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BackgroundGreater 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.ObjectivesTo 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, participantsFour 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).MeasurementsPrior 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.ResultsIndependent 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

BackgroundComputerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.ObjectiveTo assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).DesignCross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).SettingMulti-center international study.ParticipantsClinically normal (CN) older adults (65-85; n=4486).MeasurementsParticipants underwent florbetapir-Positron Emission Tomography for Aβ+/- 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 Aβ+/- groups (n=1323/3163) and PACC.ResultsC3 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). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p

BackgroundComputerized cognitive assessments may improve Alzheimer's disease (AD) secondary prevention trial efficiency and accuracy. However, they require validation against standard outcomes and relevant biomarkers.ObjectiveTo assess the feasibility and validity of the tablet-based Computerized Cognitive Composite (C3).DesignCross-sectional analysis of cognitive screening data from the A4 study (Anti-Amyloid in Asymptomatic AD).SettingMulti-center international study.ParticipantsClinically normal (CN) older adults (65-85; n=4486).MeasurementsParticipants underwent florbetapir-Positron Emission Tomography for Aβ+/- 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 Aβ+/- groups (n=1323/3163) and PACC.ResultsC3 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). Aβ+ performed worse on C3 compared with Aβ- [unadjusted Cohen's d=-0.22 (95%CI: -0.31,-0.13) p

BackgroundIt 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.MethodsBilateral 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).ResultsAt 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.ConclusionsFor 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 registrationNCT01898689.

PurposeTo 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.MethodsA 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.ConclusionTheory-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.

The goal of the Biostatistics Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has been to ensure that sound study designs and statistical methods are used to meet the overall goals of ADNI. We have supported the creation of a well-validated and well-curated longitudinal database of clinical and biomarker information on ADNI participants and helped to make this accessible and usable for researchers. We have developed a statistical methodology for characterizing the trajectories of clinical and biomarker change for ADNI participants across the spectrum from cognitively normal to dementia, including multivariate patterns and evidence for heterogeneity in cognitive aging. We have applied these methods and adapted them to improve clinical trial design. ADNI-4 will offer us a chance to help extend these efforts to a more diverse cohort with an even richer panel of biomarker data to support better knowledge of and treatment for Alzheimer's disease and related dementias. HIGHLIGHTS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) Biostatistics Core provides study design and analytic support to ADNI investigators. Core members develop and apply novel statistical methodology to work with ADNI data and support clinical trial design. The Core contributes to the standardization, validation, and harmonization of biomarker data. The Core serves as a resource to the wider research community to address questions related to the data and study as a whole., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The Alzheimer's Disease Neuroimaging Initiative (ADNI) Clinical Core is responsible for coordination of all clinical activities at the ADNI sites, including project management, regulatory oversight, and site management and monitoring, as well as the collection of all clinical data and management of all study data. The Clinical Core is also charged with determining the clinical classifications and criteria for enrollment in evolving AD trials and enabling the ongoing characterization of the cross-sectional features and longitudinal trajectories of the ADNI cohorts with application of these findings to optimal clinical trial designs. More than 2400 individuals have been enrolled in the cohorts since the inception of ADNI, facilitating refinement of our understanding of the AD trajectory and allowing academic and industry investigators to model therapeutic trials across the disease spectrum from the presymptomatic stage through dementia. HIGHLIGHTS: Since 2004, the Alzheimer's Disease Neuroimaging Initiative (ADNI) Clinical Core has overseen the enrollment of > 2400 participants with mild cognitive impairment, mild Alzheimer's disease (AD) dementia, and normal cognition. The longitudinal dataset has elucidated the full cognitive and clinical trajectory of AD from its presymptomatic stage through the onset of dementia. The ADNI data have supported the design of most major trials in the field., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Black or African American (hereinafter, Black) and Hispanic or Latino/a/x (hereinafter, Latinx) adults are disproportionally affected by Alzheimer disease, but most research studies do not enroll adequate numbers of both of these populations. The Alzheimer's Disease Neuroimaging Initiative-3 (ADNI3) launched a diversity taskforce to pilot a multipronged effort to increase the study inclusion of Black and Latinx older adults., Objective: To describe and evaluate the culturally informed and community-engaged inclusion efforts to increase the screening and enrollment of Black and Latinx older adults in ADNI3., Design, Setting, and Participants: This cross-sectional study used baseline data from a longitudinal, multisite, observational study conducted from January 15, 2021, to July 12, 2022, with no follow-up. The study was conducted at 13 ADNI3 sites in the US. Participants included individuals aged 55 to 90 years without cognitive impairment and those with mild cognitive impairment or Alzheimer disease., Exposures: Efforts included (1) launch of an external advisory board, (2) changes to the study protocol, (3) updates to the digital prescreener, (4) selection and deployment of 13 community-engaged research study sites, (5) development and deployment of local and centralized outreach efforts, and (6) development of a community-science partnership board., Main Outcomes and Measures: Screening and enrollment numbers from centralized and local outreach efforts, digital advertisement metrics, and digital prescreener completion., Results: A total of 91 participants enrolled in the trial via centralized and local outreach efforts, of which 22 (24.2%) identified as Latinx and 55 (60.4%) identified as Black (median [IQR] age, 65.6 [IQR, 61.5-72.5] years; 62 women [68.1%]). This represented a 267.6% increase in the monthly rate of enrollment (before: 1.11 per month; during: 4.08 per month) of underrepresented populations. For the centralized effort, social media advertisements were run between June 1, 2021, and July 31, 2022, which resulted in 2079 completed digital prescreeners, of which 1289 met criteria for subsequent site-level screening. Local efforts were run between June 1, 2021, to July 31, 2022. A total of 151 participants underwent site-level screening (100 from local efforts, 41 from centralized efforts, 10 from other sources)., Conclusions and Relevance: In this cross-sectional study of pilot inclusion efforts, a culturally informed, community-engaged approach increased the inclusion of Black and Latinx participants in an Alzheimer disease cohort study.

Background: Leveraging Alzheimer's disease (AD) imaging biomarkers and longitudinal cognitive data may allow us to establish evidence of cognitive resilience (CR) to AD pathology in-vivo. Here, we applied latent class mixture modeling, adjusting for sex, baseline age, and neuroimaging biomarkers of amyloid, tau and neurodegeneration, to a sample of cognitively unimpaired older adults to identify longitudinal trajectories of CR., Methods: We identified 200 Harvard Aging Brain Study (HABS) participants (mean age = 71.89 years, SD = 9.41 years, 59% women) who were cognitively unimpaired at baseline with 2 or more timepoints of cognitive assessment following a single amyloid-PET, tau-PET and structural MRI. We examined latent class mixture models with longitudinal cognition as the dependent variable and time from baseline, baseline age, sex, neocortical Aβ, entorhinal tau, and adjusted hippocampal volume as independent variables. We then examined group differences in CR-related factors across the identified subgroups from a favored model. Finally, we applied our favored model to a dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI; n = 160, mean age = 73.9 years, SD = 7.6 years, 60% women)., Results: The favored model identified 3 latent subgroups, which we labelled as Normal (71% of HABS sample), Resilient (22.5%) and Declining (6.5%) subgroups. The Resilient subgroup exhibited higher baseline cognitive performance and a stable cognitive slope. They were differentiated from other groups by higher levels of verbal intelligence and past cognitive activity. In ADNI, this model identified a larger Normal subgroup (88.1%), a smaller Resilient subgroup (6.3%) and a Declining group (5.6%) with a lower cognitive baseline., Conclusion: These findings demonstrate the value of data-driven approaches to identify longitudinal CR groups in preclinical AD. With such an approach, we identified a CR subgroup who reflected expected characteristics based on previous literature, higher levels of verbal intelligence and past cognitive activity., (© 2024. The Author(s).)

Background and Objectives: Preclinical Alzheimer disease (AD) trials simultaneously test candidate treatments and the implications of disclosing biomarker information to cognitively unimpaired individuals., Methods: The EARLY trial was a randomized, double-blind, placebo-controlled, phase 2b/3 study conducted in 143 centers across 14 countries from November 2015 to December 2018 after being stopped prematurely because of treatment-related hepatotoxicity. Participants age 60-85 years deemed cognitively unimpaired were disclosed an elevated or not elevated brain amyloid result by a certified clinician. Among 3,686 participants, 2,066 underwent amyloid imaging, 1,394 underwent CSF biomarker assessment, and 226 underwent both. Among biomarker-tested participants with at least one change score on an outcome of interest, 680 with elevated and 2,698 with not elevated amyloid were included in this analysis. We compared the Geriatric Depression Scale (GDS), the State-Trait Anxiety Scale (STAI), and the Columbia Suicide Severity Rating Scale (CSSRS) before disclosure between amyloid groups. After disclosure, we assessed for differences in the Impact of Events Scale (IES, collected 24-72 hours after disclosure), a measure of intrusive thoughts. Additional scales included the Concerns for AD scale., Results: Among 3378 included participants, the mean (SD) age was 69.0 (5.3); most were female (60%) and White race (84%). No differences were observed before disclosure between participants with elevated and not elevated amyloid for the GDS, STAI, or CSSRS. Participants with elevated amyloid demonstrated higher Concerns for AD scores compared with participants with not elevated amyloid before disclosure. Participants with elevated amyloid demonstrated higher IES scores (9.6 [10.8] vs 5.1 [8.0]) after disclosure and increased Concerns about AD. Patterns of reactions (elevated vs not elevated) were similar for biomarker modalities, although scores were lower among those undergoing CSF compared with PET testing. Although score differences were apparent comparing geographical regions, patterns of group differences were similar., Discussion: Although sample bias must be considered, these results suggest that amyloid disclosure resulted in increased perceived risk and mild distress in those learning an elevated result. Although this study did not assess psychological safety, observed associations intrusive thoughts and distress could be important considerations in the future clinical practice., Competing Interests: J.D. Grill reports grant funding from the NIH (P30 AG066519), Eli Lilly, Biogen, Eisai, BrightFocus Foundation, and the Alzheimer's Association. R. Raman reports grant funding from the NIH, Eli Lilly, Eisai, American Heart Association and the Alzheimer's Association. K. Ernstrom reports grant funding from the NIH, Eli Lilly, and Eisai. S. Wang reports grant funding from the NIH, Eli Lilly, and Eisai. M.C. Donohue reports consulting fees from Roche and his spouse is a full time employee of Janssen. P.S. Aisen reports research funding from NIH, the Alzheimer's Association, Janssen, Lilly and Eisai, and consults with Merck, Roche, Genentech, Abbvie, Biogen, ImmunoBrain Checkpoint and Arrowhead. J. Karlawish reports grant funding from Eisai and Biogen. D. Henley is a full time employee of Janssen. G. Romano is a former full time employee of Janssen. G. Novak is a former full time employee of Janssen. H.R. Brashear is a former full time employee of Janssen. R.A. Sperling reports serving as a paid consultant for AC Immune, Alector, Acumen, Alnylam, Cytox, Genentech, Janssen, Neuraly, NervGen, Neurocentria, Oligomerix, Prothena, Renew, Vigil Neuroscience, Ionis and Vaxxinity. She receives research support from Eisai and Eli Lilly as part of public-private partnership clinical trials, and also receives research support from the following grants: P01 AG036694, U24 AG057437, R01 AG063689, R01 AG054029, R01 AG053798, GHR Foundation, National Institute on Aging, Fidelity Biosciences, and the Alzheimer's Association. Full disclosure form information provided by the authors is available with the full text of this article at Neurology.org/cp., (© 2024 American Academy of Neurology.)

Introduction: Incorporating blood-based Alzheimer's disease biomarkers such as tau and amyloid beta (Aβ) into screening algorithms may improve screening efficiency., Methods: Plasma Aβ, phosphorylated tau (p-tau)181, and p-tau217 concentration levels from AHEAD 3-45 study participants were measured using mass spectrometry. Tau concentration ratios for each proteoform were calculated to normalize for inter-individual differences. Receiver operating characteristic (ROC) curve analysis was performed for each biomarker against amyloid positivity, defined by > 20 Centiloids. Mixture of experts analysis assessed the value of including tau concentration ratios into the existing predictive algorithm for amyloid positron emission tomography status., Results: The area under the receiver operating curve (AUC) was 0.87 for Aβ42/Aβ40, 0.74 for phosphorylated variant p-tau181 ratio (p-tau181/np-tau181), and 0.92 for phosphorylated variant p-tau217 ratio (p-tau217/np-tau217). The Plasma Predicted Centiloid (PPC), a predictive model including p-tau217/np-tau217, Aβ42/Aβ40, age, and apolipoprotein E improved AUC to 0.95., Discussion: Including plasma p-tau217/np-tau217 along with Aβ42/Aβ40 in predictive algorithms may streamline screening preclinical individuals into anti-amyloid clinical trials., Clinicaltrials: gov Identifier: NCT04468659 HIGHLIGHTS: The addition of plasma phosphorylated variant p-tau217 ratio (p-tau217/np-tau217) significantly improved plasma biomarker algorithms for identifying preclinical amyloid positron emission tomography positivity. Prediction performance at higher NAV Centiloid levels was improved with p-tau217/np-tau217. All models generated for this study are incorporated into the Plasma Predicted Centiloid (PPC) app for public use., (© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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., Competing Interests: RR has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. KCH, RY, and JRS are employees and minor shareholders of Eli Lilly and Company. KH, OL and KE have received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, and Eisai. MD has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai, reports consulting fees from Roche and his spouse is a full-time employee of Janssen. DMH is part of the AHEAD 3-45 Study team. AHEAD A3-45 Study is a public-private partnership with funding from the National Institutes of Aging/NIH, Eisai, and Co., GHR Foundation, Alzheimer’s Association, and philanthropic donors. Additionally, she receives direct funding from the Alzheimer’s Association and American Heart Association. ALP has received research support from the National Institutes of Health (NIH), Alzheimer’s Association, Hart Family Foundation, Alector, Cognition Therapeutics, Eisai, Eli Lilly, and Vivoryon. She has served as a consultant for Medscape. AGS has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, Eli Lilly, Biogen, Eisai, Janssen, Vivoryon, Cassava, Bristol Myers Squibb, and the American College of Radiology. PSA has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. RAS reports grant support from Eisai, and Eli Lilly and reported serving as a consultant for AbbVie, AC Immune, Alector, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. JG has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, BrightFocus Foundation, Eli Lilly, Biogen, Genentech, and Eisai. He has received personal fees for providing consulting to SiteRx and editorial service to Alzheimer’s and Dementia.

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., Competing Interests: The authors have no conflicts of interest related to this manuscript.

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., Competing Interests: RAR: has research support from the National Institute on Aging, the Alzheimer’s Association and is a consultant for Amydis Inc, Bioivt, Lexeo, Keystone Bio, Allyx, DiamiR, Ionis and PrecisionMed. MD: Nothing to report. OL: Nothing to report. SAL: Nothing to report. RR has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. GJM has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Gates Ventures, Eli Lilly, and Eisai. KAJ has received research funding from National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, and the GHR Foundation. He has served as a consultant for Merkc, Novartis, Janssen, and Prothena. DMR received salary and research support from the National Institutes of Health and has received payment or honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) course and External Advisory Boards from the University of California-Davis, Washington University, Boston University and Northwestern. She has also received travel support to ACTC meetings, to the University of California Advisory Board Meeting and the Washington University Advisory Board Meeting. RY is an employee and minor shareholder of Eli Lilly and Company. KCH is an employee and minor shareholder of Eli Lilly and Company. JRS is an employee and minor shareholder of Eli Lilly and Company. PSA has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. RAS reports grant support from the National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, GHR Foundation, and Gates Ventures. She has received trial research funding from Eisai and Eli Lilly for public-private partnership trials. She reported serving as a consultant for AbbVie, AC Immune, Alector, Biohaven, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity.

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 Aβ 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., Competing Interests: KVP has received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437). PM is a full-time employee of Cogstate. DMR received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437) and has receive payment or honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) course and External Advisory Boards from the University of California-Davis, Washington University, Boston University and Northwestern. She has also received travel support to ACTC meetings, to the University of California Advisory Board Meeting and the Washington University Advisory Board Meeting. MD reports that his spouse is a full-time employee of Janssen, and he has served as a consultant to Roche. AL has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. PAS has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. RAS reports grant support from Eisai, and Eli Lilly and reported serving as a consultant for AbbVie, AC Immune, Alector, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity.

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., Competing Interests: GJM has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, the American Heart Association, Gates Ventures, Eli Lilly, and Eisai. APS: Nothing to report. MD: Nothing to report. HQ: Nothing to report. SNJ: Nothing to report. OA: Nothing to report. RG: Nothing to report. OB: Nothing to report. RAR: has research support from the National Institute on Aging, the Alzheimer’s Association and is a consultant for Amydis Inc, Bioivt, Lexeo, Keystone Bio, Allyx, DiamiR, Ionis and PrecisionMed. SAL: Nothing to report. RAS reports grant support from the National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, GHR Foundation, and Gates Ventures. She has received trial research funding from Eisai and Eli Lilly for public-private partnership trials. She reported serving as a consultant for AbbVie, AC Immune, Alector, Biohaven, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. PSA has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint.

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., Competing Interests: DMR received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437) and has receive payment or honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) course and External Advisory Boards from the University of California-Davis, Washington University, Boston University and Northwestern. She has also received travel support to ACTC meetings, to the University of California Advisory Board Meeting and the Washington University Advisory Board Meeting. PBR has received grant support from the National Institutes of Aging, Alzheimer’s Clinical Trials Consortium, Richman Family Precision Medicine Center of Excellence on Alzheimer’s Disease, Eisai, Functional Neuromodulation, and Lilly; honoraria from GLG, Leerink, Cerevel, Cerevance, Bioxcel, Sunovion, Acadia, Medalink, Novo Nordisk, Noble Insights, TwoLabs, Otsuka, Lundbeck, Acadia, MedaCorp, ExpertConnect, HMP Global, Sinaptica, Synaptogenix, and Neurology Week. RAS reports grant support from Eisai, and Eli Lilly and reported serving as a consultant for AbbVie, AC Immune, Alector, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. MD reports that his spouse is a full-time employee of Janssen, and he has served as a consultant to Roche. RR has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. AL has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. PAS has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint.

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 (Aβ)., 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% Aβ 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 Aβ 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 Aβ on cognitive change (p = .025) such that stronger connectivity was associated with reduced Aβ-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 Aβ-related cognitive decline., Competing Interests: All authors confirm that they do not have conflicts of interest pertinent to this manuscript.

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 Aβ 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., Competing Interests: DMH: has received research support from the American Heart Association and the Alzheimer’s Association, American Heart Association and GHR Foundation. OL: Nothing to report. MCD: has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai, reports consulting fees from Roche and his spouse is a full-time employee of Janssen. RR: has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. PSA: has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. KAJ: has received research funding from National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, and the GHR Foundation. He has served as a consultant for Merck, Novartis, Janssen, and Prothena. RAR: has research support from the National Institute on Aging, the Alzheimer’s Association and is a consultant for Amydis Inc, Bioivt, Lexeo, Keystone Bio, Allyx, DiamiR, Ionis and PrecisionMed. RAS: reports grant support from the National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, GHR Foundation, and Gates Ventures. She has received trial research funding from Eisai and Eli Lilly for public-private partnership trials. She reported serving as a consultant for AbbVie, AC Immune, Alector, Biohaven, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity.

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 (Aβ+) 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 (Aβ-) 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. Aβ+ participants were randomized to either placebo (n=583) or solanezumab (n=564) in the A4 Study. A subset of Aβ+ underwent tau PET imaging in A4 (n=350). Aβ- 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 Aβ- and A4 Aβ+ (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., Competing Interests: RAS reports grant support from the National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, GHR Foundation, and Gates Ventures. She has received trial research funding from Eisai and Eli Lilly for public-private partnership trials. She reported serving as a consultant for AbbVie, AC Immune, Alector, Biohaven, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. MCD has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai, reports consulting fees from Roche and his spouse is a full-time employee of Janssen. KAJ has received research funding from National Institutes on Aging, National Institutes of Health, Alzheimer’s Association, and the GHR Foundation. He has served as a consultant for Merck, Novartis, Janssen, and Prothena. RAR has research support from the National Institute on Aging, the Alzheimer’s Association and is a consultant for Amydis Inc, Bioivt, Lexeo, Keystone Bio, Allyx, DiamiR, Ionis and PrecisionMed. CJ has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. DMR received salary and research support from the National Institutes of Health and has received payment or honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) course and External Advisory Boards from the University of California-Davis, Washington University, Boston University and Northwestern. She has also received travel support to ACTC meetings, to the University of California Advisory Board Meeting and the Washington University Advisory Board Meeting. JG has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, BrightFocus Foundation, Eli Lilly, Biogen, Genentech, and Eisai. He has received personal fees for providing consulting to SiteRx and editorial service to Alzheimer’s and Dementia. JLH has received research support from the National Institutes of Health, the Alzheimer’s Association, Eli Lilly, and Eisai and has received honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) RR has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. AL has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. OL has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. GJM has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Gates Ventures, Eli Lilly, and Eisai. RY is an employee and minor shareholder of Eli Lilly and Company. KCH is an employee and minor shareholder of Eli Lilly and Company. JS is an employee and minor shareholder of Eli Lilly and Company. PSA has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint.

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., Competing Interests: REA received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437). JDG reports funding from NIA, the Alzheimer’s Association, BrightFocus Foundation, Eli Lilly, Biogen, Genentech, and Eisai. He has provided consulting to SiteRx and received personal payments for editorial service to Alzheiemer’s and Dementia. GAM was a site principal investigator for A4, has received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437), has received salary support from Eisai Inc. and Eli Lilly and Company for serving as a site principal investigator for clinical trials, and has received payments for serving as a consultant for Ono Pharma USA, Inc. DMR received salary support from the A4 study (R01 AG063689, U19AG010483 and U24AG057437) and has receive payment or honoraria from USC Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT AD) course, Grand Rounds and External Advisory Boards from the University of California, Washington University, Boston University and Northwestern as well as travel support to ACTC meetings, to University of California Advisory Board Meeting and Washington University Advisory Board Meeting. MCD reports that his spouse is a full-time employee of Janssen, and he has served as a consultant to Roche. AL has received research support from the National Institutes of Health (NIH), the Alzheimer’s Association, American Heart Association, Eli Lilly and Eisai. PAS has received grants or contracts from the National Institutes of Health (NIH), Alzheimer’s Association, Foundation for NIH (FNIH), Lilly, Janssen and Eisai and consulting fees from Merck, Biogen, AbbVie, Roche, and Immunobrain Checkpoint. RAS reports grant support from Eisai, and Eli Lilly and reported serving as a consultant for AbbVie, AC Immune, Alector, Bristol-Myers-Squibb, Ionis, Janssen, Genentech, Merck, Prothena, Roche, and Vaxxinity. Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

There has been considerable progress in the prevention and treatment of cardiovascular disease, reducing the population burden of cardiovascular morbidity and mortality. Recently, some randomized trials, including the SPRINT (Systolic Blood Pressure Intervention Trial), have suggested that improvements in cardiovascular risk factors may also slow cognitive decline and reduce the eventual development of dementia. Unfortunately, the randomized trial template that has been used repeatedly to successfully demonstrate reductions in major adverse cardiac events faces several design and analytic obstacles when applied in the context of cognitive decline and dementia. Here, we review these obstacles, motivated by SPRINT and the context of selecting an appropriate cognitive end point for future preventive randomized trials. A few options are available, spanning neuropsychological test scores or composites reflecting specific domains of cognitive function, adjudicated cognitive impairment, or potentially physiological biomarkers. This choice entails considerations around statistical power, modes of ascertainment, the clinical relevance of treatment effects, a myriad of statistical issues (interval censoring, missing data, the competing risk of death, practice effects, etc), as well as ethical considerations around equipoise. Collectively, these considerations indicate that trials aiming to mitigate the cardiovascular contribution to cognitive decline and dementia will generally need to be large, inclusive of a wide age range of older adults, and with multiple years of follow-up., Competing Interests: Disclosures None.

Background: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease., Methods: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116., Results: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%., Conclusions: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.)., (Copyright © 2023 Massachusetts Medical Society.)

Background: Trials of monoclonal antibodies that target various forms of amyloid at different stages of Alzheimer's disease have had mixed results., Methods: We tested solanezumab, which targets monomeric amyloid, in a phase 3 trial involving persons with preclinical Alzheimer's disease. Persons 65 to 85 years of age with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini-Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18 F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomly assigned in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary end point was the change in the Preclinical Alzheimer Cognitive Composite (PACC) score (calculated as the sum of four z scores, with higher scores indicating better cognitive performance) over a period of 240 weeks., Results: A total of 1169 persons underwent randomization: 578 were assigned to the solanezumab group and 591 to the placebo group. The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia. At 240 weeks, the mean change in PACC score was -1.43 in the solanezumab group and -1.13 in the placebo group (difference, -0.30; 95% confidence interval, -0.82 to 0.22; P = 0.26). Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group. Amyloid-related imaging abnormalities (ARIA) with edema occurred in less than 1% of the participants in each group. ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group., Conclusions: Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer's disease. (Funded by the National Institute on Aging and others; A4 ClinicalTrials.gov number, NCT02008357.)., (Copyright © 2023 Massachusetts Medical Society.)

Mixed model repeated measures (MMRM) is the most common analysis approach used in clinical trials for Alzheimer's disease and other progressive diseases measured with continuous outcomes over time. The model treats time as a categorical variable, which allows an unconstrained estimate of the mean for each study visit in each randomized group. Categorizing time in this way can be problematic when assessments occur off-schedule, as including off-schedule visits can induce bias, and excluding them ignores valuable information and violates the intention to treat principle. This problem has been exacerbated by clinical trial visits which have been delayed due to the COVID19 pandemic. As an alternative to MMRM, we propose a constrained longitudinal data analysis with natural cubic splines that treats time as continuous and uses test version effects to model the mean over time. Compared to categorical-time models like MMRM and models that assume a proportional treatment effect, the spline model is shown to be more parsimonious and precise in real clinical trial datasets, and has better power and Type I error in a variety of simulation scenarios., (© 2023 The Authors. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Introduction: Lumbar puncture (LP) to collect and examine cerebrospinal fluid (CSF) is an important option for the evaluation of Alzheimer's disease (AD) biomarkers but it is not routinely performed due to its invasiveness and link to adverse effects (AE)., Methods: We include all participants who received at least one LP in the Alzheimer's Disease Neuroimaging Initiative (ADNI) Study. For comparison between groups, two-sample t -tests for continuous, and Pearson's chi-square test for categorical variables were performed., Results: Two hundred twenty-seven LP-related AEs were reported by 172 participants after 1702 LPs (13.3%). The mean age of participants who reported at least one AE was 69.79 (standard deviation (SD) 6.3) versus none 72.44 (7.17) years ( p  < 0.001) with female predominance (115/172 = 67.4% vs 435/913 = 48%), and had greater entorhinal cortical thickness and hippocampal volume (3.903 (0.782) vs 3.684 (0.775) mm, p  = 0.002; 7.38 (1.06) vs 7.05 (1.15) mm 3 , p  < 0.001), respectively., Discussion: We found that younger age, female sex, and greater thickness of the entorhinal cortex were associated with a higher rate of LP-related AE reports., Competing Interests: All authors have no conflicts to disclose. Author disclosures are available in the Supporting Information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Introduction: The Alzheimer's disease (AD) continuum begins with a long asymptomatic or preclinical stage, during which amyloid beta (Aβ) is accumulating for more than a decade prior to widespread cortical tauopathy, neurodegeneration, and manifestation of clinical symptoms. The AHEAD 3-45 Study (BAN2401-G000-303) is testing whether intervention with lecanemab (BAN2401), a humanized immunoglobulin 1 (IgG1) monoclonal antibody that preferentially targets soluble aggregated Aβ, initiated during this asymptomatic stage can slow biomarker changes and/or cognitive decline. The AHEAD 3-45 Study is conducted as a Public-Private Partnership of the Alzheimer's Clinical Trial Consortium (ACTC), funded by the National Institute on Aging, National Institutes of Health (NIH), and Eisai Inc., Methods: The AHEAD 3-45 Study was launched on July 14, 2020, and consists of two sister trials (A3 and A45) in cognitively unimpaired (CU) individuals ages 55 to 80 with specific dosing regimens tailored to baseline brain amyloid levels on screening positron emission tomography (PET) scans: intermediate amyloid (≈20 to 40 Centiloids) for A3 and elevated amyloid (>40 Centiloids) for A45. Both trials are being conducted under a single protocol, with a shared screening process and common schedule of assessments. A3 is a Phase 2 trial with PET-imaging end points, whereas A45 is a Phase 3 trial with a cognitive composite primary end point. The treatment period is 4 years. The study utilizes innovative approaches to enriching the sample with individuals who have elevated brain amyloid. These include recruiting from the Trial-Ready Cohort for Preclinical and Prodromal Alzheimer's disease (TRC-PAD), the Australian Dementia Network (ADNeT) Registry, and the Japanese Trial Ready Cohort (J-TRC), as well as incorporation of plasma screening with the C2N mass spectrometry platform to quantitate the Aβ 42/40 ratio (Aβ 42/40), which has been shown previously to reliably identify cognitively normal participants not likely to have elevated brain amyloid levels. A blood sample collected at a brief first visit is utilized to "screen out" individuals who are less likely to have elevated brain amyloid, and to determine the participant's eligibility to proceed to PET imaging. Eligibility to randomize into the A3 Trial or A45 Trial is based on the screening PET imaging results., Result: The focus of this article is on the innovative design of the study., Discussion: The AHEAD 3-45 Study will test whether with lecanemab (BAN2401) can slow the accumulation of tau and prevent the cognitive decline associated with AD during its preclinical stage. It is specifically targeting both the preclinical and the early preclinical (intermediate amyloid) stages of AD and is the first secondary prevention trial to employ plasma-based biomarkers to accelerate the screening process and potentially substantially reduce the number of screening PET scans., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The poor generalizability of clinical research data due to the enrollment of highly educated, non-Latinx White participants hampers the development of therapies for Alzheimer's disease (AD). Black and Latinx older adults have a greater risk for dementia, yet it is unclear how health-care disparities and sociocultural factors influence potential AD therapies and prognosis. Low enrollment of under-represented populations may be attributable to several factors including greater exclusion due to higher rates of comorbidities, lower access to AD clinics, and the legacy of unethical treatment in medical research. This perspective outlines solutions tested in the Brain Health Registry (BHR) and the Alzheimer's Disease Neuroimaging Initiative (ADNI), including culturally-informed digital research methods, community-engaged research strategies, leadership from under-represented communities, and the reduction of exclusion criteria based on comorbidities. Our successes demonstrate that it is possible to increase the inclusion and engagement of under-represented populations into US-based clinical studies, thereby increasing the generalizability of their results., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-β-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid β levels. For participants with highly elevated baseline amyloid β levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid β, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

More than 50 million older people worldwide are suffering from dementia, and this number is estimated to increase to 150 million by 2050. Greater caregiver burdens and financial impacts on the healthcare system are expected as we wait for an effective treatment for dementia. Researchers are constantly exploring new therapies and screening approaches for the early detection of dementia. Artificial intelligence (AI) is widely applied in dementia research, including machine learning and deep learning methods for dementia diagnosis and progression detection. Computerized apps are also convenient tools for patients and caregivers to monitor cognitive function changes. Furthermore, social robots can potentially provide daily life support or guidance for the elderly who live alone. This review aims to provide an overview of AI applications in dementia research. We divided the applications into three categories according to different stages of cognitive impairment: (1) cognitive screening and training, (2) diagnosis and prognosis for dementia, and (3) dementia care and interventions. There are numerous studies on AI applications for dementia research. However, one challenge that remains is comparing the effectiveness of different AI methods in real clinical settings., Competing Interests: The authors declare none., (© The Author(s) 2022.)

Introduction: An analysis of the ethnocultural and socioeconomic composition of Alzheimer's Disease Neuroimaging Initiative (ADNI) participants is needed to assess the generalizability of ADNI data to diverse populations., Methods: ADNI data collected between October 2004 and November 2020 were used to determine ethnocultural and educational composition of the sample and differences in the following metrics: screening, screen fails, enrollment, biomarkers., Results: Of 3739 screened individuals, 11% identified as being from ethnoculturally underrepresented populations (e.g., Black, Latinx) and 16% had <12 years of education. Of 2286 enrolled participants, 11% identified as ethnoculturally underrepresented individuals and 15% had <12 years of education. This participation is considerably lower than US Census data for adults 60+ (ethnoculturally underrepresented populations: 25%; <12 years of education: 4%). Individuals with <12 years of education failed screening at a higher rate., Discussion: Our findings suggest that ADNI results may not be entirely generalizable to ethnoculturally diverse and low education populations., (© 2022 the Alzheimer's Association.)

Background: Ultrasound-guided percutaneous cryoneurolysis is an analgesic technique in which a percutaneous probe is used to reversibly ablate a peripheral nerve(s) using exceptionally low temperature, and has yet to be evaluated with randomized, controlled trials. Pain after mastectomy can be difficult to treat, and the authors hypothesized that the severity of surgically related pain would be lower on postoperative day 2 with the addition of cryoanalgesia compared with patients receiving solely standard-of-care treatment., Methods: Preoperatively, participants at one enrolling center received a single injection of ropivacaine, 0.5%, paravertebral nerve block at T3 or T4, and perineural catheter. Participants subsequently underwent an active or sham ultrasound-guided percutaneous cryoneurolysis procedure of the ipsilateral T2 to T5 intercostal nerves in a randomized, patient- and observer-masked fashion. Participants all received a continuous paravertebral block with ropivacaine, 0.2%, until the early morning of discharge (usually postoperative day 2). The primary endpoint was the average pain level measured using a 0 to 10 numeric rating scale the afternoon of postoperative day 2. Participants were followed for 1 yr., Results: On postoperative day 2, participants who had received active cryoneurolysis (n = 31) had a median [interquartile range] pain score of 0 [0 to 1.4] versus 3.0 [2.0 to 5.0] in patients given sham (n = 29): difference -2.5 (97.5% CI, -3.5 to -1.5), P < 0.001. There was evidence of superior analgesia through month 12. During the first 3 weeks, cryoneurolysis lowered cumulative opioid use by 98%, with the active group using 1.5 [0 to 14] mg of oxycodone compared with 72 [20 to 120] mg in the sham group (P < 0.001). No oral analgesics were required by any patient between months 1 and 12. After 1 yr chronic pain had developed in 1 (3%) active compared with 5 (17%) sham participants (P < 0.001)., Conclusions: Percutaneous cryoneurolysis markedly improved analgesia without systemic side effects or complications after mastectomy., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: The common technique using a basal infusion for an ambulatory continuous peripheral nerve blocks frequently results in exhaustion of the local anesthetic reservoir before resolution of surgical pain. This study was designed to improve and prolong analgesia by delaying initiation using an integrated timer and delivering a lower hourly volume of local anesthetic as automated boluses. The hypothesis was that compared with a traditional continuous infusion, ropivacaine administered with automated boluses at a lower dose and 5-h delay would (1) provide at least noninferior analgesia (difference in average pain no greater than 1.7 points) while both techniques were functioning (average pain score day after surgery) and (2) result in a longer duration (dual primary outcomes)., Methods: Participants (n = 70) undergoing foot or ankle surgery with a popliteal-sciatic catheter received an injection of ropivacaine 0.5% with epinephrine (20 ml) and then were randomized to receive ropivacaine (0.2%) either as continuous infusion (6 ml/h) initiated before discharge or as automated boluses (8 ml every 2 h) initiated 5 h after discharge using a timer. Both groups could self-deliver supplemental boluses (4 ml, lockout 30 min); participants and outcome assessors were blinded to randomization. All randomized participants were included in the data analysis., Results: The day after surgery, participants with automated boluses had a median [interquartile range] pain score of 0.0 [0.0 to 3.0] versus 3.0 [1.8 to 4.8] for the continuous infusion group, with an odds ratio of 3.1 (95% CI, 1.23 to 7.84; P = 0.033) adjusting for body mass index. Reservoir exhaustion in the automated boluses group occurred after a median [interquartile range] of 119 h [109 to 125] versus 74 h [57 to 80] for the continuous infusion group (difference of 47 h; 95% CI, 38 to 55; P < 0.001 adjusting for body mass index)., Conclusions: For popliteal-sciatic catheters, replacing a continuous infusion initiated before discharge with automated boluses and a start-delay timer resulted in better analgesia and longer infusion duration., (Copyright © 2022, the American Society of Anesthesiologists. All Rights Reserved.)

Background: Cognitive composites commonly serve as primary outcomes in Alzheimer's disease (AD) secondary prevention trials., Objective: To evaluate the association between amyloid (Aβ) 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 Aβ status and at least PACC or RBANS at screening were included. Participants were categorized as those with non-pathological Aβ levels (Aβ-, n=2,824) and those with pathological Aβ levels (Aβ+, n=745) based on florbetapir uptake or levels of cerebrospinal fluid Aβ1-42., Measurements: Analysis of Covariance models controlling for age, sex, and education were used to examine the difference in PACC, PACC5, and RBANS between Aβ groups. Nonparametric bootstrap was used to compare sensitivity of composites to differentiate between Aβ 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. Aβ+ participants performed worse versus Aβ- participants on all cognitive composites though the magnitude of the Aβ effect was generally small. The Aβ+/- 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 Aβ+/- effect sizes., Conclusions: Cross-sectional relationships between Aβ and cognition among clinically unimpaired older adults are detectable on multi-domain cognitive composites but are relatively small in magnitude. The Aβ+/- group effect was statistically larger for PACC and marginally larger for PACC5 versus RBANS. However, interpretation of composite sensitivity to Aβ status cross-sectionally cannot be generalized to sensitivity to change over time., Competing Interests: Kathryn V. Papp has received funding from the Alzheimer’s Association and the National Institute of Health. She has served a paid consultant for Biogen Idec and Digital Cognition Technologies. Christopher Randolph receives a small royalty for Repeatable Battery for the Assessment of Neuropsychological Status. Ellen Grober receives a small royalty for the commercial use of the Free and Cued Selective Reminding test. Hany Rofael and Gerald Novak are employees of Janssen Research and Development and may own stock/stock options in Johnson and Johnson. Michael Donohue is married to an employee of Janssen Research and Development who may own stock/stock options in Johnson and Johnson; and has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai. Karin Ernstrom has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai. Rema Raman has received research funding from the National Institutes of Health, Janssen, Eli Lilly, and Eisai. Shunran Wang has received research funding from the National Institutes of Health and Eisai. Reisa Sperling has received research funding from Janssen, and has served as a consultant to AC Immune, Biogen, Eisai, Janssen, Roche, and Takeda. H Robert Brashear, Gary Romano, and David Henley were employed by Janssen Research and Development during the time the study was conducted and may own stock/stock options in Johnson and Johnson. Amy E. Veroff is a consultant neuropsychologist to Janssen Research and Development and receives a small royalty for commercial use of some FCSRT materials.

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 (Aβ+; n = 1250, A4) and without elevated cerebral amyloid (Aβ-; n = 538, LEARN)., Measurements: Participants underwent florbetapir positron emission tomography for Aβ+/- 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 Aβ+ or Aβ- cohorts. At least one ARIA-H (microhemorrhages [MCH] or superficial siderosis [SS]) was present in 18% of the Aβ+ cohort compared with 8% in Aβ- (P < 0.001). In the Aβ+ cohort, approximately 2% of screening MRIs demonstrated MCH ≥4 compared with 0% in Aβ-. The presence of two apolipoprotein E ε4 (APOEε4) alleles (vs no ε4 alleles) in the Aβ+ 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 Aβ+ cohort compared with Aβ- (P < 0.001). Females showed reduced odds of MCH in the Aβ+ 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 Aβ+ and Aβ- populations prior to anti-amyloid drug intervention. ARIA-H in Aβ+ was greater than in Aβ- populations., Competing Interests: RY, KCH and JRS are full-time employees and minor shareholders of Eli Lilly and Company. RY has received funds from Eli Lilly and Company for attending meetings and or/travel. JC has received research funding from NIH and Janssen. MCD has received research funding from NIH and Janssen; consulting fees from Roche; has participated on a Data Safety Monitoring Board or Advisory Board for the University of California, San Diego and has a spouse who is a full-time employee of Janssen. KK has received research funding from NIH and ADDF; consulting fees from Biogen; support for attending meetings and/or travel from Alzheimer’s Association; has participated on a Data Safety Monitoring Board or Advisory Board for Takeda; has a leadership or fiduciary role in other board, society, committee or advocacy group for Alzheimer’s Association (unpaid) and NIH and has received research materials from Avid Radiopharmaceuticals. CRJ Jr. has received research funding from NIH, the GHR Foundation, and the Alexander Family Alzheimer’s Disease Research Professorship of the Mayo Clinic; participated on a Data Safety Monitoring Board or Advisory Board for Roche (unpaid); has served as a speaker for Eisai, and consulted for Biogen, but he receives no personal compensation from any commercial entity. SMZ has no conflicts of interest to declare. KAJ has received research funding from NIH; consulting fees from Novartis and has participated on a Data Safety Monitoring Board or Advisory Board for Cerveau (unpaid). PSA has received research funding from NIH, Alzheimer’s Association and Eli Lilly and Company for the A4 Trial; research agreements with Janssen, Eli Lilly and Company and Eisai; research funding from NIA, the Alzheimer’s Association and FNIH and consulting fees from Biogen, Roche, Merck, Abbvie, Immunobrain Checkpoint, Rainbow Medical and Shionogi. RAS has received research funding from NIH, Alzheimer’s Association and Eli Lilly and Company for the current study; research funding from Eli Lilly and Company, Janssen, NIA, Alzheimer’s Association; consulting fees from AC Immune, Acumen, Alnylam, Cytox, Janssen, JOMDD, Nervgen, Neuraly, Neurocentria, Oligomerix, Prothema, Renew, Shionogi, Vigil Neuroscience, Ionis, Biogen, Eisai and Roche; honoraria for Harvard HUBWeek Panel (2018), Japan JSNM (2018), Marc Diamond UT Southwestern Symposium (2019), University of Chicago DOM Weekly Grand Rounds Seminar Series (2020), Virtual Rhode Island IDeA Symposium (2020) and Virtual IMPACT-AD Course (2020) and support for attending meetings and/or travel from Duke Lectureship (2018), Alzheimer Research Roundtable (2018), ADPD Symposium (2019), University of Tokyo Roundtable (2019), Biogen: ARIA State of the Art meeting (2019), University of Pittsburgh Distinguished Scientist Lecture (2019), University of Cincinnati Lurie Lecture (2019), UC Irvine Distinguished Lecture on the Brain (2020), Virtual Rhode Island IDeA Symposium (2020), Adler Foundation Symposium San Diego (2020), UC Irvine Lecture (2020)