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

{"title":"Directionality between cognitive function and daily physical activity patterns","authors":"Francesca R. Marino,&nbsp;Jennifer A. Deal,&nbsp;Alden L. Gross,&nbsp;Yang An,&nbsp;Qu Tian,&nbsp;Eleanor M. Simonsick,&nbsp;Luigi Ferrucci,&nbsp;Susan M. Resnick,&nbsp;Jennifer A. Schrack,&nbsp;Amal A. Wanigatunga","doi":"10.1002/trc2.70068","DOIUrl":"https://doi.org/10.1002/trc2.70068","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Physical activity is a modifiable risk factor for dementia, but cognitive function is also important for physical activity engagement. This study evaluated the directionality of associations between daily physical activity and cognitive function in a sample of cognitively and physically intact older adults.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Cognitive factor scores for domains including global cognition, memory, language, executive function/attention, and visuospatial processing, and physical activity patterns from wrist accelerometry were measured at two visits (mean: 1.8 years) among 237 cognitively intact older adults in the Baltimore Longitudinal Study of Aging (BLSA) (mean age: 76.5 years). Bivariate latent change score models estimated directionality of associations between changes in cognitive factor scores and physical activity patterns. Models were adjusted for age, sex, race, education, comorbidities, and body mass index.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Higher total amount of activity, longer activity bouts, less sedentary time, and less activity fragmentation at baseline were associated with less annual cognitive decline across multiple cognitive domains (<i>X</i>²&gt; 4.11, 1 df for all). In contrast, baseline cognitive factor scores were not associated with changes in any activity pattern (<i>X</i>² &lt; 3.20, 1 df for all).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Increasing movement and/or decreasing sedentary behavior is associated with less prospective cognitive decline. Targeting reductions in sedentary time and lengthening activity bouts may slow cognitive decline among older adults at risk for dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Greater activity engagement is related to less annual cognitive decline.</li>\u0000 \u0000 <li>Baseline cognition is not associated with short-term changes in activity patterns.</li>\u0000 \u0000 <li>Promoting daily movement and lowering sedentary time may have cognitive benefits.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822230","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":"Measuring time saved in Alzheimer's disease: What is a meaningful slowing of progression?","authors":"Krista Lanctot,&nbsp;Linus Jönsson,&nbsp;Alireza Atri,&nbsp;Russ Paulsen,&nbsp;Soeren Mattke,&nbsp;Julie Hviid Hahn-Pedersen,&nbsp;Pepa Polavieja,&nbsp;Thomas Maltesen,&nbsp;Teresa León,&nbsp;Anders Gustavsson,&nbsp;Alzheimer's Disease Neuroimaging Initiative","doi":"10.1002/trc2.70081","DOIUrl":"https://doi.org/10.1002/trc2.70081","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) have previously been estimated using clinician-based anchors. However, MCIDs have been criticized for not reflecting the preferences of people living with AD (PLWAD). Furthermore, interpretations of clinical trial results have been criticized for conflating within-person meaningfulness thresholds and between-group differences. Here, we simulate scenarios of disease slowing and compare those to published MCIDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Scenarios of 5%–95% disease slowing were simulated using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Time saved and point differences on the Clinical Dementia Rating scale—Sum of Boxes (CDR-SB) were estimated for these scenarios and compared to published MCIDs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Scenario analyses resulted in estimates of time saved at ∼3 weeks–17 months and mean changes at 0.08–1.5 CDR-SB points over 18 months. The often referenced MCID for mild cognitive impairment (0.98) thereby corresponded to 11 months slowing, whereas the MCID for mild dementia (1.63) corresponded to &gt;17 months slowing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Translating trial endpoints to estimates of time saved supports that often-referenced MCIDs may not be aligned with realistic and meaningful slowing of clinical progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>AD slowing of clinical progression by 5%–95% resulted in 0.74–17 months saved and 0.08–1.5 CDR-SB points change at 18 months.</li>\u0000 \u0000 <li>Slowing of at least 60% or 11 months of time saved over 18 months met an often-cited MCID threshold of 0.98 points for mild cognitive impairment.</li>\u0000 \u0000 <li>For mild AD dementia, an MCID of 1.63 meant that even an 18-month delay over 18 months would be considered only borderline meaningful—a face invalid and unrealistic proposition.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143822231","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":"Activity variability: A novel physical activity metric and its association with cognitive impairment","authors":"Patrick T. Donahue,&nbsp;Jennifer A. Schrack,&nbsp;Johannes Thrul,&nbsp;Michelle C. Carlson","doi":"10.1002/trc2.70079","DOIUrl":"https://doi.org/10.1002/trc2.70079","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;Evidence suggests that engaging in a high volume of daily or weekly physical activity may reduce the risk of cognitive impairment due to Alzheimer's disease and related dementias (ADRD). However, activity variability and its associations with cognition are underexplored. We examined whether activity variability, measured at the minute level, may capture movement patterns that provide insight into cognitive impairment risk.&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;Using a cross-sectional sample of 711 older adults (mean [standard deviation] age = 79.1 [6.0] years]) from the National Health and Aging Trends Study in 2021, we calculated a novel metric of activity variability, defined as the standard deviation of minute-to-minute changes in accelerometer activity counts across the 7 day wear period. We investigated associations between activity variability and other activity metrics with cognitive impairment using logistic regression models.&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;Lower activity variability was associated with increased odds of cognitive impairment (odds ratio [OR] = 2.23; 95% confidence interval [CI: 1.26–3.97]), even after accounting for total activity counts and other covariates. In receiver operating characteristic curve analyses, activity variability was the strongest predictor of prevalent cognitive impairment compared to other activity metrics (area under the curve = 0.787; 95% CI [0.742–0.832]).&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;Activity variability, measured at the minute level, may capture complexity of daily activities and may serve as a novel indicator of cognitive health. Low activity variability may signal underlying neurological processes that contribute to ADRD risk. Further investigation into potential biological mechanisms that may explain the observed associations between activity variability and cognition is warranted.&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;We created a novel metric using variability of minute-level changes in activity counts.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Low activity variability was associated with a greater prevalence of cognitive impairment.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Activity variability outperformed other activity metrics in area under the receiver operating characteristic curve analyses.&lt;/li&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 2","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70079","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809428","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":"Clinical efficacy of anti-amyloid antibodies in apolipoprotein E ε4 homozygotes: A Bayesian reanalysis of lecanemab and donanemab phase 3 results","authors":"Stefan Teipel,&nbsp;Yi Tang,&nbsp;Ara Khachaturian","doi":"10.1002/trc2.70083","DOIUrl":"https://doi.org/10.1002/trc2.70083","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;We aimed to determine the clinical efficacy of treating apolipoprotein E (ApoE) ε4 homozygotes with recently approved anti-amyloid antibodies.&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;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.&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;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.&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;The most likely explanation for our results is the lack of a treatment effect for lecanemab and donanemab in ApoE &lt;i&gt;ε&lt;/i&gt;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.&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;Lecanemab and donanemab were clinically ineffective in ApoE ε4 homozygotes.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;ApoE ε4 homozygotes should not receive these treatments due to inefficacy.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Future trials should adopt Bayesian analysis strategies.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Bayesian analysis provides evidence for or against treatment effects.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Bayesian inference provides clinically interpretable results.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 &lt;/section&gt;\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,&nbsp;Junhong Zhou,&nbsp;Paul W. Scott,&nbsp;Qu Tian,&nbsp;Amal A. Wanigatunga,&nbsp;Lewis Lipsitz,&nbsp;Eleanor M. Simonsick,&nbsp;Susan M. Resnick,&nbsp;Luigi Ferrucci,&nbsp;Dianxu Ren,&nbsp;Jennifer H. Lingler,&nbsp;Jennifer A. Schrack","doi":"10.1002/trc2.70077","DOIUrl":"https://doi.org/10.1002/trc2.70077","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;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).&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;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.&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;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, &lt;i&gt;p&lt;/i&gt; = 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, &lt;i&gt;p&lt;/i&gt; = 0.004), executive function (SB = 0.119, 95% CI: 0.049 to 0.189, &lt;i&gt;p&lt;/i&gt; = 0.001), and visuospatial ability (SB = 0.096, 95% CI: 0.026 to 0.167, &lt;i&gt;p&lt;/i&gt; = 0.008). CLPMs showed bidirectional associations between lower PA complexity and poorer executive function.&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;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.&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;Prior studies mainly focused on quantity or intensity of physical activity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Poorer cognitive function was associated with lower complexity of daily activity.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;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,&nbsp;Arseniy Yashkin,&nbsp;Julia Kravchenko","doi":"10.1002/trc2.70078","DOIUrl":"https://doi.org/10.1002/trc2.70078","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;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.&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 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.&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;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.&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;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.&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 ","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,&nbsp;Georgina Torrandell-Haro,&nbsp;Francesca Vitali,&nbsp;Roberta Diaz Brinton,&nbsp;The Alzheimer's Disease Neuroimaging Initiative (ADNI)","doi":"10.1002/trc2.70074","DOIUrl":"https://doi.org/10.1002/trc2.70074","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; BACKGROUND&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&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 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 &lt;i&gt;CDR® Dementia Staging Instrument&lt;/i&gt; Sum of Boxes (CDR-SB) scores relative to non-treated participants stratified by sex and apolipoprotein E (&lt;i&gt;APOE&lt;/i&gt;) genotype. Validation analysis was performed using Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset.&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;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 &lt;i&gt;APOE&lt;/i&gt; 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.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; CONCLUSIONS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;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.&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 ","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,&nbsp;Elisabeth Bakker,&nbsp;Viktoriia Starokozhko,&nbsp;Loes den Otter,&nbsp;André J. A. Elferink,&nbsp;Angela Bradshaw,&nbsp;Lorenzo Guizzaro,&nbsp;Peter G. M. Mol,&nbsp;Anna M. G. Pasmooij","doi":"10.1002/trc2.70072","DOIUrl":"https://doi.org/10.1002/trc2.70072","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;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.&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;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.&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;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; &lt;i&gt;n&lt;/i&gt; = 30), Parkinson's disease (PD; &lt;i&gt;n&lt;/i&gt; = 9), and multiple sclerosis (MS; &lt;i&gt;n&lt;/i&gt; = 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.&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;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.&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;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,&nbsp;Erica Acquarone,&nbsp;Elentina K. Argyrousi,&nbsp;Hong Zhang,&nbsp;Agnieszka Staniszewski,&nbsp;Asuka Inoue,&nbsp;Joshua J. Ziarek,&nbsp;Ottavio Arancio,&nbsp;D. Martin Watterson","doi":"10.1002/trc2.70073","DOIUrl":"https://doi.org/10.1002/trc2.70073","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;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&lt;sub&gt;2b&lt;/sub&gt; receptor (5-HT&lt;sub&gt;2b&lt;/sub&gt;R) levels are increased in Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), and post-stroke morbidity. &lt;i&gt;HTR2B&lt;/i&gt; 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&lt;sub&gt;2b&lt;/sub&gt;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&lt;sub&gt;2b&lt;/sub&gt;R inhibition as a potential pharmacological mechanism for treatment of neuropsychiatric syndromes and cognitive dysfunction associated with dementia.&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;Strategic optimization of an atypical neurotropic drug was used to develop MW073, a highly selective and orally bioavailable inhibitor of 5-HT&lt;sub&gt;2b&lt;/sub&gt;R activity and β-arrestin-1 recruitment that is devoid of dopamine receptor recognition and risk of 5-HT&lt;sub&gt;2b&lt;/sub&gt;R agonist activity.&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;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&lt;sub&gt;2b&lt;/sub&gt;R activity and β-arrestin-1 recruitment.&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;Selective inhibition of 5-HT&lt;sub&gt;2b&lt;/sub&gt;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.&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 ","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,&nbsp;Lauren Hagemann,&nbsp;Katherine Luci,&nbsp;Jyoti Savla","doi":"10.1002/trc2.70064","DOIUrl":"https://doi.org/10.1002/trc2.70064","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;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 (&lt;i&gt;n&lt;/i&gt; = 67) or REACH (&lt;i&gt;n&lt;/i&gt; = 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.&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;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 (&lt;i&gt;n&lt;/i&gt; = 67) or the REACH intervention (&lt;i&gt;n&lt;/i&gt; = 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.&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;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.&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;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}