Alzheimer's Trials Research Articles

Diversity in Phase 2 and Phase 3 Placebo‐Controlled, Double‐Blind, Lecanemab and Elenbecestat Early Alzheimer’s Disease Studies

AbstractBackgroundIncreasing diversity in clinical trials is a scientific, public health, and ethical imperative. Clinicians need to understand how a drug works in representative disease populations, diverse communities need access to clinical trials, and social justice demands addressing health and healthcare disparities. Several factors contribute to underrepresentation among racial and ethnic groups in Alzheimer’s disease (AD) clinical trials, including barriers to enrollment but also potential differential exclusion based on eligibility criteria.MethodWe evaluated enrollment in four double blind placebo‐controlled clinical trials in early AD that incorporated highly similar enrollment criteria (NCT03887455, NCT01767311, NCT02956486, NCT03036280). We assessed the impact of eligibility criteria. Racial and ethnic information were self‐reported by participants and are reported as mutually exclusive categories. Each trial incorporated PET or CSF to evaluate brain amyloid pathology, as well as typical inclusion and exclusion criteria used in early AD trials.ResultAcross the trials, 10,805 US participants were screened: 889 (8%) were of Black race, 119 (<1%) were of Asian race, and 2,883 (27%) were of Hispanic ethnicity. 2,459 participants were randomized, including 97 (4%) of Black race, 17 (<1%) of Asian race, and 450 (18%) of Hispanic ethnicity. Overall, 23% of those screened were randomized: 27% of non‐Hispanic White participants compared to 11% of Black race participants, 14% of Asian race participants, and 16% of Hispanic ethnicity participants. The distribution of age and disease stage (MCI or mild AD) among screened and randomized participants were similar across the racial and ethnic groups. Females appeared to be more highly represented among Black race and Hispanic ethnicity participants, compared to non‐Hispanic White participants. Five inclusion and exclusion criteria, including AD biomarker criteria, resulted in greater than 60% of screen failures across the trials, with some variability in specific eligibility criteria across racial and ethnic groups.ConclusionEarly AD clinical trials have high rates of screen failure and exploration of potential differential screen failure among racial and ethnic groups will be important to future trial design choices.

Development of Novel Partial Mitochondrial Complex I Inhibitors as a Therapy for Alzheimer Disease.

AbstractBackgroundConsistent failure of clinical trials for Alzheimer Disease (AD) emphasizes the necessity to identify novel therapeutic targets for this debilitating condition. We recently identified the mitochondrial complex I (MCI) as a small molecule druggable therapeutic target for AD.MethodUsing rational design and extensive structure‐activity relationship studies, we developed novel classes of partial MCI inhibitors with high selectivity, specificity, safety, and drug‐like properties. Target engagement, selectivity and specificity of new compounds were established using multiple in vitro assays, including surface plasmon resonance (SPR), competitive and direct binding, proteomics and pull down experiments. Using these techniques, we developed new lead compound C458 that was interrogated in in vivo efficacy studies in APP/PS1 mice.ResultWe demonstrated that the new lead C458 directly binds to MCI. A single dose administration of C458 to mice or treatment of primary mouse neurons activates AMPK‐a, Akt, autophagy, Sirtuins 1 and 3, and upregulates PGC‐1a leading to enhanced mitochondrial biogenesis. C458 has excellent oral bioavailability, blood–brain‐barrier penetrance, and was remarkably clean in the 250 kinase and CEREP 44 safety panels. Chronic administration of C458 (25 mg/kg/day in drinking water ad lib) to APP/PS1 mice for 6 months starting at pre‐symptomatic stage did not cause detectable side effects, and resulted in cognitive protection, improved long‐term potentiation, and decreased oxidative stress and inflammation. Furthermore, APP/PS1 mice treated with C458 showed a significant increase in glucose uptake and utilization in the brain detected with a translational in vivo biomarker FDG‐PET, as well as an enhancement of ATP production measured in vivo using 31P NMR.ConclusionMechanistic studies confirmed that C458 treatment triggered mitochondrial stress response augmenting mitochondrial biogenesis, anti‐oxidant signaling, and cellular energetics that ultimately restored energy brain homeostasis, leading to cognitive protection in a mouse model of AD. Our studies demonstrate that modulation of MCI activity using novel specific MCI inhibitors improves bioenergetics in the brain and averts cognitive decline representing novel therapeutic approach for AD.

Allowing “rescue therapy” in preclinical Alzheimer’s trials

AbstractBackgroundAduhelm’s recent approval, and the potential approval of additional effective therapies in early (prodromal‐to‐mild) Alzheimer’s disease (AD), will impact the conduct of clinical trials, including trials designed to delay or prevent cognitively unimpaired participants from progressing to mild cognitive impairment (MCI) or AD dementia. Allowing “rescue therapy” with these approved therapies during preclinical AD trials (“treatment policy design”) is expected to increase participation and improve adherence in these very large and long clinical trials. Our goal was to evaluate the impact of allowing “rescue therapy” on the study power using simulation.MethodIn the simulated study, cognitively unimpaired elderly adults with elevated levels of beta‐amyloid were randomized 1:1 to the control arm (starting on placebo and initiating “rescue therapy” upon progression to Clinical Dementia Rating [CDR] scale score > 0) or to the experimental arm (same experimental treatment throughout the study).Key simulation parameters (placebo decline and variance) were based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other cohort data. The continuous endpoint was Preclinical Alzheimer’s Cognitive Composite (PACC) scores. The triggering event to allow the start of “rescue therapy” was progression to CDR > 0. A range of different study design parameters (study duration, magnitude and timing of treatment effect, and continuous outcome vs time to event) were explored.ResultPreliminary simulation results indicated that allowing “rescue therapy” had limited impact on the study power/sample size. They also suggested that continuous endpoints provided more power compared with a time‐to‐event endpoint in this setting.ConclusionThis initial simulation study suggests that clinical trials of subjects in preclinical or at‐risk stages of AD that allow rescue medications during the trial may retain adequate power, with a limited impact on sample size, when analyzed with a primary treatment policy estimand. The potential benefit of the “treatment policy” approach in terms of recruitment and adherence/engagement cannot yet be quantified but could be substantial.

Considering sex in mild‐to‐moderate Alzheimer’s disease clinical trials: A meta‐analysis of ADCS trials

AbstractBackgroundNearly two thirds (62%) of Alzheimer’s disease (AD) patients in the United States are women (Nebel 2018; Rajan, 2021). Our goal in this project was to assess whether women are proportionately represented in AD clinical trials and whether sex was associated with other baseline patient characteristics.MethodsWe used data from nine mild‐to‐moderate AD trials conducted by the AD Cooperative Study (ADCS): Docosahexaenoic acid (DHA), FYN Kinase, Homocysteine, Huperzine (Hu), IV immunoglobulin (IVIg), nonsteroidal anti‐inflammatory drugs (NSAIDs), Resveratrol (Res), Simvastatin, Valproate. Sample sizes ranged from 120 (Res) to 642 (IVIg) participants. We compared the proportions of females enrolled to disease prevalence estimates. We conducted a random effects meta‐analysis to estimate female participation rates across the nine trials. Specifically, we used a generalized linear mixed effects model with logit link and random intercept to estimate the marginal and trial specific prevalence of female participants. To compare participant characteristics by sex we pooled samples across trials and used unadjusted chi‐square (categorical variables) and t‐tests (continuous variables).ResultsThe proportion of females enrolled exceeded 50% in each trial, with the exception of the FYN Kinase trial (44.7%). In all but the Hu trial, the rate of female enrollment was less than the estimated female disease prevalence. The estimated prevalence of female participants across all trials was estimated to be 56% (95% CI 0.53 to 0.58) (Figure 1). Females were similar to males in terms of age and APOE genotypes. Compared to males, females had lower education, less often enrolled with a spouse, less often lived with their study partner, and more often were from an underrepresented racial or ethnic group.ConclusionsThough these trials recruited more females than males, on average, women were still underrepresented compared to national disease prevalence estimates. Female and male participants exhibited psychosocial differences in education, race, and study partner characteristics that could affect trial outcomes and should be further investigated.

Strategies for diverse participant recruitment to a preclinical Alzheimer’s Disease prevention trial: The AHEAD study

AbstractBackgroundImproving the demographic diversity of clinical trial participants, including preclinical Alzheimer’s disease (AD) trial participants, is a scientific, social, and ethical imperative.MethodThe AHEAD Study is an ongoing preclinical AD trial evaluating the efficacy of lecanemab (BAN2401) in biological and cognitive disease progression in cognitively unimpaired biomarker eligible individuals ages 55‐80. The study has an overall goal of at least 15% randomizations from underrepresented populations. The AHEAD Recruitment and Retention Workgroup designed a comprehensive and collaborative recruitment plan tailored to increase diverse participation.ResultRecruitment strategies spanned central infrastructure and national initiatives, existing trial ready cohorts, enhanced site engagement, community outreach, and whenever possible, implementation of evidence‐based tactics. Central infrastructure includes a national call center, a study website with capacity for prescreening and site referral, including priority flags for underrepresented groups at the pre‐screener level; establishment of a website dedicated to Spanish speakers; and implementation of blood‐based screening across all sites and targeted communities. Site engagement approaches include disbursement of specialized funding to support local recruitment efforts tailored to diverse populations and the development of partnerships with community organizations or across sites within a region. Outreach activities, at the national, regional, and local level, include earned media and social media campaigns and award‐winning plays and videos surrounding themes of participation of diverse groups in clinical trials. Throughout, additional funding opportunities enable testing of innovative approaches and novel partnerships for recruitment of underrepresented groups at individual sites. Evaluation and additional support of these initiatives will be based on number of underrepresented participants pre‐screened, screened, and randomized in the study.ConclusionFocused, multipronged approaches and sustainable partnerships with demographically diverse communities are required to promote the participation of underrepresented groups into preclinical AD trials like AHEAD. Our initiatives demonstrate the commitment to increase recruitment of underrepresented groups by supporting successful efforts centrally, at the site‐level and the participant level using a combination of traditional and modern recruitment approaches.

Examining the Use and Value of Applied Skills Assessment for the Training of Cognitive Measures in Alzheimer’s Disease (AD) Trials

AbstractBackgroundThere are many potential variables that may confound trial results; Sadler, et al. (2017) supported use of Rater Training as an effective method to improve the reliability and accuracy of endpoint measures. Consistent administration and scoring of cognitive assessments are critical to the success of AD trials.MethodThis analysis examines the benefits of implementing an Applied Skills Assessment (ASA) component to standardized Rater Training programs across multiple AD trials. Data was collected from four trials, Phase II and POC, with raters of varying education and experience levels. A detailed review of conceptual knowledge was followed by an Applied Skills Assessment. The ASA required each rater to demonstrate their proficiency with administering a critical cognitive measure for each respective study (such as the Alzheimer’s Disease Assessment Scale‐Cognitive Subscale (ADAS‐Cog), Mini Mental State Examination (MMSE), Hopkins Verbal Learning Test‐Revised (HVLT‐R) and the Severe Impairment Battery (SIB)). Each ASA was evaluated by highly experienced and trained members of a clinical assessment team with immediate feedback delivered.ResultData was acquired from 314 raters of various education and experience levels across eight different countries. Following the detailed conceptual knowledge review, 62% of raters demonstrated errors during the Applied Skills Assessment. There was no notable difference identified across educational degree however there was a dispersion across experience level. It was found that 50% of errors demonstrated were made by raters who reported 0–5 years of Alzheimer’s research experience. Improved performance was observed among raters in the categories of 6–10 years and >10 years of Alzheimer’s Research Experience with a lower rate of error of 22% and 28%, respectively.ConclusionResults support the value in implementing an applied skills exercise to enhance the Rater Training programs for cognitive assessments. Khan (2016) suggests that rater performance tends to significantly improve with re‐training and feedback which applies across various experience levels. A training involving the evaluation of a rater’s applied performance, that includes feedback by a skilled assessor, may prove to be instrumental in contributing to the enrollment of appropriate study participants and achievement of high‐quality reliable endpoint data in Alzheimer’s Disease research.

Cohort effects in mild to moderate AD trials: an empirical assessment utilizing data from the Alzheimer’s disease cooperative study

AbstractBackgroundHeterogeneity in patient populations can impact clinical trial conclusions and generalizability. Long recruitment windows may exacerbate this in Alzheimer’s disease (AD) trials, which often recruit over extended periods.MethodWe used data from 8 Alzheimer’s Disease Cooperative Study (ADCS) clinical trials (DHA, Homocysteine, Huperzine, Intravenous Immunoglobulin, Resveratrol, Valproate, NSAIDs, and FYN Kinase inhibitor) in patients with mild to moderate AD to investigate cohort effects by time‐of‐trial‐enrollment.For each participant, we assigned a study‐ and site‐specific enrollment time defined as the number of days between a patient’s screening and the first screening visit at the site. We used study‐ and site‐specific time origins to account for calendar time differences between studies and, within a study, differences in site times to activation.To investigate differences in baseline characteristics, we split our sample into tertiles by enrollment time and compared sex, race and ethnicity, age, years of education, and baseline scores on the Alzheimer’s Disease Assessment Scale ‐ Cognitive Subscale (ADAS‐Cog).To assess cohort effects on trial outcomes, we used the 12‐month within‐subject change in ADAS‐Cog. We regressed the 12‐month change in ADAS‐Cog on a patient’s enrollment time while controlling for their baseline score and demographic information and allowing for clustering between patients in the same study.ResultGroups were demographically similar at baseline across enrollment tertiles. We found a significant difference in 12‐month change in ADAS‐Cog for patients with different enrollment times: later enrolled patients had an expected 12‐month change in ADAS‐Cog 0.146 points higher than similar patients who enrolled one quarter (91.2 days) earlier (95% CI: 0.082‐0.210). This magnitude of difference was roughly on par with an additional year of education. We also found a negative relationship with age, with older patients tending to experience a smaller 12‐month decline.ConclusionIn these 8 trials, we found minimal evidence of cohort effects that would meaningfully change study generalizability or treatment effect. Future analyses will account for the overall pace of accrual in the trials and assess for potential differential effects in fast vs. slow‐accruing studies.

Disease progression model using the integrated Alzheimer's Disease Rating Scale.

An Alzheimer's disease (AD) dementia disease progression model was developed based on the integrated Alzheimer's Disease Rating Scale (iADRS). Data from 3483 placebo participants in six AD trials were used to develop the disease progression model with NONMEM (version 7.4.2) and examined for mild cognitive impairment, and mild and moderate dementia due to AD. Baseline iADRS score was significantly influenced by AD symptomatic medication use, EXPEDITION2 enrollment (included moderate AD participants), age, and baseline Mini-Mental State Examination (MMSE) score. Rate of disease progression increased across disease stage and was significantly influenced by AD medication use, age, and baseline MMSE score. Apolipoprotein E ε4 carrier status did not influence baseline iADRS score or disease progression. These results demonstrate a disease progression model describing the time course of the iADRS across the AD severity spectrum. This model can assist future clinical trials in study design optimization and treatment effect interpretation. A disease progression model described the integrated Alzheimer's Disease Rating Scale (iADRS) time course in mild cognitive impairment to moderate Alzheimer's disease. Using the linear regression model, iADRS scores can be calculated for Mini-Mental State Examination scores. Results can help optimize future clinical trial design and aid in understanding treatment effects.

Effect of Aducanumab Approval on Willingness to Participate in Preclinical Alzheimer's Disease Trials.

Clinical trials now test promising therapies in the preclinical stages of Alzheimer's disease (AD). Participant willingness to enroll in different types of preclinical AD trials is understudied and whether the FDA approval of aducanumab affected these attitudes is unknown. To evaluate preferences toward three preclinical AD trial scenarios and whether the FDA approval of aducanumab changed willingness to participate among potential trial participants. Through an electronic survey, we asked enrollees in a recruitment registry age 50-79 to rate their willingness (using a 6-point Likert scale) to enroll in three hypothetical preclinical AD trial scenarios: an in-clinic infused monoclonal antibody intervention, a home-infused monoclonal antibody intervention, and an oral BACE inhibitor intervention. We administered the survey before and after the FDA approval of aducanumab. We used a generalized estimating equation model to assess group differences in preference for the trial scenarios. We used a paired t-test to determine if willingness to participate (using total willingness across three scenarios as the outcome) changed after the FDA decision. At baseline, the mean participant willingness was highest in the in-clinic infusion scenario. There was no significant change in willingness to participate, overall, after the FDA decision. Participants who were independently aware of the FDA's decision (prior to the second survey) demonstrated reduced willingness to participate; participants unaware of the FDA decision demonstrated no change. Willingness to participate in preclinical AD trials may have been negatively affected by the FDA's decision to approve aducanumab among those aware of the decision.

You've Got a Friend in Me: How Cognitively Unimpaired Older Adults Select a Study Partner to Participate with Them in Alzheimer's Disease Research.

Participants in Alzheimer's disease (AD) prevention studies are generally required to enroll with a study partner; this requirement constitutes a barrier to enrollment for some otherwise interested individuals. Analysis of dyads enrolled in actual AD trials suggests that the study partner requirement shapes the population under study. To understand if individuals can identify someone to serve as their study partner and whether they would be willing to ask that individual. We conducted semi-structured interviews with cognitively unimpaired, English-speaking older adults who had previously expressed interest in AD research by signing up for a research registry. We also interviewed their likely study partners. Audio-recorded interviews were transcribed and coded in an iterative, team-based process guided by a content analysis approach. We interviewed 60 potential research participants and 17 likely study partners. Most potential participants identified one or two individuals they would be willing to ask to serve as their study partner. Interviewees saw value in the study partner role but also understood it to entail burdens that could make participation as a study partner difficult. The role was seen as relatively more burdensome for individuals still in the workforce or with family responsibilities. Calls from the researcher to discuss the importance of the role and the possibility of virtual visits were identified as potential strategies for increasing study partner availability. Efforts to increase recruitment, particularly representative recruitment, of participants for AD prevention studies should reduce barriers to participation by thoughtfully designing the study partner role.

Quantitative systems pharmacology model of the amyloid pathway in Alzheimer's disease: Insights into the therapeutic mechanisms of clinical candidates.

Despite considerable investment into potential therapeutic approaches for Alzheimer's disease (AD), currently approved treatment options are limited. Predictive modeling using quantitative systems pharmacology (QSP) can be used to guide the design of clinical trials in AD. This study developed a QSP model representing amyloid beta (Aβ) pathophysiology in AD. The model included mechanisms of Aβ monomer production and aggregation to form insoluble fibrils and plaques; the transport of soluble species between the compartments of brain, cerebrospinal fluid (CSF), and plasma; and the pharmacokinetics, transport, and binding of monoclonal antibodies to targets in the three compartments. Ordinary differential equations were used to describe these processes quantitatively. The model components were calibrated to data from the literature and internal studies, including quantitative data supporting the underlying AD biology and clinical data from clinical trials for anti-Aβ monoclonal antibodies (mAbs) aducanumab, crenezumab, gantenerumab, and solanezumab. The model was developed for an apolipoprotein E (APOE) ɛ4 allele carrier and tested for an APOE ɛ4 noncarrier. Results indicate that the model is consistent with data on clinical Aβ accumulation in untreated individuals and those treated with monoclonal antibodies, capturing increases in Aβ load accurately. This model may be used to investigate additional AD mechanisms and their impact on biomarkers, as well as predict Aβ load at different dose levels for mAbs with known targets and binding affinities. This model may facilitate the design of scientifically enriched and efficient clinical trials by enabling a priori prediction of biomarker dynamics in the brain and CSF.

Plasma Phosphorylated Tau at Threonine 181 and Neuropsychiatric Symptoms in Preclinical and Prodromal Alzheimer Disease.

Plasma phosphorylated tau at threonine 181 (p-tau181), a well-validated marker of Alzheimer disease (AD) pathologic change, could be a more efficient way to diagnose AD than invasive or expensive biomarkers requiring CSF or PET. In some individuals, neuropsychiatric symptoms (NPS) are the earliest manifestation of AD, observed in advance of clear cognitive decline. However, the few studies assessing AD biomarkers in association with NPS have often had imprecision in capturing behavioral symptoms that represent sequelae of neurodegenerative disease. Thus, the mild behavioral impairment (MBI) construct was developed, framing NPS in a way to improve the precision of risk estimates for disease. MBI core criteria stipulate that NPS emerge de novo in later life and persist for at least 6 months. Here, cross-sectionally and longitudinally, we investigated associations of MBI with p-tau181, neuropsychological test performance, and incident AD. Cognitively unimpaired and mild cognitive impairment (MCI) Alzheimer's Disease Neuroimaging Initiative participants were selected. MBI status was derived from the Neuropsychiatric Inventory (NPI) using a published algorithm. NPI total scores at baseline and year 1 visits were used to operationalize MBI (score >0 at both visits), NPS not meeting the MBI criteria (NPS-not-MBI, score >0 at only 1 visit), and no NPS (score = 0 at both visits). Linear regressions were fitted for cross-sectional analyses; multilevel linear mixed-effects and Cox proportional hazards models were implemented to examine the longitudinal associations of MBI with changes in p-tau181 and cognition and incident dementia. The sample included 571 participants (age 72.2 years, 46.8% female, 64.8% MCI). Cross-sectionally (β = 8.1%, 95% CI 1.4%-15.2%, p = 0.02), MBI was associated with higher plasma p-tau181 levels compared with no NPS; NPS-not-MBI was not. Longitudinally, MBI was associated with higher p-tau181 (β = 0.014%, 95% CI 0.003-0.026, p = 0.02), in addition to a decline in memory and executive function. Survival analyses demonstrated a 3.92-fold greater dementia incidence in MBI, with no significant differences between NPS-not-MBI and no NPS. These findings extend the evidence base that MBI is associated with elevated risk of cognitive decline and dementia and a sequela of emerging Alzheimer-related proteinopathies. MBI offers a substantial improvement over current approaches that explore behavior as a proxy marker for Alzheimer-related proteinopathies, with both clinical and AD trial enrichment implications.

Ethical Frameworks for Disclosure of Alzheimer Disease Biomarkers to Research Participants: Conflicting Norms and a Nuanced Policy.

More and more frequently, clinical trials for Alzheimer disease (AD) are targeting cognitively unimpaired individuals who are at increased risk of developing the disease. It is not always clear whether AD biomarker information should be disclosed to research participants: on the one hand, research participants may be interested in learning this information because of its perceived utility, but on the other hand, learning this information may be harmful, as there are very few effective preventive or therapeutic options available for AD. In this article, we bring together three separate sets of ethical guidance literature: on the return of individual research results, on an individual's right to access personal data, and on transparent enrollment into clinical trials. Based on these literatures, we suggest policies for the disclosure of AD biomarker test results in longitudinal observational cohort studies, clinical trials, and hybrid research projects, such as the European Prevention of Alzheimer's Dementia (EPAD) project, in which we served as an ethics team. We also present and critically discuss recommendations for disclosure of AD biomarkers in practice. We underscore that, as long as the clinical validity of AD biomarkers remains limited, there are good reasons to avoid actively disclosing them to cognitively unimpaired research participants.

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.

A Visual Interpretation Algorithm for Assessing Brain Tauopathy with 18F-MK-6240 PET.

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.

Why a clinical trial is as good as its outcome measure: A framework for the selection and use of cognitive outcome measures for clinical trials of Alzheimer's disease.

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.

Effects of dose change on the success of clinical trials

The search for disease modifying therapies in Alzheimers disease (AD) has recently led to promising results but also revealed design issues in clinical trials themselves. Of particular importance is the potential statistical challenges that can arise when dosages change after an interim analysis, which is not uncommon in contemporary AD trials. Following the recent Aducanumab trials, we sought to study the implications of dose changes on the statistical power of an AD trial. We conducted extensive simulations to calculate statistical power when the relationship between treatment effect size and time is linear or non-linear, and the investigated drug has delayed treatment effect or not. Statistical power depends on many design factors including the dose change time, correlation, population homogeneity, and treatment effect time. We recommend that researchers conduct simulation studies at the interim analysis to justify the modified sample size and/or follow-up time modification meanwhile the type I and II error rates are controlled.

An Elicitation Study to Understand Black, Hispanic, and Male Older Adults' Willingness to Participate in Alzheimer's Disease-Focused Research Registries.

There is a lack of racial, ethnic, and sex diversity in recruitment research registries and Alzheimer's disease (AD) research studies and trials. Theory-based recruitment messages may provide an opportunity to increase study participant diversity in AD research studies and trials. To identify behavioral, normative, and control beliefs that are associated with joining an AD-focused recruitment registry among historically underrepresented groups. Using a Reasoned Action Approach, we conducted 60 semi-structured phone interviews in 2020 among White, Black, and Hispanic adults ages 49-79 years in Philadelphia, PA. Underlying beliefs were elicited for the target behavior of "signing up to be on a registry for brain health research studies in the next month." Percentages based on counts are reported for the overall sample and by race and ethnicity and sex. Participants were most concerned that if they were to sign up for a registry, they would be asked to participate in experimental studies. Advancing science to help others was a commonly reported positive belief about signing up. Participants' children and friends/neighbors were important from a normative perspective. Barriers to enrollment focused on logistical concerns and inconvenient sign-up processes, including using a computer. Results show generally few racial and ethnic or sex group differences. The elicited beliefs from underrepresented groups offer a basis for understanding the behavior of signing up for research registries. However, there were few differences between the groups. Implications for outreach and recruitment are discussed.

Planning for Prevention of Parkinson Disease: Now Is the Time.

Parkinson disease (PD) is a chronic progressive neurodegenerative disease with increasing worldwide prevalence. Despite many trials of neuroprotective therapies in manifest PD, no disease-modifying therapy has been established. Over the past several decades, a series of breakthroughs have identified discrete populations at substantially increased risk of developing PD. Based on this knowledge, now is the time to design and implement PD prevention trials. This endeavor builds on experience gained from early prevention trials in Alzheimer disease and Huntington disease. This article first reviews prevention trial precedents in these other neurodegenerative diseases before focusing on the critical design elements for PD prevention trials, including whom to enroll for these trials, what therapeutics to test, and how to measure outcomes in prevention trials. Our perspective reflects progress and remaining challenges that motivated a 2021 conference, "Planning for Prevention of Parkinson: A Trial Design Symposium and Workshop."

Description of the Method for Evaluating Digital Endpoints in Alzheimer Disease Study: Protocol for an Exploratory, Cross-sectional Study.

BackgroundMore sensitive and less burdensome efficacy end points are urgently needed to improve the effectiveness of clinical drug development for Alzheimer disease (AD). Although conventional end points lack sensitivity, digital technologies hold promise for amplifying the detection of treatment signals and capturing cognitive anomalies at earlier disease stages. Using digital technologies and combining several test modalities allow for the collection of richer information about cognitive and functional status, which is not ascertainable via conventional paper-and-pencil tests.ObjectiveThis study aimed to assess the psychometric properties, operational feasibility, and patient acceptance of 10 promising technologies that are to be used as efficacy end points to measure cognition in future clinical drug trials.MethodsThe Method for Evaluating Digital Endpoints in Alzheimer Disease study is an exploratory, cross-sectional, noninterventional study that will evaluate 10 digital technologies’ ability to accurately classify participants into 4 cohorts according to the severity of cognitive impairment and dementia. Moreover, this study will assess the psychometric properties of each of the tested digital technologies, including the acceptable range to assess ceiling and floor effects, concurrent validity to correlate digital outcome measures to traditional paper-and-pencil tests in AD, reliability to compare test and retest, and responsiveness to evaluate the sensitivity to change in a mild cognitive challenge model. This study included 50 eligible male and female participants (aged between 60 and 80 years), of whom 13 (26%) were amyloid-negative, cognitively healthy participants (controls); 12 (24%) were amyloid-positive, cognitively healthy participants (presymptomatic); 13 (26%) had mild cognitive impairment (predementia); and 12 (24%) had mild AD (mild dementia). This study involved 4 in-clinic visits. During the initial visit, all participants completed all conventional paper-and-pencil assessments. During the following 3 visits, the participants underwent a series of novel digital assessments.ResultsParticipant recruitment and data collection began in June 2020 and continued until June 2021. Hence, the data collection occurred during the COVID-19 pandemic (SARS-CoV-2 virus pandemic). Data were successfully collected from all digital technologies to evaluate statistical and operational performance and patient acceptance. This paper reports the baseline demographics and characteristics of the population studied as well as the study's progress during the pandemic.ConclusionsThis study was designed to generate feasibility insights and validation data to help advance novel digital technologies in clinical drug development. The learnings from this study will help guide future methods for assessing novel digital technologies and inform clinical drug trials in early AD, aiming to enhance clinical end point strategies with digital technologies.International Registered Report Identifier (IRRID)DERR1-10.2196/35442