit to Alzheimer's disease research. Generation Study 1 (NCT02565511) and Generation Study 2 (NCT03131453) are currently enrolling; their key features are presented here.

Registries and Cohorts to Accelerate Early Phase Alzheimer's Trials. A Report from the E.U./U.S. Clinical Trials in Alzheimer's Disease Task Force.

The EU/US/CTAD Task Force, an international collaboration of AD investigators from industry and academia, met in Barcelona, Spain, on November 4th, 2015, to explore existing and planned patient registries and other clinical trial infrastructure meant to expedite recruitment of large numbers of participants into clinical trials and improve their productivity. The Task Force identified a number of approaches currently being tested around the world, including the use of predictive algorithms to identify individuals likely to have prodromal or preclinical AD, the establishment of clinical trial networks to streamline trials, and reforming the informed consent process to make it less burdensome to both investigators and trial participants. Multi-national systems such as the European Prevention of Alzheimer's Dementia (EPAD) and the Global Alzheimer's Platform (GAP) offer value for sponsors, trial sites, and patients by optimizing efforts to find effective disease-modifying and symptomatic treatments.

Arizona Alzheimer's Registry: Strategy and Outcomes of a Statewide Research Recruitment Registry.

BACKGROUND: The Arizona Alzheimer's Consortium (AAC) created the Arizona Alzheimer's Registry, a screening and referral process for people interested in participating in Alzheimer's disease related research. The goals of the Registry were to increase awareness of Alzheimer's disease research and accelerate enrollment into AAC research studies. METHODS: Participation was by open invitation to adults 18 and older. Those interested provided consent and completed a written questionnaire. A subset of Registrants underwent an initial telephone cognitive assessment. Referral to AAC sites was based on medical history, telephone cognitive assessment, and research interests. RESULTS: A total of 1257 people consented and 1182 underwent an initial cognitive screening. Earned media (38.7%) was the most effective recruitment strategy. Participants had a mean age of 68.1 (SD 10.6), 97% were Caucasian, had 15.2 (SD 2.7) mean years of education, and 60% were female. 30% reported a family history of dementia and 70% normal cognition. Inter-rater agreement between self-reported memory status and the initial telephone cognitive assessment had a kappa of 0.31-0.43. 301 were referred to AAC sites. CONCLUSION: IThe Registry created an infrastructure and process to screen and refer a high volume of eager Registrants. These methods were found to be effective at prescreening individuals for studies, which facilitated AAC research recruitment. The established infrastructure and experiences gained from the Registry have served as the prototype for the web-based Alzheimer's Prevention Registry, a national registry focusing on Alzheimer's disease prevention research.

Chronic divalproex sodium use and brain atrophy in Alzheimer disease.

OBJECTIVE: We evaluated the effect of the divalproex sodium formulation of valproic acid on brain volumes using MRI in people with mild to moderate Alzheimer disease (AD) and assessed for changes associated with behavioral and cognitive effects. METHODS: Eighty-nine of 313 participants randomized to divalproex or placebo in a 24-month, parallel-group trial received MRI scans at baseline and 12 months. Interval MRI annual percent changes in whole brain, ventricular, and hippocampal volumes were the primary outcomes of interest. Change from baseline in clinical outcomes was assessed at 6-month intervals. RESULTS: There were no baseline differences between active treatment and placebo groups in age, education, brain volumes, clinical rating scores, or APOE ε4 carrier status. The group treated with divalproex showed a greater rate of decline in left and right hippocampal and brain volumes (-10.9% and -12.4% vs -5.6% and -6.3%, and -3.5% vs -1.4%, respectively), and a greater rate of ventricular expansion (24.5% vs 9.9%) (p < 0.001). Mini-Mental State Examination scores showed a more rapid decline with divalproex through month 12 (placebo = -2.0 ± 4.3, divalproex = -3.9 ± 4.0) (p = 0.037), although there were no changes on other cognitive, behavioral, or functional ratings at 12 and 24 months. CONCLUSIONS: Divalproex treatment was associated with accelerated brain volume loss over 1 year and perhaps with greater cognitive impairment. The long-term clinical effects of these changes are not known.