A multicenter, randomized, double-blind, placebo-controlled ascending dose study to evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamic (PD) effects of Posiphen in subjects with Early Alzheimer's Disease.

Background: Amyloid beta protein (Aß) is a treatment target in Alzheimer's Disease (AD). Lowering production of its parent protein, APP, has benefits in preclinical models. Posiphen binds to an iron-responsive element in APP mRNA and decreases translation of APP and Aß. To augment human data for Posiphen, we evaluated safety, tolerability and pharmacokinetic and pharmacodynamic (PD) effects on Aß metabolism using Stable Isotope Labeling Kinetic (SILK) analysis. Methods: Double-blind phase 1b randomized ascending dose clinical trial, at five sites, under an IRB-approved protocol. Participants with mild cognitive impairment or mild AD (Early AD) with positive CSF biomarkers were randomized (within each dose arm) to Posiphen or placebo. Pretreatment assessment included lumbar puncture for CSF. Participants took Posiphen or placebo for 21-23 days, then underwent CSF catheter placement, intravenous infusion of 13C6-leucine, and CSF sampling for 36 hours. Safety and tolerability were assessed through participant reports, EKG and laboratory tests. CSF SILK analysis measured Aß40, 38 and 42 with immunoprecipitation-mass spectrometry. Baseline and day 21 CSF APP, Aß and other biomarkers were measured with immunoassays. The Mini-Mental State Exam and ADAS-cog12 were given at baseline and day 21. Results: From June 2017 to December 2021, 19 participants were enrolled, in dose cohorts (6 active: 2 placebo) of 60 mg once/day and 60 mg twice/day; 1 participant was enrolled and completed 60 mg three times/day. 10 active drug and 5 placebo participants completed all study procedures. Posiphen was safe and well-tolerated. 8 participants had headaches related to CSF catheterization; 5 needed blood patches. Prespecified SILK analyses of Fractional Synthesis Rate (FSR) for CSF Aß40 showed no significant overall or dose-dependent effects of Posiphen vs. placebo. Comprehensive multiparameter modeling of APP kinetics supported dose-dependent lowering of APP production by Posiphen. Cognitive measures and CSF biomarkers did not change significantly from baseline to 21 days in Posiphen vs placebo groups. Conclusions: Posiphen was safe and well-tolerated in Early AD. A multicenter SILK study was feasible. Findings are limited by small sample size but provide additional supportive safety and PK data. Comprehensive modeling of biomarker dynamics using SILK data may reveal subtle drug effects. Trial registration: NCT02925650 on clinicaltrials.gov.

Clinical value of Alzheimer's disease biomarker testing.

INTRODUCTION: In the Investigating the Impact of Alzheimer's Disease Diagnostics in British Columbia (IMPACT-AD BC) study, we aimed to understand how Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing-used in medical care-impacted medical decision-making (medical utility), personal decision-making (personal utility), and health system economics. METHODS: The study was designed as an observational, longitudinal cohort study. A total of 149 patients were enrolled between February 2019 and July 2021. Patients referred to memory clinics were approached to participate if their dementia specialist ordered AD CSF biomarker testing as part of their routine medical care, and the clinical scenario met the appropriate use criteria for lumbar puncture and AD CSF biomarker testing. For the medical utility pillar, detailed clinical management plans were collected via physician questionnaires pre- and post-biomarker disclosure. RESULTS: Patients with completed management questionnaires (n = 142) had a median age of 64 (interquartile range: 59-69) years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases. AD biomarker testing was associated with decreased need for other diagnostic procedures, including brain imaging (-52.0%) and detailed neuropsychological assessments (-63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and -50.0% in biomarker-positive and -negative cases, respectively). DISCUSSION: AD biomarker testing was associated with significant and positive changes in clinical management, including decreased health care resource use, therapy optimization, and increased patient and family member counseling. While certain changes in management were linked to the AD biomarker profile (e.g., referral to clinical trials), the majority of changes were independent of baseline clinical presentation and level of cognitive impairment, demonstrating a broad value for AD biomarker testing in individuals meeting the appropriate use criteria for testing.

Personal value of Alzheimer's disease biomarker testing and result disclosure from the patient and care partner perspective.

INTRODUCTION: We described patients' and care partners' experiences with Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarker testing and result disclosure in routine care. METHODS: IMPACT-AD BC is an observational study of clinic patients who underwent AD CSF biomarker testing as part of their routine medical care (n = 142). In the personal utility arm of the study, semi-structured phone interviews were conducted with a subset of patients (n = 34), and separately with their care partners (n = 31). Post-disclosure interviews were conducted ∼1 month and ∼6 months after biomarker result disclosure and investigated the patients' decision-making process around testing, impact of receiving results, wellness and lifestyle changes, and future planning. RESULTS: A majority of patients (90%) rated their decision to undergo testing as "easy." Post-disclosure, the majority (82%) reported overall positive feelings from having greater certainty and the ability to plan ahead, and results spurred them to adopt/continue healthy behaviors such as exercise (84%) and cognitive activities (54%). Care partners expressed relief from having more diagnostic certainty, increased appreciation of future caregiving responsibilities, and a desire to connect with support resources. DISCUSSION: Perspectives of persons with lived experience in dementia provide new insight into the value of biomarker testing and should be included as part of evidence-guided considerations for pre-test counseling and result disclosure. Moreover, study findings identify an interval when patients and care partners are highly receptive to positive lifestyle and medical interventions.

Developing the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia program.

INTRODUCTION: With Alzheimer's disease and related dementias (ADRD) representing an enormous public health challenge, there is a need to support individuals in learning about and addressing their modifiable risk factors (e.g., diet, sleep, and physical activity) to prevent or delay dementia onset. However, there is limited availability for evidence-informed tools that deliver both quality education and support for positive behavior change such as by increasing self-efficacy and personalizing goal setting. Tools that address the needs of Latino/a, at higher risk for ADRD, are even more scarce. METHODS: We established a multidisciplinary team to develop the Healthy Actions and Lifestyles to Avoid Dementia or Hispanos y el ALTo a la Demencia (HALT-AD) program, a bilingual online personalized platform to educate and motivate participants to modify their risk factors for dementia. Grounded in social cognitive theory and following a cultural adaptation framework with guidance from a community advisory board, we developed HALT-AD iteratively through several cycles of rapid prototype development, user-centered evaluation through pilot testing and community feedback, and refinement. RESULTS: Using this iterative approach allowed for more than 100 improvements in the content, features, and design of HALT-AD to improve the program's usability and alignment with the interests and educational/behavior change support needs of its target audience. Illustrative examples of how pilot data and community feedback informed improvements are provided. DISCUSSION: Developing HALT-AD iteratively required learning through trial and error and flexibility in workflows, contrary to traditional program development methods that rely on rigid, pre-set requirements. In addition to efficacy trials, studies are needed to identify mechanisms for effective behavior change, which might be culturally specific. Flexible and personalized educational offerings are likely to be important in modifying risk trajectories in ADRD.

Efficacy assessment of an active tau immunotherapy in Alzheimer's disease patients with amyloid and tau pathology: a post hoc analysis of the "ADAMANT" randomised, placebo-controlled, double-blind, multi-centre, phase 2 clinical trial.

BACKGROUND: Tau pathology correlates with and predicts clinical decline in Alzheimer's disease. Approved tau-targeted therapies are not available. METHODS: ADAMANT, a 24-month randomised, placebo-controlled, parallel-group, double-blinded, multicenter, Phase 2 clinical trial (EudraCT2015-000630-30, NCT02579252) enrolled 196 participants with Alzheimer's disease; 119 are included in this post-hoc subgroup analysis. AADvac1, active immunotherapy against pathological tau protein. A machine learning model predicted likely Amyloid+Tau+ participants from baseline MRI. STATISTICAL METHODS: MMRM for change from baseline in cognition, function, and neurodegeneration; linear regression for associations between antibody response and endpoints. RESULTS: The prediction model achieved PPV of 97.7% for amyloid, 96.2% for tau. 119 participants in the full analysis set (70 treatment and 49 placebo) were classified as A+T+. A trend for CDR-SB 104-week change (estimated marginal means [emm] = -0.99 points, 95% CI [-2.13, 0.13], p = 0.0825]) and ADCS-MCI-ADL (emm = 3.82 points, CI [-0.29, 7.92], p = 0.0679) in favour of the treatment group was seen. Reduction was seen in plasma NF-L (emm = -0.15 log pg/mL, CI [-0.27, -0.03], p = 0.0139). Higher antibody response to AADvac1 was related to slowing of decline on CDR-SB (rho = -0.10, CI [-0.21, 0.01], p = 0.0376) and ADL (rho = 0.15, CI [0.03, 0.27], p = 0.0201), and related to slower brain atrophy (rho = 0.18-0.35, p < 0.05 for temporal volume, whole cortex, and right and left hippocampus). CONCLUSIONS: In the subgroup of ML imputed or CSF identified A+T+, AADvac1 slowed AD-related decline in an antibody-dependent manner. Larger anti-tau trials are warranted. FUNDING: AXON Neuroscience SE.

Evaluation of bumetanide as a potential therapeutic agent for Alzheimer's disease.

Therapeutics discovery and development for Alzheimer's disease (AD) has been an area of intense research to alleviate memory loss and the underlying pathogenic processes. Recent drug discovery approaches have utilized in silico computational strategies for drug candidate selection which has opened the door to repurposing drugs for AD. Computational analysis of gene expression signatures of patients stratified by the APOE4 risk allele of AD led to the discovery of the FDA-approved drug bumetanide as a top candidate agent that reverses APOE4 transcriptomic brain signatures and improves memory deficits in APOE4 animal models of AD. Bumetanide is a loop diuretic which inhibits the kidney Na+-K+-2Cl- cotransporter isoform, NKCC2, for the treatment of hypertension and edema in cardiovascular, liver, and renal disease. Electronic health record data revealed that patients exposed to bumetanide have lower incidences of AD by 35%-70%. In the brain, bumetanide has been proposed to antagonize the NKCC1 isoform which mediates cellular uptake of chloride ions. Blocking neuronal NKCC1 leads to a decrease in intracellular chloride and thus promotes GABAergic receptor mediated hyperpolarization, which may ameliorate disease conditions associated with GABAergic-mediated depolarization. NKCC1 is expressed in neurons and in all brain cells including glia (oligodendrocytes, microglia, and astrocytes) and the vasculature. In consideration of bumetanide as a repurposed drug for AD, this review evaluates its pharmaceutical properties with respect to its estimated brain levels across doses that can improve neurologic disease deficits of animal models to distinguish between NKCC1 and non-NKCC1 mechanisms. The available data indicate that bumetanide efficacy may occur at brain drug levels that are below those required for inhibition of the NKCC1 transporter which implicates non-NKCC1 brain mechansims for improvement of brain dysfunctions and memory deficits. Alternatively, peripheral bumetanide mechanisms may involve cells outside the central nervous system (e.g., in epithelia and the immune system). Clinical bumetanide doses for improved neurological deficits are reviewed. Regardless of mechanism, the efficacy of bumetanide to improve memory deficits in the APOE4 model of AD and its potential to reduce the incidence of AD provide support for clinical investigation of bumetanide as a repurposed AD therapeutic agent.

Exploring Social Cognition Tests to Differentiate Frontotemporal Dementia from Depression: A Two-Step Pilot Study.

Behavioral-variant frontotemporal dementia (bvFTD) is challenging to recognize, and often misdiagnosed as depression (DEP). Evidence suggests changes in social cognition (SoCog) precede general cognitive decline in bvFTD. Currently, there are no screening measures of social cognition. 17 bvFTD, 16 DEP, and 18 control participants underwent 6 SoCog tests measuring: emotion recognition; theory of mind; empathy; insight. We used χ 2 , Wilcoxon rank sum, Kruskal-Wallis tests to compare groups, with decision tree analysis to identify items that best differentiated bvFTD from DEP. bvFTD performed significantly worse on all SoCog tasks compared with other groups. Decision tree analysis yielded a 5-item test with ROC area under the curve of 0.973 (95% CI: 0.928, 1.0) for differentiating bvFTD versus depression. These results suggest that it may be feasible to develop a screening measure of social cognition.

Optimal Weighting of Preclinical Alzheimer's Cognitive Composite (PACC) Scales to Improve their Performance as Outcome Measures for Alzheimer's Disease Clinical Trials.

Introduction: Cognitive composite scales constructed by combining existing neuropsychometric tests are seeing wide application as endpoints for clinical trials and cohort studies of Alzheimer's disease (AD) predementia conditions. Preclinical Alzheimer's Cognitive Composite (PACC) scales are composite scores calculated as the sum of the component test scores weighted by the reciprocal of their standard deviations at the baseline visit. Reciprocal standard deviation is an arbitrary weighting in this context, and may be an inefficient utilization of the data contained in the component measures. Mathematically derived optimal composite weighting is a promising alternative. Methods: Sample size projections using standard power calculation formulas were used to describe the relative performance of component measures and their composites when used as endpoints for clinical trials. Power calculations were informed by (n=1,333) amnestic mild cognitive impaired participants in the National Alzheimer's Coordinating Center (NACC) Uniform Data Set. Results: A composite constructed using PACC reciprocal standard deviation weighting was both less sensitive to change than one of its component measures and less sensitive to change than its optimally weighted counterpart. In standard sample size calculations informed by NACC data, a clinical trial using the PACC weighting would require 38% more subjects than a composite calculated using optimal weighting. Discussion: These findings illustrate how reciprocal standard deviation weighting can result in inefficient cognitive composites, and underscore the importance of component weights to the performance of composite scales. In the future, optimal weighting parameters informed by accumulating clinical trial data may improve the efficiency of clinical trials in AD.

Nutritional metabolism and cerebral bioenergetics in Alzheimer's disease and related dementias.

Disturbances in the brain's capacity to meet its energy demand increase the risk of synaptic loss, neurodegeneration, and cognitive decline. Nutritional and metabolic interventions that target metabolic pathways combined with diagnostics to identify deficits in cerebral bioenergetics may therefore offer novel therapeutic potential for Alzheimer's disease (AD) prevention and management. Many diet-derived natural bioactive components can govern cellular energy metabolism but their effects on brain aging are not clear. This review examines how nutritional metabolism can regulate brain bioenergetics and mitigate AD risk. We focus on leading mechanisms of cerebral bioenergetic breakdown in the aging brain at the cellular level, as well as the putative causes and consequences of disturbed bioenergetics, particularly at the blood-brain barrier with implications for nutrient brain delivery and nutritional interventions. Novel therapeutic nutrition approaches including diet patterns are provided, integrating studies of the gut microbiome, neuroimaging, and other biomarkers to guide future personalized nutritional interventions.

Pharmacological thiamine levels as a therapeutic approach in Alzheimer's disease.

of the study.

Home EEG sleep assessment shows reduced slow-wave sleep in mild-moderate Alzheimer's disease.

Introduction: Sleep disturbances are common in Alzheimer's disease (AD), with estimates of prevalence as high as 65%. Recent work suggests that specific sleep stages, such as slow-wave sleep (SWS) and rapid eye movement (REM), may directly impact AD pathophysiology. A major limitation to sleep staging is the requirement for clinical polysomnography (PSG), which is often not well tolerated in patients with dementia. We have recently developed a deep learning model to reliably analyze lower quality electroencephalogram (EEG) data obtained from a simple, two-lead EEG headband. Here we assessed whether this methodology would allow for home EEG sleep staging in patients with mild-moderate AD. Methods: A total of 26 mild-moderate AD patients and 24 age-matched, healthy control participants underwent home EEG sleep recordings as well as actigraphy and subjective sleep measures through the Pittsburgh Sleep Quality Index (PSQI). Each participant wore the EEG headband for up to three nights. Sleep was staged using a deep learning model previously developed by our group, and sleep stages were correlated with actigraphy measures as well as PSQI scores. Results: We show that home EEG with a headband is feasible and well tolerated in patients with AD. Patients with mild-moderate AD were found to spend less time in SWS compared to healthy control participants. Other sleep stages were not different between the two groups. Actigraphy or the PSQI were not found to predict home EEG sleep stages. Discussion: Our data show that home EEG is well tolerated, and can ascertain reduced SWS in patients with mild-moderate AD. Similar findings have previously been reported, but using clinical PSG not suitable for the home environment. Home EEG will be particularly useful in future clinical trials assessing potential interventions that may target specific sleep stages to alter the pathogenesis of AD. Highlights: Home electroencephalogram (EEG) sleep assessments are important for measuring sleep in patients with dementia because polysomnography is a limited resource not well tolerated in this patient population.Simplified at-home EEG for sleep assessment is feasible in patients with mild-moderate Alzheimer's disease (AD).Patients with mild-moderate AD exhibit less time spent in slow-wave sleep in the home environment, compared to healthy control participants.Compared to healthy control participants, patients with mild-moderate AD spend more time in bed, with decreased sleep efficiency, and more awakenings as measured by actigraphy, but these measures do not correlate with EEG sleep stages.

Multidomain trials to prevent dementia: addressing methodological challenges.

BACKGROUND: Multidomain trials to prevent dementia by simultaneously targeting multiple risk factors with non-pharmacological lifestyle interventions show promise. Designing trials to evaluate the efficacy of individual interventions and their combinations is methodologically challenging. Determining the efficacy is, nevertheless, important to individuals, payers, and for resource allocations to support intervention implementation. MAIN BODY: The central rationale for seminal trials improving cardiovascular health or reducing falls risk in older adults is that multifactorial conditions may be amenable to improvement by simultaneously targeting multiple modifiable risk factors. Similar reasoning underlies lifestyle interventions to reduce dementia risk using combinations of physical exercise, cognitive training, diet, amelioration of vascular-metabolic risk factors, and improving sleep quality. Randomizing individuals with at least two modifiable risk factors to "standardly tailored" interventions to mitigate their risk factors, versus a comparator arm, will yield an unbiased estimate of the cumulative average effect of modifying more versus fewer risk factors. The between-group difference in the cognitive primary outcome will reflect both the main effects of the mitigated risk factors, as well as their synergistic effects. However, given the positive trial results, there are inherent challenges in quantifying post hoc which components, or combination of components, were responsible for improvements in cognition. Here, we elaborate on these methodological challenges and important considerations in using a standardly tailored design with two arms (one consisting of multidomain interventions tailored to participants' risk profiles and another consisting of active control conditions). We compare this approach to fully factorial designs and highlight the disadvantages and advantages of each. We discuss partial solutions, including analytical strategies such as risk reduction scores that measure reductions in the number or severity of risk factors in each study arm. Positive results can support the causal inference that between-group differences in the primary cognitive outcome were due to risk factor modification. CONCLUSION: Standardly tailored designs are pragmatic and feasible evaluations of multidomain interventions to reduce dementia risk. We propose sensitivity and exploratory analyses of between-group reductions in the severity of risk factors, as a methodology to bolster causal inferences that between-group differences in the primary cognitive outcome are due to the risk factors modified.

Safety, Tolerability, and Immunogenicity of the ACI-24 Vaccine in Adults With Down Syndrome: A Phase 1b Randomized Clinical Trial.

Importance: Individuals with Down syndrome (DS) are at high risk of developing Alzheimer disease due to an increased dose of the amyloid precursor protein gene, APP, which leads to increased levels of full-length APP and its products, including amyloid-ß (Aß). The liposome-based antiamyloid ACI-24 vaccine is intended to treat neurological disorders caused by misfolded Aß pathological protein. However, the safety, tolerability, and immunogenicity of the ACI-24 vaccine among adults with DS have not been fully examined. Objective: To assess the safety and tolerability of the ACI-24 vaccine among adults with DS as well as its ability to induce immunogenicity measured by anti-Aß immunoglobulin G titers. Design, Setting, and Participants: This multicenter double-blind placebo-controlled dose-escalation phase 1b randomized clinical trial was conducted at 3 US academic medical centers with affiliated Down syndrome clinics between March 30, 2016, and June 29, 2020. A total of 20 adults with DS were screened; of those, 16 adults were eligible to participate. Eligibility criteria included men or women aged 25 to 45 years with cytogenetic diagnosis of either trisomy 21 or complete unbalanced translocation of chromosome 21. Between April 27, 2016, and July 2, 2018, participants were randomized 3:1 into 2 dose-level cohorts (8 participants per cohort, with 6 participants receiving the ACI-24 vaccine and 2 receiving placebo) in a 96-week study. Participants received 48 weeks of treatment followed by an additional 48 weeks of safety follow-up. Interventions: Participants were randomized to receive 7 subcutaneous injections of ACI-24, 300 µg or 1000 µg, or placebo. Main Outcomes and Measures: Primary outcomes were measures of safety and tolerability as well as antibody titers. Results: Among 16 enrolled participants, the mean (SD) age was 32.6 (4.4) years; 9 participants were women, and 7 were men. All participants were White, and 1 participant had Hispanic or Latino ethnicity. Treatment adherence was 100%. There were no cases of meningoencephalitis, death, or other serious adverse events (AEs) and no withdrawals as a result of AEs. Most treatment-emergent AEs were of mild intensity (110 of 132 events [83.3%]) and unrelated or unlikely to be related to the ACI-24 vaccine (113 of 132 events [85.6%]). No amyloid-related imaging abnormalities with edema or cerebral microhemorrhage and no evidence of central nervous system inflammation were observed on magnetic resonance imaging scans. Increases in anti-Aß immunoglobulin G titers were observed in 4 of 12 participants (33.3%) receiving ACI-24 (2 receiving 300 µg and 2 receiving 1000 µg) compared with 0 participants receiving placebo. In addition, a greater increase was observed in plasma Aß1-40 and Aß1-42 levels among individuals receiving ACI-24. Conclusions and Relevance: In this study, the ACI-24 vaccine was safe and well tolerated in adults with DS. Evidence of immunogenicity along with pharmacodynamic and target engagement were observed, and anti-Aß antibody titers were not associated with any adverse findings. These results support progression to clinical trials using an optimized formulation of the ACI-24 vaccine among individuals with DS. Trial Registration: ClinicalTrials.gov Identifier: NCT02738450.

T2 Protect AD: Achieving a rapid recruitment timeline in a multisite clinical trial for individuals with mild to moderate Alzheimer's disease.

Introduction: The reporting of approaches facilitating the most efficient and timely recruitment of Alzheimer's disease (AD) patients into pharmacologic trials is fundamental to much-needed therapeutic progress. Methods: T2 Protect AD (T2), a phase 2 randomized placebo-controlled trial of troriluzole in mild to moderate AD, used multiple recruitment strategies. Results: T2 exceeded its recruitment target, enrolling 350 participants between July 2018 and December 2019 (randomization rate: 0.87 randomizations/site/month, or 3-fold greater than recent trials of mild to moderate AD). The vast majority (98%) of participants were enrolled during a 10-month window of intense promotion in news media, TV and radio advertisements, and social media. The distribution of primary recruitment sources included: existing patient lists at participating sites (72.3%), news media (12.3%), physician referral (6.0%), word of mouth (3.1%), and paid advertising (2.9%). Discussion: The rapid recruitment of participants with mild to moderate AD was achieved through a range of approaches with varying success.

Committee on High-quality Alzheimer's Disease Studies (CHADS) consensus report.

BACKGROUND: Consensus guidance for the development and identification of high-quality Alzheimer's disease clinical trials is needed for protocol development and conduct of clinical trials. METHODS: An ad hoc consensus committee was convened in conjunction with the Alzheimer's Association to develop consensus recommendations. RESULTS: Consensus was readily reached for the need to provide scientific justification, registration of trials, institutional review board oversight, conflict of interest disclosure, funding source disclosure, defined trial population, recruitment resources, definition of the intervention, specification of trial duration, appropriate payment for participant engagement, risk-benefit disclosure as part of the consent process, and the requirement to disseminate and/or publish trial results even if the study is negative. CONCLUSIONS: This consensus guidance should prove useful for the protocol development and conduct of clinical trials, and may further provide a platform for the development of education materials that may help guide appropriate clinical trial participation decisions for potential trial participants and the general public.

Current directions in tau research: Highlights from Tau 2020.

Studies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau-related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first-ever Tau2020 Global Conference in Washington, DC, co-organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research-advancing tools and insights that are now rapidly accelerating the pace of tau research.

Impact of potential modifications to Alzheimer's disease clinical trials in response to disruption by COVID-19: a simulation study.

BACKGROUND: The COVID-19 pandemic disrupted Alzheimer disease randomized clinical trials (RCTs), forcing investigators to make changes in the conduct of such trials while endeavoring to maintain their validity. Changing ongoing RCTs carries risks for biases and threats to validity. To understand the impact of exigent modifications due to COVID-19, we examined several scenarios in symptomatic and disease modification trials that could be made. METHODS: We identified both symptomatic and disease modification Alzheimer disease RCTs as exemplars of those that would be affected by the pandemic and considered the types of changes that sponsors could make to each. We modeled three scenarios for each of the types of trials using existing datasets, adjusting enrollment, follow-ups, and dropouts to examine the potential effects COVID-19-related changes. Simulations were performed that accounted for completion and dropout patterns using linear mixed effects models, modeling time as continuous and categorical. The statistical power of the scenarios was determined. RESULTS: Truncating both symptomatic and disease modification trials led to underpowered trials. By contrast, adapting the trials by extending the treatment period, temporarily stopping treatment, delaying outcomes assessments, and performing remote assessment allowed for increased statistical power nearly to the level originally planned. DISCUSSION: These analyses support the idea that disrupted trials under common scenarios are better continued and extended even in the face of dropouts, treatment disruptions, missing outcomes, and other exigencies and that adaptations can be made that maintain the trials' validity. We suggest some adaptive methods to do this noting that some changes become under-powered to detect the original effect sizes and expected outcomes. These analyses provide insight to better plan trials that are resilient to unexpected changes to the medical, social, and political milieu.

Recruitment of a multi-site randomized controlled trial of aerobic exercise for older adults with amnestic mild cognitive impairment: The EXERT trial.

INTRODUCTION: Effective strategies to recruit older adults with mild cognitive impairment (MCI) into nonpharmacological intervention trials are lacking. METHODS: Recruitment for EXERT, a multisite randomized controlled 18-month trial examining the effects of aerobic exercise on cognitive trajectory in adults with amnestic MCI, involved a diverse portfolio of strategies to enroll 296 participants. RESULTS: Recruitment occurred September 2016 through March 2020 and was initially slow. After mass mailings of 490,323 age- and geo-targeted infographic postcards and brochures, recruitment rates increased substantially, peaking at 16 randomizations/month in early 2020. Mass mailings accounted for 52% of randomized participants, whereas 25% were recruited from memory clinic rosters, electronic health records, and national and local registries. Other sources included news broadcasts, public service announcements (PSA), local advertising, and community presentations. DISCUSSION: Age- and geo-targeted mass mailing of infographic materials was the most effective approach in recruiting older adults with amnestic MCI into an 18-month exercise trial.