Fernando Luiz Westphal Filho, Paulo Roberto Moss Lopes, Artur Menegaz de Almeida, Vitor Kendi Tsuchiya Sano, Fernanda Moraes Tamashiro, Ocílio Ribeiro Gonçalves, Francisco Cezar Aquino de Moraes, Michele Kreuz, Francinny Alves Kelly, Pablo Vinícius Silveira Feitoza
Dementia affects 55 million people globally, with the number projected to triple by 2050. Statins, widely prescribed for cardiovascular benefits, may also have neuroprotective effects, although studies on their impact on dementia risk have shown contradictory results. In this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We assessed the risk of dementia, Alzheimer's disease (AD), and vascular dementia (VaD), with subgroup analyses by gender, statin type, and diabetes status. Fifty-five observational studies including over 7 million patients were analyzed. Statin use significantly reduced the risk of dementia compared to nonusers (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.82 to 0.91; p < 0.001). It was also associated with reduced risks of AD (HR 0.82; 95% CI: 0.74 to 0.90; p < 0.001) and VaD (HR 0.89; 95% CI: 0.77 to 1.02; p = 0.093). Subgroup analyses revealed significant dementia risk reductions among patients with type 2 diabetes mellitus (HR 0.87; 95% CI: 0.85 to 0.89; p < 0.001), those with exposure to statins for more than 3 years (HR 0.37; 95% CI: 0.30 to 0.46; p < 0.001), and populations from Asia, where the greatest protective effect was observed (HR 0.84; 95% CI: 0.80 to 0.88). Additionally, rosuvastatin demonstrated the most pronounced protective effect for all-cause dementia among specific statins (HR 0.72; 95% CI: 0.60 to 0.88). Our findings underscore the neuroprotective potential of statins in dementia prevention. Despite the inherent limitations of observational studies, the large dataset and detailed subgroup analyses enhance the reliability of our results. Future randomized clinical trials are necessary to confirm these findings and enlighten clinical guidelines.
Highlights
Largest meta-analysis to date on statins and dementia risk, including 55 studies and more than 7 million patients.
Statin use linked to lower risks of all-dementia, AD, and VaD.
Numerous significant subgroup results highlight statins' diverse neuroprotective effects.
Findings support statins as a public health tool, especially in low-income countries.
Future research should explore the impact of statins across diverse patient populations.
全球有5500万人患有痴呆症，预计到2050年这一数字将增加两倍。他汀类药物广泛用于治疗心血管疾病，也可能具有神经保护作用，尽管有关其对痴呆风险影响的研究显示出相互矛盾的结果。在本系统评价和荟萃分析中，我们按照系统评价和荟萃分析（PRISMA）指南的首选报告项目检索了PubMed、Embase和Cochrane。我们评估了痴呆、阿尔茨海默病（AD）和血管性痴呆（VaD）的风险，并根据性别、他汀类药物类型和糖尿病状况进行了亚组分析。共分析了55项观察性研究，包括700多万患者。与未使用他汀类药物的患者相比，使用他汀类药物可显著降低痴呆风险(风险比[HR] 0.86；95%置信区间[CI]: 0.82 ~ 0.91；p p p = 0.093)。亚组分析显示，2型糖尿病患者痴呆风险显著降低(HR 0.87；95% CI: 0.85 ~ 0.89；亮点：迄今为止最大的关于他汀类药物与痴呆风险的荟萃分析，包括55项研究和700多万患者。他汀类药物的使用与全痴呆、AD和VaD的风险降低有关。许多重要的亚组结果突出了他汀类药物不同的神经保护作用。研究结果支持他汀类药物作为公共卫生工具，特别是在低收入国家。未来的研究应该探索他汀类药物对不同患者群体的影响。
{"title":"Statin use and dementia risk: A systematic review and updated meta-analysis","authors":"Fernando Luiz Westphal Filho, Paulo Roberto Moss Lopes, Artur Menegaz de Almeida, Vitor Kendi Tsuchiya Sano, Fernanda Moraes Tamashiro, Ocílio Ribeiro Gonçalves, Francisco Cezar Aquino de Moraes, Michele Kreuz, Francinny Alves Kelly, Pablo Vinícius Silveira Feitoza","doi":"10.1002/trc2.70039","DOIUrl":"10.1002/trc2.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Dementia affects 55 million people globally, with the number projected to triple by 2050. Statins, widely prescribed for cardiovascular benefits, may also have neuroprotective effects, although studies on their impact on dementia risk have shown contradictory results. In this systematic review and meta-analysis, we searched PubMed, Embase, and Cochrane following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We assessed the risk of dementia, Alzheimer's disease (AD), and vascular dementia (VaD), with subgroup analyses by gender, statin type, and diabetes status. Fifty-five observational studies including over 7 million patients were analyzed. Statin use significantly reduced the risk of dementia compared to nonusers (hazard ratio [HR] 0.86; 95% confidence interval [CI]: 0.82 to 0.91; <i>p</i> < 0.001). It was also associated with reduced risks of AD (HR 0.82; 95% CI: 0.74 to 0.90; <i>p</i> < 0.001) and VaD (HR 0.89; 95% CI: 0.77 to 1.02; <i>p</i> = 0.093). Subgroup analyses revealed significant dementia risk reductions among patients with type 2 diabetes mellitus (HR 0.87; 95% CI: 0.85 to 0.89; <i>p</i> < 0.001), those with exposure to statins for more than 3 years (HR 0.37; 95% CI: 0.30 to 0.46; <i>p</i> < 0.001), and populations from Asia, where the greatest protective effect was observed (HR 0.84; 95% CI: 0.80 to 0.88). Additionally, rosuvastatin demonstrated the most pronounced protective effect for all-cause dementia among specific statins (HR 0.72; 95% CI: 0.60 to 0.88). Our findings underscore the neuroprotective potential of statins in dementia prevention. Despite the inherent limitations of observational studies, the large dataset and detailed subgroup analyses enhance the reliability of our results. Future randomized clinical trials are necessary to confirm these findings and enlighten clinical guidelines.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Largest meta-analysis to date on statins and dementia risk, including 55 studies and more than 7 million patients.</li>\u0000 \u0000 <li>Statin use linked to lower risks of all-dementia, AD, and VaD.</li>\u0000 \u0000 <li>Numerous significant subgroup results highlight statins' diverse neuroprotective effects.</li>\u0000 \u0000 <li>Findings support statins as a public health tool, especially in low-income countries.</li>\u0000 \u0000 <li>Future research should explore the impact of statins across diverse patient populations.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016006","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}
Taeho Jo, Paula Bice, Kwangsik Nho, Andrew J. Saykin, Alzheimer's Disease Sequencing Project
<div> <section> <h3> INTRODUCTION</h3> <p>The exponential growth of genomic datasets necessitates advanced analytical tools to effectively identify genetic loci from large-scale high throughput sequencing data. This study presents Deep-Block, a multi-stage deep learning framework that incorporates biological knowledge into its AI architecture to identify genetic regions as significantly associated with Alzheimer's disease (AD). The framework employs a three-stage approach: (1) genome segmentation based on linkage disequilibrium (LD) patterns, (2) selection of relevant LD blocks using sparse attention mechanisms, and (3) application of TabNet and Random Forest algorithms to quantify single nucleotide polymorphism (SNP) feature importance, thereby identifying genetic factors contributing to AD risk.</p> </section> <section> <h3> METHODS</h3> <p>The Deep-Block was applied to a large-scale whole genome sequencing (WGS) dataset from the Alzheimer's Disease Sequencing Project (ADSP), comprising 7416 non-Hispanic white (NHW) participants (3150 cognitively normal older adults (CN), 4266 AD).</p> </section> <section> <h3> RESULTS</h3> <p>30,218 LD blocks were identified and then ranked based on their relevance with Alzheimer's disease. Subsequently, the Deep-Block identified novel SNPs within the top 1500 LD blocks and confirmed previously known variants, including <i>APOE</i> rs429358 and rs769449. Expression Quantitative Trait Loci (eQTL) analysis across 13 brain regions provided functional evidence for the identified variants. The results were cross-validated against established AD-associated loci from the European Alzheimer's and Dementia Biobank (EADB) and the GWAS catalog.</p> </section> <section> <h3> DISCUSSION</h3> <p>The Deep-Block framework effectively processes large-scale high throughput sequencing data while preserving SNP interactions during dimensionality reduction, minimizing bias and information loss. The framework's findings are supported by tissue-specific eQTL evidence across brain regions, indicating the functional relevance of the identified variants. Additionally, the Deep-Block approach has identified both known and novel genetic variants, enhancing our understanding of the genetic architecture and demonstrating its potential for application in large-scale sequencing studies.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Growing genomic datasets require adva
{"title":"LD-informed deep learning for Alzheimer's gene loci detection using WGS data","authors":"Taeho Jo, Paula Bice, Kwangsik Nho, Andrew J. Saykin, Alzheimer's Disease Sequencing Project","doi":"10.1002/trc2.70041","DOIUrl":"10.1002/trc2.70041","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The exponential growth of genomic datasets necessitates advanced analytical tools to effectively identify genetic loci from large-scale high throughput sequencing data. This study presents Deep-Block, a multi-stage deep learning framework that incorporates biological knowledge into its AI architecture to identify genetic regions as significantly associated with Alzheimer's disease (AD). The framework employs a three-stage approach: (1) genome segmentation based on linkage disequilibrium (LD) patterns, (2) selection of relevant LD blocks using sparse attention mechanisms, and (3) application of TabNet and Random Forest algorithms to quantify single nucleotide polymorphism (SNP) feature importance, thereby identifying genetic factors contributing to AD risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The Deep-Block was applied to a large-scale whole genome sequencing (WGS) dataset from the Alzheimer's Disease Sequencing Project (ADSP), comprising 7416 non-Hispanic white (NHW) participants (3150 cognitively normal older adults (CN), 4266 AD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>30,218 LD blocks were identified and then ranked based on their relevance with Alzheimer's disease. Subsequently, the Deep-Block identified novel SNPs within the top 1500 LD blocks and confirmed previously known variants, including <i>APOE</i> rs429358 and rs769449. Expression Quantitative Trait Loci (eQTL) analysis across 13 brain regions provided functional evidence for the identified variants. The results were cross-validated against established AD-associated loci from the European Alzheimer's and Dementia Biobank (EADB) and the GWAS catalog.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The Deep-Block framework effectively processes large-scale high throughput sequencing data while preserving SNP interactions during dimensionality reduction, minimizing bias and information loss. The framework's findings are supported by tissue-specific eQTL evidence across brain regions, indicating the functional relevance of the identified variants. Additionally, the Deep-Block approach has identified both known and novel genetic variants, enhancing our understanding of the genetic architecture and demonstrating its potential for application in large-scale sequencing studies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Growing genomic datasets require adva","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11736638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015954","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}
Chao-Yi Wu, Ashley C. Kupferschmid, Liu Chen, Alison J. McManus, Pia Kivisäkk, Jake A. Galler, Nadine A. Schwab, Libby A. DesRuisseaux, Victoria J. Williams, Jessica Gerber, Misha Riley, Cathrine Young, Edmarie Guzmán-Vélez, Hiroko H. Dodge, Rudolph E. Tanzi, Clifford M. Singer, Steven E. Arnold
<div> <section> <h3> INTRODUCTION</h3> <p>Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.</p> </section> <section> <h3> METHODS</h3> <p>The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau<sup>217</sup>), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (<i>z</i>-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired <i>t</i>-tests were used for within-individual comparisons.</p> </section> <section> <h3> RESULTS</h3> <p>Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau<sup>217</sup> concentrations after taking NR, while an 18% increase with PBO (<i>p</i> = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau<sup>217</sup> concentrations significantly decreased during the NR phase compared to the PBO (<i>p</i> = 0.02), while step counts significantly increased during the NR phase than PBO (<i>p</i> = 0.04).</p> </section> <section> <h3> DISCUSSION</h3> <p>Eight weeks NR supplementation is safe and lowered pTau<sup>217</sup> concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.</p> </section> <section> <h3> Highlights</h3>
{"title":"Cognitive and Alzheimer's disease biomarker effects of oral nicotinamide riboside (NR) supplementation in older adults with subjective cognitive decline and mild cognitive impairment","authors":"Chao-Yi Wu, Ashley C. Kupferschmid, Liu Chen, Alison J. McManus, Pia Kivisäkk, Jake A. Galler, Nadine A. Schwab, Libby A. DesRuisseaux, Victoria J. Williams, Jessica Gerber, Misha Riley, Cathrine Young, Edmarie Guzmán-Vélez, Hiroko H. Dodge, Rudolph E. Tanzi, Clifford M. Singer, Steven E. Arnold","doi":"10.1002/trc2.70023","DOIUrl":"10.1002/trc2.70023","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Age-associated depletion in nicotinamide adenine dinucleotide (NAD+) concentrations has been implicated in metabolic, cardiovascular, and neurodegenerative disorders. Supplementation with NAD+ precursors, such as nicotinamide riboside (NR), offers a potential therapeutic avenue against neurodegenerative pathologies in aging, Alzheimer's disease, and related dementias. A crossover, double-blind, randomized placebo (PBO) controlled trial was conducted to test the safety and efficacy of 8 weeks' active treatment with NR (1 g/day) on cognition and plasma AD biomarkers in older adults with subjective cognitive decline and mild cognitive impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The primary efficacy outcome was the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Secondary outcomes included plasma phosphorylated tau 217 (pTau<sup>217</sup>), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Exploratory outcomes included Lumosity gameplay (<i>z</i>-scores) for cognition and step counts from wearables. Mixed model for repeated measures was used for between-group comparisons; paired <i>t</i>-tests were used for within-individual comparisons.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Forty-six participants aged over 55 were randomized to NR-PBO or PBO-NR groups; 41 completed baseline visits, and 37 completed the trial. NR supplementation was safe and well tolerated with no differences in adverse events reported between NR and PBO treatment phases. For the between-group comparison, there was a 7% reduction in pTau<sup>217</sup> concentrations after taking NR, while an 18% increase with PBO (<i>p</i> = 0.02). No significant between-group differences were observed for RBANS, other plasma biomarkers(GFAP and NfL), Lumosity gameplay scores or step counts. For the within-individual comparison, pTau<sup>217</sup> concentrations significantly decreased during the NR phase compared to the PBO (<i>p</i> = 0.02), while step counts significantly increased during the NR phase than PBO (<i>p</i> = 0.04).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Eight weeks NR supplementation is safe and lowered pTau<sup>217</sup> concentrations but did not alter cognition as measured by conventional or novel digital assessments. Further research is warranted to validate NR's efficacy in altering pathological brain aging processes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11733434/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016144","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}
Lisa Waterink, Sietske A. M. Sikkes, Lion M. Soons, Sonja Beers, Yvonne Meijer-Krommenhoek, Ondine van de Rest, Smidt Nynke, Joukje M. Oosterman, Erik Scherder, Kay Deckers, Yannick Vermeiren, Rianne A. A. de Heus, Sebastian Köhler, Wiesje M. van der Flier, MOCIA consortium, FINGER-NL consortium, Marissa D. Zwan
<div> <section> <h3> INTRODUCTION</h3> <p>Recruitment of participants for intervention studies is challenging. We evaluated the effectiveness and efficiency of a participant recruitment campaign through an online registry for the FINGER-NL study, a multi-domain lifestyle intervention trial targeting cognitively healthy individuals aged 60–79 with dementia prevention potential. Additionally, we explored which recruitment strategy successfully reached individuals from underrepresented groups in research.</p> </section> <section> <h3> METHODS</h3> <p>The campaign entailed seven recruitment strategies referring to The Dutch Brain Research Registry (DBRR): (1) Facebook advertisements, (2) appearance on national television, (3) newspaper articles, (4) researcher outreach, (5) patient organizations, (6) search engines, and (7) other. For each strategy, we describe the number of individuals (a) registered, (b) potentially eligible, and (c) included in FINGER-NL. Subsequently, the efficiency, defined by the eligibility ratio (eligible/registered), and effectiveness, defined by the inclusion ratio (included/registered) were calculated. Associations between recruitment strategies and sociodemographic factors of underrepresented groups were tested with binomial logistic regressions.</p> </section> <section> <h3> RESULTS</h3> <p>The campaign resulted in 13,795 new DBRR registrants, of which <i>n</i> = 3475 were eligible (eligibility ratio = 0.25) and <i>n</i> = 1008 were included (inclusion ratio = 0.07). The Facebook advertisements and television appearance resulted in the highest numbers of registrants (<i>n</i> = 4678 and <i>n</i> = 2182) which translated to the highest number of inclusions (<i>n</i> = 288 and <i>n</i> = 262). The appearance on national television (eligibility ratio = 0.35), newspaper articles (0.26), and Facebook campaigns (0.26) were the most efficient strategies. The national television appearance (inclusion ratio = 0.13) was the most effective strategy. The Facebook campaign and appearance on national television performed relatively better in recruiting individuals from underrepresented groups.</p> </section> <section> <h3> DISCUSSION</h3> <p>A multipronged recruitment campaign via a national online recruitment registry is efficient and effective in recruiting and prescreening an adequate number of individuals aged 60–79 years with prevention potential for a multi-site intervention trial within a limited time frame of 15 months. Social media advertisements and television are preferred strategies to recruit individuals from underrepresent
{"title":"Evaluation of efficiency and effectiveness of different recruitment strategies for the FINGER-NL multidomain lifestyle intervention trial via the Dutch Brain Research Registry","authors":"Lisa Waterink, Sietske A. M. Sikkes, Lion M. Soons, Sonja Beers, Yvonne Meijer-Krommenhoek, Ondine van de Rest, Smidt Nynke, Joukje M. Oosterman, Erik Scherder, Kay Deckers, Yannick Vermeiren, Rianne A. A. de Heus, Sebastian Köhler, Wiesje M. van der Flier, MOCIA consortium, FINGER-NL consortium, Marissa D. Zwan","doi":"10.1002/trc2.70017","DOIUrl":"10.1002/trc2.70017","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Recruitment of participants for intervention studies is challenging. We evaluated the effectiveness and efficiency of a participant recruitment campaign through an online registry for the FINGER-NL study, a multi-domain lifestyle intervention trial targeting cognitively healthy individuals aged 60–79 with dementia prevention potential. Additionally, we explored which recruitment strategy successfully reached individuals from underrepresented groups in research.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>The campaign entailed seven recruitment strategies referring to The Dutch Brain Research Registry (DBRR): (1) Facebook advertisements, (2) appearance on national television, (3) newspaper articles, (4) researcher outreach, (5) patient organizations, (6) search engines, and (7) other. For each strategy, we describe the number of individuals (a) registered, (b) potentially eligible, and (c) included in FINGER-NL. Subsequently, the efficiency, defined by the eligibility ratio (eligible/registered), and effectiveness, defined by the inclusion ratio (included/registered) were calculated. Associations between recruitment strategies and sociodemographic factors of underrepresented groups were tested with binomial logistic regressions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The campaign resulted in 13,795 new DBRR registrants, of which <i>n</i> = 3475 were eligible (eligibility ratio = 0.25) and <i>n</i> = 1008 were included (inclusion ratio = 0.07). The Facebook advertisements and television appearance resulted in the highest numbers of registrants (<i>n</i> = 4678 and <i>n</i> = 2182) which translated to the highest number of inclusions (<i>n</i> = 288 and <i>n</i> = 262). The appearance on national television (eligibility ratio = 0.35), newspaper articles (0.26), and Facebook campaigns (0.26) were the most efficient strategies. The national television appearance (inclusion ratio = 0.13) was the most effective strategy. The Facebook campaign and appearance on national television performed relatively better in recruiting individuals from underrepresented groups.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>A multipronged recruitment campaign via a national online recruitment registry is efficient and effective in recruiting and prescreening an adequate number of individuals aged 60–79 years with prevention potential for a multi-site intervention trial within a limited time frame of 15 months. Social media advertisements and television are preferred strategies to recruit individuals from underrepresent","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11712179/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142958835","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}
Christian Brettschneider, Elżbieta Buczak-Stec, Melanie Luppa, Andrea Zülke, Bernhard Michalowsky, Anika Rädke, Alexander Bauer, Christine Brütting, Robert P. Kosilek, Isabel Zöllinger, Juliane Döhring, Martin Williamson, Birgitt Wiese, Wolfgang Hoffmann, Thomas Frese, Jochen Gensichen, Hanna Kaduszkiewicz, Jochen René Thyrian, Steffi G. Riedel-Heller, Hans-Helmut König, the AGEWELL.DE study group
<div> <section> <h3> INTRODUCTION</h3> <p>The societal costs of dementia and cognitive decline are substantial and likely to increase during the next decades due to the increasing number of people in older age groups. The aim of this multicenter cluster-randomized controlled trial was to assess the cost-effectiveness of a multi-domain intervention to prevent cognitive decline in older people who are at risk for dementia.</p> </section> <section> <h3> METHODS</h3> <p>We used data from a multi-centric, two-armed, cluster-randomized controlled trial (<i>AgeWell.de</i> trial, ID: DRKS00013555). Eligible participants with increased dementia risk at baseline (Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE Dementia Risk Score ≥ 9), 60–77 years of age, were recruited by their general practitioners, and assigned randomly to a multi-domain lifestyle intervention or general health advice. We performed a cost-effectiveness analysis from the societal perspective. The time horizon was 2 years. Health care utilization was measured using the “Questionnaire for Health-Related Resource Use in Older Populations.” As effect measure, we used quality-adjusted life-years (QALYs) based on the 5-level EQ-5D version (EQ-5D-5L). We calculated the incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves (CEAC) using the net-benefit approach. Exploratory analyses considering women and the EQ visual analogue scale (EQ VAS) were conducted.</p> </section> <section> <h3> RESULTS</h3> <p>Data were available for 819 participants (mean age 69.0 [standard deviation (SD)5-level EQ-5D version 4.9]); 378 were treated in the intervention group and 441 in the control group. The participants in the intervention group caused higher costs (+€445.88 [SD: €1,244.52]) and gained additional effects (+0.026 QALY [SD: 0.020]) compared to the participants in the control group (the difference was statistically significant). The ICER was €17,149.23/QALY. The CEAC showed that the probability of the intervention being cost-effective was moderate, reaching 59% at a willingness-to-pay (WTP) of €50,000/QALY. The exploratory analyses showed promising results, especially in the female subsample.</p> </section> <section> <h3> DISCUSSION</h3> <p>Considering aspects like the WTP and the limited time horizon, the multi-domain intervention was cost-effective compared to general health advice.</p> </section> <section> <h3> Highlights</h3> <div>
{"title":"Cost-effectiveness of a multicomponent intervention against cognitive decline","authors":"Christian Brettschneider, Elżbieta Buczak-Stec, Melanie Luppa, Andrea Zülke, Bernhard Michalowsky, Anika Rädke, Alexander Bauer, Christine Brütting, Robert P. Kosilek, Isabel Zöllinger, Juliane Döhring, Martin Williamson, Birgitt Wiese, Wolfgang Hoffmann, Thomas Frese, Jochen Gensichen, Hanna Kaduszkiewicz, Jochen René Thyrian, Steffi G. Riedel-Heller, Hans-Helmut König, the AGEWELL.DE study group","doi":"10.1002/trc2.70028","DOIUrl":"10.1002/trc2.70028","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The societal costs of dementia and cognitive decline are substantial and likely to increase during the next decades due to the increasing number of people in older age groups. The aim of this multicenter cluster-randomized controlled trial was to assess the cost-effectiveness of a multi-domain intervention to prevent cognitive decline in older people who are at risk for dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We used data from a multi-centric, two-armed, cluster-randomized controlled trial (<i>AgeWell.de</i> trial, ID: DRKS00013555). Eligible participants with increased dementia risk at baseline (Cardiovascular Risk Factors, Aging, and Incidence of Dementia/CAIDE Dementia Risk Score ≥ 9), 60–77 years of age, were recruited by their general practitioners, and assigned randomly to a multi-domain lifestyle intervention or general health advice. We performed a cost-effectiveness analysis from the societal perspective. The time horizon was 2 years. Health care utilization was measured using the “Questionnaire for Health-Related Resource Use in Older Populations.” As effect measure, we used quality-adjusted life-years (QALYs) based on the 5-level EQ-5D version (EQ-5D-5L). We calculated the incremental cost-effectiveness ratios (ICER) and cost-effectiveness acceptability curves (CEAC) using the net-benefit approach. Exploratory analyses considering women and the EQ visual analogue scale (EQ VAS) were conducted.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Data were available for 819 participants (mean age 69.0 [standard deviation (SD)5-level EQ-5D version 4.9]); 378 were treated in the intervention group and 441 in the control group. The participants in the intervention group caused higher costs (+€445.88 [SD: €1,244.52]) and gained additional effects (+0.026 QALY [SD: 0.020]) compared to the participants in the control group (the difference was statistically significant). The ICER was €17,149.23/QALY. The CEAC showed that the probability of the intervention being cost-effective was moderate, reaching 59% at a willingness-to-pay (WTP) of €50,000/QALY. The exploratory analyses showed promising results, especially in the female subsample.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Considering aspects like the WTP and the limited time horizon, the multi-domain intervention was cost-effective compared to general health advice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696024/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933501","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}
Georgios Ponirakis, Hanadi Al Hamad, Alaa S. Al-Waisy, Ioannis N. Petropoulos, Adnan Khan, Hoda Gad, Mani Chandran, Masharig Gadelseed, Salah Mahmoud, Ahmed Elsotouhy, Marwan Ramadan, Shafi Khan, Rustu E. Akcan, Priya V. Gawhale, Noushad Thodi, Tala Nakouzi, Moayad Homssi, Nebras Hadid, Aisha Al Obaidan, Rawan Hussein, Ahmed Own, Ashfaq Shuaib, Rayaz A. Malik
<div> <section> <h3> INTRODUCTION</h3> <p>Corneal confocal microscopy (CCM) detects neurodegeneration in mild cognitive impairment (MCI) and dementia and identifies subjects with MCI who develop dementia. This study assessed whether abnormalities in corneal endothelial cell (CEC) morphology are related to corneal nerve morphology, brain volumetry, cerebral ischemia, and cognitive impairment in MCI and dementia.</p> </section> <section> <h3> METHODS</h3> <p>Participants with no cognitive impairment (NCI), MCI, and dementia underwent CCM to quantify corneal endothelial cell density (CECD) and area (CECA), corneal nerve fiber morphology, magnetic resonance imaging (MRI) brain volumetry, and severity of brain ischemia.</p> </section> <section> <h3> RESULTS</h3> <p>Of the 114 participants, 14 had NCI, 77 had MCI, and 23 had dementia. CECD (1971.3 ± 594.6 vs 2316.1 ± 499.5 cells/mm<sup>2</sup>, <i>p</i> < 0.05) was significantly lower in the dementia compared to the NCI group. CECD and CECA were comparable between the MCI and NCI groups (<i>p</i> = 0.13–0.65). Corneal nerve fiber density (CNFD) (31.7 ± 5.6 vs 24.5 ± 9.2 and 17.3 ± 5.3 fibers/mm<sup>2</sup>, <i>p</i> < 0.01), corneal nerve branch density (CNBD) (111.8 ± 58.1 vs 50.4 ± 36.4 and 52.7 ± 21.3 branches/mm<sup>2</sup>, <i>p</i> < 0.0001), and corneal nerve fiber length (CNFL) (24.6 ± 6.6 vs 16.5 ± 6.8 and 16.2 ± 5.0 mm/mm<sup>2</sup>, <i>p</i> < 0.0001) were lower in the MCI and dementia groups compared to the NCI group. Lower CECD partially mediated the impact of age and diabetes on CNFL reduction (<i>p</i> < 0.05), whereas CECA lost its significance after adjustment (<i>p</i> = 0.20). CEC morphology does not affect the association between corneal nerve fiber loss and MCI/dementia. CECD and CECA had no significant association with cerebral ischemic lesions (<i>p</i> = 0.21–0.47), dementia (<i>p</i> = 0.11–0.35), or cognitive decline (<i>p</i> = 0.37–0.38). However, lower CECD and higher CECA were associated with decreased cortical gray matter volume (<i>p</i> < 0.05–0.01).</p> </section> <section> <h3> DISCUSSION</h3> <p>CEC loss occurs in patients with dementia, and both endothelial cell loss and hypertrophy are associated with cortical gray matter atrophy. CNF loss occurs in individuals with MCI and dementia. Corneal nerve and endothelial cell abnormalities could act as biomarkers for neurovascular pathology in dementia.</p> </section> <section> <h3> Highlights</h3> <div>
角膜共聚焦显微镜（CCM）检测轻度认知障碍（MCI）和痴呆的神经退行性变，并识别MCI患者发展为痴呆。本研究评估了MCI和痴呆患者角膜内皮细胞（CEC）形态异常是否与角膜神经形态、脑容量、脑缺血和认知障碍有关。方法：无认知障碍（NCI）、轻度认知障碍（MCI）和痴呆的参与者采用CCM量化角膜内皮细胞密度（CECD）和面积（CECA）、角膜神经纤维形态、磁共振成像（MRI）脑容量和脑缺血严重程度。结果：114名参与者中，14人患有NCI， 77人患有MCI， 23人患有痴呆。痴呆患者的ced（1971.3±594.6 vs 2316.1±499.5 cells/mm2, p < 0.05）明显低于NCI组。ccd和CECA在MCI组和NCI组之间具有可比性（p = 0.13-0.65）。MCI组和痴呆组的角膜神经纤维密度（CNFD）（31.7±5.6 vs 24.5±9.2和17.3±5.3纤维/mm2， p < 0.01）、角膜神经分支密度（CNBD）（111.8±58.1 vs 50.4±36.4和52.7±21.3支/mm2， p < 0.0001）和角膜神经纤维长度（CNFL）（24.6±6.6 vs 16.5±6.8和16.2±5.0 mm/mm2, p < 0.0001）均低于NCI组。CECA降低部分介导了年龄和糖尿病对CNFL降低的影响（p < 0.05），而CECA调整后失去了其显著性（p = 0.20）。CEC形态学不影响角膜神经纤维丢失与MCI/痴呆之间的关系。CECD和CECA与脑缺血病变（p = 0.21-0.47）、痴呆（p = 0.11-0.35）、认知能力下降（p = 0.37-0.38）无显著相关性。然而，较低的CECD和较高的CECA与皮质灰质体积减少相关（p < 0.05-0.01）。讨论：CEC丢失发生在痴呆患者中，内皮细胞丢失和肥大都与皮质灰质萎缩有关。CNF丢失发生在轻度认知损伤和痴呆患者中。角膜神经和内皮细胞异常可作为痴呆患者神经血管病理的生物标志物。重点：痴呆患者角膜内皮细胞密度显著降低。轻度认知障碍（MCI）和痴呆患者的角膜神经纤维密度、分支密度和长度较低。角膜内皮细胞的丢失和肥大与皮质灰质萎缩有关。角膜神经和内皮细胞异常可作为痴呆患者神经血管病理的生物标志物。角膜内皮细胞密度降低在一定程度上介导了年龄和糖尿病对角膜神经纤维丧失的影响。
{"title":"Association of corneal endothelial cell morphology with neurodegeneration in mild cognitive impairment and dementia","authors":"Georgios Ponirakis, Hanadi Al Hamad, Alaa S. Al-Waisy, Ioannis N. Petropoulos, Adnan Khan, Hoda Gad, Mani Chandran, Masharig Gadelseed, Salah Mahmoud, Ahmed Elsotouhy, Marwan Ramadan, Shafi Khan, Rustu E. Akcan, Priya V. Gawhale, Noushad Thodi, Tala Nakouzi, Moayad Homssi, Nebras Hadid, Aisha Al Obaidan, Rawan Hussein, Ahmed Own, Ashfaq Shuaib, Rayaz A. Malik","doi":"10.1002/trc2.70025","DOIUrl":"10.1002/trc2.70025","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Corneal confocal microscopy (CCM) detects neurodegeneration in mild cognitive impairment (MCI) and dementia and identifies subjects with MCI who develop dementia. This study assessed whether abnormalities in corneal endothelial cell (CEC) morphology are related to corneal nerve morphology, brain volumetry, cerebral ischemia, and cognitive impairment in MCI and dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Participants with no cognitive impairment (NCI), MCI, and dementia underwent CCM to quantify corneal endothelial cell density (CECD) and area (CECA), corneal nerve fiber morphology, magnetic resonance imaging (MRI) brain volumetry, and severity of brain ischemia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Of the 114 participants, 14 had NCI, 77 had MCI, and 23 had dementia. CECD (1971.3 ± 594.6 vs 2316.1 ± 499.5 cells/mm<sup>2</sup>, <i>p</i> < 0.05) was significantly lower in the dementia compared to the NCI group. CECD and CECA were comparable between the MCI and NCI groups (<i>p</i> = 0.13–0.65). Corneal nerve fiber density (CNFD) (31.7 ± 5.6 vs 24.5 ± 9.2 and 17.3 ± 5.3 fibers/mm<sup>2</sup>, <i>p</i> < 0.01), corneal nerve branch density (CNBD) (111.8 ± 58.1 vs 50.4 ± 36.4 and 52.7 ± 21.3 branches/mm<sup>2</sup>, <i>p</i> < 0.0001), and corneal nerve fiber length (CNFL) (24.6 ± 6.6 vs 16.5 ± 6.8 and 16.2 ± 5.0 mm/mm<sup>2</sup>, <i>p</i> < 0.0001) were lower in the MCI and dementia groups compared to the NCI group. Lower CECD partially mediated the impact of age and diabetes on CNFL reduction (<i>p</i> < 0.05), whereas CECA lost its significance after adjustment (<i>p</i> = 0.20). CEC morphology does not affect the association between corneal nerve fiber loss and MCI/dementia. CECD and CECA had no significant association with cerebral ischemic lesions (<i>p</i> = 0.21–0.47), dementia (<i>p</i> = 0.11–0.35), or cognitive decline (<i>p</i> = 0.37–0.38). However, lower CECD and higher CECA were associated with decreased cortical gray matter volume (<i>p</i> < 0.05–0.01).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>CEC loss occurs in patients with dementia, and both endothelial cell loss and hypertrophy are associated with cortical gray matter atrophy. CNF loss occurs in individuals with MCI and dementia. Corneal nerve and endothelial cell abnormalities could act as biomarkers for neurovascular pathology in dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933500","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}
Anthropometric, demographic, genetic, and clinical features may affect cognitive, behavioral, and functional decline, while clinical trials seldom consider minimal clinically important differences (MCIDs) in their analyses.
METHODS
MCIDs were reviewed taking into account features that may affect cognitive, behavioral, or functional decline in clinical trials of new disease-modifying therapies.
RESULTS
The higher the number of comparisons of different confounders in statistical analyses, the lower P values will be significant. Proper selection of confounders is crucial to accurately assess MCIDs without compromising statistical significance.
DISCUSSION
Statistical adjustment of the significance of MCIDs according to multiple comparisons is essential for the generalizability of research results. Wider inclusion of confounding variables in the statistics may help bring trial results closer to real-world conditions and improve the prediction of the efficacy of new disease-modifying therapies, though such factors must be carefully selected not to compromise the statistical significance of the analyses.
Highlights
Anthropometric, demographic, and clinical features may affect cognitive, behavioral, and functional decline.
Clinical trials seldom take minimal clinically important differences (MCIDs) or their confounders into account.
Generalizability of research results requires the assessment of multiple confounding factors.
The higher the number of comparisons involved, the lower P values will be considered significant.
Use of MCIDs adjusted for confounding factors should be implemented when outcomes are not susceptible to translation into absolute benefits.
{"title":"The problem of multiple adjustments in the assessment of minimal clinically important differences","authors":"Fabricio Ferreira de Oliveira","doi":"10.1002/trc2.70032","DOIUrl":"10.1002/trc2.70032","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Anthropometric, demographic, genetic, and clinical features may affect cognitive, behavioral, and functional decline, while clinical trials seldom consider minimal clinically important differences (MCIDs) in their analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>MCIDs were reviewed taking into account features that may affect cognitive, behavioral, or functional decline in clinical trials of new disease-modifying therapies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The higher the number of comparisons of different confounders in statistical analyses, the lower <i>P</i> values will be significant. Proper selection of confounders is crucial to accurately assess MCIDs without compromising statistical significance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Statistical adjustment of the significance of MCIDs according to multiple comparisons is essential for the generalizability of research results. Wider inclusion of confounding variables in the statistics may help bring trial results closer to real-world conditions and improve the prediction of the efficacy of new disease-modifying therapies, though such factors must be carefully selected not to compromise the statistical significance of the analyses.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Anthropometric, demographic, and clinical features may affect cognitive, behavioral, and functional decline.</li>\u0000 \u0000 <li>Clinical trials seldom take minimal clinically important differences (MCIDs) or their confounders into account.</li>\u0000 \u0000 <li>Generalizability of research results requires the assessment of multiple confounding factors.</li>\u0000 \u0000 <li>The higher the number of comparisons involved, the lower <i>P</i> values will be considered significant.</li>\u0000 \u0000 <li>Use of MCIDs adjusted for confounding factors should be implemented when outcomes are not susceptible to translation into absolute benefits.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933529","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}
Silvia Miramontes, Umair Khan, Erin L. Ferguson, Marina Sirota, M. Maria Glymour
INTRODUCTION
The impact of cholesterol on late-life cognition remains controversial. We investigated the association of high-density lipoprotein cholesterol (HDL-C) and non–HDL-C with memory in a nationally representative cohort.
METHODS
Health and Retirement Study (HRS) participants (N = 13,258) aged 50+ (mean age: 67.2 years) followed from 2006 to 2020 provided cholesterol measures every 4 years and cognitive assessments biennially. Linear mixed models predicted memory scores using both baseline and time-updated cholesterol values.
RESULTS
Higher baseline HDL-C (mean: 53.9 mg/dL) predicted better memory scores (β: 0.05, 95% confidence interval [CI]: 0.03 to 0.08), but not memory change. Baseline non–HDL-C (mean: 143 mg/dL) predicted poorer memory scores (β: −0.01, 95% CI: −0.02 to 0.00), but not memory change. Time-updated HDL-C predicted better memory (β: 0.02, 95% CI: 0.00 to 0.04), but non–HDL-C showed no such associations.
DISCUSSION
While higher peripheral HDL-C is linked to better memory, the small effect sizes and absence of associations of HDL-C and non–HD-CL with memory change suggests that peripheral cholesterol has a small effect on the variation of memory scores.
Highlights
Higher HDL-C levels predict better memory scores but not memory change across 14 years of follow-up.
Baseline higher LDL-C levels predict poorer memory scores across time, but not memory change.
The small effects and absence of consistent association between cholesterol levels and memory change suggest that cholesterol plays a minor role in cognitive decline.
{"title":"The association of cholesterol levels with memory and memory change over a 14-year period in a US national cohort","authors":"Silvia Miramontes, Umair Khan, Erin L. Ferguson, Marina Sirota, M. Maria Glymour","doi":"10.1002/trc2.70021","DOIUrl":"10.1002/trc2.70021","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The impact of cholesterol on late-life cognition remains controversial. We investigated the association of high-density lipoprotein cholesterol (HDL-C) and non–HDL-C with memory in a nationally representative cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Health and Retirement Study (HRS) participants (<i>N</i> = 13,258) aged 50+ (mean age: 67.2 years) followed from 2006 to 2020 provided cholesterol measures every 4 years and cognitive assessments biennially. Linear mixed models predicted memory scores using both baseline and time-updated cholesterol values.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Higher baseline HDL-C (mean: 53.9 mg/dL) predicted better memory scores (<i>β</i>: 0.05, 95% confidence interval [CI]: 0.03 to 0.08), but not memory change. Baseline non–HDL-C (mean: 143 mg/dL) predicted poorer memory scores (<i>β</i>: −0.01, 95% CI: −0.02 to 0.00), but not memory change. Time-updated HDL-C predicted better memory (<i>β</i>: 0.02, 95% CI: 0.00 to 0.04), but non–HDL-C showed no such associations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>While higher peripheral HDL-C is linked to better memory, the small effect sizes and absence of associations of HDL-C and non–HD-CL with memory change suggests that peripheral cholesterol has a small effect on the variation of memory scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Higher HDL-C levels predict better memory scores but not memory change across 14 years of follow-up.</li>\u0000 \u0000 <li>Baseline higher LDL-C levels predict poorer memory scores across time, but not memory change.</li>\u0000 \u0000 <li>The small effects and absence of consistent association between cholesterol levels and memory change suggest that cholesterol plays a minor role in cognitive decline.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11696025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142933527","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}
Jakub P. Hlávka, Andrew T. Kinoshita, Divya Jeyasingh, Cheng Huang, Leila Mirsafian, Mireille Jacobson
<div> <section> <h3> INTRODUCTION</h3> <p>Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms—groups of candidates that share an underlying biological mechanism of action and general disease target.</p> </section> <section> <h3> METHODS</h3> <p>We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.</p> </section> <section> <h3> RESULTS</h3> <p>We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic–Amyloid paradigm, 64% of trials were engaged in Phase 3.</p> </section> <section> <h3> DISCUSSION</h3> <p>Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>An analysis of Alzheimer's disease trial treatment paradigms was conducted.</li> <li>Fr
{"title":"Emerging Alzheimer's disease treatment paradigms: A late-stage clinical trial review","authors":"Jakub P. Hlávka, Andrew T. Kinoshita, Divya Jeyasingh, Cheng Huang, Leila Mirsafian, Mireille Jacobson","doi":"10.1002/trc2.70022","DOIUrl":"10.1002/trc2.70022","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Without disease-modifying interventions, Medicare and Medicaid spending on Alzheimer's disease (AD) management is expected to reach 637 billion USD annually by 2050. The recent advent of promising AD therapies after decades of a near-total failure rate in clinical trials suggests that more disease-modifying therapies are on the horizon. In this review, we assess the late-stage pipeline of disease-modifying candidates for AD and offer a novel classification of intervention candidates by treatment paradigms—groups of candidates that share an underlying biological mechanism of action and general disease target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We extracted data from the National Library of Medicine clinical trials database regarding Phase 2 and 3 trials of disease-modifying AD therapies. We categorized trials into eight unique treatment paradigms, which we defined by combinations of therapy (biologic, small molecule, cell and gene therapy, other) and target (amyloid, tau, other). We analyzed primary endpoints, eligibility criteria including clinical ratings of cognition, trial phase and length, and funding sources.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>We identified 123 unique disease-modifying intervention candidates in 175 late-stage clinical trials. Biologic and small molecule drugs comprised 30% and 54% of trials, respectively. Eligibility criteria favored patients between the ages of 60 and 80 years with mild cognitive impairment. Including multi-phase trials, 81% of studies were engaged in Phase 2 and 27% in Phase 3. Notably, within the Biologic–Amyloid paradigm, 64% of trials were engaged in Phase 3.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Current studies of disease-modifying therapies for AD comprise a diverse set of approaches to treating the disease. However, effort is largely concentrated in a few treatment paradigms and a narrow patient population, causing varying rates of progress among treatment paradigms in the late-stage clinical trial pipeline. Strategies may be warranted to accelerate successes in the most promising therapeutical paradigms and nurture growth within nascent areas lacking resources but not potential.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>An analysis of Alzheimer's disease trial treatment paradigms was conducted.</li>\u0000 \u0000 <li>Fr","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694526/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923944","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}
William Kielbasa, Paul Goldsmith, Kevin B. Donnelly, Hugh N. Nuthall, Sergey Shcherbinin, Adam S. Fleisher, Jörg Hendle, Susan L. DuBois, Stephen L. Lowe, Feiyu Fred Zhang, Eric M. Woerly, Nicolas J.-F. Dreyfus, David Evans, Jeremy Gilmore, Michele Mancini, Cristian C. Constantinescu, Roger N. Gunn, David S. Russell, Emily C. Collins, Miroslaw Brys, Michael L. Hutton, Dustin J. Mergott
<div> <section> <h3> INTRODUCTION</h3> <p>The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.</p> </section> <section> <h3> METHODS</h3> <p>A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.</p> </section> <section> <h3> RESULTS</h3> <p>Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.</p> </section> <section> <h3> DISCUSSION</h3> <p>Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.</p> </section> <section> <h3> Highlights</h3> <div> <ul> <li>Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.</li> <li>Ceperognastat is both orally available and CNS-penetrant even when given at lo
{"title":"Discovery and clinical translation of ceperognastat, an O-GlcNAcase (OGA) inhibitor, for the treatment of Alzheimer's disease","authors":"William Kielbasa, Paul Goldsmith, Kevin B. Donnelly, Hugh N. Nuthall, Sergey Shcherbinin, Adam S. Fleisher, Jörg Hendle, Susan L. DuBois, Stephen L. Lowe, Feiyu Fred Zhang, Eric M. Woerly, Nicolas J.-F. Dreyfus, David Evans, Jeremy Gilmore, Michele Mancini, Cristian C. Constantinescu, Roger N. Gunn, David S. Russell, Emily C. Collins, Miroslaw Brys, Michael L. Hutton, Dustin J. Mergott","doi":"10.1002/trc2.70020","DOIUrl":"10.1002/trc2.70020","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The aggregation and spread of hyperphosphorylated, pathological tau in the human brain is hypothesized to play a key role in Alzheimer's disease (AD) as well as other neurogenerative tauopathies. O-GlcNAcylation, an important post-translational modification of tau and many other proteins, is significantly decreased in brain tissue of AD patients relative to healthy controls. Increased tau O-GlcNAcylation has been shown to reduce tau pathology in mouse in vivo tauopathy models. O-GlcNAcase (OGA) catalyzes the removal of O-GlcNAc from tau thereby driving interest in OGA inhibition as a potential therapeutic approach to reduce tau pathology and slow the progression of AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>A multidisciplinary approach was used to identify ceperognastat (LY3372689) as a potent OGA inhibitor, including an extensive discovery effort with synthetic chemistry, structure-based drug design, and in vivo OGA enzyme occupancy studies. Preclinical studies assessed the target engagement, inhibition of OGA enzyme activity, OGA enzyme occupancy, and changes in tau O-GlcNAc. Four clinical Phase 1 studies of ceperognastat in healthy participants were performed to assess clinical safety and tolerability, pharmacokinetics (PK), and enzyme occupancy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Ceperognastat is a potent, central nervous system (CNS)-penetrant, low-dose inhibitor of OGA, which can achieve > 95% OGA enzyme occupancy in animal and human brain. Overall, ceperognastat had an acceptable safety profile in Phase 1 clinical studies with no serious adverse events reported following single and multiple dosing. The PK, enzyme occupancy, and safety profile supported Phase 2 development of ceperognastat.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Ceperognastat is an orally available, highly potent, CNS-penetrant OGA inhibitor that achieved high (> 80%) OGA enzyme occupancy and increased brain O-GlcNAc-tau preclinically. Ceperognastat demonstrated > 95% OGA enzyme occupancy in Phase 1 trials. These occupancy data informed the dose selection for the Phase 2 clinical program.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Ceperognastat is a highly potent, CNS-penetrant OGA inhibitor.</li>\u0000 \u0000 <li>Ceperognastat is both orally available and CNS-penetrant even when given at lo","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11694536/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142923935","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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