A randomized, triple-masked, active-controlled investigation of the relative effects of dose, concentration, and infusion rate for continuous popliteal-sciatic nerve blocks in volunteers.

BACKGROUND: It remains unknown whether local anaesthetic dose is the only factor influencing continuous popliteal-sciatic nerve block effects, or whether concentration, volume, or both exert an influence as well. METHODS: Bilateral sciatic catheters were inserted in volunteers (n=24). Catheters were randomly assigned to ropivacaine of either 0.1% (8 ml h(-1)) or 0.4% (2 ml h(-1)) for 6 h. The primary endpoint was the tolerance to transcutaneous electrical stimulation within the tibial nerve distribution at hour 6. Secondary endpoints included current tolerance at other time points and plantar flexion maximum voluntary isometric contraction (22 h total). RESULTS: At hour 6, tolerance to cutaneous stimulation for limbs receiving 0.1% ropivacaine was [mean (standard deviation)] 27.0 (20.2) vs26.9 (20.4) mA for limbs receiving 0.4% [estimated mean difference 0.2 mA; 90% confidence interval (CI) -8.2 to 8.5; P=0.02 and 0.03 for lower and upper boundaries, respectively]. Because the 90% CI fell within the prespecified tolerance ±10 mA, we conclude that the effect of the two concentration/volume combinations were equivalent. Similar negative findings were found for the secondary outcomes. CONCLUSIONS: For continuous popliteal-sciatic nerve blocks, we found no evidence that local anaesthetic concentration and volume influence block characteristics, suggesting that local anaesthetic dose (mass) is the primary determinant of perineural infusion effects in this anatomic location. These findings suggest that for ambulatory perineural local anaesthetic infusion-for which there is usually a finite local anaesthetic reservoir-decreasing the basal rate while increasing the local anaesthetic concentration may allow for increased infusion duration without compromising postoperative analgesia. CLINICAL TRIAL REGISTRATION: NCT01898689.

Characterizing Clinical Progression in Cognitively Unimpaired Older Individuals with Brain Amyloid: Results from the A4 Study.

BACKGROUND: Clinical Dementia Rating (CDR) global (CDR-G) and sum of box scores (CDR-SB) are commonly used as primary outcome variables to measure progression or treatment effects in symptomatic Alzheimer disease (AD) clinical trials. OBJECTIVES: We sought to determine whether the CDR is sensitive to change in pre-symptomatic AD and whether there are specific CDR boxes that are dynamic during the multi-year Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) secondary prevention study. DESIGN: All participants entered the study with a CDR-G of 0. Box scores were examined individually and as composites of cognition (memory, orientation and judgment /problem solving) and function (community affairs and home/ hobbies). A progression in box score was tabulated only when the change occurred at two consecutive visits. SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States. PARTICIPANTS: 1,147 individuals, ages 65-85, were randomized to either placebo (n= 583) or solanezumab (n= 564). All participants received a baseline flobetapir PET scan, an annual CDR, and cognitive testing every 6 months with the Primary Alzheimer Cognitive Composite (PACC) over the course of 240 weeks. MEASUREMENTS: Generalized estimating equations and generalized least square models were used to explore the modeled mean progression rate in the CDR-G, CDR-SB, individual CDR boxes, and CDR composite scores in the combined solanezumab and placebo groups. Models were refitted to explore the probability of CDR progression in centiloid tertiles of amyloid at baseline (< 46.1 CL, 46.1 to 77.2 CL, > 77.2 CL). All models included effects for age, education, APOEε4 carrier status, baseline amyloid with flobetapir PET, treatment, and time-by-treatment. RESULTS: There were no statistical differences between the placebo or solanezumab groups in CDR-G, CDR-SB, specific CDR boxes or CDR composite scores over the course of the trial. Changes in judgment/ problem solving were present at baseline and persisted over time, but progression on the CDR memory box and the CDR cognitive composite quickly predominated. Community affairs and home/ hobbies showed little progression. Personal care remained stable. The probability of cognitive and functional progression in CDR boxes began either at the intermediate or advanced amyloid level (46.1 to 77.2 CL, > 77.2 CL), while amyloid at the lowest level (< 46.1 CL) showed relatively little CDR progression. CONCLUSIONS: The findings suggest that the CDR memory box and the CDR cognitive composite progressed over 240 weeks and were associated with intermediate and advanced stages of amyloid at baseline. Functional changes in community affairs and home/hobbies were relatively stable. These finding suggest that specific CDR box score changes may help refine our measurement of expected treatment effects in future AD prevention trials.

Relationship between Plasma P-Tau217 and Amyloid PET in Racial and Ethnic Underrepresented Groups (RE-URG) Compared with Non RE-URG in LEARN and A4.

BACKGROUND: Individuals from diverse racial and ethnic groups are severely underrepresented in Alzheimer's disease trials in part due to disproportionate biomarker ineligibility. Evidence from recent studies support plasma phosphorylated tau 217 (P-tau217) as an early marker for brain Aß pathology and a reliable marker in predicting elevated brain amyloid PET in cognitively unimpaired adults. OBJECTIVES: To examine whether the relationship between P-tau217 and 18-F florbetapir PET standard uptake value ratios (SUVR) is influenced by race and ethnicity in the Anti-Amyloid treatment in Asymptomatic Alzheimer's disease (A4) preclinical AD studies. DESIGN: We conducted a retrospective analysis of A4 clinical trial and the LEARN natural history companion study data to evaluate the relationship between baseline P-tau217 and PET SUVR concentration levels by race and ethnicity. SETTING: The analysis was conducted on samples from participants enrolled across 65 study sites in the United States and Canada. PARTICIPANTS: Cognitively unimpaired adults aged 65-85 enrolled at North American sites in the A4 preclinical AD trial, pre-dose, (N=1018), and the LEARN (N=480) study. Participants were grouped into 2 categories, racial and ethnic underrepresented group (RE-URG) and non-RE-URG (nRE-URG) based on self-identification. MEASUREMENTS: A mixed-effects regression model was fit to determine differences in the relationship between P-tau217 and PET SUVR by race and ethnicity, adjusting for age, and APOE ε4 carrier status. RESULTS: Results from the linear mixed-effects model support that there was no statistically significant effect of race and ethnicity on the relationship between P-tau217 and PET SUVR. CONCLUSION: These findings suggest that the relationship between plasma P-tau217 and PET SUVR is the same across race and ethnicity. Future analyses should corroborate these findings in a larger sample and examine whether plasma P-tau217 reflects the differential amyloid prevalence previously reported for other biomarkers of amyloid.

Longitudinal Trajectories of the Cognitive Function Index in the A4 Study.

BACKGROUND: The Anti-Amyloid in Asymptomatic Alzheimer's Disease (A4) Study failed to show a treatment benefit with solanezumab, but the longitudinal consequences of elevated amyloid were observed in study participants with objective decline on the Preclinical Alzheimer Cognitive Composite (PACC) and subjective decline on the combined Cognitive Function Index (participant + study partner CFI), during the trial period. OBJECTIVES: We sought to expand on previous findings by comparing longitudinal patterns of participant and study partner CFI separately and their associations with the PACC stratified by baseline amyloid tertile over the course of the A4 Study. DESIGN: Cognitively unimpaired older adult participants and their study partners were independently administered the CFI at screen prior to amyloid PET disclosure and then at 3 subsequent visits (week 48, week 168, week 240) of the study. PACC collected at visits concurrent with CFI administration were also examined longitudinally. SETTING: The A4 Study was conducted at 67 sites in Australia, Canada, Japan, and the United States. PARTICIPANTS: 1,147 participants with elevated amyloid based on florbetapir PET were enrolled in the A4 Study and included in these analyses. 583 were on placebo and 564 were treated with solanezumab. MEASUREMENTS: The PACC was used to assess objective cognitive performance and the CFI was used to assess change in everyday cognitive functioning by the participant and their study partner independently. Amyloid level was characterized by Centiloid tertiles (<46.1 CL, 46.1 to 77.2 CL, >77.2 CL). Participants were aware of their elevated amyloid status, but not their CL tertile, or specific level of amyloid. Longitudinal correlations between participant and study partner CFI and PACC were examined at all visits where assessments were available. The impact of baseline amyloid tertile on CFI and PACC associations was also examined. RESULTS: Both participant and study partner CFI increased over the duration of the study indicating worsening cognitive functioning. Results did not differ by treatment group. The association between higher CFI and worse PACC for both for participant and study partner became progressively stronger over the course of the study. PACC had a significantly higher correlation with study partner CFI than with participant CFI by week 168. The stronger correlations between study partner CFI and PACC were driven by those in the highest amyloid tertile. CONCLUSION: Both participant and study partner report captured subtle changes in everyday cognitive functioning for participants with biomarker confirmed and disclosed preclinical AD. Moreover, study partner report was most highly aligned with cognitive decline, particularly among those with the highest amyloid load.

Change in Digital Cognitive Test Performance between Solanezumab and Placebo Groups in Preclinical Alzheimer's Disease: Secondary Analyses from the A4 Study.

BACKGROUND: Primary results from the Anti-Amyloid in Asymptomatic Alzheimer's disease Study (A4) suggested no benefit of solanezumab on its primary cognitive outcome, a composite of paper and pencil tests (the Preclinical Alzheimer's Cognitive Composite; PACC). OBJECTIVE: To determine whether change in cognitive performance, assessed using the Computerized Cognitive Composite (C3) summary score and C3 individual tests, differed between treatment groups over 240 weeks, differed based on baseline Aß burden, and tracked with PACC decline. DESIGN: Longitudinal analysis of cognitive change over 240 weeks on the C3 Summary Score and C3 individual tests between participants randomly assigned to solanezumab at a dose of up to 1600 mg intravenously every 4 weeks versus placebo. SETTING: The A4 study took place at 67 sites in Australia, Canada, Japan and the United States. PARTICIPANTS: Cognitively unimpaired older adults (n=1117, Mean Age=71.9, 60.7% female) with elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) at baseline (n=549 in the solanezumab group; n=568 in the placebo group). MEASUREMENTS: Participants completed the C3 battery and PACC every 6 months. The C3 Summary Score combines the Cogstate Brief Battery (CBB)-One Card Learning, the Behavioral Pattern Separation (BPS) Test- Object- Lure Discrimination Index, and the Face Name Associative Memory Exam (FNAME)- Face-Name Matching. RESULTS: Change on the C3 Summary Score was moderately correlated with change on the PACC (Spearman's corr=0.53, 95% CI: 0.49 to 0.57; p<0.001). At 240 weeks, mean change in the C3 Summary Score did not differ between groups; +0.24 in the solanezumab group and +0.27 in the placebo group (mean difference= -0.02; 95% CI: -0.13 to 0.08; p = 0.650). Lack of a treatment effect was similarly observed across most individual C3 tests. Performance on the C3 tests were influenced by level of amyloid burden, where higher levels were associated with worse performance. CONCLUSION: This study provides corroborating evidence that solanezumab does not slow cognitive decline in preclinical AD as exhibited with a computerized cognitive assessment with some evidence that solanezumab may exacerbate cognition on select digital outcomes. This study also provides important information that amyloid related cognitive change manifests differently on individual C3 tests.

Longitudinal Phospho-tau217 Predicts Amyloid Positron Emission Tomography in Asymptomatic Alzheimer's Disease.

BACKGROUND: Blood-based AD biomarkers such as plasma P-tau217 are increasingly used in clinical trials as a screening tool. OBJECTIVES: To assess the utility of an electrochemiluminescence (ECL) immunoassay in predicting brain amyloid PET status in cognitively unimpaired individuals. SETTING: Plasma samples collected at baseline, week 12, and week 240 or endpoint originated from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) trial and the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: Both A4 and LEARN enrolled eligible cognitively unimpaired persons 65 to 85 years. Individuals with elevated brain amyloid PET levels were eligible for the A4 Study, while those without elevated brain amyloid PET levels were eligible for the LEARN Study. INTERVENTION: Participants in the A4 Study received intravenous solanezumab (up to 1600 mg) or placebo every 4 weeks. The LEARN Study is an observational study without intervention. MEASUREMENTS: Plasma P-tau217 concentration levels from A4 Study participants were measured using an ECL immunoassay. Receiver Operating Characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by ≥22 CL and ≥ 33 CL. RESULTS: Receiver operating characteristic curve (ROC) analysis indicates high diagnostic value of P-tau217 in individuals with amyloid PET ≥ 20 (Area under the ROC (AUROC): 0.87) and ≥ 33 CL (AUROC: 0.89). Repeated testing with the placebo group taken 12 weeks apart (range: 68 to 143 days) and the LEARN participants taken between 1.4 and 1.75 years resulted in a strong positive correlation (Corr. 0.91 (0.90 to 0.92)). CONCLUSION: An ECL immunoassay testing plasma P-tau217 accurately predicts amyloid PET positivity in cognitively unimpaired individuals. Our future analyses aim to determine if use of this assay may reduce the screening burden of preclinical individuals into anti-amyloid clinical trials.

Maximizing the Utility of Alzheimer's Disease Trial Data: Sharing of Baseline A4 and LEARN Data.

BACKGROUND: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies were conducted between 2014 and 2023, with enrollment completed in 2017 and final study results reported in 2023. The study screening process involved the collection of initial clinical, cognitive, neuroimaging, and genetic measures to determine eligibility. Once randomized, enrolled participants were assessed every four weeks over a 4.5-year follow-up period during which longitudinal clinical, cognitive, and neuroimaging measures were collected. A large number of longitudinal fluid biospecimens were also collected and banked. Consistent with the NIH data sharing policy and the principles of Open Science, the A4/LEARN investigators aimed to share data as broadly and early as possible while still protecting participant privacy and confidentiality and the scientific integrity of the studies. OBJECTIVES: We describe the approach, methods, and platforms used to share the A4 and LEARN pre-randomization study data for secondary research use. Preliminary results measuring the impact of these efforts are also summarized. We conclude with a discussion of lessons learned and next steps. DESIGN: The materials shared included de-identified quantitative and image data, analysis software, instruments, and documentation. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan, and Australia. PARTICIPANTS: The A4 study screened (n=6763), enrolled, and randomized (n=1169) participants between the ages of 65 and 85 with a blinded follow-up period of 240 weeks followed by an open-label period of variable length. The LEARN study screened and enrolled individuals (n=538) who were ineligible for the A4 study based on nonelevated measures of amyloid accumulation using positron emission tomography imaging (amyloid PET). MEASUREMENTS: We provide descriptive measures of the data shared and summarize the frequency, characteristics, and status of all data access requests submitted to date. We evaluate the scientific impact of the data-sharing effort by conducting a literature search to identify related publications. RESULTS: The A4 and LEARN pre-randomization study data were released in December 2018. As of May 8, 2024, 1506 requests have been submitted by investigators and citizen scientists from more than 50 countries. We identified 49 peer-reviewed publications that acknowledge the A4/LEARN study. CONCLUSIONS: Our initial results provide evidence supporting the feasibility and scientific utility of broad and timely sharing of Alzheimer's disease trial data.

Pre-Randomization Predictors of Study Discontinuation in a Preclinical Alzheimer's Disease Randomized Controlled Trial.

BACKGROUND: Participant discontinuation from study treatment in a clinical trial can leave a trial underpowered, produce bias in statistical analysis, and limit interpretability of study results. Retaining participants in clinical trials for the full study duration is therefore as important as participant recruitment. OBJECTIVE: This analysis aims to identify associations of pre-randomization characteristics of participants with premature discontinuation during the blinded phase of the Anti-Amyloid treatment in Asymptomatic AD (A4) Study. DESIGN: All A4 trial randomized participants were classified as having prematurely discontinued study during the blinded period of the study for any reason (dropouts) or completed the blinded phase of the study on treatment (completers). SETTING: The trial was conducted across 67 study sites in the United States, Canada, Japan and Australia through the global COVID-19 pandemic. PARTICIPANTS: The sample consisted of all 1169 A4 trial randomized participants. MEASUREMENTS: Pre-randomization demographic, clinical, amyloid PET and genetic predictors of study discontinuation were evaluated using a univariate generalized linear mixed model (GLMM), with discontinuation status as the binary outcome, each predictor as a fixed effect, and site as a random effect to account for differences among study sites in the trial. Characteristics significant at p<0.10 were then included in a multivariable GLMM. RESULTS: Among randomized participants, 339 (29%) discontinued the study during the blinded period (median follow-up time in trial: 759 days). From the multivariable analysis, the two main predictors of study discontinuation were screening State-Trait Anxiety Inventory (STAI) scores (OR = 1.07 [95%CI = 1.02; 1.12]; p=0.002) and age (OR = 1.06 [95%CI = 1.03; 1.09]; p<0.001). Participants with a family history of dementia (OR = 0.75 [95%CI = 0.55; 1.01]; p=0.063) and APOE ε4 carriers (OR = 0.79 [95%CI = 0.6; 1.04]; p=0.094) were less likely to discontinue from the study, with the association being marginally significant. In these analyses, sex, race and ethnicity, cognitive scores and amyloid/tau PET scores were not associated with study dropout. CONCLUSIONS: In the A4 trial, older participants and those with higher levels of anxiety at baseline as measured by the STAI were more likely to discontinue while those who had a family history of dementia or were APOE ε4 carriers were less likely to drop out. These findings have direct implications for future preclinical trial design and selection processes to identify those individuals at greatest risk of dropout and provide information to the study team to develop effective selection and retention strategies in AD prevention studies.

Amyloid and Tau Prediction of Cognitive and Functional Decline in Unimpaired Older Individuals: Longitudinal Data from the A4 and LEARN Studies.

BACKGROUND: Converging evidence suggests that markers of Alzheimer's disease (AD) pathology in cognitively unimpaired older individuals are associated with high risk of cognitive decline and progression to functional impairment. The Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) and Longitudinal Evaluation of Amyloid and Neurodegeneration Risk (LEARN) Studies enrolled a large cohort of cognitively normal older individuals across a range of baseline amyloid PET levels. Recent advances in AD blood-based biomarkers further enable the comparison of baseline markers in the prediction of longitudinal clinical outcomes. OBJECTIVES: We sought to evaluate whether biomarker indicators of higher levels of AD pathology at baseline predicted greater cognitive and functional decline, and to compare the relative predictive power of amyloid PET imaging, tau PET imaging, and a plasma P-tau217 assay. DESIGN: All participants underwent baseline amyloid PET scan, plasma P-tau217; longitudinal cognitive testing with the Primary Alzheimer Cognitive Composite (PACC) every 6 months; and annual functional assessments with the clinical dementia rating (CDR), cognitive functional index (CFI), and activities of daily living (ADL) scales. Baseline tau PET scans were obtained in a subset of participants. Participants with elevated amyloid (Aß+) on screening PET who met inclusion/exclusion criteria were randomized to receive placebo or solanezumab in a double-blind phase of the A4 Study over 240+ weeks. Participants who did not have elevated amyloid (Aß-) but were otherwise eligible for the A4 Study were referred to the companion observational LEARN Study with the same outcome assessments over 240+ weeks. SETTING: The A4 and LEARN Studies were conducted at 67 clinical trial sites in the United States, Canada, Japan and Australia. PARTICIPANTS: Older participants (ages 65-85) who were cognitively unimpaired at baseline (CDR-GS=0, MMSE 25-30 with educational adjustment, and Logical Memory scores within the normal range LMIIa 6-18) were eligible to continue in screening. Aß+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aß+ underwent tau PET imaging in A4 (n=350). Aß- were enrolled into the LEARN Study (n=553). MEASUREMENTS: Baseline 18-F Florbetapir amyloid PET, 18-F Flortaucipir tau PET in a subset and plasma P-tau217 with an electrochemiluminescence (ECL) immunoassay were evaluated as predictors of cognitive (PACC), and functional (CDR, CFI and ADL) change. Models were evaluated to explore the impact of baseline tertiles of amyloid PET and tertiles of plasma P-tau217 on cognitive and functional outcomes in the A4 Study compared to LEARN. Multivariable models were used to evaluate the unique and common variance explained in longitudinal outcomes based on baseline predictors, including effects for age, gender, education, race/ethnic group, APOEε4 carrier status, baseline PACC performance and treatment assignment in A4 participants (solanezumab vs placebo). RESULTS: Higher baseline amyloid PET CL and P-tau217 levels were associated with faster rates of PACC decline, and increased likelihood of progression to functional impairment (CDR 0.5 or higher on two consecutive measurements), both across LEARN Aß- and A4 Aß+ (solanezumab and placebo arms). In analyses considering all baseline predictor variables, P-tau217 was the strongest predictor of PACC decline. Among participants in the highest tertiles of amyloid PET or P-tau217, >50% progressed to CDR 0.5 or greater. In the tau PET substudy, neocortical tau was the strongest predictor of PACC decline, but plasma P-tau217 contributed additional independent predictive variance in commonality variance models. CONCLUSIONS: In a large cohort of cognitively unimpaired individuals enrolled in a Phase 3 clinical trial and companion observational study, these findings confirm that higher baseline levels of amyloid and tau markers are associated with increased rates of cognitive decline and progression to functional impairment. Interestingly, plasma P-tau217 was the best predictor of decline in the overall sample, superior to baseline amyloid PET. Neocortical tau was the strongest predictor of cognitive decline in the subgroup with tau PET, suggesting that tau deposition is most closely linked to clinical decline. These findings indicate that biomarkers of AD pathology are useful to predict decline in an older asymptomatic population and may prove valuable in the selection of individuals for disease-modifying treatments.

Left Frontoparietal Control Network Connectivity Moderates the Effect of Amyloid on Cognitive Decline in Preclinical Alzheimer's Disease: The A4 Study.

BACKGROUND: Stronger resting-state functional connectivity of the default mode and frontoparietal control networks has been associated with cognitive resilience to Alzheimer's disease related pathology and neurodegeneration in smaller cohort studies. OBJECTIVES: We investigated whether these networks are associated with longitudinal CR to AD biomarkers of beta-amyloid (Aß). DESIGN: Longitudinal mixed. SETTING: The Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study and its natural history observation arm, the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. PARTICIPANTS: A sample of 1,021 cognitively unimpaired older adults (mean age = 71.2 years [SD = 4.7 years], 61% women, 42% APOEε4 carriers, 52% Aß positive). MEASUREMENTS: Global cognitive performance (Preclinical Alzheimer's Cognitive Composite) was assessed over an average 5.4 year follow-up period (SD = 2 years). Cortical Aß and functional connectivity (left and right frontoparietal control and default mode networks) were estimated from fMRI and PET, respectively, at baseline. Covariates included baseline age, APOEε4 carrier status, years of education, adjusted gray matter volume, head motion, study group, cumulative treatment exposure, and cognitive test version. RESULTS: Mixed effects models revealed that functional connectivity of the left frontoparietal control network moderated the negative effect of Aß on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aß-related cognitive decline. CONCLUSIONS: Our results demonstrate a potential protective effect of functional connectivity in preclinical AD, such that stronger connectivity in this network is associated with slower Aß-related cognitive decline.

Greater White Matter Hyperintensity Volume Is Associated with the Number of Microhemorrhages in Preclinical Alzheimer's Disease.

BACKGROUND: Increased white matter hyperintensity (WMH) volume visible on MRI is a common finding in Alzheimer's disease (AD). We hypothesized that WMH in preclinical AD is associated with the presence of advanced vessel amyloidosis manifested as microhemorrhages (MCH). OBJECTIVES: 1) To assess the relationship between baseline WMH volume and baseline MCH. 2) To assess the relationship between longitudinal WMH accumulation and last MRI MCH during the double-blind phase of the A4 trial. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, Phase 3 study comparing solanezumab with placebo given as infusions once every 4 weeks over 4.5 years in subjects with preclinical AD, defined as having evidence of elevated brain amyloid before the stage of clinically evident cognitive impairment, with an optional open-label extension period. SETTING: Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study. PARTICIPANTS: A sample of 1157 cognitively unimpaired older adults (mean age = 71.9 years [SD = 4.8 years], 59% women, 59% APOE ε4 carriers). MEASUREMENTS: A linear regression model was used to assess the impact of baseline MCH amount (0, 1, 2+) on WMH volume. A linear mixed-effects model was used to assess the impact of last MRI MCH on longitudinal WMH. All models were corrected for age, sex, grey matter volume, cortical amyloid PET, APOE ε4 status, and treatment group. RESULTS: Baseline WMH volume was greater in individuals with more than one MCH compared to those with no MCH (t=4.8, p<0.001). The longitudinal increase in WMH amongst individuals with one (t=2.3, p=0.025) and more than one MCH (t=6.7, p<0.001) at the last MRI was greater than those with no MCH. CONCLUSION: These results indicate a strong association between WMH and MCH, a common manifestation of cerebral amyloid angiopathy and ARIA-H. These results suggest that increased WMH volume may represent an early sign of vessel amyloidosis, likely prior to the emergence of MCH.

The AlzMatch Pilot Study - Feasibility of Remote Blood Collection of Plasma Biomarkers for Preclinical Alzheimer's Disease Trials.

BACKGROUND: Advances in plasma biomarkers to detect Alzheimer's disease (AD) biology allows researchers to improve the efficiency of participant recruitment into preclinical trials. Recently, protein levels of plasma amyloid-beta and tau proteins have been shown to be predictive of elevated amyloid in brain. Online registries, such as the Alzheimer's Prevention Trials (APT) Webstudy, include and follow participants using remote assessments to facilitate efficient screening and enrollment of large numbers of individuals who may be at higher risk for AD. OBJECTIVES: The AlzMatch Pilot Study investigated the feasibility of recruiting individuals from an online registry for blood sample collection at community-based phlebotomy centers and plasma biomarker quantification to assess an individual's eligibility for AD preclinical trials. DESIGN: Pilot feasibility study with co-primary outcomes. SETTING: This pilot feasibility study included participants from the APT Webstudy, the remote assessment arm of the Trial-ready cohort for Preclinical and Prodromal AD (TRC-PAD) Platform. Novel design included collection of electronic consent, use of community laboratories for plasma collection, mass spectrometry-based biomarker assay, and telephone communication of plasma biomarker screening eligibility. PARTICIPANTS: Participants invited to the AlzMatch pilot feasibility study were active in the APT Webstudy, 50 years of age or older, resided within 50 miles of both a Quest Diagnostics Patient Services Center (a national diagnostic laboratory with convenient locations for sample collection and processing) and one of six TRC-PAD vanguard clinical trial sites, had no self-reported dementia diagnosis, were able to communicate in English and engaged with the APT Webstudy within the prior 6 months. MEASUREMENTS: Primary feasibility outcomes were completion of electronic consent (e-consent) for invited participants and collection of usable blood samples. Additional feasibility outcomes included invitation response rate, plasma biomarker eligibility status (based on amyloid beta-42/40 [Aß42/40] concentration ratio), ApoE proteotype, and trial inclusion criterion), and completion of telephone contact to learn eligibility to screen for a study. RESULTS: 300 APT Webstudy participants were invited to consent to the AlzMatch study. The AlzMatch e-consent rate was 39% (n=117) (95% CI of 33.5%-44.5%) overall, which was higher than the expected rate of 25%. Similar consent rates were observed across participants based on self-defined sex (41% Female (n=75), 37% Male (n=42)) and race and ethnicity (37% from underrepresented groups (URG) (n=36), 40% not from URG (n=79)). Among those that consented (n=117), plasma was successfully collected from 74% (n=87) (95% CI of 66%-82%), with similar rates across sex (76% Female (n=57), 71% Male (n=30)) and race and ethnicity (75% URG (n=27) and 75% not from URG (n=59)). 60% (n=51) of participants with plasma biomarker results were eligible to screen for future preclinical AD trials. CONCLUSION: Electronic consent of participants through an online registry, blood sample collection at community-based centers, plasma biomarker quantification and reporting, and biomarker assessments for study eligibility were all feasible with similar engagement rates across demographic groups. Although this pilot was a small and selective sample, participants engaged and consented at higher than expected rates. We conclude that collecting blood at community laboratories for biomarker analyses may improve accessibility beyond research, and may facilitate broader access for clinical use of AD plasma biomarkers. Based on our results, an expanded version of the AlzMatch study is underway, which involves expanding invitations to additional APT Webstudy participants and clinical trial sites.

Sensitivity of the Preclinical Alzheimer's Cognitive Composite (PACC), PACC5, and Repeatable Battery for Neuropsychological Status (RBANS) to Amyloid Status in Preclinical Alzheimer's Disease -Atabecestat Phase 2b/3 EARLY Clinical Trial.

BACKGROUND: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials. OBJECTIVE: To evaluate the association between amyloid (Aß) burden level (+/-) and performance on three separate composite endpoints: Preclinical Alzheimer's Cognitive Composite (PACC), PACC+Semantic Fluency (PACC5), and Repeatable Battery for Neuropsychological Status (RBANS). DESIGN: Screening data from the randomized, double-blind, placebo-controlled, phase 2b/3 atabecestat EARLY study in preclinical AD participants were used in this analysis. SETTING: The EARLY study was conducted at 143 centers across 14 countries. PARTICIPANTS: 3,569 cognitively unimpaired older adults (Clinical Dementia Rating of 0; aged 60-85 years) screened for inclusion in the EARLY study with Aß status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aß levels (Aß-, n=2,824) and those with pathological Aß levels (Aß+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aß1-42. MEASUREMENTS: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aß groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aß status. RESULTS: Of 3,569 participants, 2,116 were women (59%); 3,006 were Caucasian (84%); mean (SD) age was 68.98 (5.28) years. Aß+ participants performed worse versus Aß- participants on all cognitive composites though the magnitude of the Aß effect was generally small. The Aß+/- effect size for the PACC (Cohen's d=-0.15) was significantly greater than the RBANS (d=-0.097) while the PACC5 effect size (d=-0.139) was numerically larger than the RBANS. When examining subscores from the composites, memory tests (i.e., Free and Cued Selective Reminding Test, Figure Recall) and speed of processing (i.e., Digit-Symbol/Coding on the PACC/RBANS) exhibited the largest Aß+/- effect sizes. CONCLUSIONS: Cross-sectional relationships between Aß and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aß+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aß status cross-sectionally cannot be generalized to sensitivity to change over time.

Amyloid-Related Imaging Abnormalities and Other MRI Findings in a Cognitively Unimpaired Population With and Without Cerebral Amyloid.

BACKGROUND: Screening data from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) studies provide a unique opportunity to compare magnetic resonance imaging (MRI) findings such as amyloid-related imaging abnormalities (ARIA) in cognitively unimpaired elderly with and without elevated cerebral amyloid. OBJECTIVES: To compare screening MRI findings, such as ARIA, in the cognitively unimpaired potential participants of a clinical trial with and without elevated cerebral amyloid. DESIGN: Cross-sectional analysis of structural MRI findings in screening data from the A4 and LEARN studies. SETTING: The A4 Study is a multi-center international clinical trial. The LEARN Study is a multi center observational study in the United States. PARTICIPANTS: Clinically normal older adults (65-85 years) with elevated cerebral amyloid (Aß+; n = 1250, A4) and without elevated cerebral amyloid (Aß-; n = 538, LEARN). MEASUREMENTS: Participants underwent florbetapir positron emission tomography for Aß+/- classification. A centrally read 3T MRI to assess for study eligibility was conducted on study qualified MRI scanners. RESULTS: No ARIA-effusions (ARIA-E) was detected on screening MRI in the Aß+ or Aß- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aß+ cohort compared with 8% in Aß- (P < 0.001). In the Aß+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aß-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aß+ cohort increased the odds for presence of MCH (odds ratio [OR] = 2.03; 95% CI, 1.23 to 3.27, P = 0.004). Cortical infarctions (4% vs 0%) and subcortical infarctions (10% vs 1%) were observed at statistically significantly higher prevalence in the Aß+ cohort compared with Aß- (P < 0.001). Females showed reduced odds of MCH in the Aß+ cohort by a factor of 0.63 (95% CI, 0.47 to 0.84, P = 0.002). CONCLUSIONS: ARIA-E is rare in cognitively unimpaired Aß+ and Aß- populations prior to anti-amyloid drug intervention. ARIA-H in Aß+ was greater than in Aß- populations.

The Computerized Cognitive Composite (C3) in an Alzheimer's Disease Secondary Prevention Trial.

BACKGROUND: Computerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers. OBJECTIVE: To assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3). DESIGN: Cross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD). SETTING: Multi-center international study. PARTICIPANTS: Clinically normal (CN) older adults (65-85; n=4486). MEASUREMENTS: Participants underwent florbetapir-Positron Emission Tomography for Aß+/- classification. They completed the C3 and standard paper and pencil measures included in the Preclinical Alzheimer's Cognitive Composite (PACC). The C3 combines memory measures sensitive to change over time (Cogstate Brief Battery-One Card Learning) and measures shown to be declining early in AD including pattern separation (Behavioral Pattern Separation Test- Object- Lure Discrimination Index) and associative memory (Face Name Associative Memory Exam- Face-Name Matching). C3 acceptability and completion rates were assessed using qualitative and quantitative methods. C3 performance was explored in relation to Aß+/- groups (n=1323/3163) and PACC. RESULTS: C3 was feasible for CN older adults to complete. Rates of incomplete or invalid administrations were extremely low, even in the bottom quartile of cognitive performers (PACC). C3 was moderately correlated with PACC (r=0.39). Aß+ performed worse on C3 compared with Aß- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p<0.001] and at a magnitude comparable to the PACC [d=-0.32 (95%CI: -0.41,-0.23) p<0.001]. Better C3 performance was observed in younger, more educated, and female participants. CONCLUSIONS: These findings provide support for both the feasibility and validity of C3 and computerized cognitive outcomes more generally in AD secondary prevention trials.

Item-Level Investigation of Participant and Study Partner Report on the Cognitive Function Index from the A4 Study Screening Data.

BACKGROUND: Greater subjective cognitive changes on the Cognitive Function Index (CFI) was previously found to be associated with elevated amyloid (Aß) status in participants screening for the A4 Study, reported by study partners and the participants themselves. While the total score on the CFI related to amyloid for both sources respectively, potential differences in the specific types of cognitive changes reported by either participants or their study partners was not investigated. OBJECTIVES: To determine the specific types of subjective cognitive changes endorsed by participants and their study partners that are associated with amyloid status in individuals screening for an AD prevention trial. DESIGN, SETTING, PARTICIPANTS: Four thousand four hundred and eighty-six cognitively unimpaired (CDR=0; MMSE 25-30) participants (ages 65-85) screening for the A4 Study completed florbetapir (Aß) Positron Emission Tomography (PET) imaging. Participants were classified as elevated amyloid (Aß+; n=1323) or non-elevated amyloid (Aß-; n=3163). MEASUREMENTS: Prior to amyloid PET imaging, subjective report of changes in cognitive functioning were measured using the CFI (15 item questionnaire; Yes/Maybe/No response options) and administered separately to both participants and their study partners (i.e., a family member or friend in regular contact with the participant). The impact of demographic factors on CFI report was investigated. For each item of the CFI, the relationship between Aß and CFI response was investigated using an ordinal mixed effects model for participant and study partner report. RESULTS: Independent of Aß status, participants were more likely to report 'Yes' or 'Maybe' compared to the study partners for nearly all CFI items. Older age (r= 0.06, p<0.001) and lower education (r=-0.08, p<0.001) of the participant were associated with higher CFI. Highest coincident odds ratios related to Aß+ for both respondents included items assessing whether 'a substantial decline in memory' had occurred in the last year (ORsp= 1.35 [95% CI 1.11, 1.63]; ORp= 1.55 [95% CI 1.34, 1.79]) and whether the participant had 'seen a doctor about memory' (ORsp= 1.56 [95% CI 1.25, 1.95]; ORp =1.71 [95% CI 1.37, 2.12]). For two items, associations were significant for only study partner report; whether the participant 'Repeats questions' (ORsp = 1.30 [95% CI 1.07, 1.57]) and has 'trouble following the news' (ORsp= 1.46[95% CI 1.12, 1.91]). One question was significant only for participant report; 'trouble driving' (ORp= 1.25 [95% CI 1.04, 1.49]). CONCLUSIONS: Elevated Aß is associated with greater reporting of subjective cognitive changes as measured by the CFI in this cognitively unimpaired population. While participants were more likely than study partners to endorse change on most CFI items, unique CFI items were associated with elevated Aß for participants and their study partners, supporting the value of both sources of information in clinical trials.

Predicting Amyloid Burden to Accelerate Recruitment of Secondary Prevention Clinical Trials.

BACKGROUND: Screening to identify individuals with elevated brain amyloid (Aß+) for clinical trials in Preclinical Alzheimer's Disease (PAD), such as the Anti-Amyloid Treatment in Asymptomatic Alzheimer's disease (A4) trial, is slow and costly. The Trial-Ready Cohort in Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) aims to accelerate and reduce costs of AD trial recruitment by maintaining a web-based registry of potential trial participants, and using predictive algorithms to assess their likelihood of suitability for PAD trials. OBJECTIVES: Here we describe how algorithms used to predict amyloid burden within TRC-PAD project were derived using screening data from the A4 trial. DESIGN: We apply machine learning techniques to predict amyloid positivity. Demographic variables, APOE genotype, and measures of cognition and function are considered as predictors. Model data were derived from the A4 trial. SETTING: TRC-PAD data are collected from web-based and in-person assessments and are used to predict the risk of elevated amyloid and assess eligibility for AD trials. PARTICIPANTS: Pre-randomization, cross-sectional data from the ongoing A4 trial are used to develop statistical models. MEASUREMENTS: Models use a range of cognitive tests and subjective memory assessments, along with demographic variables. Amyloid positivity in A4 was confirmed using positron emission tomography (PET). RESULTS: The A4 trial screened N=4,486 participants, of which N=1323 (29%) were classified as Aß+ (SUVR ≥ 1.15). The Area under the Receiver Operating Characteristic curves for these models ranged from 0.60 (95% CI 0.56 to 0.64) for a web-based battery without APOE to 0.74 (95% CI 0.70 to 0.78) for an in-person battery. The number needed to screen to identify an Aß+ individual is reduced from 3.39 in A4 to 2.62 in the remote setting without APOE, and 1.61 in the remote setting with APOE. CONCLUSIONS: Predictive algorithms in a web-based registry can improve the efficiency of screening in future secondary prevention trials. APOE status contributes most to predictive accuracy with cross-sectional data. Blood-based assays of amyloid will likely improve the prediction of amyloid PET positivity.

The Trial-Ready Cohort for Preclinical/Prodromal Alzheimer's Disease (TRC-PAD) Project: An Overview.

The Trial-Ready Cohort for Preclinical/prodromal Alzheimer's Disease (TRC-PAD) project is a collaborative effort to establish an efficient mechanism for recruiting participants into very early stage Alzheimer's disease trials. Clinically normal and mildly symptomatic individuals are followed longitudinally in a web-based component called the Alzheimer's Prevention Trial Webstudy (APT Webstudy), with quarterly assessment of cognition and subjective concerns. The Webstudy data is used to predict the likelihood of brain amyloid elevation; individuals at relatively high risk are invited for in-person assessment in the TRC screeing phase, during which a cognitive battery is administered and Apolipoprotein E genotype is obtained followed by reassessment of risk of amyloid elevation. After an initial validation study, plasma amyloid peptide ratios will be included in this risk assessment. Based on this second risk calculation, individuals may have amyloid testing by PET scan or lumbar puncture, with those potentially eligible for trials followed in the TRC, while the rest are invited to remain in the APT Webstudy. To date, over 30,000 individuals have participated in the Webstudy; enrollment in the TRC is in its early stage.

Defining the Optimal Target Population for Trials of Polyunsaturated Fatty Acid Supplementation Using the Erythrocyte Omega-3 Index: A Step Towards Personalized Prevention of Cognitive Decline?

OBJECTIVES: to identify the optimal erythrocyte omega-3 index cut-off for predicting cognitive decline and/or polyunsaturated fatty acid (PUFA) treatment response, in order to better define the target population for future dementia prevention trials. DESIGN AND SETTING: Secondary exploratory analysis of the randomized controlled MAPT prevention trial. PARTICIPANTS: 724 dementia-free subjects aged 70 or older with subjective memory complaints, limitations in one instrumental activity of daily living, and/or slow gait speed. INTERVENTION: 800mg docosahexaenoic acid (DHA) and 225mg eicosapentaenoic acid (EPA) daily versus placebo. MEASUREMENTS: Erythrocyte omega-3 index was measured at baseline. Cognition was measured over 3 years with a composite cognitive score (mean of 4 z-scores). RESULTS: Placebo group subjects in the lowest quartile of baseline erythrocyte omega-3 index (i.e. ≤4.83%) underwent significantly more 3-year cognitive decline than the other quartiles (mean composite score difference 0.14, 95%CI [0.00, 0.28], p=0.048). In a ROC curve analysis, the optimal omega-3 index cut-off for predicting notable cognitive decline was 5.3%. There was a consistent but non-significant difference in 3-year cognitive decline of approximately 0.12 points between PUFA-treated and placebo subjects with "low" baseline omega-3 index when the cut-off was set at ≤5.27%. CONCLUSIONS: Dementia-free older adults with an omega-3 index below approximately 5% are at increased risk of cognitive decline, and could be a good target population for testing the cognitive effects of PUFA supplementation.

Design and implementation of a randomized controlled social and mobile weight loss trial for young adults (project SMART).

PURPOSE: To describe the theoretical rationale, intervention design, and clinical trial of a two-year weight control intervention for young adults deployed via social and mobile media. METHODS: A total of 404 overweight or obese college students from three Southern California universities (M(age) = 22( ± 4) years; M(BMI) = 29( ± 2.8); 70% female) were randomized to participate in the intervention or to receive an informational web-based weight loss program. The intervention is based on behavioral theory and integrates intervention elements across multiple touch points, including Facebook, text messaging, smartphone applications, blogs, and e-mail. Participants are encouraged to seek social support among their friends, self-monitor their weight weekly, post their health behaviors on Facebook, and e-mail their weight loss questions/concerns to a health coach. The intervention is adaptive because new theory-driven and iteratively tailored intervention elements are developed and released over the course of the two-year intervention in response to patterns of use and user feedback. Measures of body mass index, waist circumference, diet, physical activity, sedentary behavior, weight management practices, smoking, alcohol, sleep, body image, self-esteem, and depression occur at 6, 12, 18, and 24 months. Currently, all participants have been recruited, and all are in the final year of the trial. CONCLUSION: Theory-driven, evidence-based strategies for physical activity, sedentary behavior, and dietary intake can be embedded in an intervention using social and mobile technologies to promote healthy weight-related behaviors in young adults.