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INTRODUCTION: Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE‐1 inhibitor umibecestat in cognitively unimpaired 60‐ to 75‐year‐old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. METHODS: Sixty‐five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450 μg (n = 42) or placebo (n = 23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow‐up Aβ positron emission tomography (PET) scans at 18 to 24 months. RESULTS: CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: −0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P < 0.001), and three amyloid‐related imaging abnormality cases (one symptomatic). DISCUSSION: Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. Highlights: This was the first amyloid‐lowering prevention trial in persons at genetic risk of late‐onset Alzheimer's disease (AD).Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial.CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes.CAD106 was generally safe and well tolerated, with only three amyloid‐related imaging abnormality cases (one symptomatic).Such an approach deserves further evaluation in larger AD prevention trials. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Alzheimer's‐focused participant recruitment registries are tools for accelerating enrollment into studies, however, registry members are primarily White women. METHODS: We conducted a national online survey of 1501 adults ages 50–80, oversampling for Black and Hispanic/Latino respondents, assessing intention to join a generic "brain health" registry and to join a registry that required specific tasks. RESULTS: Intention to join a registry was low (M 3.48, SD 1.77), and lower than intention to join a registry requiring specific tasks. Intention was greatest for registries requiring completing surveys (M 4.70, SD 1.77). Differences in intention were primarily between White women and Black women; differences between other groups were limited to specific tasks required. DISCUSSION: The results indicate uncertainty about what a registry is, its purpose, and/or the concept of "brain health." Using the Reasoned Action Approach (RAA) to develop evidence‐based outreach messages describing a registry and required tasks may increase diversity. [ABSTRACT FROM AUTHOR]

Clinical trials for Alzheimer's disease (AD) are slower to enroll study participants, take longer to complete, and are more expensive than trials in most other therapeutic areas. The recruitment and retention of a large number of qualified, diverse volunteers to participate in clinical research studies remain among the key barriers to the successful completion of AD clinical trials. An advisory panel of experts from academia, patient‐advocacy organizations, philanthropy, non‐profit, government, and industry convened in 2020 to assess the critical challenges facing recruitment in Alzheimer's clinical trials and develop a set of recommendations to overcome them. This paper briefly reviews existing challenges in AD clinical research and discusses the feasibility and implications of the panel's recommendations for actionable and inclusive solutions to accelerate the development of novel therapies for AD. [ABSTRACT FROM AUTHOR]

A crucial aspect of any clinical trial is using the right outcome measure to assess treatment efficacy. Compared to the rapidly evolved understanding and measurement of pathophysiology in preclinical and early symptomatic stages of Alzheimer's disease (AD), relatively less progress has been made in the evolution of clinical outcome assessments (COAs) for those stages. The current paper aims to provide a benchmark for the design and evaluation of COAs for use in early AD trials. We discuss lessons learned on capturing cognitive changes in predementia stages of AD, including challenges when validating novel COAs for those early stages and necessary evidence for their implementation in clinical trials. Moving forward, we propose a multi‐step framework to advance the use of more effective COAs to assess clinically meaningful changes in early AD, which will hopefully contribute to the much‐needed consensus around more appropriate outcome measures to assess clinical efficacy of putative treatments. Highlights: We discuss lessons learned on capturing cognitive changes in predementia stages of AD.We propose a framework for the design and evaluation of performance based cognitive tests for use in early AD trials.We provide recommendations to facilitate the implementation of more effective cognitive outcome measures in AD trials. [ABSTRACT FROM AUTHOR]

Introduction: Females may have greater susceptibility to Alzheimer's disease (AD)‐pathology. We examined the effect of sex on pathology, neurodegeneration, and memory in cognitively‐unimpaired Presenilin‐1 (PSEN1) E280A mutation carriers and non‐carriers. Methods: We analyzed baseline data from 167 mutation carriers and 75 non‐carriers (ages 30 to 53) from the Alzheimer's Prevention Initiative Autosomal Dominant AD Trial, including florbetapir‐ and fludeoxyglucose‐PET, MRI based hippocampal volume and cognitive testing. Results: Females exhibited better delayed recall than males, controlling for age, precuneus glucose metabolism, and mutation status, although the effect was not significant among PSEN1 mutation carriers only. APOE ε4 did not modify the effect of sex on AD biomarkers and memory. Discussion: Our findings suggest that, among cognitively‐unimpaired individuals at genetic risk for autosomal‐dominant AD, females may have greater cognitive resilience to AD pathology and neurodegeneration than males. Further investigation of sex‐specific differences in autosomal‐dominant AD is key to elucidating mechanisms of AD risk and resilience. [ABSTRACT FROM AUTHOR]

Background: Recruiting cognitively‐unimpaired volunteers at high genetic risk of developing dementia into the Alzheimer's Prevention Initiative (API) Colombia trial, and maintaining study adherence for at least 5 years has been a monumental challenge. Major barriers included inclusion criteria, protocol visit schedule, long informed consent form (ICF), low levels of education of participants, misconceptions about participating in a clinical trial, and blinding to genetic status and treatment arm. We explain how our group went out of the conventional and traditional schemes of informed consent while adhering to good clinical practice and developed a novel approach to the consent process for potential candidates. Method: The identification, community education, and follow‐up of affected PSEN1 E280A families for the past three decades was the initial fundamental step to initiate a proper ICF process for the study. Then the launch of API Colombia Registry in 2010 was the base for appropriate preparation for the prevention trial. The process for API Colombia trial included step by step strategies, such as: a pre‐screening process developed by the team, pre‐consent informational meeting with the principal investigator in small groups of potential candidates, illustrated materials like a booklet titled "What I should know about informed consent and my decision to participate", and detailed infographics as a complementary material to main study ICF, use of a voluntary pre‐selection survey. The screening visit was divided in parts: discussion with the sub‐investigator about clinical trial participation, review of participant's questions, and signatures according to regulatory requirements. Result: From 623 potentially eligible registrants for pre‐screening, 319 were consented and underwent full eligibility screening and 252 were randomized. After eight years of study duration, 94% of participants completed the protocol, 90.5% completed the trial on treatment. Most participants who dropped out of the study did it due to incompatibility with work, unexpected pregnancy, or the decision to have children. Conclusion: We attribute successful trial adherence to the consent process that led to a well‐informed, voluntary, and responsible decision, and the participant's understanding of the unique contribution they can make to change the world by participating in clinical research. [ABSTRACT FROM AUTHOR]

Background: In most prevention clinical trials contraceptive use is required. The API ADAD Colombia Trial was a phase II, double‐blind, placebo‐controlled clinical trial to evaluate the safety and efficacy of the investigational product crenezumab. Trial period A was carried out from 2013 to 2021, during which 252 cognitively unimpaired PSEN1 E280A mutation carriers and non‐carriers were enrolled to be treated with crenezumab or placebo, including 159 women from 30 to 60 years of age. We describe strategies to address contraception in female volunteers. Method: For women of childbearing age, using two contraceptive methods and taking a pregnancy test before each administration of the investigational product was required. Different strategies were used to try to guarantee the adherence of the participants to the contraception methods: comprehensive educational activities, educational brochures, annual newsletters, medical advice on contraception methods and in some cases referral to a gynecology specialist to select the best contraception method. The General Fertility Rate (GFR) was used to evaluate the efficacy of the implemented strategies for contraceptive use. Using the parametric Welch's t‐test, we compared the GFR rates between trial volunteers and the Colombian population using data reported by the National Administrative Department of Statistics. Result: Tubectomy plus condom use 33.9% (54/159) and oral contraceptives plus condom use 15.1% (24/159) were the most common combinations used by volunteers. Ten women (6.3%) became pregnant during trial period A. Four of these pregnancies were due to therapeutic failure because at each visit the use of contraceptive methods was controlled and recorded in the medical history, three due to inappropriate contraceptive drug use reported by the participants, two were planned by the volunteers and one participant with difficulties in adherence to follow up visits. Significantly lower mean of GFR (p‐value = 2.68×10‐5) was observed in API ADAD volunteers compared to the Colombian population over the 7 years. Conclusion: According the p‐value obtained to compare the GFR between trial volunteers and the Colombian population, the strategies used to address contraception by the site were effective for the prevention of pregnancies. [ABSTRACT FROM AUTHOR]

Background: A number of extended families in Colombia with early‐onset ADAD have a PSEN1 mutation at codon 280 (E280A), comprise the largest ADAD kindred in the world. Trial participants have been treated with crenezumab (an experimental anti‐amyloid monoclonal antibody) or placebo. Topline results were presented in August, 2022 at AAIC. Although the trial did not demonstrate a statistically significant clinical benefit in either of its co‐primary endpoints, multiple statistical innovations were incorporated into this trial. Method: The API ADAD Colombia trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 2b study evaluating the efficacy, safety, and tolerability of crenezumab in cognitively unimpaired ADAD PSEN1 E280A mutation carriers in Colombia (NCT01998841). Due to under enrollment and concerns with the sensitivity of the primary endpoint, the protocol was amended mid‐trial to change from 260 weeks of treatment to a common‐close design whereby treatment continued in the double‐blind portion until the last enrolled participant received 260 weeks of treatment. Because of the change in trial design and power considerations, the primary analysis was adapted from a traditional mixed model with repeated measures (MMRM) based analysis to a random coefficient regression model (RCRM) based analysis. To quantitatively examine the adequacy of the RCRM assumptions, a robust variance estimator (Huber 1967; White 1982) was prespecified as a sensitivity analysis to calculate the standard errors and p‐values of the co‐primary endpoints. This study used a type‐I‐error‐controlled statistical procedure to identify and elevate the Free and Cued Selective Reminding Test (FCSRT) cueing index to a co‐primary endpoint. To comprehensively assess the crenezumab effect across primary and secondary endpoints, the prespecified relative reduction point estimates along with the bootstrapped 95% confidence intervals were generated. Result: Innovative statistical methods in this trial will be presented. Conclusion: Although the API Colombia study did not meet its co‐primary endpoints, statistical learnings from this trial can benefit development of future AD trials. To further maximize the value of this unique trial dataset, participant‐level data will be made publicly available, including clinical, imaging, and biomarker data. Funding: NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer's Foundation. FlorbetapirPET was partly supported by Avid and Lilly. [ABSTRACT FROM AUTHOR]

Introduction: The API AutosomalDominant AD (ADAD) Colombia Trial is a placebo‐controlled clinical trial of crenezumab in 252 cognitively unimpaired 30 to 60‐year‐old Presenilin 1 (PSEN1) E280A kindred members, including mutation carriers randomized to active treatment or placebo and non‐carriers who receive placebo. Methods: Of the 252 enrolled, we present data on a total of 242 mutation carriers and non‐carriers matched by age range, excluding data on 10 participants to protect participant confidentiality, genetic status, and trial integrity. Results: We summarize demographic, clinical, cognitive, and behavioral data from 167 mutation carriers and 75 non‐carriers, 30 to 53 years of age. Carriers were significantly younger than non‐carriers ((mean age ± SD) 37 ± 5 vs 42 ± 6), had significantly lower Mini Mental Status Exam (MMSE) scores (28.8 ± 1.4 vs 29.2 ± 1.0), and had consistently lower memory scores. Discussion: Although PSEN1 E280A mutation carriers in the Trial are cognitively unimpaired, they have slightly lower MMSE and memory scores than non‐carriers. Their demographic characteristics are representative of the local population. [ABSTRACT FROM AUTHOR]

Introduction: Recruitment for Alzheimer's disease (AD) prevention research studies is challenging because of lack of awareness among cognitively healthy adults coupled with the high screen fail rate due to participants not having a genetic risk factor or biomarker evidence of the disease. Participant recruitment registries offer one solution for efficiently and effectively identifying, characterizing, and connecting potential eligible volunteers to studies. Methods: Individuals aged 55‐75 years who live in the United States and self‐report not having a diagnosis of cognitive impairment such as MCI or dementia are eligible to join GeneMatch. Participants enroll online and are provided a cheek swab kit for DNA extraction and apolipoprotein E (APOE) genotyping. Participants are not told their APOE results, although the results may be used in part to help match participants to AD prevention studies. Results: As of August 2018, 75,351 participants had joined GeneMatch. Nearly 30% of participants have one APOE4 allele, and approximately 3% have two APOE4 alleles. The percentages of APOE4 heterozygotes and homozygotes are inversely associated with age (P <.001). Discussion: GeneMatch, the first trial‐independent research enrollment program designed to recruit and refer cognitively healthy adults to AD prevention studies based in part on APOE test results, provides a novel mechanism to accelerate prescreening and enrollment for AD prevention trials. [ABSTRACT FROM AUTHOR]

Background: In Colombia, 13 pathogenic variants of presenilin 1 (PSEN1) causing Autosomal Dominant Alzheimer's Disease (ADAD) have been identified. Some cases have atypical presentations, with variability in the age of onset and course of the disease. We characterized clinical profiles of cognitively unimpaired PSEN1 E280A mutation carriers who progress to MCI or dementia in the API ADAD Colombia Trial. Method: The API ADAD Colombia Trial enrolled 252 cognitively unimpaired 30–60 year‐old participants into a 5‐8‐year double‐blind placebo controlled randomized prevention trial with a common close design. About 1/3 of participants were PSEN1 E280A mutation carriers who were randomized to the investigational anti‐oligomeric amyloid‐β antibody therapy crenezumab, 1/3 were mutation carriers who were randomized to placebo, and 1/3 were non‐carriers from the same kindred who were randomized to placebo. Trial results are pending. We used standardized procedures to blindly assess clinical features of participants who progressed to MCI and/or dementia during the trial, reviewed by an independent progression adjudication committee (PAC), to confirm the first instance of clinical progression. Result: During the trial 45 participants had an initial progression to MCI due to AD and 2 to dementia due to AD confirmed by the PAC. Among the 45 adjudicated with MCI due to AD, 32 subsequently progressed to dementia (30 due to AD and 2 due to other causes as determined by the site clinicians by consensus). The mean age onset of MCI was 45 (range 36–60 years) and of dementia was 47 (range 36–62 years). Three participants developed dementia before 40 years and one participant at 62 years. At the time of MCI, 43 participants had a predominantly amnesic profile, one had a predominantly behavioral disinhibition, and one had a Capgras syndrome, severe aggression and myoclonus. One participant developed severe global aphasia two years after the onset of dementia; two of the participant's first‐degree relatives had language impairment in conjunction with MCI; one developed primary progressive logopenic aphasia. Conclusion: Some persons with ADAD have an atypical clinical presentation. Additional studies are needed to clarify the biological changes, genetic/environmental risk factors, clinical course and response to treatment in these individuals. [ABSTRACT FROM AUTHOR]

Background: The Colombian kindred affected by the autosomal dominant AD causative mutation PSEN1 E280A are an invaluable population in determining the utility of blood biomarkers (BB) and how additional risk factors may affect BB years to decades prior to symptom onset. Neurofilament light (NfL) (Quiroz et al., 2020) and phospho‐tau 217 (p‐tau217) (Palmqvist et al., 2020) diverge about 20 years prior to onset of clinical symptoms in carriers compared to non‐carriers. How APOE4 carriage may influence NfL and p‐tau217 in the kindred is unknown. We assessed cross‐sectional effects of APOE4 carriage on plasma NfL and p‐tau217 in the PSEN1 E280A kindred. Method: We used a single molecule array immunoassay to quantify plasma NfL and a Meso Scale Discovery based plasma immunoassay to quantify p‐tau217. 1428 persons (age 18 to 75, mean 35.8, 23% APOE4 carriers, 54% PSEN1 E280A carriers) had available data for NfL analyses. A total of 612 persons (age 18 to 60, mean 35.9, 25% APOE4 carriers, 62% PSEN1 E280A carriers) had available data for p‐tau217 analyses. Age related trajectories were derived from cross‐sectional log‐transformed p‐tau217 and NfL concentrations modelled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method in E280A mutation and APOE4 carriage defined groups. The primary comparison was made between APOE4 carrier and noncarriers within E280A carriers and noncarriers separately. Result: In PSEN1 E280A mutation carriers, plasma NfL concentrations begin to differentiate those who were APOE4 carriers from non‐carriers at age 47.4 (figure 1). Plasma NfL concentrations did not differentiate APOE4 carriers versus non‐carriers in those without the PSEN1 E280A mutation though concentration of NfL trended higher in APOE4 carriers in the higher age range of the sample. Plasma p‐tau217 concentrations did not differentiate APOE4 carriers from non‐carriers in PSEN1 E280A mutation carriers or non‐carriers. Conclusion: APOE4 carriage results in accelerated NfL plasma increases in PSEN1 E280A mutation carriers starting at about the age of symptom onset. The inability to detect APOE4‐related ptau217 and NfL differences in the other groups may be related to the younger age of participants and limitations in statistical power. [ABSTRACT FROM AUTHOR]

Background: The impact of sex steroid hormones on Alzheimer's disease (AD) remains to be further clarified. Research suggests that shorter reproductive span, late menarcheal age, early menopause, oophorectomies and hysterectomies, are associated with increased dementia risk. We examined reproductive health and its associations with brain imaging and cognitive measurements in unimpaired female Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers from the Alzheimer's Prevention Initiative Autosomal Dominant AD (API ADAD) Trial (NCT01998841). Method: A total of 151 cognitively unimpaired 30‐53 year‐old females (101 PSEN1 mutation carriers and 50 non‐carriers) were included. Reproductive health data (i.e., menarcheal age, number of pregnancies, deliveries, miscarriages, and living children) from all participants were examined, as well as the extent to which menarcheal age was related to age‐adjusted baseline 1) cortical amyloid plaque burden (florbetapir PET), 2) Precuneus cerebral glucose metabolism (fluorodeoxyglucose PET), 3) hippocampal volume (3TMRI), and 4) the API ADAD preclinical cognitive composite score, which includes the MMSE Orientation score, CERAD Word List Delayed Recall and Constructional Praxis, Multilingual Naming Test and Raven's Progressive Matrices subset. We examined associations with the cognitive and brain imaging measures corrected for multiple comparisons (Bonferroni). Result: Carrier and non‐carrier females did not differ on number of pregnancies, deliveries, miscarriages, or living children. Female carriers had a significantly younger menarcheal age than non‐carriers (12.8 ±1.5 versus 13.7±1.6 years, p = 0.007, Bonferroni). Among carrier females, older menarcheal age was associated with lower scores on the Raven's test (Bonferroni: r = ‒0.28,p =0.035). Menarcheal age was not associated with scores on the cognitive composite or other individual subtests, or with brain imaging measures. Conclusion: Our findings suggest reproductive health data did not differ between carrier and non‐carrier females, except for a slightly younger menarcheal age compared to non‐carriers, and that menarcheal age may have a very limited impact on brain pathology and function at preclinical stages of ADAD. Longitudinal studies with larger samples are needed to clarify the extent to which earlier menarcheal age may be related to changes in cognitive function in mutation carrier females transitioning from preclinical to clinical stages. [ABSTRACT FROM AUTHOR]

Summary The Colombian Alzheimer's Prevention Initiative (API) Registry is a collaborative project among the Neurosciences Group of Antioquia, the Banner Alzheimer's Institute, and Genentech. The main goal is to provide a source of interested research participants and data to support the API-Colombia Autosomal Dominant Alzheimer's Disease Trial and help find treatments to delay or prevent the clinical onset of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The Alzheimer's Prevention Initiative (API) ADAD Colombia trial enrolled 252 cognitively unimpaired 30‐ 60‐year‐old Presenilin 1 (PSEN1) E280A mutation carriers and non‐carriers; carriers were randomized 1:1 to crenezumab or placebo, non‐carriers received placebo only. Crenezumab is an anti‐amyloid monoclonal antibody that binds beta‐amyloid (Aβ) oligomers that is hypothesized to prevent the buildup of pathogenic Aβ plaques and modify Alzheimer's disease (AD) progression with a low risk of amyloid related imaging abnormalities. The presentation will begin with a summary of the partnership between the Neurosciences Group of Antioquia and ADAD kindreds, including those who volunteered for the trial. Next will be a brief summary of the trial design and baseline participant characteristics, including the distribution of Aβ‐positive and ‐negative individuals, followed by the results for the co‐primary endpoints, change in cognitive function (using the API ADAD Cognitive Composite Test Battery) or episodic memory function (using the Free and Cued Selective Reminding Test); secondary efficacy results including time to clinical progression to MCI or dementia due to AD, time to Clinical Dementia Rating (CDR) score >0, and increase in CDR Sum of Boxes; other outcomes including FAST, NPI, MMSE, CERAD word recall and RBANS results; and safety and tolerability. Last will be a presentation of results for changes in Aβ, FDG and tau PET; volumetric brain MRI; CSF biomarkers; a preview of pending plasma biomarker data; and a brief summary of the historical context and strategic aims of API and the trial. There will be an interactive question and answer session. [ABSTRACT FROM AUTHOR]

Background: Due to the global SARS‐CoV2 pandemic it has been hard to conduct research, including research related to prevention of neurodegenerative diseases. The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) Colombia trial is being conducted in participants with family history of early‐onset dementia due to the PSEN1 E280A mutation who are cognitively unimpaired at baseline. Participants are enduring three stressors: 1) fear of developing dementia; 2) logistic changes to the study caused by the public health emergency due to the pandemic; and 3) concern about getting infected by SARS‐CoV2. Objective: To describe the frequency of new or exacerbated psychological disorders among the participants of the API ADAD Colombia trial assisted by a comprehensive mental health team during the COVID‐19 pandemic. Method: Participants in the API ADAD Colombia trial have free access to psychology and psychiatry services, either in person or through teleassistance, as well as psychoeducational offerings. These mental health services are provided by the site, outside of the study protocol, and are supported by Health and Social plans which were created to support participants' wellbeing during the trial. Descriptive statistics (mean, standard deviation and percentages) were used to analyze characteristics and frequency of mental health issues in the participants. Result: 66 participants (53 women, 80.3%) were treated by the Mental Health Team from March 1st, 2020 through December 31st, 2020. Mean age was 44.09 (SD 6.97) y.o. Before and after the pandemic onset, the most common psychological problems were anxiety (before 36.4%, after 63.6%) and depression (before 34.8 %, after 37.9%). From people who received psychological and psychiatric services, 70% vs. 81.6% felt that those services helped them, respectively. Among participants who received psychological vs. psychiatric assistance, 71.4% vs. 86.9% of patients with depression, 70.3% vs 75% of patients with anxiety and 60% vs 76.2% of patients with other disorders, felt the services helped them with these conditions. Conclusion: A comprehensive mental health program immersed in a trial to prevent or treat devastating diseases as dementia, could mitigate the psychological effects of the COVID‐19 pandemic in study participants. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Prevention Initiative (API) Generation Study 1 (NCT0256551) evaluated CAD106, an active immunotherapy against Aβ, in delaying the clinical onset of Alzheimer's disease in a cohort of cognitively unimpaired APOE4 homozygotes. Effect of CAD106 on brain amyloid burden after 2 years was measured by amyloid PET. Previous studies in mild AD showed that doses up to 450μg CAD106 induced sustained Aβ‐antibody response with no major safety concerns (Vandenberghe, 2017). Method: Cognitively unimpaired APOE4 homozygotes age 60‐75 were enrolled using a 5:3 randomization ratio (CAD106 450μg:placebo). Intramuscular injections were administered at 0, 6, 12 weeks and then quarterly with alum as adjuvant. PET scans were conducted at baseline and 2 years mainly with florbetapir. Standard uptake value ratios (SUVRs) were calculated using cortical composite region in reference to cerebellum and converted to centiloids. Result: Out of 65 randomized participants (42:23 CAD106:placebo) 59 were followed for 18 months or longer. Mean age at baseline was 65 years, 68% were female. Mean baseline RBANS total score was 106. Year 2 PET scans were acquired in 35 CAD106 and 16 placebo participants with centiloid mean baseline of 49.5 (38.7). CAD106 induced measurable Aβ‐specific IgG titers in all treated participants. Mean (SD) annualized centiloid change from baseline was +8.4 (6.7) on placebo without change with CAD106 ((‐0.9 (5.7), p<0.0001). The effect was more pronounced in amyloid positives: +9.4 (7.7) on placebo and ‐1.8 (6.0) with CAD106, vs in amyloid negatives: +6.7 (4.7) on placebo and +2.2 (2.8) with CAD106. In the CAD106 arm, the effect on PET correlated with antibody titers, especially for amyloid positive subgroup. Higher incidences for psychiatric (21% vs 13%) and general disorders / injection site (64% vs 22%) adverse events were reported with CAD106 vs placebo. Three cases of ARIA (2 ARIA‐H and 1 ARIA‐E) occurred on CAD106 (none on placebo). Cognition scores remained stable for 18 months in both groups. Conclusion: CAD106 is the first active immunotherapy shown to slow amyloid deposition in humans. Treatment with CAD106 might have a positive risk/benefit profile for prevention of amyloid deposition in high‐risk populations. [ABSTRACT FROM AUTHOR]

Background There is growing interest in the evaluation of preclinical Alzheimer's disease (AD) treatments. As a result, there is a need to identify a cognitive composite that is sensitive to track preclinical AD decline to be used as a primary endpoint in treatment trials. Methods Longitudinal data from initially cognitively normal, 70- to 85-year-old participants in three cohort studies of aging and dementia from the Rush Alzheimer's Disease Center were examined to empirically define a composite cognitive endpoint that is sensitive to detect and track cognitive decline before the onset of cognitive impairment. The mean-to-standard deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of cognitive tests/subtests drawn from the neuropsychological battery in cognitively normal participants who subsequently progressed to clinical stages of AD during 2- and 5-year periods, using data from those who remained unimpaired during the same period to correct for aging and practice effects. Combinations that performed well were then evaluated for representation of relevant cognitive domains, robustness across individual years before diagnosis, and occurrence of selected items within top performing combinations. Results The optimal composite cognitive test score comprised seven cognitive tests/subtests with an MSDR = 0.964. By comparison, the most sensitive individual test score was Logical Memory Delayed Recall with an MSDR = 0.64. Conclusions We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared with the most sensitive single test item to track preclinical AD decline and evaluate preclinical AD treatments. We are confirming the power of the composite in independent cohorts and with other analytical approaches, which may result in refinements, have designated it as the primary endpoint in the Alzheimer's Prevention Initiative's preclinical treatment trials for individuals at high imminent risk for developing symptoms due to late-onset AD. [ABSTRACT FROM AUTHOR]

Background: Some late‐onset Alzheimer's disease studies suggest that affective disorders begin before cognitive impairment and promote decline. Nevertheless, it has been observed that in Autosomal Dominant Alzheimer's Disease (ADAD), asymptomatic mutation carriers have a lower risk of disorders such as depression compared to non‐carriers. The relationship between affective disorders and Alzheimer's disease would be clearer if there were more studies in preclinical Alzheimer's disease. Currently, the biggest population of familial Alzheimer's disease, caused by the PSEN1 E280A mutation, is located in Colombia. The Alzheimer's Prevention Initiative (API) ADAD Colombia trial is being conducted with PSEN1 E280A carriers and non‐carriers, cognitively unimpaired at baseline. During screening, investigators asked about antecedents of mental health disorders. We examined whether asymptomatic mutation carriers reported a different rate of affective disorders compared to non‐carriers. Objective: To compare the prevalence of affective disorders between PSEN1 E280A mutation carriers and non‐carriers at the time of API ADAD trial screening. Method: We performed a retrospective analysis to understand the history of affective disorders (reported by participants), after screening 315 mutation carriers and non‐carriers aged 30 ‐60 years. The comparison between carriers and non‐carriers was made by a generalized linear regression model. Results were adjusted by age, gender, educational level and the Clinical Dementia Rating (CDR) scale. Odds ratios (OR) were used as measure of association, with a 95% confidence interval (95%CI). Result: 315 candidates underwent screening: 210 carriers and 105 non‐carriers. Of people with antecedent of affective disorders, 65 (30.9%) were mutation carriers and 32 (30.5%) were non‐carriers. Comparing carriers with non‐carriers, the OR for depression was 1.010 (95%CI 0.492 – 2.113) and for anxiety was 1.325 (95%CI 0.485 – 3.938). Results were similar after excluding 15 participants with CDR of 0.5. Conclusion: Although there were no differences between groups, the prevalence of affective disorders through life was high in carriers and non‐carriers, compared to the adult Colombian population (30.8% vs 6.7%). Possible reasons include: 1) Concern about having a family with an elevated risk of AD; 2) observing the progressive decline of close relatives; 3) living with or caring for persons with dementia. [ABSTRACT FROM AUTHOR]

Background: The Colombia Alzheimer's Prevention Initiative (API) Registry was a resource for enrollment into the API Colombia clinical trial. Potentially eligible candidates from the Colombia API Registry went through a prescreening and then in‐person screening process with the goal of enrolling them in the API ADAD Colombia Trial. Analysis of screening data might provide additional information to consider for other AD prevention trials. We present descriptive screening data from the API ADAD Colombia trial in Presenilin 1 (PSEN1) E280A mutation carriers vs non‐carriers. Method: Consent was obtained from 319 potentially eligible participants after prescreening. Screening data from 315, including 210 mutation carriers, were used to compare demographics, medical comorbidities, toxic and reproductive antecedents, selected clinical, functional, and anthropometric measurements, vital signs, and brain MRI and laboratory results in the mutation carrier and non‐carrier groups. Descriptive statistics comparing mutation carriers and non‐carriers were performed using generalized linear regression models using link function according to whether the outcome was categorical or numerical. Results were adjusted for age, sex, level of education, depression or body mass index (BMI) depending upon which measurements were compared. Result: Results of the above characteristics at screening for carriers and non‐carriers will be presented. Briefly, compared to mutation non‐carriers in screening, carriers were younger (mean 40 vs 48 years), had similar educational attainment (mean 8.3 vs 7.5 years), and showed generally lower cognitive performance, especially in memory (e.g., mean (sd) CERAD world list scores were 20.30 (3.82) vs 19.46 (3.68), respectively). There were no differences in other demographic characteristics, medical comorbidities, toxic and reproductive antecedents, anthropometric measurements, vital signs, MRI findings or laboratory results. Mutation non‐carriers compared to carriers showed a non‐significant trend towards more vascular risks according to medical comorbidities (hypertension, dyslipidemia), borderline higher level of triglycerides and cholesterol, microvascular changes in the brain and higher BMI. The higher prevalence of vascular risk factors among non‐carriers may be explained by an 8‐year age difference between non‐carriers vs carriers. Conclusion: The API ADAD Colombia Trial screening data provide insights into demographics as well as clinical, cognitive and non‐cognitive characteristics, and medical comorbidities of a (PSEN1) E280A population. [ABSTRACT FROM AUTHOR]

Background: Delays in finding the right research participants can result in studies taking longer to deliver, often requiring funding extensions and ultimately limit the effectiveness of research and evaluation when study samples are insufficient for robust analysis and generalisation of findings. Recruitment challenges in dementia research are a global issue. Method: To improve the effectiveness and efficiency of participant recruitment efforts in dementia research, innovative digital platforms have emerged over the past ten years: TrialMatch, Alzheimer's Prevention Registry & GeneMatch, and Brain Health Registry (USA), Join Dementia Research (UK), Hersenonderzoek (Netherlands), and StepUp for Dementia Research (Australia). Established in 2019, a global collaborative of these platforms aims to generate new insights and evidence that can help further enhance the service provision and potentially support other similar global initiatives. This paper provides an overview and comparison of the platforms, including key successes and challenges in their service delivery. Result: TrialMatch was the first platform developed to support recruitment processes in 2010. To date, collectively, the seven platforms have over 920,000 volunteer members; >50% of them had opportunities to take part in studies as a result. The services are mostly free and rely on government grants and/or philanthropic funding for their delivery. They share common features (e.g., matching volunteer demographic and clinical information with studies) although some collect and use more detailed genetic and clinical profiles than others. Examination of the matching mechanisms and volunteer data access processes across the platforms suggests various opportunities to enhance the platforms. Key outcomes of these platforms also include a positive change in the way the public perceives dementia research and a systematic way for the public to engage in research. Understanding social and economic impact and ensuring sustainability of the platform and its service delivery are crucial steps for the future. Conclusion: The seven digital platforms have been showing their power and potential impact not only in fast‐tracking dementia research but also in improving public engagement and participation. Through this global partnership, the members share practices and strategies for sustainability of the programs that can contribute to the development of 'good' sustainable models for dementia research recruitment services. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer's Prevention Initiative (API) is a collaborative program conducting preclinical Alzheimer's disease (AD) trials in people who are at elevated risk of developing AD symptoms. To support these and other trials, we developed the web‐based Alzheimer's Prevention Registry ("APR") program to provide resources to the AD scientific community, aiming to accelerate recruitment and enrollment into studies and complement local efforts. Method: Adults age 18+ are eligible to join APR at www.endALZnow.org. At enrollment, individuals provide their name, email address, zip/postal code and year of birth; after enrollment they provide additional demographic information at their convenience with the option to select "prefer not to answer." The APR team works with researchers to promote AD‐focused studies to members via its website and email. APR members receive email communication for engagement purposes and are notified when new study opportunities are available. Members interested in a study fill out an online contact form with their name, email address and phone number, review and acknowledge the study's eligibility criteria and authorization for APR to share their contact information with the enrolling study team. The APR team provides enrolling studies with a secure dashboard for tracking referrals. Result: The APR launched in May 2012; as of January 2020, >347,000 have joined. APR members have a mean age of 63.3 years (SD 11.7), are predominately female (75%), self‐report being cognitively unimpaired (94%), and 50% report a family history of AD/dementia. To date, the APR has promoted 82 AD‐focused studies, results from which will be presented. Only anecdotal enrollment metrics are available prior to the launch of the online contact form, however web‐traffic metrics that are available from our promotions of online studies (e.g., TRC‐PAD, Brain Health Registry) suggest >16,000 APR members expressed interest in joining these studies. The 6‐month pilot phase of the online contact form included 7 studies and referred 320 APR members. Conclusion: Enrollment into the APR continues to increase, as does the number of studies the APR promotes to its members. We are exploring novel approaches for increasing enrollment and engagement of members, and collaborating with researchers and sponsors to help promote studies in their communities. [ABSTRACT FROM AUTHOR]

Background: We developed the web‐based Alzheimer's Prevention Registry (APR) program to provide resources to the AD scientific community, aiming to accelerate recruitment and enrollment into studies and to complement local efforts. Considerable efforts have been given to strengthening retention and engagement of APR members over time, regardless of whether they enroll in an AD study. Methods: Adults age 18+ are eligible to join the APR at www.endALZnow.org. At enrollment, individuals provide their name, email address, zip/postal code and year of birth; after enrollment they provide additional demographic information. Immediately after enrollment members begin receiving APR emails welcoming and orienting them to the APR. The APR sends members monthly newsletters and study opportunity announcements via email for engagement and retention purposes. We developed a 4‐part re‐engagement campaign for members who either have not opened an APR email within 6 months or fall below our engagement scoring model. If a member does not act on a re‐engagement email, then APR removes them from its email distribution list. Only "actively engaged" members remain on the APR email distribution list. Results: The APR has enrolled >347,000 members since its launch in 2012. As of January 2020, 86,175 people are considered "actively engaged" members of the APR. In 2019, 12 monthly e‐newsletters were sent to APR members. The average e‐newsletter open rate was 45% (compared to nonprofit healthcare industry average of 16%); and the average e‐newsletter click rate (percentage of APR members who clicked on the email in relation to those who opened/viewed the email) was 24% (compared to the industry average of 1.6%). In 2019, 36 study opportunity emails were sent to APR members with similar open and click rates. To date, approximately 54,000 members have been added to the re‐engagement campaign, and nearly 10,000 (18.5%) have been successfully re‐engaged. Conclusion: Deploying online engagement campaigns as a retention tool is a valuable resource for the APR. Thoughtfully engaging and re‐engaging APR members promotes increased likelihood of email opens and clicks when study opportunities are offered. Future work will examine the relationship between email engagement and responsiveness to study opportunities. [ABSTRACT FROM AUTHOR]

Background: We developed GeneMatch in 2015 to assist enrollment into Alzheimer's disease (AD) prevention studies by enriching referrals based in part on APOE4 genotype. The API Generation Program, which enrolled cognitively unimpaired (CU) APOE4 carriers ages 60‐75 was the first multisite clinical trial to use GeneMatch as a recruitment source. Method: GeneMatch is a US‐based, trial‐independent recruitment program of the Alzheimer's Prevention Registry (APR), conducting APOE testing in CU individuals aged 55‐75. GeneMatch does not disclose APOE results to participants directly, however, results are used to match participants to enrolling studies in a manner that does not inadvertently disclose genotype. Participants are notified by email when they have been invited to a study. A reminder email is sent 7 days later, a letter is mailed to the participant's home 2mo after if no response is received. Once a participant accepts his/her invitation, their contact information is shared with their preferred study site through an online portal. In July 2016, GeneMatch began inviting participants to the Generation Program. Result: To date, >90,000 people have joined GeneMatch, > 30% are APOE4 carriers. Recruitment in the Generation Program and treatment with umibecestat was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function. At that time, 16,521 GeneMatch participants had been invited to the Generation Program, 33% (5,461) of whom accepted their invitations. Of those who accepted, 2,202 consented to the Generation Program (randomization data not yet available), 292 were scheduled for screening, 511 were awaiting scheduling for screening, 242 were waiting to be contacted by their selected study site, 1,209 were found to be ineligible after a phone screen by sites, 695 were no longer interested, and 310 were lost to follow‐up. Conclusion: The Generation Program was on track to complete enrollment in 2019 and GeneMatch was a successful program in helping to recruit APOE4 carriers. Lessons learned include the importance for GeneMatch to coordinate with study sites to ensure they are prepared to receive referrals Future analyses will examine success of GeneMatch (vs. other recruitment sources) for randomization. [ABSTRACT FROM AUTHOR]

Background: Growing evidence suggests that females have greater biological risk for Alzheimer's disease (AD). As levels of AD pathology increase, females show greater tau accumulation, faster hippocampal volume loss, and faster cognitive decline than males. We sought to investigate sex differences in individuals with preclinical autosomal dominant AD (ADAD), who are destined to develop early‐onset dementia and have minimal age‐related confounds known to vary by sex (e.g., mortality, cardiovascular disease, or menopause). We plan to examine the role of sex in the associations among markers of pathology, neurodegeneration, and cognition leveraging baseline data from the Alzheimer's Prevention Initiative (API) ADAD Colombia Trial. Methods: We analyzed baseline data from 242 cognitively unimpaired 30‐53 year‐old prevention trial participants, including 167 PSEN1 E280A mutation carriers and 75 non‐carrier family members. Clinical ratings, CERAD word list delayed recall, hippocampal grey matter volume, florbetapir cortical‐to‐pontine standard‐uptake value ratios (SUVR), and precuneus 18F‐fludeoxyglucose (FDG) positron emission tomography were included in the analyses. T‐tests and multiple regressions models controlling for age, PSEN1 mutation status and amyloid burden were conducted. Results: Across groups, females had greater hippocampal volumes (p=.05) and better delayed recall (p=.005) than males. Female carriers were younger than male carriers (p=.04). Females continued to have better delayed recall after adjusting for glucose metabolism in the precuneus (Sex: β=.562, p=.023), and showed a trend towards significance after adjusting for hippocampal volumes (Sex: β=.462, p=.059). In carriers only, as age increased, males had lower hippocampal volumes than females (Slope difference: p ≤.05), while no differences were found in amyloid levels or metabolism. There was no sex difference in the relationship between amyloid accumulation, hippocampal volumes (Sex: β=.000, p=.094), and metabolism (Sex: β=‐.004, p=.815). Conclusion: Findings suggest that cognitively unimpaired female mutation carriers may have greater cognitive resilience to AD‐related neurodegeneration compared to male mutation carriers. Further investigation of sex‐specific differences in AD‐related clinical and pathological markers is key to inform AD detection, prevention, and development of treatments. [ABSTRACT FROM AUTHOR]

Background: Recruitment in the API Generation program and treatment with umibecestat were terminated in July 2019 after detection of an early signal of mild worsening in some measures of cognitive function with umibecestat. Participants were followed to assess the reversibility of these and other observed effects. We will summarize the key clinical results for umibecestat vs placebo during treatment and follow up. Method: Following randomization to umibecestat or placebo, clinical assessments were scheduled at month 3, month 6 and every 6 month thereafter. After discontinuation of study medication, participants underwent a full evaluation within 3 months of the last dose. Data will be presented for visits on‐ and off‐treatment. For visits off‐treatment, results will be compared for visits occurring before vs after wash‐out of umibecestat (> 31 days after last dose). Analysis of cognitive scales in relation to age, sex, genotype and amyloid status, and a safety summary will also be presented. Result: At termination about 650 participants had reached week 26. The final evaluation was performed on most of the 1561 ongoing participants (45% after wash‐out). Worsening was detected in a group‐level comparison at month 3 and month 6 in both studies for the two doses of umibecestat (effect size 0.2‐0.3 for RBANS Total, Immediate and Delayed Memory indices). Analysis from the visits conducted after wash‐out indicated that key cognitive findings seen before wash‐out were reversible: we saw no more between‐group differences in RBANS and no more imbalance in the proportion of participants having a >14‐point decrease in total RBANS or > 1‐point increase in CDR‐SB after wash‐out. Similar findings were also seen in homozygotes without elevated amyloid. Conclusion: The negative effect of umibecestat vs placebo on RBANS and CDR‐SOB was detected as early as month 3 and was detectable throughout the treatment period, but was no longer present after wash‐out of umibecestat. This effect seems to be independent of the presence of brain amyloid. Confirmation of the contemporary reversibility of worsening in measures of cognition is an important result to inform development of future prevention therapies for Alzheimer's disease (AD). [ABSTRACT FROM AUTHOR]

Background: In addition to early mild non‐progressive cognitive worsening, BACE inhibitors have been associated with early non‐progressive reductions in hippocampal and whole brain volume in trial participants with elevated amyloid (A+, Egan et al, 2019). We have begun to evaluate the effects of umibecestat treatment and discontinuation on cognitively unimpaired amyloid‐positive (A+) and A‐ APOE4 homozygotes and A+ heterozygotes, testing the hypotheses that BACE inhibitor‐related hippocampal and whole brain shrinkage is apparent soon after treatment initiation, non‐progressive, limited to A+ participants, and reversible following discontinuation. Method: The API Generation Program had begun to evaluate umibecestat in 1,623 cognitively unimpaired 60‐75 year‐old participants including 921 A+ APOE4 heterozygotes and 702 homozygotes (A+ or A‐).Following randomization, volumetric brain MRIs were scheduled at month 6, month 12 and then annually. After discontinuation of study medication, participants continued to be assessed under double‐blind conditions, and MRIs were acquired within 3 months after the last dose. We investigated 6‐month hippocampal and whole brain volume changes and their relationship to RBANS immediate, delayed and total memory score changes; and we plan to investigate the persistence or reversibility of these changes within 3 months of discontinuation after study completion in Q2 2020. Result: Umibecestat was associated with significant 6‐month hippocampal and whole brain shrinkage in the aggregate APOE4 homozygote and A+ heterozygote group, but not in the A‐ homozygotes. While an early non‐progressive worsening in RBANS immediate, delayed, and total memory scores (Graf et al, AAIC 2020 submitted) was seen in the overall population as well as in A‐ HMs, we failed to demonstrate any significant association between brain shrinkage and cognitive worsening in the overall group (R2 coefficient <0.1) in the active treatment group for any of the visits (on‐ and off‐ treatment). Conclusion: BACE inhibitor‐related brain shrinkage appears to be early, non‐progressive, related to pre‐existing amyloid plaque burden, and unrelated to its cognitive worsening. Pending findings will help to clarify the extent to which it is also reversible. Together, our cognitive and MRI findings could help to assess potential benefits versus risks of BACE inhibitors in future prevention trials. [ABSTRACT FROM AUTHOR]

Background: The Alzheimer Prevention Initiative (API) Generation Program evaluated the effectiveness of the BACE1 inhibitor, umibecestat, and the active immunotherapy, CAD106, in delaying the onset of AD symptoms in APOE4 carriers. The Generation Program included two studies implemented in 23 countries at 207 sites. Recruitment in the program and treatment with umibecestat was terminated in July 2019 after detecting an early signal of mild worsening in some measures of cognitive function with umibecestat. We will summarize the baseline characteristics of participants in the Generation Program. Method: Treatment duration was planned for 5‐8 years in two double‐blind, placebo‐controlled, parallel design studies (Lopez Lopez et al., 2019) in cognitively unimpaired participants aged 60‐75 years, at risk for onset of clinical symptoms due to AD. Generation Study 1 (NCT0256551) recruited APOE4 homozygotes (HMs) while Generation Study 2 (NCT03131453) enrolled both HMs as well as APOE4 heterozygotes (HTs) if they also had elevated brain amyloid (assessed by either PET and/or CSF). Both studies included a 12‐week screening phase starting with genotyping. Amyloid testing was the last screening assessment performed before randomization. Result: Among the 9623 participants recruited, more than 2700 completed the 12‐week Screening phase with amyloid testing. Approximately 27% were HMs. About 60% of HMs and 35% of HTs had elevated brain amyloid. A total of 1623 participants were randomized: 478 to Generation Study 1 (all HMs) and 1145 to Generation Study 2 (including 20% HMs and 80% HTs with elevated amyloid). Education, sex, family history of AD, clinical scales (including MMSE, RBANS total score and indices, CDR sum of boxes, and ECog), brain volumes and amyloid status will be shown. Scores from cognitive scales will be presented by sex, genotype (E4/E4, E3/E4, E2/E4), age group and amyloid status. Conclusion: The Generation program collected a broad set of parameters for the world's largest cohort of cognitively unimpaired APOE4 carriers. Baseline characteristics of participants enrolled in the Generation Program were consistent with the target population at risk for AD. Findings in relation to genotype, age, sex and amyloid status will be discussed. [ABSTRACT FROM AUTHOR]

Background: The API Generation Program consists of two trials: Generation Studies 1 and 2. Generation Study 1 enrolled cognitively unimpaired APOE4 homozygotes (HMs) ages 60‐75; Generation Study 2 enrolled cognitively unimpaired APOE4 carriers (HMs and heterozygotes (HTs), HTs had to have elevated brain amyloid). To address the unique challenges with recruitment of this population, we developed a multifaceted approach to maintaining engagement with sites and sharing best practices for recruitment among study site teams. Method: We designed a flexible menu of novel recruitment tactics and implemented strategies, some of which were country‐specific, and collaborated with site teams on a regular basis. We conducted individualized "recruitment planning and implementation" calls with sites soon after they were activated, traveled to sites for in‐person meetings, held regional and country‐wide workshops and roundtable meetings, bi‐monthly study coordinator calls, and monthly media training calls. In addition, we developed an online recruitment and retention toolkit to provide a one‐stop shop for sites to review available, IRB approved materials that could be ordered and customized to meet their site‐specific needs. In the US, we consulted with UsA2 for cultural competency to develop a tip sheet for minority community engagement, postcards, ads, and brochures specific to the Latino and African American communities near study sites. Result: Recruitment was terminated in July 2019 after an early signal of mild worsening in some measures of cognitive function with umibecestat. At the time the program closed, 35,333 participants had come to a study site for genetic testing, 9,623 screened and 1,626 were randomized. 50% of activated sites had enrolled at least five participants between both studies. Despite the unprecedented challenges for recruitment of cognitively normal APOE4 HMs and HTs, we were on target to complete enrollment by end of 2019. Results from specific engagement and recruitment strategies, along with characteristics of high enrolling sites, will be presented. Conclusion: Collaboration between study sponsor and site teams and the development of flexible recruitment plans and materials that can be adapted to meet sites' needs played a crucial role in the successful recruitment, enrollment, and retention of participants for the API Generation Program. [ABSTRACT FROM AUTHOR]

Background: Research registries have been developed as a strategy to accelerate enrollment into Alzheimer's disease studies. However, there remains a need to increase both total enrollment and diversity of race and gender among registry enrollees and study participants. The goal of this study was to learn how enrollees describe registries with a focus on identifying preferred terminology in order to improve outreach and recruitment efforts. Method: Individuals enrolled in two registries (Penn Memory Center Brain Health Research Registry and Banner Alzheimer's Institute Alzheimer's Prevention Registry) were invited to complete an anonymous online survey. Items included demographic characteristics and open‐ended questions about how they would describe a brain health research registry. Data were collected December 2020 through January 2021 from 1,741 respondents who completed the survey. Respondents were primarily non‐Hispanic White (75.8%) and female (58.4%). To ensure diverse representation in the analysis and allow comparisons by race and gender, equally sized (n=49) random samples of respondents (Hispanic/Latinx; non‐White; non‐Hispanic White females; non‐Hispanic White males) were selected for coding and analysis in NVivo. The University of Pennsylvania IRB approved this study. Results: Respondents use a wide range of terminology to describe registries ("pool," "bank of names," "roster," "clearinghouse," "gathering place," "database," "hub of communication," "compendium," "online community") and the people enrolled in them ("volunteers," "participants," "members of the public," "willing," "interested"). Some describe participation as providing basic contact information, while others note features such as bloodwork, genetic tests, and periodic online tests and surveys. Respondents describe registries as allowing them to find, be notified of, or "matched" to studies. They frequently discuss registries as contributing to scientific knowledge and aiding development of preventions, treatments, and/or cures. Some also indicate that registries keep them informed about brain health. Voluntariness and data protection/privacy are mentioned less frequently. A small portion gave vague responses, indicated that they did not know what a registry is, or did not answer. Conclusion: Terms and concepts that respondents use to describe registries vary and differ from those typically used by researchers. Applying respondent‐driven language and notions to outreach and recruitment efforts may facilitate more diverse and representative registry enrollment. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD) disproportionately affects Latinx and Black individuals, yet they are underrepresented in AD studies. Recruitment challenges for these populations limit generalizability of findings. The purpose of this 2020 study was to improve an existing online AD participant registry to optimize recruitment of Latinx and Black individuals. Refinements were geared toward recruitment on mobile devices, as research suggests mobile‐first approaches may be more successful within these populations. Method: We used an iterative, mixed methods approach to improve the registry with 45‐75‐year‐old Latinx and Black individuals who self‐reported no mild cognitive impairment, dementia, or AD diagnoses. Strategies included (in order): four focus groups (n=39); an online survey to assess attitudes and acceptability toward the existing registry (n=677); usability testing of existing registry (n=40); development of a refined registry prototype; qualitative (n=24) and quantitative (n=392) usability testing of refined prototype; a final online survey to assess attitudes and acceptability toward refined prototype (n=769). To assess acceptability of registry improvements, quantitative and qualitative data from the initial and final surveys were compared. Result: There was an increase between the surveys in the percentage of Latinx and Black respondents who agreed that: they would likely sign up for the registry (48.2% to 54.1% and 42.1% to 53.4%); the registry was designed with people like them in mind (54.4% to 63.0% and 50.1% to 61.2%); and most of their family and friends would relate to the registry (41.2% to 51.9% and 36.8% to 49.4%). Survey participants responded favorably to specific content in the refined registry (e.g., discussing challenges of recruiting Latinx and Black individuals for AD studies and showing diversity of program staff). Qualitative responses in the final survey included that the refined registry was easy to understand and navigate, and was trustworthy. Nearly half of respondents (49.4%) said they would be likely to sign up for the registry using their smartphone or tablet. Conclusion: Refinements to an online study recruitment registry aimed at improving participation among traditionally underrepresented populations were successful at increasing acceptability and sign‐up intentions. These findings have important implications regarding reaching underrepresented populations for participation in AD studies. [ABSTRACT FROM AUTHOR]

Background: Registries have been proposed as a novel way to identify accelerate recruitment for Alzheimer's disease prevention clinical trials. However, the role of registries in real‐world clinical settings remains largely unknown. Registry enrollment involves a combination of local site promotion of the registry as well as social media and advertising efforts to encourage participation. This manuscript explores one site's experience with GeneMatch, a novel genetic registry for Alzheimer's disease research. Method: Referrals from GeneMatch to the site were tracked to understand the demographics of those referred and ultimate research enrollment decisions. Using the site's existing recruitment database, referrals were cross‐referenced for prior research contact, to better understand the role of GeneMatch in the context of existing recruitment efforts. Result: There were a total of 86 GeneMatch referrals to the site, which ultimately resulting in 54 individuals coming into the site to pursue research involvement further. The majority of referrals (52/86, 60.47%) did not have prior contact with the site about recruitment interest, and having such contact did not predict likelihood of ultimately signing a research consent. Conclusion: GeneMatch helped identify new individuals for participation in AD prevention studies. These results highlight the value of continuing local site‐level efforts while also taking advantage of registries to enhance research recruitment. Ongoing efforts to develop novel strategies for outreach and engagement are still needed. [ABSTRACT FROM AUTHOR]