Preclinical Alzheimer's Disease Trials Research Articles

Community recruitment of underrepresented populations to the AHEAD 3-45 preclinical AD trial using novel partnerships with nursing and community-based organizations: Lessons and outcomes.

Alzheimer's disease (AD) disproportionately affects minoritized populations who remain underrepresented in AD trials. We partnered with local nursing community-based organizations to implement a culturally tailored educational intervention and recruit Hispanic/Latino American, Filipino American, and Korean American adults aged 55 to 80 for the AHEAD study, a preclinical AD trial, at the University of California, Irvine. We engaged 654 individuals across 21 events, leading to 71 prescreenings: 21.1% Filipino, 11.2% Hispanic/Latino, and 67.6% Korean adults. Ineligibility due to age and language barriers was common among Hispanic/Latino and Korean adults, respectively. Filipino adults often withdrew interest or were lost to follow-up. Ultimately, 25 participants enrolled: eight Filipino, two Hispanic/Latino, and 15 Korean adults. Tailored, culturally relevant content significantly contributed to the engagement success. This study demonstrates the value and impact of novel partnerships with health-related provider organizations that provide trusted care and access to underrepresented communities. Six hundred and fifty fourunderrepresented individuals were reached, and 25 enrolled in the AHEAD 3-45 trial. Twenty-one community events were held via partnerships with nursing and community organizations. The study engaged 21% Filipino, 11% Hispanic/Latino, 68% Korean adults. Community-Based Participatory Research (CBPR) principles enhanced the recruitment process. Transparent communication and joint planning were key.

Reasons for undergoing amyloid imaging among diverse enrollees in the A4 study.

Understanding attitudes toward participation among diverse preclinical Alzheimer's disease (AD) trial participants could yield insights to instruct future recruitment. Using data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study, we examined differences among mutually exclusive racial and ethnic groups in views and perceptions of amyloid imaging (VPAI), a measure of motivations to undergo amyloid biomarker testing in the setting of preclinical AD. We used linear regression to quantify differences at baseline. Compared to non-Hispanic or Latino (NH) White participants, Hispanic or Latino (3.52 points, 95% confidence interval [CI]: [2.61, 4.42]); NH Asian (2.97 points, 95% CI: [1.71, 4.22]); and NH Black participants (2.79 points, 95% CI: [1.96, 3.63]) participants demonstrated higher levels of endorsement of the VPAI items at baseline. Differences may exist among participants from differing ethnic and racial groups in motivations to undergo biomarker testing in the setting of a preclinical AD trial. Representative samples in AD clinical trials are vital to result in generalizability. We assessed motivations to undergo amyloid imaging in a preclinical AD trial. Racial and ethnic minority groups showed higher endorsement of VPAI items. Differences were driven by perceived risk, plan/prepare, and curiosity domains. Few observations among racial and ethnic groups changed after biomarker disclosure.

Racial and ethnic differences in plasma biomarker eligibility for a preclinical Alzheimer's disease trial.

In trials of amyloid-lowering drugs for Alzheimer's disease (AD), differential eligibility may contribute to under-inclusion of racial and ethnic underrepresented groups. We examined plasma amyloid beta 42/40 and positron emission tomography (PET) amyloid eligibility for the ongoing AHEAD Study preclinical AD program (NCT04468659). Univariate logistic regression models were used to examine group differences in plasma and PET amyloid screening eligibility. Of 4905 participants screened at time of analysis, 1724 were plasma eligible to continue in screening: 13.3% Hispanic Black, 24.7% Hispanic White, 20.8% non-Hispanic (NH) Asian, 24.7% NH Black, and 38.9% NH White. Plasma eligibility differed across groups in models controlling for covariates (odds ratio from 1.9 to 4.0 compared to the NH White reference group, P<0.001). Among plasma eligible participants, PET eligibility did not differ by group. These results suggest that prevalence of brain amyloid pathology differed, but that eligibility based on plasma was equally effective across racial and ethnic group members. Plasma amyloid eligibility is lower in underrepresented racial and ethnic groups. In plasma eligible adults, positron emission tomography eligibility rates are similar across race and ethnicity. Plasma biomarker tests may be similarly effective across racial and ethnic groups.

Post-disclosure distress among racial and ethnic groups in a preclinical AD trial.

Trialists need a thorough understanding of whether reactions to Alzheimer's disease (AD) biomarker information differ among racial and ethnic groups in preclinical AD trials. We used data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease Study to analyze cognitively unimpaired participants' responses on the Impact of Event Scale (IES) 24 to 72hours after amyloid disclosure. We fit a linear regression model to test whether mean IES scores differed among participants from specific racial and ethnic groups. We considered potential effect modification by amyloid status. Reactions to disclosure did not significantly differ among participant groups based on self-reported race and ethnicity. Although the results were not significant when stratified by amyloid status, all racial and ethnic groups except for participants self-reporting Hispanic/Latino ethnicity were observed to have higher mean IES in the elevated amyloid group. These results support continued use of current disclosure methods in preclinical AD trials.

Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations.

Alzheimer's disease (AD) staging criteria lack standardized, empirical description. Well-defined AD staging criteria are an important consideration in protocol design, influencing a more standardized inclusion/exclusion criteria and defining what constitutes meaningful differentiation among the stages. However, many trials are being designed on the basis of biomarker features and the two need to be coordinated. The Alzheimer's Association Research Roundtable (AARR) Spring 2021 meeting discussed the implementation of preclinical AD staging criteria, and provided recommendations for how they may best be incorporated into clinical trials research. Discussion also included what currently available tools for global clinical trials may best define populations in preclinical AD trials, and if are we able to differentiate preclinical from clinical stages of the disease. Well-defined AD staging criteria are key to improving early detection, diagnostics, clinical trial enrollment, and identifying statistically significant clinical changes, and researchers discussed how emerging blood biomarkers may help with more efficient screening in preclinical stages.

Preclinical Alzheimer Disease and the Electronic Health Record: Balancing Confidentiality and Care.

Because information technologies are increasingly used to improve clinical research and care, personal health information (PHI) has wider dissemination than ever before. The 21st Century Cures Act in the United States now requires patient access to many components of the electronic health record (EHR). Although these changes promise to enhance communication and information sharing, they also bring higher risks of unwanted disclosure, both within and outside of health systems. Having preclinical Alzheimer disease (AD), where biological markers of AD are identified before the onset of any symptoms, is sensitive PHI. Because of the melding of ideas between preclinical and "clinical" (symptomatic) AD, unwanted disclosure of preclinical AD status can lead to personal harms of stigma, discrimination, and changes to insurability. At present, preclinical AD is identified mainly in research settings, although the consensus criteria for a clinical diagnosis may soon be established. There is not yet adequate legal protection for the growing number of individuals with preclinical AD. Some PHI generated in preclinical AD trials has clinical significance, necessitating urgent evaluations and longitudinal monitoring in care settings. AD researchers are obligated to both respect the confidentiality of participants' sensitive PHI and facilitate providers' access to necessary information, often requiring disclosure of preclinical AD status. The AD research community must continue to develop ethical, participant-centered practices related to confidentiality and disclosure, with attention to sensitive information in the EHR. These practices will be essential for translation into the clinic and across health systems and society at large.

Plasma p-tau181/Aβ1-42 ratio predicts Aβ-PET status and correlates with CSF-p-tau181/Aβ1-42 and future cognitive decline.

In Alzheimer's disease (AD), plasma amyloid beta (Aβ)1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown. Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. The p-tau181/Aβ1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86-0.95) and in CN (AUC = 0.873; 0.80-0.94), and symptomatic (AUC = 0.908; 0.82-1.00) adults. Plasma p-tau181/Aβ1-42 ratio correlated with cerebrospinal fluid (CSF) p-tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74-0.89). The p-tau181/Aβ1-42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes (P < 0.0001). Plasma p-tau181/Aβ1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials.

Reasons for undergoing amyloid imaging among cognitively unimpaired older adults.

ObjectivesPreclinical Alzheimer’s disease (AD) clinical trials screen cognitively unimpaired older adults for biomarker criteria and disclose their results. We examined whether participants in the Anti‐Amyloid Treatment in Asymptomatic Alzheimer’s disease Study with “elevated” and “not elevated” amyloid differed in scores on the “Views and Perceptions of Amyloid Imaging” questionnaire. We hypothesized that, prior to disclosure, those with elevated amyloid would score higher than those with not elevated amyloid. We also quantified how responses changed after result disclosure.MethodsWe assessed data from 4327 individuals who completed the questionnaire at screening visit 1 and after amyloid disclosure. We used linear regression models to assess the relationship between questionnaire category scores and amyloid status. We also quantified the relationship between category score changes and amyloid status.ResultsOverall, participants scored altruism and contribution to research as the strongest motivations for undergoing amyloid imaging. Those with elevated amyloid scored 0.23 points higher in the Perceived Risk category, on average, than those who had not elevated amyloid prior to disclosure; this effect attenuated towards zero after adjusting for Cognitive Function Instrument score. After disclosure, participants with elevated amyloid demonstrated less within‐subject change in Perceived Risk, on average, compared to those with similar pre‐disclosure scores who had not elevated amyloid, while demonstrating greater changes in the altruism and planning categories.InterpretationAltruism and learning disease risk motivated enrollment in this preclinical AD trial. Participants with elevated amyloid differed from their not elevated counterparts in their perceptions of amyloid imaging, even before undergoing the procedure.

Disparities by Race and Ethnicity Among Adults Recruited for a Preclinical Alzheimer Disease Trial

Underrepresentation of many racial/ethnic groups in Alzheimer disease (AD) clinical trials limits generalizability of results and hinders opportunities to examine potential effect modification of candidate treatments. To examine racial and ethnic differences in recruitment methods and trial eligibility in a multisite preclinical AD trial. This cross-sectional study analyzed screening data from the Anti-Amyloid in Asymptomatic AD study, collected from April 2014 to December 2017. Participants were categorized into 5 mutually exclusive ethnic/racial groups (ie, Hispanic, Black, White, Asian, and other) using participant self-report. Data were analyzed from May through December 2020 and included 5945 cognitively unimpaired older adults between the ages of 65 and 85 years screened at North American study sites. Primary outcomes included recruitment sources, study eligibility, and ineligibility reasons. To assess the probability of trial eligibility, regression analyses were performed for the likelihood of being eligible after the first screening visit involving clinical and cognitive assessments. Screening data were included for 5945 participants at North American sites (mean [SD] age, 71.7 [4.9] years; 3524 women [59.3%]; 5107 White [85.9%], 323 Black [5.4%], 261 Hispanic [4.4%], 112 Asian [1.9%], and 142 [2.4%] who reported race or ethnicity as other). Recruitment sources differed by race and ethnicity. While White participants were recruited through a variety of sources, site local recruitment efforts resulted in the majority of Black (218 [69.2%]), Hispanic (154 [59.7%]), and Asian (61 [55.5%]) participants. Participants from underrepresented groups had lower mean years of education (eg, mean [SD] years: Hispanic participants, 15.5 [3.2] years vs White participants, 16.7 [2.8] years) and more frequently were women (226 [70.0%] Black participants vs 1364 [58.5%] White participants), were unmarried (184 [56.9%] Black participants vs 1364 [26.7%] White participants), and had nonspousal study partners (237 [73.4%] Black participants vs 2147 [42.0%] White participants). They were more frequently excluded for failure to meet cognitive inclusion criteria (eg, screen failures by specific inclusion criteria: 147 [45.5%] Black participants vs 1338 [26.2%] White participants). Compared with White participants, Black (odds ratio [OR], 0.43; 95% CI, 0.34-0.54; P < .001), Hispanic (OR, 0.53; 95% CI, 0.41-0.69; P < .001), and Asian participants (OR, 0.56; 95% CI, 0.38-0.82; P = .003) were less likely to be eligible after screening visit 1. Racial/ethnic groups differed in sources of recruitment, reasons for screen failure, and overall probability of eligibility in a preclinical AD trial. These results highlight the need for improved recruitment strategies and careful consideration of eligibility criteria when planning preclinical AD clinical trials.

Gene- and age-informed screening for preclinical Alzheimer's disease trials.

Elevated β-amyloid is used to enroll individuals into preclinical Alzheimer's disease trials, but the screening process is inefficient and expensive. Novel enrichment methods are needed to improve efficiency of enrollment. Alzheimer's disease incidence rates and a polygenic hazard score were used to create a gene- and age-defined ADAge. An ADAge cutpoint was chosen to optimally predict β-amyloid positivity among clinically normal Alzheimer's Disease Neuroimaging Initiative participants and applied to an independent Alzheimer's Disease Research Center validation cohort. The impact of ADAge enrichment on screening costs was evaluated in the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease trial data. In the validation cohort, the ADAge-enriched sample had a higher proportion of individuals with elevated β-amyloid (difference [95% CI] 0.19[0.07 to 0.33]) than the unenriched sample. ADAge enrichment lowered screening costs by $4.41 million (31.00%) in the real-world clinical trial scenario. ADAge enrichment provides for a more efficient and cost-effective means to enroll clinically normal individuals with elevated β-amyloid in clinical trials.

WHY IS THE STUDY PARTNER REQUIREMENT A BARRIER TO RECRUITMENT IN PRECLINICAL ALZHEIMER’S DISEASE TRIALS?

Alzheimer's disease (AD) clinical trials, including preclinical trials that enroll cognitively unimpaired participants with biomarker evidence of AD, require co-enrollment of a participant and a study partner. We previously found that the study partner requirement is among the most important barriers to preclinical trial recruitment and that this barrier may be greater in trials that require biomarker disclosure compared to trials that do not. This study examines why the study partner requirement is a barrier to enrollment in preclinical trials. We are conducting a mixed methods in-person interview study with 200 cognitively unimpaired participants, ages 60 to 85, recruited from the University of California, Irvine Consent-to-Contact Registry. We review example preclinical AD trial consent forms and then ask open-ended and forced choice questions to elucidate attitudes toward participation, including assessment of positive and negative associations with the study partner requirement. We collect participant demographics and responses to the AD Knowledge Scale, Risk for AD Scale, and Research Attitudes Questionnaire. To elucidate the study partner barrier, we will use a proportional odds model regressing the ordinal level of agreement for a statement that the study partner requirement reduces probability of enrollment upon the reported level of agreement for varying statements related to the study partner (Table 1). We will perform content analyses for themes and correlations and summary analyses from quantitative survey items. We will present participant reported availability of a study partner for preclinical AD trials and the frequency of positive and negative associations with the study partner requirement. We will explore potential covariate relationships with study outcomes, including overall willingness to enroll in a preclinical AD trial.

PARTICIPANT AND INFORMANT PREDICTION AND IDENTIFICATION OF COGNITIVE IMPAIRMENT IN PRE-CLINICAL ALZHEIMER’S DISEASE: IMPLICATIONS OF INFORMANT RELATIONSHIP

Alzheimer's disease (AD) trials require enrollment of a participant and an informant. In preclinical AD trials, participants are cognitively unimpaired, raising questions of whether informants or participants provide more insight into participant cognition and whether the additional benefit of informant information differs by informant type. We used data from the Alzheimer's Disease Cooperative Study (ADCS) Prevention Instrument Project, a 48-month longitudinal study of cognitively unimpaired participants aged 75 years and older, to compare participant and informant ability to predict the cognitive performance of the participant. We used the Cognitive Function Instrument (CFI) to represent assessment of the participant's cognition and an altered version of the modified ADCS Preclinical Alzheimer's Cognitive Composite (mADCS-PACC) as an objective measure of cognition (Table 1). Random forests stratified by cognitive status and informant type (including mMMSE, CDR-SB, ethnicity, sex, cardiovascular disease, age, and education), were used to assess how well participants and informants predict cross-sectional and future cognitive status. When using baseline CFI scores to predict mADCS-PACC, participants performed better than their informants. In cross-sectional analyses, informant and participant CFI performed similarly. Dyad type impacted this relationship. Among spousal dyads, informant baseline CFI better predicted mADCS-PACC scores in years three and four. Among non-spousal dyads, participant baseline CFI better predicted future scores. In the fourth year, among spousal dyads in the lowest mADCS-PACC quartile, the observed variable importance (oVI) associated with participant baseline CFI was 0.13 (95%CI: 0.11, 0.14), compared to 0.19 (95%CI: 0.18, 0.21) for informant baseline CFI. Among non-spousal dyads, the oVI for participant baseline CFI was 0.37 (95%CI: 0.35, 0.41) compared to 0.07 (95%CI: 0.06, 0.11) for informant CFI. In cross-sectional models, oVI was 0.08 (95% CI: 0.07, 0.09) for participant and 0.21 (95% CI: 0.19, 0.23) for informant CFI among spousal dyads and 0.17 (95% CI: 0.16, 0.18) for participant and 0.10 (95% CI: 0.09, 0.11) for informant CFI among non-spousal dyads.

Constructing a Local Potential Participant Registry to Improve Alzheimer's Disease Clinical Research Recruitment.

Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer's disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries.

Recruiting to preclinical Alzheimer's disease clinical trials through registries

Participant registries are repositories of individuals who have expressed willingness to learn about studies for which they may be eligible. Registries are increasingly being used to improve recruitment to preclinical Alzheimer's disease (AD) clinical trials, which require large screening efforts to identify adequate numbers of participants who meet enrollment criteria. Recruiting to preclinical AD trials from registries is made more efficient through registry collection of data that permits exclusion of those who will not be eligible and identifies individuals most likely to qualify for trials. Such data could include self-reported disease family history or other risk factors but could also include cognitive, genetic, or biomarker testing outcomes. Few data are available to guide investigators overseeing registries and important ethical questions are likely to arise related to their conduct, especially in registries collecting AD risk information. This article outlines three areas of consideration for registry investigators: informed consent, disclosure, and sponsorship.

Collaboration for Alzheimer's Prevention: Principles to guide data and sample sharing in preclinical Alzheimer's disease trials

Collaboration for Alzheimer's Prevention: Principles to guide data and sample sharing in preclinical Alzheimer's disease trials

Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer's disease clinical trials

Preclinical Alzheimer's disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with 1 of 2 hypothetical informed consent forms (ICFs) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials.

CAP--advancing the evaluation of preclinical Alzheimer disease treatments.

If we are to find treatments to postpone, reduce the risk of, or completely prevent the clinical onset of Alzheimer disease (AD), we need faster methods to evaluate promising preclinical AD treatments, new ways to work together in support of common goals, and a determination to expedite the initiation and performance of preclinical AD trials. In this article, we note some of the current challenges, opportunities and emerging strategies in preclinical AD treatment. We describe the Collaboration for Alzheimer's Prevention (CAP)-a convening, harmonizing and consensus-building initiative to help stakeholders advance AD prevention research with rigour, care and maximal impact-and we demonstrate the impact of CAP on the goals and design of new preclinical AD trials.

Establishing Composite Cognitive Endpoints for Use in Preclinical Alzheimer's Disease Trials.

Establishing Composite Cognitive Endpoints for Use in Preclinical Alzheimer's Disease Trials.

Researchers Test Strategies to Prevent Alzheimer Disease

Adecadeofdisappointingclinical trial results for Alzheimer disease (AD)modifying therapies in people suggests that treatment should be targeted at earlier stages in the disease—even before overt symptoms arise. Profoundbrain alterations—such as accumulation of the protein fragment called beta-amyloid—are found 10 to 20 years beforedementiaorevenmildcognitive impairment isdiagnosed.Alzheimerdisease investigators estimate that by the time memory begins to erode and other cognitive problems emerge, too much damage has occurred in thebrain to be reversedby the experimental treatments. In response to this idea, researchers havemovedtowarddesigningtrialsof therapies to delay or prevent the onset of AD in cognitivelyhealthybutat-riskvolunteers.As a number of researchers noted, because there may well be differences between people with early-onset AD and those with sporadic, late-onset disease, it will be crucial to carry out these studies in different risk groups. Several such trials, referred to variously as secondary prevention trials or preclinical or presymptomatic treatment trials, are either under way now or will begin soon. These trials emerged from a unique collaborative effort among AD researchers. In 2012, 3 prevention initiatives—Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4), Dominantly Inherited Alzheimer Network (DIAN), and Alzheimer’s Prevention Initiative (API)—formed an umbrella group called the Collaboration for Alzheimer’s Prevention to maintain a regular dialogue among themse lves as wel l as wi th regulatory groups, stakeholders, and pharmaceutical representatives as they plan and implement preclinical treatment trials. “An even modestly effective preclinical treatment could have a profound public health effect,” noted Eric Reiman, MD, of the Banner Alzheimer’s Institute, Phoenix, Arizona, and co-director of the API. “It’s been commonly cited that since AD risk doubles every 5 years after the age of 65, if we could delay the onset of AD by only 5 years without increasing lifespan we could reduce disease frequency by half,” said Reiman. “And the goal is to do even better than that.” Several of the preclinical AD trials will test investigational antiamyloid treatments inat-riskpatientsbefore thediseasehas ravaged thebrain. The trialswill useagents that targetvarioustoxic formsof theamyloidprotein. Many researchers think this approach will provide a better test of the amyloid hypothesis—which holds that buildup of amyloid is a primary driver of AD—because the