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Assessing the clinical meaningfulness of slowing CDR-SB progression with disease-modifying therapies for Alzheimer's disease
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-13 DOI: 10.1002/trc2.70033
Sarah M. Hartz, Suzanne E. Schindler, Marissa L. Streitz, Krista L. Moulder, Jessica Mozersky, Guoqiao Wang, Chengjie Xiong, John C. Morris
<div> <section> <h3> INTRODUCTION</h3> <p>For many patients and caregivers, a major goal of disease-modifying treatments (DMTs) for Alzheimer's disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs.</p> </section> <section> <h3> METHODS</h3> <p>Participants at the Knight Alzheimer Disease Research Center (Knight ADRC) who met eligibility criteria for recent DMT trials were studied: age ≥60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating [CDR] score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum of Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed-effects models.</p> </section> <section> <h3> RESULTS</h3> <p>A total of 282 participants were followed for an average of 2.9 years (standard deviation [SD] 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB >4.5 and in BADLs at CDR-SB >11.5. For individuals with a baseline CDR-SB = 2, treatment with lecanemab would extend independence in IADLs for 10 months (95% confidence interval [CI] 4–18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6–24 months).</p> </section> <section> <h3> DISCUSSION</h3> <p>Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>We estimated time to loss of independence for people with AD dementia</li> <li>Estimating time to loss of independence can help with clinical decision-making</li>
{"title":"Assessing the clinical meaningfulness of slowing CDR-SB progression with disease-modifying therapies for Alzheimer's disease","authors":"Sarah M. Hartz,&nbsp;Suzanne E. Schindler,&nbsp;Marissa L. Streitz,&nbsp;Krista L. Moulder,&nbsp;Jessica Mozersky,&nbsp;Guoqiao Wang,&nbsp;Chengjie Xiong,&nbsp;John C. Morris","doi":"10.1002/trc2.70033","DOIUrl":"https://doi.org/10.1002/trc2.70033","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;For many patients and caregivers, a major goal of disease-modifying treatments (DMTs) for Alzheimer's disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs.&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;Participants at the Knight Alzheimer Disease Research Center (Knight ADRC) who met eligibility criteria for recent DMT trials were studied: age ≥60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating [CDR] score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum of Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed-effects 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;A total of 282 participants were followed for an average of 2.9 years (standard deviation [SD] 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB &gt;4.5 and in BADLs at CDR-SB &gt;11.5. For individuals with a baseline CDR-SB = 2, treatment with lecanemab would extend independence in IADLs for 10 months (95% confidence interval [CI] 4–18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6–24 months).&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;Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families.&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 estimated time to loss of independence for people with AD dementia&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Estimating time to loss of independence can help with clinical decision-making&lt;/li&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143397190","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}
引用次数: 0
Diabetes mellitus exacerbates changes in white matter hyperintensity shapes and volume: A longitudinal study
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-11 DOI: 10.1002/trc2.70042
Shihao Xu, Yan Wang, Jiahui Chen, Zhiming Pan, Wenjun Wu, Zhipeng Su, Zhen Wang
<div> <section> <h3> INTRODUCTION</h3> <p>Although white matter hyperintensity (WMH) can progress over time, little is known about the underlying mechanisms. In addition, type 2 diabetes mellitus (T2DM) exacerbates the accumulation of WMH. Here we aimed to investigate longitudinal changes in WMH shapes and volume in older adults with and without T2DM.</p> </section> <section> <h3> METHODS</h3> <p>Participants underwent baseline and follow-up magnetic resonance imaging (MRI). WMH volume and shape markers were automatically assessed. We compared WMH volume and shape markers at baseline and follow-up.</p> </section> <section> <h3> RESULTS</h3> <p>A total of 200 participants were included at baseline and 181 at follow-up. The mean age ± SD of our study participants was 69.86 ± 6.03 years; 79 (39.90%) had a history of diabetes mellitus (T2DM) and 73 (36.50%) were male. For shape markers, participants with T2DM showed more complex periventricular (eccentricity, <i>p</i> = 0.027) and deep WMH shape markers (fractal dimension, <i>p</i> = 0.002) than participants without T2DM. At baseline, there were no statistically significant differences (<i>p</i> > 0.05) in WMH volume when participants with T2DM were compared to participants without T2DM. At follow-up, a more complex shape of periventricular/confluent WMH on follow-up (concavity index, <i>p</i> = 0.005; inverse sphericity index, <i>p</i> = 0.001). In addition, total (<i>p</i> < 0.001), periventricular (<i>p</i> < 0.001), and deep (<i>p</i> = 0.001) WMH volumes increased significantly.</p> </section> <section> <h3> DISCUSSION</h3> <p>A more irregular shape of periventricular and deep WMH and higher WMH volumes were associated with T2DM participants. These findings suggest that WMH shape markers may be useful in determining prognosis for cerebral small vessel disease and aid in future preventive treatments.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Patients with diabetes mellitus have more irregular white matter hyperintensity (WMH) shapes and increased WMH volumes.</li> <li>Diabetes mellitus exacerbates the changes in WMH shapes and volumes</li> <li>WMH shape markers might have the potential to aid in future preventive treatments and prevent clinical deterioration.</li> </ul> </div>
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引用次数: 0
The Common Alzheimer's Disease Research Ontology (CADRO) for biomarker categorization
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-11 DOI: 10.1002/trc2.70050
Amanda M. Leisgang Osse, Jefferson W. Kinney, Jeffrey L. Cummings

Biomarkers are vital to Alzheimer's disease (AD) drug development and clinical trials, and will have an increasing role in clinical care. In this narrative review, we demonstrate the use of the National Institutes on Aging/Alzheimer's Association (NIA/AA) Common Alzheimer's Disease Research Ontology (CADRO) system for the categorization of biomarkers based on the primary mechanism on which they report. We show that biomarkers are available (in various levels of validation) for all CADRO processes. Application of the CADRO system demonstrates gaps in the field where novel biomarkers are needed for specific aspects of the disease, and assays to detect and measure biological changes, in individuals with symptomatic or preclinical AD. We demonstrate the CADRO system as a means of categorizing established and candidate AD biomarkers, showing the feasibility and practicality of the system. CADRO can assist with biomarker selection for AD clinical trials and drug development, and may eventually be applied to implementing biomarkers in patient care. 

Highlights

  • The Common Alzheimer's Disease Research Ontology (CADRO) system can be used to categorize biomarkers for drug development.
  • We demonstrate the use of CADRO with Alzheimer's disease (AD) biomarkers.
  • We identified AD biomarkers in each of the CADRO categories.
  • CADRO can be incorporated into current AD drug development and clinical trial systems.
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引用次数: 0
Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations: Proceedings from the Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-11 DOI: 10.1002/trc2.70038
Ronald C. Petersen, Ana Graf, Chris Brady, Susan De Santi, Hana Florian, Jaren Landen, Mike Pontecorvo, Christopher Randolph, Kaycee Sink, Maria Carrillo, Christopher J. Weber

The design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) approval of the first anti-amyloid, disease-modifying treatment for AD, a monoclonal antibody called aducanumab, the landscape of clinical trial design is evolving. Enrolment in clinical trials may be impacted by the availability of this and other treatments, and trial design must take into consideration that patients may desire a disease-modifying treatment rather than potentially being randomized to the placebo arm. The Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting discussed the consideration of well-defined AD staging criteria in protocol design and how they influence more standardized inclusion/exclusion criteria for trials, as well as what constitutes meaningful differentiation between the stages. Discussion explored the current state of knowledge regarding biomarkers and how they can inform AD staging criteria, as many trials are now designed based on specific biomarker features, further underscoring the importance of coordinating AD staging criteria and biomarkers. The relationship between cognition and biomarkers has been studied and this must continue as trials move forward. Researchers, patients, clinicians, regulatory scientists, and payers discussed the state of the field as well as the future of symptomatic Alzheimer's disease clinical trials.

Highlights

  • The Alzheimer's Association Research Roundtable (AARR) convened leaders from academia and industry as well as patients, care partners, clinicians, regulators, and payers to discuss the topic of operationalizing selection criteria for clinical trials and the role of biomarkers.
  • Well-defined Alzheimer's disease (AD) staging criteria are an important consideration in study protocol design.
  • Staging criteria and biomarkers must be coordinated to yield high-quality clinical trial results that have meaning for patients with AD by selecting a population most likely to benefit from a specific treatment.
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引用次数: 0
CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-11 DOI: 10.1002/trc2.70051
Mihály Hajós, Kiran Pandey, Annabelle C. Singer, Duc Duong, Sara Bitarafan, Monika Shpokayte, Zach Malchano, Ralph Kern, James J. Lah, Allan I. Levey, Nicholas T. Seyfried
<div> <section> <h3> INTRODUCTION</h3> <p>Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild–moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.</p> </section> <section> <h3> METHODS</h3> <p>Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI (<i>n</i> = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady-state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.</p> </section> <section> <h3> RESULTS</h3> <p>Differential expression analysis of proteins at baseline and after 8 weeks of treatment (<i>N</i> = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, <i>P</i> < 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co-expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD-related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.</p> </section> <section> <h3> DISCUSSION</h3> <p>The CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.</p> </section> <section>
{"title":"CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment","authors":"Mihály Hajós,&nbsp;Kiran Pandey,&nbsp;Annabelle C. Singer,&nbsp;Duc Duong,&nbsp;Sara Bitarafan,&nbsp;Monika Shpokayte,&nbsp;Zach Malchano,&nbsp;Ralph Kern,&nbsp;James J. Lah,&nbsp;Allan I. Levey,&nbsp;Nicholas T. Seyfried","doi":"10.1002/trc2.70051","DOIUrl":"https://doi.org/10.1002/trc2.70051","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild–moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.&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;Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI (&lt;i&gt;n&lt;/i&gt; = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady-state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.&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;Differential expression analysis of proteins at baseline and after 8 weeks of treatment (&lt;i&gt;N&lt;/i&gt; = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, &lt;i&gt;P&lt;/i&gt; &lt; 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co-expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD-related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.&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 CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380898","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}
引用次数: 0
Rural–urban disparities of Alzheimer's disease and related dementias: A scoping review
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-11 DOI: 10.1002/trc2.70047
Mackenzie Kramer, Maxwell Cutty, Sara Knox, Alexander V. Alekseyenko, Abolfazl Mollalo
<div> <section> <p>The rising age of the global population has made Alzheimer's disease and related dementias (ADRD) a critical public health problem, with significant health-related disparities observed between rural and urban areas. However, no previous reviews have examined the scope and determinant factors contributing to rural–urban disparities of ADRD-related health outcomes. This study aims to systematically collate and synthesize peer-reviewed articles on rural–urban disparities in ADRD, identifying key determinants and research gaps to guide future research. We conducted a systematic search using key terms related to rural–urban disparities and ADRD without restrictions on geography or study design. Five search engines—MEDLINE, CINAHL, Web of Science, PubMed, and Scopus—were used to identify relevant articles. The search was performed on August 16, 2024, and included English-language articles published from 2000 onward. Sixty-three articles met the eligibility criteria for data extraction and synthesis. Most articles were published after 2010 (85.7%) and were concentrated in the United States, China, and Canada (66.7%). A majority had cross-sectional (58.7%) or cohort study designs (23.8%), primarily examining prevalence (41.3%) or incidence (11.1%). Findings often indicated a higher prevalence and incidence in rural areas, although inconsistent rural–urban classification systems were noted. Common risk factors included female sex, lower education level, lower income, and comorbidities such as diabetes and cerebrovascular diseases. Environmental (12.7%) and lifestyle (14.3%) factors for ADRD have been less explored. The statistical methods used were mainly traditional analyses (e.g., logistic regression) and lacked advanced techniques such as machine learning or causal inference methods. The gaps identified in this review emphasize the need for future research in underexplored geographic regions and encourage the use of advanced methods to investigate understudied factors contributing to ADRD disparities, such as environmental, lifestyle, and genetic influences.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Few studies on rural–urban ADRD disparities focus on low- and middle-income countries.</li> <li>Common risk factors include female sex, low education attainment, low income, and comorbidities.</li> <li>Inconsistent definitions of “rural” complicate cross-country comparisons.</li> <li>Environmental and lifestyle factors affecting ADRD are underexplored.</li> <li>Advanced statistical methods, such as machine learning and caus
{"title":"Rural–urban disparities of Alzheimer's disease and related dementias: A scoping review","authors":"Mackenzie Kramer,&nbsp;Maxwell Cutty,&nbsp;Sara Knox,&nbsp;Alexander V. Alekseyenko,&nbsp;Abolfazl Mollalo","doi":"10.1002/trc2.70047","DOIUrl":"https://doi.org/10.1002/trc2.70047","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;The rising age of the global population has made Alzheimer's disease and related dementias (ADRD) a critical public health problem, with significant health-related disparities observed between rural and urban areas. However, no previous reviews have examined the scope and determinant factors contributing to rural–urban disparities of ADRD-related health outcomes. This study aims to systematically collate and synthesize peer-reviewed articles on rural–urban disparities in ADRD, identifying key determinants and research gaps to guide future research. We conducted a systematic search using key terms related to rural–urban disparities and ADRD without restrictions on geography or study design. Five search engines—MEDLINE, CINAHL, Web of Science, PubMed, and Scopus—were used to identify relevant articles. The search was performed on August 16, 2024, and included English-language articles published from 2000 onward. Sixty-three articles met the eligibility criteria for data extraction and synthesis. Most articles were published after 2010 (85.7%) and were concentrated in the United States, China, and Canada (66.7%). A majority had cross-sectional (58.7%) or cohort study designs (23.8%), primarily examining prevalence (41.3%) or incidence (11.1%). Findings often indicated a higher prevalence and incidence in rural areas, although inconsistent rural–urban classification systems were noted. Common risk factors included female sex, lower education level, lower income, and comorbidities such as diabetes and cerebrovascular diseases. Environmental (12.7%) and lifestyle (14.3%) factors for ADRD have been less explored. The statistical methods used were mainly traditional analyses (e.g., logistic regression) and lacked advanced techniques such as machine learning or causal inference methods. The gaps identified in this review emphasize the need for future research in underexplored geographic regions and encourage the use of advanced methods to investigate understudied factors contributing to ADRD disparities, such as environmental, lifestyle, and genetic influences.&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;Few studies on rural–urban ADRD disparities focus on low- and middle-income countries.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Common risk factors include female sex, low education attainment, low income, and comorbidities.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Inconsistent definitions of “rural” complicate cross-country comparisons.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Environmental and lifestyle factors affecting ADRD are underexplored.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Advanced statistical methods, such as machine learning and caus","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380746","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}
引用次数: 0
Anticholinergic drugs and dementia risk: Using stem cell–based studies to complement pharmacoepidemiology
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-02-05 DOI: 10.1002/trc2.70040
Tiara A. Schwarze-Taufiq, Inez K. A. Pranoto, Katherine Hui, Chizuru Kinoshita, Onchee Yu, Paul K. Crane, Shelly L. Gray, Jessica E. Young
<div> <section> <h3> BACKGROUND</h3> <p>Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including increased risk in dementia. Pharmacoepidemiology studies from various populations report associations between specific anticholinergic classes – antidepressants and bladder antimuscarinics – and increased dementia incidence. However, it is difficult to determine whether these associations are directly caused by the neurotoxic effects of anticholinergic drugs or by the underlying health conditions which the medications are taken for, known as confounding by indication. Here, we leverage human induced pluripotent stem cells-derived-neurons (hiPSC-Ns) to complement the pharmacoepidemiology studies by directly examining the effects of various anticholinergic classes on dementia-related cellular phenotypes.</p> </section> <section> <h3> METHODS</h3> <p>We treated human induced pluripotent stem cell (hiPSC)–derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures.</p> </section> <section> <h3> RESULTS</h3> <p>We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1-42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments.</p> </section> <section> <h3> CONCLUSIONS</h3> <p>These results corroborate population-based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC-derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC-based models.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Certain classes of anticholinergic (AC) medications are linked to dementia.</li> <li>Human-induced pluripotent stem cell (hiPSC) models are used to
{"title":"Anticholinergic drugs and dementia risk: Using stem cell–based studies to complement pharmacoepidemiology","authors":"Tiara A. Schwarze-Taufiq,&nbsp;Inez K. A. Pranoto,&nbsp;Katherine Hui,&nbsp;Chizuru Kinoshita,&nbsp;Onchee Yu,&nbsp;Paul K. Crane,&nbsp;Shelly L. Gray,&nbsp;Jessica E. Young","doi":"10.1002/trc2.70040","DOIUrl":"https://doi.org/10.1002/trc2.70040","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;Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including increased risk in dementia. Pharmacoepidemiology studies from various populations report associations between specific anticholinergic classes – antidepressants and bladder antimuscarinics – and increased dementia incidence. However, it is difficult to determine whether these associations are directly caused by the neurotoxic effects of anticholinergic drugs or by the underlying health conditions which the medications are taken for, known as confounding by indication. Here, we leverage human induced pluripotent stem cells-derived-neurons (hiPSC-Ns) to complement the pharmacoepidemiology studies by directly examining the effects of various anticholinergic classes on dementia-related cellular phenotypes.&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 treated human induced pluripotent stem cell (hiPSC)–derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1-42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments.&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;These results corroborate population-based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC-derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC-based models.&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;Certain classes of anticholinergic (AC) medications are linked to dementia.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Human-induced pluripotent stem cell (hiPSC) models are used to ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248755","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}
引用次数: 0
Data-driven discovery of associations between prescribed drugs and dementia risk: A systematic review 数据驱动的处方药物与痴呆风险之间关联的发现:一项系统综述。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-21 DOI: 10.1002/trc2.70037
Benjamin R. Underwood, Ilianna Lourida, Jessica Gong, Stefano Tamburin, Eugene Yee Hing Tang, Emad Sidhom, Xin You Tai, Matthew J. Betts, Janice M. Ranson, Margarita Zachariou, Olajide E. Olaleye, Saswati Das, Neil P. Oxtoby, Shanquan Chen, David J. Llewellyn, for the Deep Dementia Phenotyping (DEMON) Network

Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data-driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti-inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms.

Highlights

  • · We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia.
  • · Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment.
  • · Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue.
  • · Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.
摘要:最近关于减缓痴呆症进展的临床试验使人们重新关注寻找更安全、更有效的治疗方法。确定合理的候选药物的一种方法是评估现有的治疗其他疾病的药物是否会影响痴呆症的风险。我们进行了一项系统综述,以确定采用数据驱动方法调查各种处方药与痴呆风险之间关系的研究。我们纳入了14项研究,这些研究使用了超过1.3亿个人和100万痴呆病例的行政或医疗记录数据。尽管在确定可能改变阿尔茨海默病或痴呆症风险的特定药物方面存在不一致,但一些具有生物学合理性的药物类别出现了一些主题。抗微生物药物、疫苗接种和消炎药与风险降低有关,而糖尿病药物、维生素和补充剂以及抗精神病药物与风险增加有关。我们发现关于抗高血压药和抗抑郁药的证据相互矛盾。针对痴呆症的药物再利用是当务之急。我们的发现为确定候选药物的优先级和探索潜在机制提供了基础。·我们对包括1.39亿人和100万例痴呆症患者在内的研究进行了系统回顾,报告了其他疾病处方药物与痴呆症风险之间的关联。·我们的工作支持一些先前报道的关联,例如,显示治疗炎症性疾病的药物降低痴呆风险,抗精神病药物治疗增加风险。·抗菌治疗可能更令人惊讶地与降低风险相关,支持最近对这一潜在治疗途径的兴趣增加。·我们的工作应该有助于优先考虑进入阿尔茨海默病适应性平台试验的药物,并将为那些研究药物或药物类别和痴呆症风险的人提供有用的资源。
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引用次数: 0
Unraveling the impact of blood RANKL and OPG levels on Alzheimer's disease: Independent of bone mineral density and inflammation 揭示血液RANKL和OPG水平对阿尔茨海默病的影响:独立于骨矿物质密度和炎症。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-20 DOI: 10.1002/trc2.70044
Xingzhi Guo, Wenzhi Shi, Juanjuan Lu, Peng Tang, Rui Li
<div> <section> <h3> INTRODUCTION</h3> <p>Observational studies have revealed a close relationship between reduced bone mineral density (BMD) and Alzheimer's disease (AD) risk. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) system, pivotal in regulating bone metabolism, has been implicated in brain function, but the causal impact on AD risk remains unclear.</p> </section> <section> <h3> METHODS</h3> <p>We employed bi-directional Mendelian randomization (MR) and multivariable MR (MVMR) approaches to elucidate the effect of blood soluble RANKL (sRANKL) and OPG levels on AD, assessing whether this influence was independent of BMD and inflammation. Three distinct AD genome-wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary-level data on blood sRANKL and OPG were sourced from deCODE Genetics.</p> </section> <section> <h3> RESULTS</h3> <p>Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.72–0.94, <i>p</i> = 0.004; UKB: OR = 0.85, 95% CI = 0.78–0.91, <i>p</i> < 0.001; FinnGen: OR = 0.83, 95% CI = 0.73–0.94, <i>p</i> = 0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin-1α and chemoattractant protein-1.</p> </section> <section> <h3> DISCUSSION</h3> <p>Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. These findings enhance our understanding of the complex interactions between bone metabolism and AD.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Blood soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) levels are linked to a reduced risk of Alzheimer's disease (AD).</li> <li>The association between sRANKL levels and AD is independent of bone mineral density (BMD) and inflammation.</li> <li>No causal link exists between blood os
观察性研究揭示了骨密度(BMD)降低与阿尔茨海默病(AD)风险之间的密切关系。核因子κ b配体受体激活剂(RANKL)和骨保护素(OPG)系统在调节骨代谢中起关键作用,已被认为与脑功能有关,但其对AD风险的因果影响尚不清楚。方法:我们采用双向孟德尔随机化(MR)和多变量MR (MVMR)方法来阐明血溶性RANKL (sRANKL)和OPG水平对AD的影响,评估这种影响是否独立于BMD和炎症。三个不同的AD全基因组关联研究(GWAS)数据集分别来自国际阿尔茨海默氏症基因组计划(IGAP)、英国生物银行(UKB)和FinnGen。血液sRANKL和OPG的汇总数据来自deCODE Genetics。结果:在所有三个AD GWAS数据集中,遗传预测的每标准差(SD)血中sRANKL水平升高与AD风险降低显著相关(IGAP:优势比[OR] = 0.82, 95%可信区间[CI] = 0.72-0.94, p = 0.004;UKB: OR = 0.85, 95% CI = 0.78-0.91, p < 0.001;FinnGen:或= 0.83,95% CI -0.94 = 0.73, p = 0.004)。OPG水平与AD之间没有明显的因果关系。此外,AD对血液中sRANKL和OPG水平没有因果影响。MVMR结果显示,在调整BMD、白细胞介素-1α和趋化蛋白-1后,sRANKL与AD风险的负相关关系仍然存在。讨论:我们的研究提供了证据,表明升高的sRANKL水平与AD风险降低有因果关系,与BMD和炎症无关。这些发现增强了我们对骨代谢和AD之间复杂相互作用的理解。重点:血溶性受体激活物核因子κ b配体(sRANKL)水平与阿尔茨海默病(AD)风险降低有关。sRANKL水平与AD之间的关联与骨密度(BMD)和炎症无关。血液中骨保护素水平与AD之间不存在因果关系。AD不影响血液中sRANKL或骨保护素的水平。
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引用次数: 0
Dynamic neurocognitive adaptation in aging: Development and validation of a new scale 衰老中的动态神经认知适应:新量表的开发和验证。
IF 4.9 Q1 CLINICAL NEUROLOGY Pub Date : 2025-01-20 DOI: 10.1002/trc2.70049
Filippo Cieri, Giulia Di Francesco, Chad Lee Cross, Andrew Bender, Jessica Zoe Kirkland Caldwell

INTRODUCTION

Forty-five percent of Alzheimer's disease (AD) cases may have been preventable through protective factors. Reserve, resilience, and resistance share common neurocognitive adaptive processes, acting through protective mechanisms. In this article we propose the development and validation of a new scale, called dynamic Neurocognitive Adaptation, developed in this direction.

METHODS

We included 815 participants (50% women; 65+ years inclusive of age), divided into two subsamples for exploratory and confirmatory factor analysis. Our initial scale was composed of 30 items, investigating seven dimensions, explored by a 5-point Likert scale reflecting the frequency of activities, for seven time windows.

RESULTS

Our final scale had 20 items divided among four dimensions: physical, cognitive, creative, and social. There were no issues related to multi-collinearity or non-collinearity. Kaiser–Meyer–Olkin (KMO) = 0.80 and Bartlett's test of sphericity indicated all values ≤0.01; Cronbach's alpha = 0.83.

DISCUSSION

We have validated a reliable, novel, easy to complete, and comprehensive scale to assess lifetime behaviors, which can be applied in research on AD risk reduction, mild cognitive impairment, and in clinical practice.

Highlights

  • Reserve, resistance, and resilience share similar adaptive mechanisms.
  • Dynamic Neurocognitive Adaptation is a new scale to assess lifetime protective factors.
  • Dynamic Neurocognitive Adaptation is a reliable, novel, and easy to complete scale.
  • This approach can characterize specific life stages that are ripe for risk-reduction interventions.
  • Our scale can be used to personalize health recommendations in aging.
导语:45%的阿尔茨海默病(AD)病例可以通过保护因素来预防。储备、恢复力和抵抗具有共同的神经认知适应过程,通过保护机制起作用。在这篇文章中,我们提出了一个新的尺度的发展和验证,称为动态神经认知适应,在这个方向上发展。方法:我们纳入815名参与者(50%为女性;65岁以上(含年龄),分为两个子样本进行探索性和验证性因素分析。我们最初的量表由30个项目组成,调查了7个维度,通过5点李克特量表反映了7个时间窗口的活动频率。结果:我们的最终量表有20个项目,分为四个维度:身体、认知、创造力和社交。不存在多重共线性或非共线性的问题。Kaiser-Meyer-Olkin (KMO) = 0.80, Bartlett球度检验结果均≤0.01;Cronbach’s alpha = 0.83。讨论:我们验证了一种可靠、新颖、易于完成、全面的终身行为评估量表,可用于阿尔茨海默病风险降低、轻度认知障碍的研究和临床实践。重点:储备、抵抗和恢复具有相似的适应机制。动态神经认知适应是一种评价终身保护因素的新量表。动态神经认知适应量表是一种可靠、新颖、易于完成的量表。这种方法可以描述适合采取降低风险干预措施的特定生命阶段。我们的量表可以用来为老年人提供个性化的健康建议。
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引用次数: 0
期刊
Alzheimer''s and Dementia: Translational Research and Clinical Interventions
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