Alzheimer''s and Dementia: Translational Research and Clinical Interventions最新文献

{"title":"Clinical efficacy of anti-amyloid antibodies in apolipoprotein E ε4 homozygotes: A Bayesian reanalysis of lecanemab and donanemab phase 3 results","authors":"Stefan Teipel, Yi Tang, Ara Khachaturian","doi":"10.1002/trc2.70083","DOIUrl":"https://doi.org/10.1002/trc2.70083","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>We aimed to determine the clinical efficacy of treating apolipoprotein E (ApoE) ε4 homozygotes with recently approved anti-amyloid antibodies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Data were derived from supplementary analyses in the regulatory studies Clarity (lecanemab) and TRAILBLAZER-ALZ2 (donanemab). We used Bayesian reanalysis with an independent t-statistic to determine evidence for or against an effect of antibody treatment on Clinical Dementia Rating scale Sum of Boxes (CDR-SB) in ApoE ε4 homozygotes, and a Bayesian random-effect meta-analysis to determine the effect size.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The Bayesian reanalysis showed moderate evidence of no effect for both antibodies. For donanemab and lecanemab, the odds of no difference in treatment effect were nearly three times greater than the odds of a difference. The meta-analysis revealed a small effect of −0.06 CDR-SB points in favor of treatment with a moderate heterogeneity estimate. The Bayes factor was 0.26, indicating that the absence of an effect was almost four times more likely than the presence of an effect.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The most likely explanation for our results is the lack of a treatment effect for lecanemab and donanemab in ApoE <i>ε</i>4 homozygotes. This could reflect inadequate exposure to the antibody due to more severe side effects, subsequent treatment interruptions, and lower dosing or a biologically driven lack of efficacy in a genetically determined disease. Our results support the view that excluding these cases from treatment is justifiable because of the higher risk of side effects and the lack of clinical efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Lecanemab and donanemab were clinically ineffective in ApoE ε4 homozygotes.</li>\u0000 \u0000 <li>ApoE ε4 homozygotes should not receive these treatments due to inefficacy.</li>\u0000 \u0000 <li>Future trials should adopt Bayesian analysis strategies.</li>\u0000 \u0000 <li>Bayesian analysis provides evidence for or against treatment effects.</li>\u0000 \u0000 <li>Bayesian inference provides clinically interpretable results.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809607","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical activity complexity, cognition, and risk of cognitive impairment and dementia in the Baltimore Longitudinal Study of Aging","authors":"Yurun Cai, Junhong Zhou, Paul W. Scott, Qu Tian, Amal A. Wanigatunga, Lewis Lipsitz, Eleanor M. Simonsick, Susan M. Resnick, Luigi Ferrucci, Dianxu Ren, Jennifer H. Lingler, Jennifer A. Schrack","doi":"10.1002/trc2.70077","DOIUrl":"https://doi.org/10.1002/trc2.70077","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Studies on physical activity (PA) and dementia mainly focus on activity quantity or intensity. Yet PA requires neuro-coordination of movement, and it is unclear whether complexity of daily activity varies by cognitive status. Thus, we examined the association between PA complexity, using multiscale entropy, and cognitive function, mild cognitive impairment (MCI), and dementia in older adults in the Baltimore Longitudinal Study of Aging (BLSA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>A total of 637 older adults (age 73.9 ± 11.3 years) in the BLSA completed a 7-day wrist-worn accelerometer assessment and neuropsychological tests from 2015 to 2020. Using logistic regression and structural equation modeling, we examined cross-sectional associations of PA complexity with MCI/dementia and cognition. Cross-lagged panel models (CLPMs) were used to assess bidirectional associations at baseline and 2-year follow-up. Multivariable models were adjusted for age, sex, race, education years, body mass index, and comorbidities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Participants in the lowest tertile of PA complexity had over double the odds of MCI/dementia (odds ratio = 2.63, 95% confidence interval [CI]: 1.02 to 6.79, <i>p</i> = 0.045) compared to those in the highest tertile in the fully adjusted model. Structural equation modeling showed that PA complexity was associated with global cognitive function (standardized B [SB] = 0.102, 95% CI: 0.033 to 0.171, <i>p</i> = 0.004), executive function (SB = 0.119, 95% CI: 0.049 to 0.189, <i>p</i> = 0.001), and visuospatial ability (SB = 0.096, 95% CI: 0.026 to 0.167, <i>p</i> = 0.008). CLPMs showed bidirectional associations between lower PA complexity and poorer executive function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Lower complexity of accelerometry-detected movement is associated with poorer cognition and higher risk of MCI/dementia. Future studies should explore whether low PA complexity is an early indicator of dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Prior studies mainly focused on quantity or intensity of physical activity.</li>\u0000 \u0000 <li>Poorer cognitive function was associated with lower complexity of daily activity.</li>\u0000 \u0000 <li>Lower complexity of physical activity may be an ear","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Medicare predictors in health disparities in the risk of Alzheimer's disease","authors":"Igor Akushevich, Arseniy Yashkin, Julia Kravchenko","doi":"10.1002/trc2.70078","DOIUrl":"https://doi.org/10.1002/trc2.70078","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Disparities in Alzheimer's disease (AD) and related dementias (ADRD) persist across race/ethnicity, sex, and US geographic regions, but limited quantitative information exists to explain how specific predictors contribute to these disparities. Many traditional methods lack precision in addressing both exposure (higher prevalence of a predictor) and vulnerability (higher risk associated with a predictor) effects. This study introduces an approach that leverages population attributable fraction (PAF) to analyze and explain AD/ADRD disparities using Medicare data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We applied our method to Medicare claims data from a nationally representative sample of the US adults aged 70, 75, 80, and 85. The analysis focused on six types of disparities: Black–White, Hispanic–White, Native American–White, Asian–White, female–male, and stroke-belt versus non–stroke-belt states. Predictors included Medicare/Medicaid dual eligibility as an indicator of low income and 10 AD/ADRD-related diseases. The method quantified the exposure and vulnerability effects of each predictor on the observed disparities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Low income and vulnerability to arterial hypertension were the primary contributors to AD/ADRD disparities, with cerebrovascular diseases and depression as notable secondary predictors. The exposure effect dominated for income-related disparities, while hypertension's effect was largely driven by increased vulnerability. Racial disparities (Black–White, Hispanic–White) were most affected by income and hypertension, while female–male and stroke-belt disparities were less influenced by the examined predictors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings indicate that different intervention strategies are needed to address AD/ADRD disparities. Income-related disparities require targeting exposure (e.g., socioeconomic improvements), while hypertension-related disparities suggest a focus on managing vulnerability (e.g., better control of hypertension). The developed approach offers a robust framework for explaining disparities and designing targeted interventions. Further application to other datasets and exploration of additional predictors could enhance understanding and lead to more effective prevention strategies for AD/ADRD disparities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination therapy targeting Alzheimer's disease risk factors is associated with a significant delay in Alzheimer's disease–related cognitive decline","authors":"Yuan Shang, Georgina Torrandell-Haro, Francesca Vitali, Roberta Diaz Brinton, The Alzheimer's Disease Neuroimaging Initiative (ADNI)","doi":"10.1002/trc2.70074","DOIUrl":"https://doi.org/10.1002/trc2.70074","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>Alzheimer's disease (AD) cognitive decline can be a major contributor to loss of independent living. Therapeutic strategies that alter the course of cognitive deterioration have the potential to sustain activities of daily living, promote quality of life, and delay transition to nursing-home care.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We performed longitudinal linear regression analysis of National Alzheimer's Coordinating Center (NACC) cognitive data from 7653 mild dementia AD participants at baseline with at least one medication for diabetes (DBMD), lipid-lowering (LIPL), anti-hypertensive (AHTN), and non-steroidal anti-inflammatory (NSD) medications or any combination in 5684 (74%) participants and in 1969 (26%) participants with no study-relevant prescriptions over 10 years. Change in cognitive function was determined by Mini-Mental State Examination (MMSE) and <i>CDR® Dementia Staging Instrument</i> Sum of Boxes (CDR-SB) scores relative to non-treated participants stratified by sex and apolipoprotein E (<i>APOE</i>) genotype. Validation analysis was performed using Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Combination of DBMD+LIPL+AHTN+NSD (QuadRx) resulted in a significant 46% MMSE and 32% CDR-SB delay in cognitive decline at 5 years, which was sustained at 10 years with a delay in decline of 47% MMSE and 33% CDR-SB. QuadRx was equally effective for the delay of cognitive decline in both females and males at 5 and 10 years. QuadRx mitigated the impact of the <i>APOE</i> ε4 genotype. Findings were validated in ADNI AD participants in which QuadRx was associated with a significant 60% MMSE delay in cognitive decline at 1 and 2 years.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSIONS</h3>\u0000 \u0000 <p>Combination therapy was associated with a significant delay in cognitive decline in NACC AD participants at a magnitude comparable to or greater than amyloid beta immunomodulators. Further, the delay in decline was sustained for 10 years. The impact of QuadRx to delay cognitive decline was validated in deeply characterized ADNI participants. These data support combination therapy in persons with AD risk factors to alter the course of AD that persists for a decade, enabling cognitive function at a magnitude associated with independent living.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70074","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers for neurodegenerative diseases in regulatory decision-making by the European Medicines Agency","authors":"Audrey M. M. Hermans, Elisabeth Bakker, Viktoriia Starokozhko, Loes den Otter, André J. A. Elferink, Angela Bradshaw, Lorenzo Guizzaro, Peter G. M. Mol, Anna M. G. Pasmooij","doi":"10.1002/trc2.70072","DOIUrl":"https://doi.org/10.1002/trc2.70072","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Biomarkers (BMs) are valuable tools to facilitate early diagnosis of (subtypes of) diseases, improve patient selection and stratification, and detect therapeutic effects or safety concerns. This study explores the extent to which BMs are utilized in the development of treatments for neurodegenerative diseases (NDDs), as well as topics of discussion regarding BMs in regulatory advice- and decision-making processes and sharing of BM-related data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The European Medicines Agency's marketing authorization application (MAA), qualification (QA/QO), and scientific advice (SA) procedures regarding NDDs were screened, and those that mention BMs were analyzed. Data were extracted on the intended disease, BM type, and context of use proposed by applicants. BMs were categorized based on both nature and function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>In total, 105 procedures that discussed BMs were analyzed, 57 SAs (January 2020 to December 2022), 19 QAs/QOs (January 2008 to December 2023), and 29 MAAs (January 1995 to December 2023). The majority involved Alzheimer's disease (AD; <i>n</i> = 30), Parkinson's disease (PD; <i>n</i> = 9), and multiple sclerosis (MS; <i>n</i> = 33). Imaging BMs were the most common type of BMs discussed, and most BMs were used as pharmacodynamic/response measures. The acceptance and role of BMs differed between AD, PD, MS, and other NDDs. In regulatory procedures for AD, for example, diagnostic BMs guiding patient selection were commonly discussed, whereas in MAAs for MS, imaging BMs (particularly lesions) were generally accepted as supportive/secondary endpoints.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Despite the established role of certain BMs, mainly imaging BMs for MS, there remains a major need for more precise and reliable BMs to improve diagnostic accuracy and treatment monitoring for NDDs. To implement novel BMs and facilitate development of new treatments and to eventually improve clinical practice, robust evidence bases showcasing biological plausibility or clear clinical benefits are essential. Collaboration and data-sharing among stakeholders is vital in generating this evidence and enhancing the understanding and management of NDDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The European Medicines Agency's marketing authorization applicati","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimized 5-HT2b inhibitors for neuropsychiatric syndromes with cognitive dysfunction","authors":"Saktimayee M. Roy, Erica Acquarone, Elentina K. Argyrousi, Hong Zhang, Agnieszka Staniszewski, Asuka Inoue, Joshua J. Ziarek, Ottavio Arancio, D. Martin Watterson","doi":"10.1002/trc2.70073","DOIUrl":"https://doi.org/10.1002/trc2.70073","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Neuropsychiatric syndromes such as anxiety and agitation are clinical presentations common to diverse neurodegenerative diseases and brain injury sequelae. They are a concern due to the impact on cognition, social interactions, and non-pharmacological treatments. Cognitive or behavioral disturbances occur at early disease stages and increase with disease progression. Coincident pathologies include the loss of serotonin (5-HT) neurons and appearance of neurofibrillary tangles in the raphe nucleus. Brain 5-HT<sub>2b</sub> receptor (5-HT<sub>2b</sub>R) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. <i>HTR2B</i> gene variants are implicated in psychiatric disorders. 5-HTRs are associated with atypical neurotropic drug mechanisms and behavioral dysfunction in drug abuse. The accumulating body of evidence suggests that selective 5-HT<sub>2b</sub>R inhibition might mitigate neuropsychiatric syndromes and the associated cognitive dysfunction. Atypical neurotropic drugs interact with a variety of monoamine receptors and outcomes are viewed as a combination of 5-HT and dopamine D2 receptor mediated actions. Clearly, there is a need for insight into precision 5-HT<sub>2b</sub>R inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT<sub>2b</sub>R activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT<sub>2b</sub>R agonist activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>MW073 ameliorates amyloid and tau induction of behavioral dysfunction in preventive or disease stage intervention paradigms. Using MW073 as a standard of comparison, risperidone was shown to be a dose-dependent inhibitor 5-HT<sub>2b</sub>R activity and β-arrestin-1 recruitment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Selective inhibition of 5-HT<sub>2b</sub>R activity is a viable mechanism for the treatment of neuropsychiatric syndromes with synaptic dysfunction as a root cause and is a previously unrealized pharmacodynamic mechanism potentially embedded in current neurotherapeutics.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70073","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A mindfulness-based multicomponent caregiver intervention (PAACC): objectives, study design, and cohort description","authors":"Mamta Sapra, Lauren Hagemann, Katherine Luci, Jyoti Savla","doi":"10.1002/trc2.70064","DOIUrl":"https://doi.org/10.1002/trc2.70064","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Effective interventions are needed to reduce caregiver burden and stress, particularly among family caregivers of veterans with dementia. Unique risk factors such as traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) further complicate caregiving. This study compares a four-session mindfulness-based multicomponent intervention (PAACC) with a cognitive behavioral intervention (REACH), both designed to alleviate caregiver burden, and provides a baseline evaluation of caregivers in the intervention. A two-arm, blinded, randomized controlled trial assigned 133 dementia caregivers to PAACC (<i>n</i> = 67) or REACH (<i>n</i> = 66). Baseline assessments included caregiver stress, burden, mindfulness receptivity, rumination, compassion, depressive symptoms, anxiety, and care recipient behavior. Participants averaged 67.17 years, 85% were women, and 70% were spousal caregivers. Caregivers in PAACC reported higher depressive symptoms and anxiety and lower mindfulness receptivity. This study introduces the first mindfulness-based intervention for veteran caregivers, designed to enhance cognitive flexibility, cultivate compassion, and provide practical skills to improve quality of life.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The study utilized a two-arm, blinded, prospective randomized controlled trial to compare the PAACC and REACH interventions. A total of 133 dementia caregivers experiencing moderate to severe caregiver burden were assigned to receive either the PAACC intervention (<i>n</i> = 67) or the REACH intervention (<i>n</i> = 66). Baseline evaluations included caregiver stress, burden, mindfulness receptivity, rumination, compassion, depressive symptoms, anxiety, and the memory and behavior problems of the veteran living with dementia, using widely accepted measures from caregiving literature.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Baseline assessments were conducted on 133 family caregivers of veterans living with dementia. The average caregiver age was 67.17 years (SD = 9.8), 85% were women, and 70% were spousal caregivers. No significant demographic differences were found between the two intervention groups. However, baseline comparisons showed that caregivers in the PAACC intervention reported higher depressive symptoms and anxiety, and lower mindfulness receptivity. A detailed protocol for the mindfulness-based multicomponent caregiver intervention PAACC is described.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>There is a growing need for multicomponent, skill-buil","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70064","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143689272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspective: Minimal clinically important difference (MCID) and Alzheimer's disease clinical trials","authors":"Jeffrey Cummings","doi":"10.1002/trc2.70059","DOIUrl":"https://doi.org/10.1002/trc2.70059","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The minimum clinically important difference (MCID) is a measure of the minimal clinically relevant change. The MCID represents the smallest difference in score on the measure or domain of interest which patients or clinicians perceive as beneficial or as meaningful decline. The MCID is not an alternative clinical trial outcome; it does not apply to group measures and is used as a means of determining whether an individual patient has reached a threshold of change. MCIDs have been derived for symptomatic treatments and for disease targeted therapies. MCIDs have been derived for nearly all clinical trial instruments used in AD therapeutic research. Application of the MCID to patients on disease-targeted therapies requires awareness of the expected increasing treatment-no treatment difference exhibited by these agents. The MCID complements other strategies for assessing the meaningfulness of interventions including effect size, number needed to treat, responder analyses, time saved, quality of life, and quality-adjusted life years. MCID is not a required measure for regulatory approval of a therapeutic since it is applicable to individual patients and not to group outcomes or mean differences used to determine treatment benefit in clinical trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MCID is a key measure of within-person change in cognition, function, or behavior when it is applied to metrics of Alzheimer's disease progression.</li>\u0000 \u0000 <li>In Alzheimer's disease, MCID or minimum within person change (MWPC) can function as useful means of determining if a patient has progressed to thresholds of detectable change.</li>\u0000 \u0000 <li>In Alzheimer's disease, MCID/MWPC can be used to determine the number or percent of individuals who have progressed to detectable levels of within-person change, with differences anticipated in active treatment and placebo groups.</li>\u0000 \u0000 <li>MCID/MWPC are not measures that are appropriately applied to group outcomes of clinical trials.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70059","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Broad repetitive transcranial magnetic stimulation (rTMS) of the precuneus in Alzheimer's disease: A rationale and study design","authors":"Michael K. Leuchter,&nbsp;Hanadi A. Oughli,&nbsp;Kelly A. Durbin,&nbsp;Nicholas J. Jackson,&nbsp;David Elashoff,&nbsp;Timothy S. Chang,&nbsp;Juliana Corlier,&nbsp;Doan Ngo,&nbsp;Cole Matthews,&nbsp;Darice Wong,&nbsp;Brent L. Fogel,&nbsp;Gal Bitan,&nbsp;Andrew F. Leuchter,&nbsp;Keith Vossel,&nbsp;Nanthia Suthana","doi":"10.1002/trc2.70043","DOIUrl":"https://doi.org/10.1002/trc2.70043","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Brain network dysfunction, particularly within the default mode network (DMN), is an increasingly apparent contributor to the clinical progression of Alzheimer's disease (AD). Repetitive transcranial magnetic stimulation (rTMS) can target key DMN hubs, maintain signaling function, and delay or improve clinical outcomes in AD. Here, we present the rationale and design of a study using off-the-shelf equipment and the latest clinical evidence to expand on prior rTMS work and reduce participant burden in the process.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We will conduct a two-stage trial of large-coil rTMS targeting the precuneus (a key hub in the DMN affected by AD) in 54 participants with mild to moderate Alzheimer's Clinical Syndrome focused primarily on determining tolerability and feasibility and secondarily focused on determining short-term efficacy for memory. The first stage will involve 5 to 10 participants receiving open-label active treatment to refine the protocol. The following second stage will consist of a 1:1 randomized, double-blind, sham-controlled clinical trial to study feasibility and tolerability while exploring target engagement and short-term efficacy for memory. Participants will undergo 16 total rTMS brain stimulation sessions over the course of 5 weeks. A full course of open-label active treatment will be offered as an extension to the sham group after unblinding. Outcomes will focus on completion rates and adverse events to demonstrate feasibility and tolerability. Further exploratory outcomes will include neuropsychological assessments, electroencephalography, neuroimaging, and blood biomarkers to demonstrate the feasibility of collection and explore preliminary changes in these measures.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We anticipate this treatment is feasible and tolerable and may show evidence of target engagement and clinical improvement.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Should we achieve expected positive outcomes in feasibility and tolerability, this will justify future work focusing on clear demonstrations of clinical efficacy and biomarker engagement, as well as enhancement of generalizability and scalability.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Induction-to-maintenance repetitive transcranial magnetic stimulation (rTMS) of the precuneus is a promising t","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Factors associated with adherence to tablet-based cognitive training: J-MINT study","authors":"Taiki Sugimoto,&nbsp;Kazuaki Uchida,&nbsp;Kenji Sato,&nbsp;Yoko Yokoyama,&nbsp;Ayaka Onoyama,&nbsp;Kosuke Fujita,&nbsp;Yujiro Kuroda,&nbsp;Satomu Wakayama,&nbsp;Hidenori Arai,&nbsp;Takashi Sakurai,&nbsp;J-MINT study group","doi":"10.1002/trc2.70062","DOIUrl":"https://doi.org/10.1002/trc2.70062","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Cognitive training is a key component of multidomain interventions to prevent cognitive decline; however, low adherence remains a challenge. In this post hoc analysis of the Japan-Multimodal Intervention Trial for Prevention of Dementia (J-MINT), factors associated with cognitive training adherence in older adults with mild cognitive impairment were investigated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>J-MINT was an 18-month randomized controlled trial. The analyses included 191 participants (intervention group) who completed the trial. Adherence was assessed by calculating the number of days the participants engaged in tablet-based cognitive training for at least 30 min.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Vision difficulty and a larger friend network were negatively associated with adherence. Female sex, higher cognitive function, and satisfaction with training tasks and implementation goals were positively associated with adherence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The results imply that not only the participants’ characteristics but also the training task design and implementation goal setting (training duration and frequency) are associated with adherence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Clinical trial registration number</h3>\u0000 \u0000 <p>This trial was registered with the University hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000038671).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Factors associated with adherence to cognitive training were evaluated.</li>\u0000 \u0000 <li>Vision difficulty was negatively associated with adherence.</li>\u0000 \u0000 <li>A larger network of friends was negatively associated with adherence.</li>\u0000 \u0000 <li>Female sex and higher cognitive function were positively associated with adherence.</li>\u0000 \u0000 <li>Satisfaction with training tasks and implementation goals was related to adherence.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70062","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143581453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}