Maansi Barnwal, Sheriza Baksh, Zahinoor Ismail, David M. Shade, Abhay Moghekar, Sara G. Ho, Paul B. Rosenberg, Anton P. Porsteinsson, Constantine G. Lyketsos, for the S-CitAD Research Group
<div> <section> <h3> INTRODUCTION</h3> <p>Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) is a National Institutes of Health–funded randomized controlled trial that randomized 173 participants with clinically diagnosed Alzheimer's disease (AD) and agitation to escitalopram or placebo for 12 weeks, assessing efficacy and safety. There was no advantage for escitalopram in treating agitation, potentially attributed to including participants at various stages of AD brain pathology, reflected in levels of blood biomarkers. Here, we (1) estimated the fraction of participants meeting blood biomarker criteria for AD pathology, (2) examined associations between baseline blood biomarkers and agitation severity or cognitive functioning, and (3) evaluated whether baseline blood biomarkers predicted treatment response.</p> </section> <section> <h3> METHODS</h3> <p>Eighty-two randomized participants provided blood for biomarker measurement prior to randomization. Plasma amyloid beta (Aβ)42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (p-tau)217 were measured using standard methods. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow-up with (1) agitation severity (Neuropsychiatric Inventory Clinical Rating of the agitation and aggression domains [NPI-C-A+A]), (2) cognitive status (Mini-Mental State Examination [MMSE]), and (3) escitalopram treatment.</p> </section> <section> <h3> RESULTS</h3> <p>Seventy-seven out of 82 (94%) scored above threshold for p-tau217, supporting the clinical diagnosis of AD. Baseline higher p-tau217 predicted higher NPI-C-A+A scores at weeks 6 (beta = 3.26, <i>p</i> < 0.001) and 12 (beta = 2.86, <i>p</i> = 0.01) after randomization. Baseline higher levels of GFAP (beta = −0.02, <i>p</i> = 0.0002) and p-tau217 (beta = −2.68, <i>p</i> = 0.003) were associated with lower baseline MMSE scores. After adjusting for treatment, higher baseline p-tau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (odds ratio [OR] = 2.79, <i>p</i> = 0.02) and 12 (OR = 2.55, <i>p</i> = 0.02).</p> </section> <section> <h3> DISCUSSION</h3> <p>In this clinical trial cohort, elevated plasma p-tau217 confirmed AD pathology in 94% of participants and forecast greater agitation severity and worse cognitive functioning, underscoring its practical value for stratifying and monitoring patients in neuropsychiatric intervention studies.</p> </section> <section>
艾司西酞普兰治疗阿尔茨海默病躁动（S-CitAD）是一项由美国国立卫生研究院资助的随机对照试验，该试验将173名临床诊断为阿尔茨海默病（AD）和躁动的参与者随机分配给艾司西酞普兰或安慰剂12周，评估其疗效和安全性。艾司西酞普兰在治疗躁动方面没有优势，这可能是由于纳入了阿尔茨海默病不同阶段的脑病理参与者，反映在血液生物标志物水平上。在这里，我们(1)估计了符合AD病理血液生物标志物标准的参与者的比例，(2)检查了基线血液生物标志物与躁动严重程度或认知功能之间的关系，(3)评估了基线血液生物标志物是否预测了治疗反应。方法：在随机化之前，82名随机受试者提供血液进行生物标志物测量。采用标准方法测定血浆β淀粉样蛋白（Aβ）42、Aβ40、胶质纤维酸性蛋白（GFAP）、神经丝轻链（NfL）和磷酸化tau蛋白（p-tau）217。我们检查了基线血液生物标志物和基线和随访时的临床测量与(1)躁动严重程度（躁动和攻击域神经精神量表临床评分[NPI-C-A+A]），(2)认知状态（迷你精神状态检查[MMSE]）和(3)艾司西酞普兰治疗的关系。结果：82例患者中有77例（94%）p-tau217得分高于阈值，支持AD的临床诊断。基线较高的p-tau217预测随机分组后第6周（beta = 3.26, p < 0.001）和第12周（beta = 2.86, p = 0.01） NPI-C-A+A评分较高。基线较高水平的GFAP （beta = -0.02, p = 0.0002）和p-tau217 （beta = -2.68, p = 0.003）与较低的基线MMSE评分相关。在调整治疗后，较高的基线p-tau217与第6周NPI-C-A+A评分恶化的几率较大相关（优势比[OR] = 2.79, p = 0.02）和第12周（OR = 2.55, p = 0.02）。讨论：在这个临床试验队列中，血浆p-tau217升高在94%的参与者中证实了AD病理，并预测了更严重的躁动和更差的认知功能，强调了其在神经精神干预研究中对患者分层和监测的实用价值。重点：我们研究了阿尔茨海默病（AD）血液生物标志物是否能预测躁动和认知障碍的严重程度，以及/或在为期12周的阿尔茨海默病躁动（S-CitAD）随机对照试验中的治疗反应。血液磷酸化tau (p-tau)217证实94%的临床诊断参与者存在显著的AD脑淀粉样蛋白病理。与治疗分配无关，较高的基线p-tau217预示着较低的基线和未来的迷你精神状态检查（MMSE）分数和较差的激越时间。与治疗分配无关，较高的胶质原纤维酸性蛋白基线水平与较低的基线和随访MMSE评分相关。
{"title":"Blood biomarkers for Alzheimer's disease are correlated with measures of agitation and cognition in a randomized trial assessing the effects of escitalopram on agitation","authors":"Maansi Barnwal, Sheriza Baksh, Zahinoor Ismail, David M. Shade, Abhay Moghekar, Sara G. Ho, Paul B. Rosenberg, Anton P. Porsteinsson, Constantine G. Lyketsos, for the S-CitAD Research Group","doi":"10.1002/trc2.70203","DOIUrl":"10.1002/trc2.70203","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Escitalopram for Agitation in Alzheimer's Disease (S-CitAD) is a National Institutes of Health–funded randomized controlled trial that randomized 173 participants with clinically diagnosed Alzheimer's disease (AD) and agitation to escitalopram or placebo for 12 weeks, assessing efficacy and safety. There was no advantage for escitalopram in treating agitation, potentially attributed to including participants at various stages of AD brain pathology, reflected in levels of blood biomarkers. Here, we (1) estimated the fraction of participants meeting blood biomarker criteria for AD pathology, (2) examined associations between baseline blood biomarkers and agitation severity or cognitive functioning, and (3) evaluated whether baseline blood biomarkers predicted treatment response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Eighty-two randomized participants provided blood for biomarker measurement prior to randomization. Plasma amyloid beta (Aβ)42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau (p-tau)217 were measured using standard methods. We examined associations of baseline blood biomarkers and clinical measures at baseline and follow-up with (1) agitation severity (Neuropsychiatric Inventory Clinical Rating of the agitation and aggression domains [NPI-C-A+A]), (2) cognitive status (Mini-Mental State Examination [MMSE]), and (3) escitalopram treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Seventy-seven out of 82 (94%) scored above threshold for p-tau217, supporting the clinical diagnosis of AD. Baseline higher p-tau217 predicted higher NPI-C-A+A scores at weeks 6 (beta = 3.26, <i>p</i> < 0.001) and 12 (beta = 2.86, <i>p</i> = 0.01) after randomization. Baseline higher levels of GFAP (beta = −0.02, <i>p</i> = 0.0002) and p-tau217 (beta = −2.68, <i>p</i> = 0.003) were associated with lower baseline MMSE scores. After adjusting for treatment, higher baseline p-tau217 was associated with greater odds of worsening NPI-C-A+A scores at weeks 6 (odds ratio [OR] = 2.79, <i>p</i> = 0.02) and 12 (OR = 2.55, <i>p</i> = 0.02).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>In this clinical trial cohort, elevated plasma p-tau217 confirmed AD pathology in 94% of participants and forecast greater agitation severity and worse cognitive functioning, underscoring its practical value for stratifying and monitoring patients in neuropsychiatric intervention studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12812854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146013173","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}
Philip Scheltens, Alireza Atri, Howard H. Feldman, Henrik Zetterberg, Mary Sano, Peter Johannsen, Teresa León Colombo, Lars Bardtrum, Rose Jeppesen, Charlotte T. Hansen, Jeffrey L. Cummings
<div> <section> <h3> INTRODUCTION</h3> <p>The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as “evoke (+)” hereafter.</p> </section> <section> <h3> METHODS</h3> <p>Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions.</p> </section> <section> <h3> RESULTS</h3> <p>Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia.</p> </section> <section> <h3> DISCUSSION</h3> <p>Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <
{"title":"Baseline characteristics from evoke and evoke+: Two phase 3 randomized placebo-controlled trials of semaglutide in participants with early-stage symptomatic Alzheimer's disease","authors":"Philip Scheltens, Alireza Atri, Howard H. Feldman, Henrik Zetterberg, Mary Sano, Peter Johannsen, Teresa León Colombo, Lars Bardtrum, Rose Jeppesen, Charlotte T. Hansen, Jeffrey L. Cummings","doi":"10.1002/trc2.70200","DOIUrl":"10.1002/trc2.70200","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The glucagon-like peptide-1 receptor agonist semaglutide may impact neuroinflammation and reduce neurodegeneration. We present baseline characteristics of participants enrolled in the evoke (NCT04777396) and evoke+ (NCT04777409) trials, referred to as “evoke (+)” hereafter.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Evoke (+) are two ongoing global, multicenter, randomized, double-blind, parallel-group, placebo-controlled phase 3 trials investigating semaglutide in participants with early-stage symptomatic Alzheimer's disease (AD) with confirmed amyloid positivity (by positron emission tomography or cerebrospinal fluid testing). Inclusion criteria are the same for both trials, except that by design, evoke+ also includes participants with significant small vessel pathology. Both trials include a 12-week screening phase before randomization (1:1) to receive oral semaglutide titrated to 14 mg or placebo for 156 weeks. Baseline data were summarized and analyzed descriptively. Additionally, data were pooled and assessed by five main geographical regions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Evoke (+) recruited 9996 participants from 566 sites in 40 countries. The mean (standard deviation) age of participants was 71.8 (7.1) and 72.6 (7.1) years in evoke and evoke+, respectively; more participants were female than male (female: 53.0% and 51.9%, respectively) and most had a Clinical Dementia Rating (CDR) global score of 0.5 (72.8% and 71.4%; CDR global score of 1: 26.5% and 27.6%). Both trial populations had similar demographics, and clinical and cognitive baseline characteristics, except that 2.8% of participants in evoke+ had magnetic resonance imaging-documented significant small vessel pathology as per protocol inclusion criteria. Regional-level data demonstrated some differences in AD treatment characteristics, including cholinesterase inhibitor use of 41.7% in North America versus 61.6% in Asia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Evoke (+) are the only large-scale, phase 3 trials investigating the longer-term efficacy and safety of semaglutide in early AD as a potential disease-modifying treatment. The baseline characteristics from evoke (+) reflect a varied, global population with early-stage symptomatic AD. Primary readouts are expected in the second half of 2025.</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":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12789876/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953805","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}
Anaëlle Bain, Charlotte Tomeo, Claire André, Antoine Garnier-Crussard, Robin de Flores, Sophie Dautricourt
INTRODUCTION
The locus coeruleus (LC) is a small nucleus located deep within the brainstem, serving as the brain's main source of noradrenergic neurons. Through its extensive projections, it plays a critical role in regulating cognitive processes and arousal. Although LC degeneration has been well documented in Alzheimer's disease and Parkinson's disease, its specific involvement in the pathophysiology of dementia with Lewy bodies (DLB) remains poorly understood.
METHODS
This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, explores the role of LC in the pathogenesis of DLB by synthesizing findings from human neuropathological and neuroimaging research and animal models of α-synucleinopathy.
RESULTS
Although studies directly examining the LC in DLB remain limited, particularly in human living patients, available evidence points to early and severe LC alterations in DLB and suggests that LC dysfunction may contribute to key clinical symptoms such as impaired arousal and anxiety.
DISCUSSION
A better understanding of the mechanisms driving LC dysfunction and neurodegeneration in DLB could facilitate the development of novel biomarkers and, ultimately, symptomatic therapies.
Highlights
Locus coeruleus (LC) alterations are among the earliest changes in dementia with Lewy bodies (DLB).
Accumulation of α-synuclein in the LC disrupts noradrenergic function.
LC neurodegeneration may contribute to cognitive and neuropsychiatric symptoms.
Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) reveals LC signal loss from the prodromal stage of DLB.
LC dysfunction emerges as a potential biomarker and therapeutic target in DLB.
蓝斑核（LC）是位于脑干深处的一个小核，是大脑去肾上腺素能神经元的主要来源。通过其广泛的投射，它在调节认知过程和唤醒中起着关键作用。尽管LC变性在阿尔茨海默病和帕金森病中有很好的文献记载，但其在路易体痴呆（DLB）病理生理中的具体参与仍知之甚少。方法：本系统综述按照PRISMA （Preferred Reporting Items for systematic reviews and meta - analysis）指南进行，通过综合人类神经病理学和神经影像学研究以及α-突触核蛋白病动物模型的研究结果，探讨LC在DLB发病机制中的作用。结果：尽管直接检查DLB中LC的研究仍然有限，特别是在活着的人类患者中，现有证据表明DLB中早期和严重的LC改变，并表明LC功能障碍可能导致关键的临床症状，如觉醒受损和焦虑。讨论：更好地了解DLB中驱动LC功能障碍和神经退行性变的机制可以促进新型生物标志物的开发，并最终促进对症治疗。重点：蓝斑（LC）改变是路易体痴呆（DLB）最早的变化之一。α-突触核蛋白在LC中的积累破坏了去甲肾上腺素能功能。LC神经退行性变可能导致认知和神经精神症状。神经黑色素敏感磁共振成像（NM-MRI）显示DLB前驱期LC信号丢失。LC功能障碍成为DLB的潜在生物标志物和治疗靶点。
{"title":"Locus coeruleus alterations in dementia with Lewy bodies: A systematic review","authors":"Anaëlle Bain, Charlotte Tomeo, Claire André, Antoine Garnier-Crussard, Robin de Flores, Sophie Dautricourt","doi":"10.1002/trc2.70199","DOIUrl":"10.1002/trc2.70199","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The locus coeruleus (LC) is a small nucleus located deep within the brainstem, serving as the brain's main source of noradrenergic neurons. Through its extensive projections, it plays a critical role in regulating cognitive processes and arousal. Although LC degeneration has been well documented in Alzheimer's disease and Parkinson's disease, its specific involvement in the pathophysiology of dementia with Lewy bodies (DLB) remains poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>This systematic review, conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, explores the role of LC in the pathogenesis of DLB by synthesizing findings from human neuropathological and neuroimaging research and animal models of α-synucleinopathy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Although studies directly examining the LC in DLB remain limited, particularly in human living patients, available evidence points to early and severe LC alterations in DLB and suggests that LC dysfunction may contribute to key clinical symptoms such as impaired arousal and anxiety.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>A better understanding of the mechanisms driving LC dysfunction and neurodegeneration in DLB could facilitate the development of novel biomarkers and, ultimately, symptomatic therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Locus coeruleus (LC) alterations are among the earliest changes in dementia with Lewy bodies (DLB).</li>\u0000 \u0000 <li>Accumulation of α-synuclein in the LC disrupts noradrenergic function.</li>\u0000 \u0000 <li>LC neurodegeneration may contribute to cognitive and neuropsychiatric symptoms.</li>\u0000 \u0000 <li>Neuromelanin-sensitive magnetic resonance imaging (NM-MRI) reveals LC signal loss from the prodromal stage of DLB.</li>\u0000 \u0000 <li>LC dysfunction emerges as a potential biomarker and therapeutic target in DLB.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12784214/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953830","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}
<div> <section> <h3> INTRODUCTION</h3> <p>While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.</p> </section> <section> <h3> METHODS</h3> <p>This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.</p> </section> <section> <h3> RESULTS</h3> <p>We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored “CCL” signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.</p> </section> <section> <h3> DISCUSSION</h3> <p>Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.</li> <li>3D6 exposure resulted in fewer homeostatic and motile microglia subtype
{"title":"Acute anti-Aβ antibody exposure induces microglial changes and significantly alters chemokine signaling","authors":"Kate E. Foley, Erica M. Weekman, Donna M. Wilcock","doi":"10.1002/trc2.70201","DOIUrl":"10.1002/trc2.70201","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>While the anti-amyloid-lowering immunotherapies provide the first disease-targeting therapies for the treatment of Alzheimer's disease, there remain harmful adverse events causing hesitation among patients, families, physicians, and regulatory bodies. Though these drugs have been repeatedly proven to lower brain amyloid plaque burden, the specific cellular mechanisms and pathways by which the immunotherapy impacts the brain remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>This study aimed to transcriptionally profile the brain's immediate immune response to anti-amyloid beta (anti-Aβ) antibodies. To evaluate acute cellular priorities, we intracranially injected anti-Aβ antibody (3D6) or an isotype-matched control immunoglobulin G (IgG) antibody and performed single-cell sequencing analysis after 3 days.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>We found reduced numbers of a motile microglia cluster and homeostatic microglia in the 3D6 antibody-injected cortex compared to the IgG-injected cortex. It was also found that chemokine/cytokine signaling was enriched across homeostatic-proinflammatory microglia, interferon-responding microglia, and disease-associated microglia 2 (DAM2) following 3D6 antibody injection. We explored “CCL” signaling, which suggested a change in outgoing signaling coordinated by all microglia types targeting homeostatic microglia, surprisingly not targeting DAM1 or DAM2. We then analyzed enriched signaling pathways clustered by k-means river plots and identified pathways enriched and dampened with acute 3D6 treatment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Together these data supply evidence for significant involvement of microglia in the anti-Aβ response in the brain after just 3 days. Most interestingly, there are changes in cytokine/chemokine signaling across microglia subtypes, specifically with communication in CCL pathways targeting homeostatic microglia and T cells. These acute signaling changes provide novel insights and generate unique hypotheses on the brain's immediate immune reaction to anti-Aβ antibody.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Intracranially injected anti-amyloid beta (anti-Aβ) antibody promotes an immediate microglial response.</li>\u0000 \u0000 <li>3D6 exposure resulted in fewer homeostatic and motile microglia subtype","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12789186/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145953796","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}
Jean-Francois Trani, Ramkrishna K. Singh, Alexis IB Walker, Semere Bekena, Yiqi Zhu, Ganesh M. Babulal, Robbie Hart
<div> <section> <h3> INTRODUCTION</h3> <p>To investigate drivers of dementia risk disparities among older Black Americans using a community-based system dynamics (CBSD) approach.</p> </section> <section> <h3> METHODS</h3> <p>Over 18 months, 234 participants created 36 causal loop diagrams (CLDs) on dementia risk. An ecological analysis compared structural differences across groups based on scores on a structural and social determinants of health composite index (S/SDOH-CI).</p> </section> <section> <h3> RESULTS</h3> <p>Groups in the highest SDOH-CI quantile were more likely to identify key protective pathways linking mental health, substance use, exercise, medication, and community support to reduce dementia risk. In contrast, fewer than 25% of low-SDOH-CI groups identified these connections, and under 15% recognized the mental health benefits of community support or the educational and emotional advantages of higher income. However, low-SDOH-CI groups more often linked income to health insurance and family ties to health literacy and stress reduction.</p> </section> <section> <h3> DISCUSSION</h3> <p>Participants’ perceptions of dementia risk reflect their lived experiences, with distinct system substructures emphasized across SDOH-CI strata. Understanding how causal beliefs vary by socioeconomic context is essential for developing effective, equity-focused dementia prevention strategies for Black Americans. These findings highlight the need to tailor public health interventions to target the most socioeconomically disadvantaged groups.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Workshop discussions revealed that dementia risk among Black adults is closely linked to S/SDOH, with perceived causal pathways varying according to the degree of S/SDOH deprivation.</li> <li>Groups experiencing higher S/SDOH deprivation, as measured by a composite index of 37 indicators based on the NIA HDRF, more frequently emphasized the role of higher income and better health insurance, as well as the protective effects of strong family relationships in enhancing health literacy, reducing stress, and lowering dementia risk.</li> <li>Recognizing the socioeconomic drivers of dementia and addressing inequities in S/SDOH through sustained public health interventions may be critical to improving long-term health
{"title":"Perception of dementia risk among Black adults: an ecological analysis of causal loop diagrams with a structural and social determinant of health composite index","authors":"Jean-Francois Trani, Ramkrishna K. Singh, Alexis IB Walker, Semere Bekena, Yiqi Zhu, Ganesh M. Babulal, Robbie Hart","doi":"10.1002/trc2.70196","DOIUrl":"10.1002/trc2.70196","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>To investigate drivers of dementia risk disparities among older Black Americans using a community-based system dynamics (CBSD) approach.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Over 18 months, 234 participants created 36 causal loop diagrams (CLDs) on dementia risk. An ecological analysis compared structural differences across groups based on scores on a structural and social determinants of health composite index (S/SDOH-CI).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Groups in the highest SDOH-CI quantile were more likely to identify key protective pathways linking mental health, substance use, exercise, medication, and community support to reduce dementia risk. In contrast, fewer than 25% of low-SDOH-CI groups identified these connections, and under 15% recognized the mental health benefits of community support or the educational and emotional advantages of higher income. However, low-SDOH-CI groups more often linked income to health insurance and family ties to health literacy and stress reduction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Participants’ perceptions of dementia risk reflect their lived experiences, with distinct system substructures emphasized across SDOH-CI strata. Understanding how causal beliefs vary by socioeconomic context is essential for developing effective, equity-focused dementia prevention strategies for Black Americans. These findings highlight the need to tailor public health interventions to target the most socioeconomically disadvantaged groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Workshop discussions revealed that dementia risk among Black adults is closely linked to S/SDOH, with perceived causal pathways varying according to the degree of S/SDOH deprivation.</li>\u0000 \u0000 <li>Groups experiencing higher S/SDOH deprivation, as measured by a composite index of 37 indicators based on the NIA HDRF, more frequently emphasized the role of higher income and better health insurance, as well as the protective effects of strong family relationships in enhancing health literacy, reducing stress, and lowering dementia risk.</li>\u0000 \u0000 <li>Recognizing the socioeconomic drivers of dementia and addressing inequities in S/SDOH through sustained public health interventions may be critical to improving long-term health ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12774806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145936168","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}
Michael Mitterwallner, Eva Matt, Robert Chen, Roland Beisteiner
<div> <section> <h3> INTRODUCTION</h3> <p>Ultrasound neuromodulation has emerged as a promising adjunctive therapy in Alzheimer's disease (AD), yet a controversial issue remains: whether its reported long-term therapeutic effects could be attributed to potential confounds rather than genuine neuromodulatory mechanisms. Although auditory confounds via air- or bone-conducted sound have been discussed for immediate effects, their relevance for enduring therapeutic outcomes—essential for clinical application—remains unknown. This exploratory study is the first to examine whether long-term cognitive and neural effects of transcranial pulse stimulation (TPS) in AD are linked to persistent auditory network activation.</p> </section> <section> <h3> METHODS</h3> <p>A comprehensive re-analysis of task-based and resting-state functional magnetic resonance imaging (fMRI) data was conducted using data from the currently largest sham-controlled clinical ultrasound neuromodulation study (Matt et al., 2025). To isolate possible auditory contributions, we applied a contrast-based framework targeting (1) air-conducted sound, (2) combined air- and possibly bone-conducted sound, and (3) bone-conduction–specific effects. Analyses included: (a) task-based auditory cortex co-activation, (b) functional connectivity between auditory and dorsal attention networks (the latter was modulated in the original study), (c) global efficiency within the auditory network, and (d) correlations with neuropsychological test battery scores.</p> </section> <section> <h3> RESULTS</h3> <p>No significant long-term activation of auditory cortices was observed in task-based fMRI. Resting-state analyses showed no altered connectivity between auditory and attention networks, no changes in auditory network global efficiency, and no associations between auditory metrics and cognitive performance. Effect-size estimates were small, and 95% confidence intervals placed conservative upper bounds that argue against sizeable, sustained auditory confounds. These findings were consistent across all contrast conditions.</p> </section> <section> <h3> CONCLUSION</h3> <p>Using data from a rigorously controlled cognitive trial, we found no evidence of long-term auditory network effects following TPS. This makes it unlikely that auditory confounds are a key factor underlying the cognitive network effects observed with long-term ultrasound neuromodulation in typical verum-sham settings as investigated here.</p> </section> <section> <h3> Highli
超声神经调节已成为阿尔茨海默病（AD）的一种有前景的辅助治疗方法，但一个有争议的问题仍然存在：其报道的长期治疗效果是否可归因于潜在的混淆而不是真正的神经调节机制。虽然通过空气或骨传导的声音引起的听觉混淆已经被讨论过其直接效果，但它们与持久治疗结果的相关性（对临床应用至关重要）仍然未知。这项探索性研究首次探讨了经颅脉冲刺激（TPS）对AD患者的长期认知和神经影响是否与持续性听觉网络激活有关。方法：使用目前最大的假对照临床超声神经调节研究（Matt et al., 2025）的数据，对基于任务和静息状态的功能磁共振成像（fMRI）数据进行了全面的重新分析。为了分离可能的听觉影响，我们应用了一个基于对比的框架，针对(1)空气传导声音，(2)空气和可能的骨传导声音的组合，以及(3)骨传导特定效应。分析包括：(a)基于任务的听觉皮层共同激活，(b)听觉和背侧注意网络之间的功能连接（后者在原始研究中被调节），(c)听觉网络内的整体效率，以及(d)与神经心理测试电池得分的相关性。结果：在任务型fMRI中未观察到明显的听觉皮层长期激活。静息状态分析显示，听觉和注意网络之间的连通性没有改变，听觉网络的整体效率没有变化，听觉指标和认知表现之间没有关联。效应大小估计很小，95%的置信区间设置了保守的上限，反对大规模、持续的听觉混淆。这些发现在所有对比条件下都是一致的。结论：使用严格控制的认知试验数据，我们没有发现TPS后长期听觉网络效应的证据。这使得听觉混淆不太可能是本研究中在典型的假椎设置中观察到的长期超声神经调节所观察到的认知网络效应的关键因素。重点：使用功能磁共振成像（fMRI）评估长期经颅脉冲刺激对潜在听觉混淆的影响。分析包括任务-功能磁共振成像、静息状态功能连接和听觉网络效率。未发现听觉上的长期影响。听觉混淆不太可能是认知网络效应的关键因素。
{"title":"Ultrasound neuromodulation as a novel dementia therapy—Investigation of possible long-term confounds","authors":"Michael Mitterwallner, Eva Matt, Robert Chen, Roland Beisteiner","doi":"10.1002/trc2.70198","DOIUrl":"10.1002/trc2.70198","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Ultrasound neuromodulation has emerged as a promising adjunctive therapy in Alzheimer's disease (AD), yet a controversial issue remains: whether its reported long-term therapeutic effects could be attributed to potential confounds rather than genuine neuromodulatory mechanisms. Although auditory confounds via air- or bone-conducted sound have been discussed for immediate effects, their relevance for enduring therapeutic outcomes—essential for clinical application—remains unknown. This exploratory study is the first to examine whether long-term cognitive and neural effects of transcranial pulse stimulation (TPS) in AD are linked to persistent auditory network activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>A comprehensive re-analysis of task-based and resting-state functional magnetic resonance imaging (fMRI) data was conducted using data from the currently largest sham-controlled clinical ultrasound neuromodulation study (Matt et al., 2025). To isolate possible auditory contributions, we applied a contrast-based framework targeting (1) air-conducted sound, (2) combined air- and possibly bone-conducted sound, and (3) bone-conduction–specific effects. Analyses included: (a) task-based auditory cortex co-activation, (b) functional connectivity between auditory and dorsal attention networks (the latter was modulated in the original study), (c) global efficiency within the auditory network, and (d) correlations with neuropsychological test battery scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>No significant long-term activation of auditory cortices was observed in task-based fMRI. Resting-state analyses showed no altered connectivity between auditory and attention networks, no changes in auditory network global efficiency, and no associations between auditory metrics and cognitive performance. Effect-size estimates were small, and 95% confidence intervals placed conservative upper bounds that argue against sizeable, sustained auditory confounds. These findings were consistent across all contrast conditions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSION</h3>\u0000 \u0000 <p>Using data from a rigorously controlled cognitive trial, we found no evidence of long-term auditory network effects following TPS. This makes it unlikely that auditory confounds are a key factor underlying the cognitive network effects observed with long-term ultrasound neuromodulation in typical verum-sham settings as investigated here.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highli","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12771597/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145918955","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}
Beverly M. Berry, Garrett Davis, Yarissa Reyes, Edie Yau, Lauren Stratton, Monica Emery, Carl Hill
<div> <section> <h3> INTRODUCTION</h3> <p>The lack of racial/ethnic and socioeconomic diversity in research is an historic and ongoing crisis, especially for diseases like Alzheimer's disease and related dementias (ADRD), whose prevalence, incidence, and risk are highest among the populations most likely to be excluded. Targeted and culturally appropriate population education and engagement strategies are key to increasing participation and reducing health disparities and costs. Art-based knowledge translation (ABKT) uses art to disseminate information and resources related to research and its findings. The Alzheimer's Association applied ABKT in the form of a groundbreaking intervention called <i>Unforgettable</i>.</p> </section> <section> <h3> METHODS</h3> <p>Eligible communities were at least 35% Black/African American and/or Hispanic/Latino and had a strong local Alzheimer's Association chapter. Test market touring was used to refine the intervention's messaging. Highly tailored promotion and outreach was conducted by local chapters with national Alzheimer's Association support. A live concert, information tables, and an intermission talk provided additional promotion and messaging. Post-intervention surveys queried the intervention's messaging effectiveness and attendees’ personal experiences around caregiving and research participation.</p> </section> <section> <h3> RESULTS</h3> <p>Three hundred thirty-four surveys were completed. Most respondents were women (89%), Black/African American (78%), and had never participated in a clinical trial (85%). Satisfaction with the intervention and its messaging was high. Barriers to clinical trial participation centered on fears of potential risks and overall lack of knowledge.</p> </section> <section> <h3> DISCUSSION</h3> <p>The success of <i>Unforgettable</i> demonstrates the potential for future partnerships and arts-based health education initiatives through ABKT. By continuing to integrate culturally relevant storytelling with public health outreach and education, the Alzheimer's Association and others can further the critical and urgent mission of ending ADRD disparities.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li><i>Unforgettable</i> is a groundbreaking intervention that leverages culturally resonant art and live performance to engage under-represented communities in Alzheimer's disease and related dementias (ADRD) rese
{"title":"Unforgettable: The power of community in the pursuit of health equity for Alzheimer's disease and other dementia","authors":"Beverly M. Berry, Garrett Davis, Yarissa Reyes, Edie Yau, Lauren Stratton, Monica Emery, Carl Hill","doi":"10.1002/trc2.70195","DOIUrl":"10.1002/trc2.70195","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The lack of racial/ethnic and socioeconomic diversity in research is an historic and ongoing crisis, especially for diseases like Alzheimer's disease and related dementias (ADRD), whose prevalence, incidence, and risk are highest among the populations most likely to be excluded. Targeted and culturally appropriate population education and engagement strategies are key to increasing participation and reducing health disparities and costs. Art-based knowledge translation (ABKT) uses art to disseminate information and resources related to research and its findings. The Alzheimer's Association applied ABKT in the form of a groundbreaking intervention called <i>Unforgettable</i>.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Eligible communities were at least 35% Black/African American and/or Hispanic/Latino and had a strong local Alzheimer's Association chapter. Test market touring was used to refine the intervention's messaging. Highly tailored promotion and outreach was conducted by local chapters with national Alzheimer's Association support. A live concert, information tables, and an intermission talk provided additional promotion and messaging. Post-intervention surveys queried the intervention's messaging effectiveness and attendees’ personal experiences around caregiving and research participation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Three hundred thirty-four surveys were completed. Most respondents were women (89%), Black/African American (78%), and had never participated in a clinical trial (85%). Satisfaction with the intervention and its messaging was high. Barriers to clinical trial participation centered on fears of potential risks and overall lack of knowledge.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The success of <i>Unforgettable</i> demonstrates the potential for future partnerships and arts-based health education initiatives through ABKT. By continuing to integrate culturally relevant storytelling with public health outreach and education, the Alzheimer's Association and others can further the critical and urgent mission of ending ADRD disparities.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li><i>Unforgettable</i> is a groundbreaking intervention that leverages culturally resonant art and live performance to engage under-represented communities in Alzheimer's disease and related dementias (ADRD) rese","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12746347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866384","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}
Reina Tonegawa-Kuji, Ehud Karavani, Michael Danziger, Pengyue Zhang, Yuan Hou, Yadi Zhou, Marina Bykova, Andrew A. Pieper, Michal Rosen-Zvi, Jeffrey Cummings, Feixiong Cheng
<div> <section> <h3> INTRODUCTION</h3> <p>Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).</p> </section> <section> <h3> METHODS</h3> <p>Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.</p> </section> <section> <h3> RESULTS</h3> <p>A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).</p> </section> <section> <h3> DISCUSSION</h3> <p>This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.</li> <li>We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.</li> <li>Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower
{"title":"Critical evaluation of real-world evidence of repurposable medicines in the Alzheimer's disease drug development pipeline using a target trial emulation","authors":"Reina Tonegawa-Kuji, Ehud Karavani, Michael Danziger, Pengyue Zhang, Yuan Hou, Yadi Zhou, Marina Bykova, Andrew A. Pieper, Michal Rosen-Zvi, Jeffrey Cummings, Feixiong Cheng","doi":"10.1002/trc2.70193","DOIUrl":"10.1002/trc2.70193","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Repurposing Food and Drug Administration (FDA)-approved drugs could accelerate treatment development for Alzheimer's disease (AD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Using the MarketScan claims database (2011 to 2020), we applied a trial emulation approach in two base cohorts: (1) individuals with mild cognitive impairment (MCI cohort) and (2) individuals aged ≥70 years (over-70 cohort). We evaluated drugs represented in clinical trials for AD, comparing them with same-class or active comparators. Covariate-adjusted hazard ratios (HRs) were estimated using inverse-probability-weighted Cox models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>A total of 6 out of 38 (16%) drugs in the MCI cohort and 10 out of 53 (19%) drugs in the over-70 cohort were associated with a lower AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion (vs escitalopram; HR 0.57, 95% confidence interval [CI] [0.49, 0.66]), trazodone (vs sertraline; HR 0.82, 95% CI [0.74, 0.91]), venlafaxine (vs escitalopram; 0.72, 95% CI [0.62, 0.84]), and zolpidem (vs lorazepam; HR 0.69, 95% CI [0.56, 0.85]) were associated with a lower AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower incidence of AD dementia in the over-70 cohort (vs metformin; HR 0.74, 95% CI [0.59, 0.93]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>This is the first comprehensive set of trial emulations for FDA-approved drugs that are represented in AD trials. Findings may inform future trial designs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Repurposing FDA-approved drugs originally developed for other diseases could accelerate treatment development for AD.</li>\u0000 \u0000 <li>We identified repurposable drugs that are in current or complete clinical trials of AD and emulated trials for these agents using a large-scale insurance claims-based database.</li>\u0000 \u0000 <li>Among 54 drugs evaluated, 6/38 (16%) drugs in the MCI cohort and 10/53 (19%) in the over-70 cohort were associated with reduced AD incidence versus same-class comparators. Active comparator analyses indicated that bupropion, trazodone, venlafaxine, and zolpidem were associated with reduced AD incidence in the MCI cohort; these four plus liraglutide were associated with a lower","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"12 1","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12746425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145866469","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}
Pei-Chuan Ho, Guerry M. Peavy, Haeok Lee, Yian Gu, Walter A. Kukull, Yun-Beom Choi, Wai Haung Yu, Dolly Reyes-Dumeyer, Victor W. Henderson, Boon Lead Tee, Howard H. Feldman, Clara Li, Hyun-Sik Yang, Jody-Lynn Lupo, Ging-Yuek R. Hsiung, Collin Liu, Ellen C. Wong, Richard Mayeux, The Asian Cohort for Alzheimer's Disease Study, Van M. Ta Park, Gyungah R. Jun, Helena C. Chui, Li-San Wang, Tiffany W. Chow
<div> <section> <h3> INTRODUCTION</h3> <p>To address knowledge gaps in Alzheimer's disease (AD) research, the Asian Cohort for Alzheimer's Disease (ACAD) Study will recruit over 5000 participants of Asian descent aged 60 or older in the United States and Canada. The current focus is on participants with Chinese, Korean, or Vietnamese ancestry, with the goal of characterizing both genetic and non-genetic risk factors. ACAD has assembled a culturally and linguistically appropriate data collection protocol, as well as a biosample collection protocol. Recruitment strategies follow community-based participatory research (CBPR) approaches to encourage research participation and engage Asian communities in brain health education.</p> </section> <section> <h3> METHODS</h3> <p>The ACAD Clinical Core has developed a data collection packet (DCP) that gathers information on demographics, lifestyle factors, medical history, functional impairment, and cognitive status to support a dementia-related consensus diagnosis. Questionnaires and cognitive tests in the DCP are carefully selected or adapted to strike balance between alignment with existing AD cohorts and capturing the uniqueness in Asian subpopulations that may be related to AD. ACAD conducts a 2-year follow-up visit with all participants and a second 2-year follow-up visit with those participants who received a diagnosis of mild cognitive impairment at the first follow-up visit to confirm the robustness of the DCP and capture the trajectory of cognitive decline.</p> </section> <section> <h3> DISCUSSION</h3> <p>ACAD is well positioned to address major challenges in recruitment, language barriers, and cultural appropriateness to ensure accurate assessment with the use of the DCP (developed in ACAD targeted languages) and multilingual research coordinators. Along with DNA and plasma biomarkers derived from biosamples, ACAD integrates comprehensive survey and cognitive data to facilitate multidimensional analyses. The data collection protocol is adaptable for other Asian subpopulations beyond ACAD's current focus, with an expectation of further bridging the gap in participant diversity within AD research.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Asian Americans and Asian Canadians constitute one of the fastest growing non-White older populations.</li> <li>Asians have been under-represented in American and Canadian AD research.</li> <li>The ACAD
{"title":"Protocol for the Asian Cohort for Alzheimer's Disease (ACAD) Study","authors":"Pei-Chuan Ho, Guerry M. Peavy, Haeok Lee, Yian Gu, Walter A. Kukull, Yun-Beom Choi, Wai Haung Yu, Dolly Reyes-Dumeyer, Victor W. Henderson, Boon Lead Tee, Howard H. Feldman, Clara Li, Hyun-Sik Yang, Jody-Lynn Lupo, Ging-Yuek R. Hsiung, Collin Liu, Ellen C. Wong, Richard Mayeux, The Asian Cohort for Alzheimer's Disease Study, Van M. Ta Park, Gyungah R. Jun, Helena C. Chui, Li-San Wang, Tiffany W. Chow","doi":"10.1002/trc2.70189","DOIUrl":"10.1002/trc2.70189","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>To address knowledge gaps in Alzheimer's disease (AD) research, the Asian Cohort for Alzheimer's Disease (ACAD) Study will recruit over 5000 participants of Asian descent aged 60 or older in the United States and Canada. The current focus is on participants with Chinese, Korean, or Vietnamese ancestry, with the goal of characterizing both genetic and non-genetic risk factors. ACAD has assembled a culturally and linguistically appropriate data collection protocol, as well as a biosample collection protocol. Recruitment strategies follow community-based participatory research (CBPR) approaches to encourage research participation and engage Asian communities in brain health education.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The ACAD Clinical Core has developed a data collection packet (DCP) that gathers information on demographics, lifestyle factors, medical history, functional impairment, and cognitive status to support a dementia-related consensus diagnosis. Questionnaires and cognitive tests in the DCP are carefully selected or adapted to strike balance between alignment with existing AD cohorts and capturing the uniqueness in Asian subpopulations that may be related to AD. ACAD conducts a 2-year follow-up visit with all participants and a second 2-year follow-up visit with those participants who received a diagnosis of mild cognitive impairment at the first follow-up visit to confirm the robustness of the DCP and capture the trajectory of cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>ACAD is well positioned to address major challenges in recruitment, language barriers, and cultural appropriateness to ensure accurate assessment with the use of the DCP (developed in ACAD targeted languages) and multilingual research coordinators. Along with DNA and plasma biomarkers derived from biosamples, ACAD integrates comprehensive survey and cognitive data to facilitate multidimensional analyses. The data collection protocol is adaptable for other Asian subpopulations beyond ACAD's current focus, with an expectation of further bridging the gap in participant diversity within AD research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Asian Americans and Asian Canadians constitute one of the fastest growing non-White older populations.</li>\u0000 \u0000 <li>Asians have been under-represented in American and Canadian AD research.</li>\u0000 \u0000 <li>The ACAD ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 4","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12720140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145821942","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}
Audrey M. Collins, Maddison L. Mellow, Lu Wan, Ashleigh E. Smith, Lauren E. Oberlin, Kelsey R. Sewell, Neha P. Gothe, Jason Fanning, Jairo H. Migueles, Dorothea Dumuid, Aaron Miatke, John M. Jakicic, Chaeryon Kang, George Grove, Haiqing Huang, Bradley P. Sutton, Anna L. Marsland, M. Ilyas Kamboh, Arthur F. Kramer, Charles H. Hillman, Eric D. Vidoni, Jeffrey M. Burns, Edward McAuley, Kirk I. Erickson
<div> <section> <h3> INTRODUCTION</h3> <p>The relationships between 24-h time-use composition (i.e., sleep, sedentary behavior, light physical activity, and moderate-to-vigorous physical activity [MVPA]) and brain morphology in older adulthood remain poorly understood. We examined associations between 24-h time-use composition and brain age using compositional data analysis, predicting that 24-h time use would be associated with brain age and that a greater amount of time engaged in MVPA would drive associations with younger brain age.</p> </section> <section> <h3> METHODS</h3> <p>Baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE; <i>n</i> = 648) were analyzed. Brain age was estimated using T1-weighted magnetic resonance imaging data. Time-use composition was derived from wrist-worn triaxial accelerometers. Regression models examined associations between 24-h time-use composition (expressed as isometric log ratios) and brain age, adjusting for age, sex, apolipoprotein E4 (<i>APOE4</i>) carriage, education, body mass index, image quality, and site. Compositional isotemporal substitution evaluated how hypothetical reallocations of time between behaviors related to brain age.</p> </section> <section> <h3> RESULTS</h3> <p>The final sample included 573 adults (69.8±3.7 years, 407 females). It was found that 24-h time-use composition was associated with brain age (F = 2.72, <i>p</i> = 0.004). Post hoc modeling indicated that time spent in MVPA primarily drove these associations, such that less MVPA was associated with greater brain age, irrespective of whether time was taken from sleep, sedentary behavior, or light physical activity.</p> </section> <section> <h3> DISCUSSION</h3> <p>These results suggest that 24-h time use, especially time spent in MVPA, relates to structural brain age in late adulthood. Maintaining or increasing MVPA may help preserve younger brain age, irrespective of which behaviors this time was reallocated from. Future research should examine whether systematically shifting 24-h time use toward MVPA alters brain aging trajectories.</p> <p>Clinical Trial Registration Number and Name of Trial Registry: ClinicalTrial.gov: NCT02875301</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Time use relates to brain age in older adults.</li> <li>
老年人24小时时间使用构成（即睡眠、久坐行为、轻度体育活动和中高强度体育活动[MVPA]）与大脑形态之间的关系尚不清楚。我们使用成分数据分析检查了24小时时间使用构成与脑年龄之间的关系，预测24小时时间使用将与脑年龄相关，并且更多的时间参与MVPA将与更年轻的脑年龄相关。方法分析来自运动干预试验（IGNITE; n = 648）神经认知获益调查的基线数据。使用t1加权磁共振成像数据估计脑年龄。时间使用成分来源于腕带三轴加速度计。回归模型检验了24小时时间使用构成（以等距对数比表示）与脑年龄之间的关系，调整了年龄、性别、载脂蛋白E4 （APOE4）携带、教育程度、体重指数、图像质量和部位。组成等时间替代评估了假设的行为之间的时间重新分配如何与大脑年龄相关。结果最终纳入成人573例（69.8±3.7岁，女性407例）。结果发现，24小时时间利用构成与脑年龄相关（F = 2.72, p = 0.004）。事后建模表明，在MVPA上花费的时间主要推动了这些关联，因此，无论从睡眠、久坐行为还是轻度体育活动中获得的时间，MVPA的减少与大脑年龄的增加有关。这些结果表明，24小时的时间使用，特别是在MVPA中花费的时间，与成年后期的大脑结构年龄有关。维持或增加MVPA可能有助于保持年轻的大脑年龄，无论这些时间是从哪些行为中重新分配的。未来的研究应该检查是否系统地将24小时的时间使用转向MVPA会改变大脑的衰老轨迹。临床试验注册号和名称：ClinicalTrial.gov: NCT02875301重点提示老年人的时间使用与脑年龄有关。在MVPA中花费更多的时间可能有助于年轻的大脑年龄。时间使用和脑年龄之间的关联与AD的人口统计学差异或遗传风险无关。
{"title":"Association between 24-h time-use composition and brain age: The IGNITE study","authors":"Audrey M. Collins, Maddison L. Mellow, Lu Wan, Ashleigh E. Smith, Lauren E. Oberlin, Kelsey R. Sewell, Neha P. Gothe, Jason Fanning, Jairo H. Migueles, Dorothea Dumuid, Aaron Miatke, John M. Jakicic, Chaeryon Kang, George Grove, Haiqing Huang, Bradley P. Sutton, Anna L. Marsland, M. Ilyas Kamboh, Arthur F. Kramer, Charles H. Hillman, Eric D. Vidoni, Jeffrey M. Burns, Edward McAuley, Kirk I. Erickson","doi":"10.1002/trc2.70187","DOIUrl":"https://doi.org/10.1002/trc2.70187","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The relationships between 24-h time-use composition (i.e., sleep, sedentary behavior, light physical activity, and moderate-to-vigorous physical activity [MVPA]) and brain morphology in older adulthood remain poorly understood. We examined associations between 24-h time-use composition and brain age using compositional data analysis, predicting that 24-h time use would be associated with brain age and that a greater amount of time engaged in MVPA would drive associations with younger brain age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Baseline data from the Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE; <i>n</i> = 648) were analyzed. Brain age was estimated using T1-weighted magnetic resonance imaging data. Time-use composition was derived from wrist-worn triaxial accelerometers. Regression models examined associations between 24-h time-use composition (expressed as isometric log ratios) and brain age, adjusting for age, sex, apolipoprotein E4 (<i>APOE4</i>) carriage, education, body mass index, image quality, and site. Compositional isotemporal substitution evaluated how hypothetical reallocations of time between behaviors related to brain age.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The final sample included 573 adults (69.8±3.7 years, 407 females). It was found that 24-h time-use composition was associated with brain age (F = 2.72, <i>p</i> = 0.004). Post hoc modeling indicated that time spent in MVPA primarily drove these associations, such that less MVPA was associated with greater brain age, irrespective of whether time was taken from sleep, sedentary behavior, or light physical activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These results suggest that 24-h time use, especially time spent in MVPA, relates to structural brain age in late adulthood. Maintaining or increasing MVPA may help preserve younger brain age, irrespective of which behaviors this time was reallocated from. Future research should examine whether systematically shifting 24-h time use toward MVPA alters brain aging trajectories.</p>\u0000 \u0000 <p>Clinical Trial Registration Number and Name of Trial Registry: ClinicalTrial.gov: NCT02875301</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Time use relates to brain age in older adults.</li>\u0000 \u0000 <li>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 4","pages":""},"PeriodicalIF":6.8,"publicationDate":"2025-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145824811","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}
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