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

{"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}

{"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}

{"title":"A new measure of professional caregiver coping in long-term care: The LTC COPE","authors":"Philip D. Sloane, Sheryl Zimmerman, Lea Efird-Green, Jasmine L. Travers, Krista M. Perreira, Karen Bluth, Christine Lathren, David Reed","doi":"10.1002/trc2.70010","DOIUrl":"https://doi.org/10.1002/trc2.70010","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The professional caregiver workforce (nursing assistants and personal care aides) is critical to quality of care and quality of life in nursing home (NH) and assisted living (AL) settings. The work is highly stressful, so improving responses to stress in this workforce could contribute to satisfaction and retention. This research developed a coping measure appropriate for the diverse professional caregiver workforce.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>A multistage process identified and refined existing and new items. Ten racially and ethnically diverse professional caregivers advised on item selection and refinement. Subsequently, using an online QR code-accessed questionnaire, data were collected from 391 professional caregivers from 10 NHs and 3 AL communities in three states, yielding a sample that was 87% female, widely distributed in age and experience, and racially/ethnically diverse (42% Black, non-Hispanic/Latinx; 25% White, non-Hispanic/Latinx; 20% Hispanic/Latinx; 7% Asian, non-Hispanic/Latinx; and 21% born outside the United States). Analyses examined psychometric properties and principal components analysis identified factors within which items and scales aggregated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The final instrument, named the Long-Term Care Cope (LTC Cope), includes 26 items aggregated into six factors, which explained 60% of the variance: avoidance (five items, loadings 0.58–0.76); adaptive psychological strategies (six items, loadings 0.33–0.89); active engagement (five items, 0.47–0.89); maladaptive psychological strategies (three items, loadings 0.90–0.93); actions to minimize emotional impact (four items, loadings 0.28–0.74); and substance use (three items, loadings 0.61–0.88). Respondents often reported using multiple items within multiple factors when responding to stressful situations at work.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The coping strategies of professional caregivers are highly individual, with caregivers tending to utilize multiple strategies. The LTC Cope instrument and its component subscales are promising for future research to improve understanding of stress-related coping in this diverse workforce and inform and evaluate interventions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>A new measure was developed to help us better understand how professional c","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends and determinants of choline alfoscerate use in newly diagnosed Alzheimer's disease patients in Korea","authors":"Yeon Hee Kim, Nakyung Jeon, Nam Kyung Je","doi":"10.1002/trc2.70019","DOIUrl":"https://doi.org/10.1002/trc2.70019","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>Choline alfoscerate, a cholinergic precursor, is widely used in Korea for dementia-related symptoms and is covered by national health insurance (NHI). This study investigates the utilization trends and factors influencing choline alfoscerate prescription in newly diagnosed Alzheimer's disease (AD) patients using real-world data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We analyzed data from the Health Insurance Review and Assessment Service (HIRA) for patients aged 60 years and older who were newly diagnosed with AD between 2012 and 2019. Patients with prescriptions for acetylcholinesterase inhibitors (AChEIs) or memantine within 60 days of diagnosis were included. Choline alfoscerate utilization was defined as prescriptions within 60 days of initial diagnosis. Factors influencing its use were identified through multiple logistic regression analyses, and trends over time were assessed using the Cochran–Armitage Trend test.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Among the 330,326 study participants, 99,845 (33.08%) were prescribed choline alfoscerate, with usage increasing from 15.96% in 2012 to 47.65% in 2019. Factors positively associated with its use included male sex, MedAid insurance, and osteoarthritis. Conversely, usage decreased with comorbidities such as hypertension, congestive heart failure, stroke/transient ischemic attack, chronic kidney disease, and depression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CONCLUSION</h3>\u0000 \u0000 <p>Choline alfoscerate usage in Korea has significantly increased, partly due to its national insurance coverage and the absence of disease-modifying therapies for AD. Given the uncertain efficacy and potential risks of choline alfoscerate, continuous monitoring and rigorous evaluation of its long-term benefits and safety are essential. Further research is necessary to establish definitive evidence for its effectiveness and guide its therapeutic use in AD management.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Choline alfoscerate usage among newly diagnosed AD patients in Korea increased from 15.96% in 2012 to 47.65% in 2019.</li>\u0000 \u0000 <li>Male sex (OR = 1.05) and MedAid insurance coverage (OR = 1.07) were associated with higher odds of choline alfoscerate usage.</li>\u0000 \u0000 <li>Usage was more likely in patients with osteoarthritis (","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142861087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Application of the revised criteria for diagnosis and staging of Alzheimer's disease: Drug development and clinical practice","authors":"Clifford R. Jack,&nbsp;Ana Graf,&nbsp;Samantha C. Burnham,&nbsp;Erin G Doty,&nbsp;Hans J. Moebius,&nbsp;Philip Montenigro,&nbsp;Eric Siemers,&nbsp;Kaycee M. Sink,&nbsp;Leslie M. Shaw,&nbsp;Charlotte Thim Hansen,&nbsp;Kristin R. Wildsmith,&nbsp;Simin Mahinrad,&nbsp;Maria C. Carrillo,&nbsp;Christopher J. Weber","doi":"10.1002/trc2.70013","DOIUrl":"https://doi.org/10.1002/trc2.70013","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The newly proposed revised criteria for diagnosis and staging of Alzheimer's disease (AD) by the Alzheimer's Association (AA) Workgroup represent a significant milestone in the field. These criteria offer objective measures for diagnosing and staging biological AD, bridging the gap between research and clinical care. Although implementation feasibility may vary across regions and settings, improving the availability and accuracy of biomarkers, especially plasma biomarkers, is expected to enhance the applicability of these criteria in clinical practice. The Fall 2023 Alzheimer's Association Research Roundtable (AARR) meeting served as a forum for gathering industry perspectives and feedback on these revised criteria, ensuring that the new criteria inform research, clinical trial design, and clinical care. In this article, we outline a summary of the newly proposed “Revised Criteria for Diagnosis and Staging of AD: AA Workgroup” and provide highlights from the AARR meeting in fall 2023.</p>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government, to review the <i>Revised Criteria for Diagnosis and Staging of AD: AA Workgroup</i>, and gather industry perspectives and feedback on these revised criteria before its publication.</li>\u0000 \u0000 <li>The newly proposed revised criteria for diagnosis and staging of Alzheimer's disease (AD) by the AA's Workgroup represent a significant milestone, offering objective measures for the biological and staging of AD and bridging the gap between research and clinical care.</li>\u0000 \u0000 <li>Improving the availability and accuracy of biomarkers, especially blood-based biomarkers (BBMs) is expected to improve clinical research and enhance the applicability of these criteria in clinical practice.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851299","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stress-related coping and its relationship to well-being in nursing assistants and personal care aides in nursing homes and assisted living","authors":"Philip D. Sloane,&nbsp;Lea Efird-Green,&nbsp;David Reed,&nbsp;Jasmine L. Travers,&nbsp;Krista M. Perreira,&nbsp;Christine Lathren,&nbsp;Karen Bluth,&nbsp;Sheryl Zimmerman","doi":"10.1002/trc2.70011","DOIUrl":"https://doi.org/10.1002/trc2.70011","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;Professional caregivers (nursing assistants and personal care aides) in nursing homes (NH) and assisted living (AL) provide the majority of long-term residential care for persons with Alzheimer's disease and related dementias. Their work is stressful, but until recently, no measures were available to assess stress in this workforce. Using the new Long-Term Care Cope (LTC COPE) scale, this study evaluates the relationship of coping with staff demographic characteristics and outcomes; the findings can be used to develop and evaluate interventions to improve staff well-being.&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 used a cross-sectional online questionnaire completed by professional caregivers working in a purposive selection of 10 NHs and three AL communities in California, New York, and North Carolina. The sample included 391 professional caregivers and had a representative distribution by age; it was 87% female; 42% non-Hispanic/Latinx (NHL) Black, 25% NHL White, 20% Hispanic/Latinx, and 7% NHL Asian. Worker job satisfaction, mental health, and health-related quality of life were examined in relation to caregiver demographics and the following approaches to coping as measured by the LTC COPE: avoidance, adaptive psychological strategies, active engagement, maladaptive psychological strategies, minimizing emotional impact, and substance use. Statistical comparisons used non-parametric Spearman correlation coefficients.&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;Little difference in coping strategies was noted by sex and education; older caregivers used adaptive psychological strategies more than younger caregivers; and traditionally minoritized adults (NHL Black, NHL Asian, and Hispanic/Latinx), compared to NHL White adults, more often used adaptive and less often used maladaptive psychological coping strategies. The use of maladaptive and avoidance strategies was strongly associated with depressive symptoms, anxiety, and burnout.&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;Professional caregivers report using a wide variety of coping strategies, with multiple strategies being the norm, and both adaptive/engaged and maladaptive/disengaged approaches are common. Certain coping approaches are strongly linked to depression, anxiety, and burnout; attention to training and support of adaptive and positive coping may augment other efforts to improve job satisfaction and performance. The LTC COPE scale has the potential to guide and evaluate practices to improve workers’ well-being.&lt;/p&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142851296","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Designing and implementing the IDEAL Study: A randomized clinical trial of APOE genotype disclosure for late-onset Alzheimer's disease in an urban Latino population","authors":"John B. Wetmore,&nbsp;Sophia Rodriguez,&nbsp;Daniela Diaz Caro,&nbsp;María Cabán,&nbsp;Wendy Uhlmann,&nbsp;Jill Goldman,&nbsp;Cheng-Shiun Leu,&nbsp;Jonathan D. Godinez,&nbsp;Itzel A. Camarillo,&nbsp;Rebecca Ferber,&nbsp;Drew Blasco,&nbsp;Rafael A. Lantigua,&nbsp;Ana Abraído-Lanza,&nbsp;Wendy K. Chung,&nbsp;J. Scott Roberts,&nbsp;Karolynn Siegel,&nbsp;Ruth Ottman","doi":"10.1002/trc2.70016","DOIUrl":"https://doi.org/10.1002/trc2.70016","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;The &lt;i&gt;Información de la Enfermedad de Alzheimer para Latinos&lt;/i&gt; (IDEAL) Study is a randomized clinical trial investigating the psychosocial, behavioral, and cognitive impacts of apolipoprotein E (&lt;i&gt;APOE&lt;/i&gt;) genotype disclosure for late-onset Alzheimer's disease (AD) among Latinos.&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 used address-based sampling to recruit English- and Spanish-speaking Latinos aged 40–64 living in northern Manhattan for a community-based Baseline Survey about their knowledge and opinions about AD. Participants eligible for the clinical trial were invited to complete an Introductory Session, including AD and genetics education and informed consent, before undergoing genotyping for &lt;i&gt;APOE&lt;/i&gt;. Participants were then randomized to learn their risk of AD by age 85 (range: 21%–55%) based on either Latino ethnicity and family history alone, or the same factors and their &lt;i&gt;APOE&lt;/i&gt; genotype. Risk information is provided in a semi-structured genetic counseling session. Psychological impacts, health-related behavioral changes, and cognitive performance are evaluated 6 weeks, 9 months, and 15 months later via surveys and qualitative interviews. To promote cultural competence, study materials were developed by a multidisciplinary team including bilingual and bicultural staff, Latinx content experts, and genetic counselors.&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 sent invitations to 91,433 households; 5542 (6.1%) responded, 2120 completed the Baseline Survey (78.5% online; 21.5% via computer-assisted telephone interview), and 2087 were deemed eligible, yielding a response rate of 2.3%. Many participants expressed appreciation for the opportunity to contribute to AD research. We randomized 374 participants for the clinical trial.&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;We describe the study design, recruitment and retention strategies, and interventions employed in the IDEAL Study. Our design provides a framework for future studies using rigorous mixed methods. Our findings may facilitate the development of culturally-sensitive educational materials about AD and genetic testing, as well as genetic counseling protocols, to improve coping and adjustment in response to receiving risk information.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;The &lt;i&gt;Información de la Enfermedad de Alzheimer para La","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759858","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impacts of informant replacement in two industry-sponsored Alzheimer's disease clinical trials","authors":"Mikaela K. Nishida,&nbsp;Michelle M. Nuño,&nbsp;Joshua D. Grill,&nbsp;Daniel L. Gillen","doi":"10.1002/trc2.70009","DOIUrl":"https://doi.org/10.1002/trc2.70009","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;In Alzheimer's disease (AD) clinical trials, participants must enroll with a study partner informant who completes validated study instruments. We hypothesized that mid-trial informant replacement impacts study data in industry-sponsored trials.&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 conducted a retrospective analysis of two industry-sponsored AD clinical trials testing semagacestat in mild-to-moderate AD dementia. We assessed the relationships between informant replacement and Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) scores. Using generalized estimating equations, we assessed bias and variability using mean (bias) and mean absolute (variance) change in ADCS-ADL between successive visits as outcomes. Both models adjusted for a priori–specified potential confounding variables including participant sex, age, informant type, trial, time, previous ADCS-ADL score, and region. To analyze the impact on end-of-study change-from-baseline results, we used an analysis of covariance model to estimate the association between replacement and end-of-study change-from-baseline in ADCS-ADL, in which we adjusted for participant sex, age, informant type, trial, baseline measurement, and region. We conducted an &lt;i&gt;F&lt;/i&gt;-test to compare the variances of this change.&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;Among &lt;i&gt;N&lt;/i&gt; = 2637 randomized participants, 69 participants (2.6%) experienced 78 occurrences of replacement. For visits standardized to be 3 months apart, the difference in mean between-visit change in ADCS-ADL was approximately −1.61 points (95% confidence interval [CI]: −3.79, 0.57; &lt;i&gt;P&lt;/i&gt; = 0.147), comparing participants who experienced replacement to similar participants who had stable informants. The difference in the mean between-visit absolute change was approximately 2.02 points (95% CI: 0.34, 3.70; &lt;i&gt;P&lt;/i&gt; = 0.019). We did not estimate a statistically significant difference in end-of-study change-from-baseline (Est. = −0.70 points; 95% CI: −5.88, 4.48; &lt;i&gt;P&lt;/i&gt; = 0.790) or a significant ratio of variances (Est. = 1.13; 95% CI: 0.67, 2.28; &lt;i&gt;P&lt;/i&gt; = 0.600) for participants with replacement compared to those with stable informants.&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;Informant replacement was associated with increased between-visit variability but had limited impact on overall trial outcomes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer's disease drug development in an evolving therapeutic landscape","authors":"Stacie Weninger,&nbsp;Michael C. Irizarry,&nbsp;Adam S. Fleisher,&nbsp;Teresa León,&nbsp;Paul Maruff,&nbsp;David S. Miller,&nbsp;Sheila Seleri,&nbsp;Maria C. Carrillo,&nbsp;Christopher J. Weber","doi":"10.1002/trc2.70015","DOIUrl":"https://doi.org/10.1002/trc2.70015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The Alzheimer's disease (AD) research field has entered a new era, where our fundamental understanding of the pathophysiology of AD and advances in biomarkers have not only allowed for earlier, timely, and accurate detection and diagnosis of the disease, but that amyloid removal has been shown to be associated with signals of slowing cognitive and functional decline. Although recent FDA-approved amyloid plaque-lowering monoclonal antibody therapies have shifted the trajectory of AD, additional treatment options will be key to further slowing clinical decline or stopping disease progression. Thus, new and emerging therapies for AD have created an evolving therapeutic landscape. The Alzheimer's Association Research Roundtable (AARR) Spring meeting held on May 23–34, 2023, brought together a broad array of scientific leaders from the AARR membership, academia, industry, and government and regulatory agencies to discuss the future of clinical trials in an era of regulator-approved amyloid-targeting therapies. Participants discussed lessons learned from other neurological diseases where disease-modifying treatments were first approved and key considerations for future clinical trials, for example, trial population real-world representativeness, duration, biomarker screening, efficacy endpoints, combination therapy, as well as overall trial design and the ethical and equity concerns that clinicians, patients, and their families face when considering clinical trial participation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic, “Alzheimer's Disease Drug Development in an Evolving Therapeutic Landscape.”</li>\u0000 \u0000 <li>While recently approved amyloid-targeting therapies show great promise in providing clinically meaningful outcomes for patients and families, additional treatments, and a better understanding of dosing and administration of these approved treatments, are needed to further slow and eventually prevent clinical decline in AD.</li>\u0000 \u0000 <li>Approved therapies will impact many aspects of clinical trial design including the use of placebo-controls, participant re-enrollment, safety monitoring, as well as biomarker selection.</li>\u0000 \u0000 <li>This exciting new era in AD research represents a hopeful future for clinicians, patients, and their care partners.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adaptive measurement of cognitive function based on multidimensional item response theory","authors":"Robert D. Gibbons,&nbsp;Diane S. Lauderdale,&nbsp;Robert S. Wilson,&nbsp;David A. Bennett,&nbsp;Tesnim Arar,&nbsp;David A. Gallo","doi":"10.1002/trc2.70018","DOIUrl":"https://doi.org/10.1002/trc2.70018","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;Up to 20% of older adults in the United States have mild cognitive impairment (MCI), and about one-third of people with MCI are predicted to transition to Alzheimer's disease (AD) within 5 years. Standard cognitive assessments are long and require a trained technician to administer. We developed the first computerized adaptive test (CAT) based on multidimensional item response theory (MIRT) to more precisely, rapidly, and repeatedly assesses cognitive abilities across the adult lifespan. We present results for a prototype CAT (pCAT-COG) for assessment of global cognitive function.&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 sampled items across five cognitive domains central to neuropsychological testing (episodic memory [EM], semantic memory/language [SM], working memory [WM], executive function/flexible thinking, and processing speed [PS]). The item bank consists of 54 items, with 9 items of varying difficulty drawn from six different cognitive tasks. Each of the 54 items has 3 response trials, yielding an ordinal score (0–3 trials correct). We also include three long-term memory items not designed for adaptive administration, for a total bank of 57 items. Calibration data were collected in-person and online, calibrated using a bifactor MIRT model, and pCAT-COG scores validated against a technician-administered neuropsychological battery.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The bifactor MIRT model improved fit over a unidimensional IRT model (&lt;i&gt;p&lt;/i&gt; &lt; 0.0001). The global pCAT-COG scores were inversely correlated with age (&lt;i&gt;r&lt;/i&gt; = –0.44, &lt;i&gt;p&lt;/i&gt; &lt; 0.0001). Simulated adaptive administration of 11 items maintained a correlation of &lt;i&gt;r&lt;/i&gt; = 0.94 with the total item bank scores. Significant differences between mild and no cognitive impairment (NCI) were found (effect size of 1.08 SD units). The pCAT-COG correlated with clinician-based global measure (&lt;i&gt;r&lt;/i&gt; = 0.64).&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;MIRT-based CAT is feasible and valid for the assessment of global cognitive impairment, laying the foundation for the development of a full CAT-COG that will draw from a much larger item bank with both global and domain specific measures of cognitive impairment.&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;As Americans age, numbers at risk for developing cognitive impairment are increasing.&lt;/li","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"10 4","pages":""},"PeriodicalIF":4.9,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142758115","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}