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

{"title":"The Common Alzheimer's Disease Research Ontology (CADRO) for biomarker categorization","authors":"Amanda M. Leisgang Osse,&nbsp;Jefferson W. Kinney,&nbsp;Jeffrey L. Cummings","doi":"10.1002/trc2.70050","DOIUrl":"https://doi.org/10.1002/trc2.70050","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Biomarkers are vital to Alzheimer's disease (AD) drug development and clinical trials, and will have an increasing role in clinical care. In this narrative review, we demonstrate the use of the National Institutes on Aging/Alzheimer's Association (NIA/AA) Common Alzheimer's Disease Research Ontology (CADRO) system for the categorization of biomarkers based on the primary mechanism on which they report. We show that biomarkers are available (in various levels of validation) for all CADRO processes. Application of the CADRO system demonstrates gaps in the field where novel biomarkers are needed for specific aspects of the disease, and assays to detect and measure biological changes, in individuals with symptomatic or preclinical AD. We demonstrate the CADRO system as a means of categorizing established and candidate AD biomarkers, showing the feasibility and practicality of the system. CADRO can assist with biomarker selection for AD clinical trials and drug development, and may eventually be applied to implementing biomarkers in patient care. </p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The Common Alzheimer's Disease Research Ontology (CADRO) system can be used to categorize biomarkers for drug development.</li>\u0000 \u0000 <li>We demonstrate the use of CADRO with Alzheimer's disease (AD) biomarkers.</li>\u0000 \u0000 <li>We identified AD biomarkers in each of the CADRO categories.</li>\u0000 \u0000 <li>CADRO can be incorporated into current AD drug development and clinical trial systems.</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":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380830","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":"Diabetes mellitus exacerbates changes in white matter hyperintensity shapes and volume: A longitudinal study","authors":"Shihao Xu,&nbsp;Yan Wang,&nbsp;Jiahui Chen,&nbsp;Zhiming Pan,&nbsp;Wenjun Wu,&nbsp;Zhipeng Su,&nbsp;Zhen Wang","doi":"10.1002/trc2.70042","DOIUrl":"https://doi.org/10.1002/trc2.70042","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;Although white matter hyperintensity (WMH) can progress over time, little is known about the underlying mechanisms. In addition, type 2 diabetes mellitus (T2DM) exacerbates the accumulation of WMH. Here we aimed to investigate longitudinal changes in WMH shapes and volume in older adults with and without T2DM.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Participants underwent baseline and follow-up magnetic resonance imaging (MRI). WMH volume and shape markers were automatically assessed. We compared WMH volume and shape markers at baseline and follow-up.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A total of 200 participants were included at baseline and 181 at follow-up. The mean age ± SD of our study participants was 69.86 ± 6.03 years; 79 (39.90%) had a history of diabetes mellitus (T2DM) and 73 (36.50%) were male. For shape markers, participants with T2DM showed more complex periventricular (eccentricity, &lt;i&gt;p&lt;/i&gt; = 0.027) and deep WMH shape markers (fractal dimension, &lt;i&gt;p&lt;/i&gt; = 0.002) than participants without T2DM. At baseline, there were no statistically significant differences (&lt;i&gt;p&lt;/i&gt; &gt; 0.05) in WMH volume when participants with T2DM were compared to participants without T2DM. At follow-up, a more complex shape of periventricular/confluent WMH on follow-up (concavity index, &lt;i&gt;p&lt;/i&gt; = 0.005; inverse sphericity index, &lt;i&gt;p&lt;/i&gt; = 0.001). In addition, total (&lt;i&gt;p&lt;/i&gt; &lt; 0.001), periventricular (&lt;i&gt;p&lt;/i&gt; &lt; 0.001), and deep (&lt;i&gt;p&lt;/i&gt; = 0.001) WMH volumes increased significantly.&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;A more irregular shape of periventricular and deep WMH and higher WMH volumes were associated with T2DM participants. These findings suggest that WMH shape markers may be useful in determining prognosis for cerebral small vessel disease and aid in future preventive treatments.&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;Patients with diabetes mellitus have more irregular white matter hyperintensity (WMH) shapes and increased WMH volumes.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Diabetes mellitus exacerbates the changes in WMH shapes and volumes&lt;/li&gt;\u0000 \u0000 &lt;li&gt;WMH shape markers might have the potential to aid in future preventive treatments and prevent clinical deterioration.&lt;/li&gt;\u0000 &lt;/ul&gt;\u0000 &lt;/div&gt;\u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380745","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":"Operationalizing selection criteria for clinical trials in Alzheimer's disease: Biomarker and clinical considerations: Proceedings from the Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting","authors":"Ronald C. Petersen,&nbsp;Ana Graf,&nbsp;Chris Brady,&nbsp;Susan De Santi,&nbsp;Hana Florian,&nbsp;Jaren Landen,&nbsp;Mike Pontecorvo,&nbsp;Christopher Randolph,&nbsp;Kaycee Sink,&nbsp;Maria Carrillo,&nbsp;Christopher J. Weber","doi":"10.1002/trc2.70038","DOIUrl":"https://doi.org/10.1002/trc2.70038","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>The design of clinical trials in Alzheimer's disease (AD) must consider the development of new plasma, cerebrospinal fluid (CSF), and imaging biomarkers. They must also define clinically meaningful outcomes for patients and set endpoints that measure these outcomes accurately. With the accelerated United States Food and Drug Administration (FDA) approval of the first anti-amyloid, disease-modifying treatment for AD, a monoclonal antibody called aducanumab, the landscape of clinical trial design is evolving. Enrolment in clinical trials may be impacted by the availability of this and other treatments, and trial design must take into consideration that patients may desire a disease-modifying treatment rather than potentially being randomized to the placebo arm. The Alzheimer's Association Research Roundtable (AARR) Fall 2021 meeting discussed the consideration of well-defined AD staging criteria in protocol design and how they influence more standardized inclusion/exclusion criteria for trials, as well as what constitutes meaningful differentiation between the stages. Discussion explored the current state of knowledge regarding biomarkers and how they can inform AD staging criteria, as many trials are now designed based on specific biomarker features, further underscoring the importance of coordinating AD staging criteria and biomarkers. The relationship between cognition and biomarkers has been studied and this must continue as trials move forward. Researchers, patients, clinicians, regulatory scientists, and payers discussed the state of the field as well as the future of symptomatic Alzheimer's disease clinical trials.</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 academia and industry as well as patients, care partners, clinicians, regulators, and payers to discuss the topic of operationalizing selection criteria for clinical trials and the role of biomarkers.</li>\u0000 \u0000 <li>Well-defined Alzheimer's disease (AD) staging criteria are an important consideration in study protocol design.</li>\u0000 \u0000 <li>Staging criteria and biomarkers must be coordinated to yield high-quality clinical trial results that have meaning for patients with AD by selecting a population most likely to benefit from a specific treatment.</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":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70038","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380744","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":"CSF proteomics reveals changes in myelin and synaptic biology after Spectris treatment","authors":"Mihály Hajós,&nbsp;Kiran Pandey,&nbsp;Annabelle C. Singer,&nbsp;Duc Duong,&nbsp;Sara Bitarafan,&nbsp;Monika Shpokayte,&nbsp;Zach Malchano,&nbsp;Ralph Kern,&nbsp;James J. Lah,&nbsp;Allan I. Levey,&nbsp;Nicholas T. Seyfried","doi":"10.1002/trc2.70051","DOIUrl":"https://doi.org/10.1002/trc2.70051","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; INTRODUCTION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Brain steady-state gamma oscillations evoked using a non-invasive medical device (Spectris) have shown potential clinical benefits in patients with mild–moderate Alzheimer's disease (AD), including reduced functional and cognitive decline, reduced brain volume and myelin loss, and increased brain functional connectivity. We analyzed changes in cerebrospinal fluid (CSF) proteins after Spectris treatment in mild cognitive impairment (MCI) and their relationship to established biological pathways implicated in AD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Unbiased proteomic analysis of CSF samples from participants with amyloid-positive MCI (&lt;i&gt;n&lt;/i&gt; = 10) was conducted from the FLICKER (NCT03543878) clinical trial. Participants used the Cognito Therapeutics medical device (Spectris), confirmed to evoke steady-state gamma oscillations. Participants were instructed to use the device daily for 1 hour each day during the trial. CSF was collected prior to the start of stimulation and after 4 and 8 weeks of treatment. The proteome was analyzed using tandem mass tag mass spectrometry.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Differential expression analysis of proteins at baseline and after 8 weeks of treatment (&lt;i&gt;N&lt;/i&gt; = 5) revealed that 110 out of 2951 proteins met the significance threshold (analysis of variance, &lt;i&gt;P&lt;/i&gt; &lt; 0.05, no false discovery rate). Sixty proteins were upregulated, and 50 proteins were downregulated after treatment. Changes in protein expression were mapped to the consensus human AD protein network, representing co-expressed and functionally linked modules linked to cell type and biochemical pathways. Treatment altered CSF proteins linked to AD-related brain proteome modules, including those involved in myelination (proteolipid protein 1, ecotropic viral integration site 2A), synaptic and neuroimmune functions, and regulation of cellular lipid transportation. Biological pathway analysis revealed that most impacted pathways were associated with lipoproteins, cholesterol, phospholipids processing, and phosphatidylcholine biosynthesis.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The CSF proteomic changes observed in this study suggest pleiotropic effects on multiple pathways involved in AD, including myelination, synaptic and neuroimmune function, and lipid transport. These findings are also consistent with observations of white matter and myelin preservation after Spectris treatment of AD.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70051","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rural–urban disparities of Alzheimer's disease and related dementias: A scoping review","authors":"Mackenzie Kramer,&nbsp;Maxwell Cutty,&nbsp;Sara Knox,&nbsp;Alexander V. Alekseyenko,&nbsp;Abolfazl Mollalo","doi":"10.1002/trc2.70047","DOIUrl":"https://doi.org/10.1002/trc2.70047","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;p&gt;The rising age of the global population has made Alzheimer's disease and related dementias (ADRD) a critical public health problem, with significant health-related disparities observed between rural and urban areas. However, no previous reviews have examined the scope and determinant factors contributing to rural–urban disparities of ADRD-related health outcomes. This study aims to systematically collate and synthesize peer-reviewed articles on rural–urban disparities in ADRD, identifying key determinants and research gaps to guide future research. We conducted a systematic search using key terms related to rural–urban disparities and ADRD without restrictions on geography or study design. Five search engines—MEDLINE, CINAHL, Web of Science, PubMed, and Scopus—were used to identify relevant articles. The search was performed on August 16, 2024, and included English-language articles published from 2000 onward. Sixty-three articles met the eligibility criteria for data extraction and synthesis. Most articles were published after 2010 (85.7%) and were concentrated in the United States, China, and Canada (66.7%). A majority had cross-sectional (58.7%) or cohort study designs (23.8%), primarily examining prevalence (41.3%) or incidence (11.1%). Findings often indicated a higher prevalence and incidence in rural areas, although inconsistent rural–urban classification systems were noted. Common risk factors included female sex, lower education level, lower income, and comorbidities such as diabetes and cerebrovascular diseases. Environmental (12.7%) and lifestyle (14.3%) factors for ADRD have been less explored. The statistical methods used were mainly traditional analyses (e.g., logistic regression) and lacked advanced techniques such as machine learning or causal inference methods. The gaps identified in this review emphasize the need for future research in underexplored geographic regions and encourage the use of advanced methods to investigate understudied factors contributing to ADRD disparities, such as environmental, lifestyle, and genetic influences.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Few studies on rural–urban ADRD disparities focus on low- and middle-income countries.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Common risk factors include female sex, low education attainment, low income, and comorbidities.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Inconsistent definitions of “rural” complicate cross-country comparisons.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Environmental and lifestyle factors affecting ADRD are underexplored.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Advanced statistical methods, such as machine learning and caus","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70047","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anticholinergic drugs and dementia risk: Using stem cell–based studies to complement pharmacoepidemiology","authors":"Tiara A. Schwarze-Taufiq,&nbsp;Inez K. A. Pranoto,&nbsp;Katherine Hui,&nbsp;Chizuru Kinoshita,&nbsp;Onchee Yu,&nbsp;Paul K. Crane,&nbsp;Shelly L. Gray,&nbsp;Jessica E. Young","doi":"10.1002/trc2.70040","DOIUrl":"https://doi.org/10.1002/trc2.70040","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; BACKGROUND&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including increased risk in dementia. Pharmacoepidemiology studies from various populations report associations between specific anticholinergic classes – antidepressants and bladder antimuscarinics – and increased dementia incidence. However, it is difficult to determine whether these associations are directly caused by the neurotoxic effects of anticholinergic drugs or by the underlying health conditions which the medications are taken for, known as confounding by indication. Here, we leverage human induced pluripotent stem cells-derived-neurons (hiPSC-Ns) to complement the pharmacoepidemiology studies by directly examining the effects of various anticholinergic classes on dementia-related cellular phenotypes.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; METHODS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We treated human induced pluripotent stem cell (hiPSC)–derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; RESULTS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1-42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; CONCLUSIONS&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These results corroborate population-based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC-derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC-based models.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Highlights&lt;/h3&gt;\u0000 \u0000 &lt;div&gt;\u0000 &lt;ul&gt;\u0000 \u0000 &lt;li&gt;Certain classes of anticholinergic (AC) medications are linked to dementia.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;Human-induced pluripotent stem cell (hiPSC) models are used to ","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143248755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Data-driven discovery of associations between prescribed drugs and dementia risk: A systematic review","authors":"Benjamin R. Underwood,&nbsp;Ilianna Lourida,&nbsp;Jessica Gong,&nbsp;Stefano Tamburin,&nbsp;Eugene Yee Hing Tang,&nbsp;Emad Sidhom,&nbsp;Xin You Tai,&nbsp;Matthew J. Betts,&nbsp;Janice M. Ranson,&nbsp;Margarita Zachariou,&nbsp;Olajide E. Olaleye,&nbsp;Saswati Das,&nbsp;Neil P. Oxtoby,&nbsp;Shanquan Chen,&nbsp;David J. Llewellyn,&nbsp;for the Deep Dementia Phenotyping (DEMON) Network","doi":"10.1002/trc2.70037","DOIUrl":"10.1002/trc2.70037","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 \u0000 <p>Recent clinical trials on slowing dementia progression have led to renewed focus on finding safer, more effective treatments. One approach to identify plausible candidates is to assess whether existing medications for other conditions may affect dementia risk. We conducted a systematic review to identify studies adopting a data-driven approach to investigate the association between a wide range of prescribed medications and dementia risk. We included 14 studies using administrative or medical records data for more than 130 million individuals and 1 million dementia cases. Despite inconsistencies in identifying specific drugs that may modify Alzheimer's or dementia risk, some themes emerged for drug classes with biological plausibility. Antimicrobials, vaccinations, and anti-inflammatories were associated with reduced risk, while diabetes drugs, vitamins and supplements, and antipsychotics were associated with increased risk. We found conflicting evidence for antihypertensives and antidepressants. Drug repurposing for use in dementia is an urgent priority. Our findings offer a basis for prioritizing candidates and exploring underlying mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li><span>· </span>We present a systematic review of studies reporting association between drugs prescribed for other conditions and risk of dementia including 139 million people and 1 million cases of dementia.</li>\u0000 \u0000 <li><span>· </span>Our work supports some previously reported associations, for example, showing decreased risk of dementia with drugs to treat inflammatory disease and increased risk with antipsychotic treatment.</li>\u0000 \u0000 <li><span>· </span>Antimicrobial treatment was perhaps more surprisingly associated with decreased risk, supportive of recent increased interest in this potential therapeutic avenue.</li>\u0000 \u0000 <li><span>· </span>Our work should help prioritize drugs for entry into adaptive platform trials in Alzheimer's disease and will serve as a useful resource for those investigating drugs or classes of drugs and risk of dementia.</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":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11747987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015706","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":"Unraveling the impact of blood RANKL and OPG levels on Alzheimer's disease: Independent of bone mineral density and inflammation","authors":"Xingzhi Guo,&nbsp;Wenzhi Shi,&nbsp;Juanjuan Lu,&nbsp;Peng Tang,&nbsp;Rui Li","doi":"10.1002/trc2.70044","DOIUrl":"10.1002/trc2.70044","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;Observational studies have revealed a close relationship between reduced bone mineral density (BMD) and Alzheimer's disease (AD) risk. The receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) system, pivotal in regulating bone metabolism, has been implicated in brain function, but the causal impact on AD risk remains unclear.&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 employed bi-directional Mendelian randomization (MR) and multivariable MR (MVMR) approaches to elucidate the effect of blood soluble RANKL (sRANKL) and OPG levels on AD, assessing whether this influence was independent of BMD and inflammation. Three distinct AD genome-wide association study (GWAS) data sets from the International Genomics of Alzheimer's Project (IGAP), UK Biobank (UKB), and FinnGen were utilized. Summary-level data on blood sRANKL and OPG were sourced from deCODE Genetics.&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;Genetically predicted per standard deviation (SD) increase in blood sRANKL levels was significantly associated with a reduced risk of AD across all three AD GWAS data sets (IGAP: odds ratio [OR] = 0.82, 95% confidence interval [CI] = 0.72–0.94, &lt;i&gt;p&lt;/i&gt; = 0.004; UKB: OR = 0.85, 95% CI = 0.78–0.91, &lt;i&gt;p&lt;/i&gt; &lt; 0.001; FinnGen: OR = 0.83, 95% CI = 0.73–0.94, &lt;i&gt;p&lt;/i&gt; = 0.004). No significant causal relationship was observed between OPG levels and AD. In addition, there was no causal impact of AD on the blood levels of sRANKL and OPG. MVMR results showed that the inverse association between sRANKL and AD risk persisted after adjusting for BMD and interleukin-1α and chemoattractant protein-1.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; DISCUSSION&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Our study provides evidence that elevated sRANKL levels are causally linked to a reduced risk of AD, independent of BMD and inflammation. These findings enhance our understanding of the complex interactions between bone metabolism and AD.&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;Blood soluble receptor activator of nuclear factor kappa-B ligand (sRANKL) levels are linked to a reduced risk of Alzheimer's disease (AD).&lt;/li&gt;\u0000 \u0000 &lt;li&gt;The association between sRANKL levels and AD is independent of bone mineral density (BMD) and inflammation.&lt;/li&gt;\u0000 \u0000 &lt;li&gt;No causal link exists between blood os","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 1","pages":""},"PeriodicalIF":4.9,"publicationDate":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016141","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":"Dynamic neurocognitive adaptation in aging: Development and validation of a new scale","authors":"Filippo Cieri,&nbsp;Giulia Di Francesco,&nbsp;Chad Lee Cross,&nbsp;Andrew Bender,&nbsp;Jessica Zoe Kirkland Caldwell","doi":"10.1002/trc2.70049","DOIUrl":"10.1002/trc2.70049","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Forty-five percent of Alzheimer's disease (AD) cases may have been preventable through protective factors. Reserve, resilience, and resistance share common neurocognitive adaptive processes, acting through protective mechanisms. In this article we propose the development and validation of a new scale, called dynamic Neurocognitive Adaptation, developed in this direction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We included 815 participants (50% women; 65+ years inclusive of age), divided into two subsamples for exploratory and confirmatory factor analysis. Our initial scale was composed of 30 items, investigating seven dimensions, explored by a 5-point Likert scale reflecting the frequency of activities, for seven time windows.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Our final scale had 20 items divided among four dimensions: physical, cognitive, creative, and social. There were no issues related to multi-collinearity or non-collinearity. Kaiser–Meyer–Olkin (KMO) = 0.80 and Bartlett's test of sphericity indicated all values ≤0.01; Cronbach's alpha = 0.83.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>We have validated a reliable, novel, easy to complete, and comprehensive scale to assess lifetime behaviors, which can be applied in research on AD risk reduction, mild cognitive impairment, and in clinical practice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Reserve, resistance, and resilience share similar adaptive mechanisms.</li>\u0000 \u0000 <li>Dynamic Neurocognitive Adaptation is a new scale to assess lifetime protective factors.</li>\u0000 \u0000 <li>Dynamic Neurocognitive Adaptation is a reliable, novel, and easy to complete scale.</li>\u0000 \u0000 <li>This approach can characterize specific life stages that are ripe for risk-reduction interventions.</li>\u0000 \u0000 <li>Our scale can be used to personalize health recommendations in aging.</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":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746070/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143016023","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":"Perspective: Minimally clinically important “symptomatic” benefit associated with disease modification resulting from anti-amyloid immunotherapy","authors":"John Alam,&nbsp;Marwan N. Sabbagh","doi":"10.1002/trc2.70035","DOIUrl":"10.1002/trc2.70035","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <p>Despite some skepticism regarding the amyloid hypothesis, there is growing evidence that clearing amyloid by targeting specific species of amyloid (plaque, oligomers, fibrils, and protofibrils) for removal has therapeutic benefits. Specifically, there is growing evidence that, in mild cognitive impairment and mild dementia due to Alzheimer's disease (AD), robust and aggressive removal of amyloid can slow cognitive decline as measured by global instruments, composite measures, and cognitive testing. Furthermore, clinical efficacy signals coupled with clear biomarker changes provide the first evidence of disease modification. This effect seems to be in addition to symptomatic treatments and opens speculation that the effect of anti-amyloid monoclonal antibodies might be clinically meaningful through symptomatic amelioration that is a result of disease modification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Clearance of brain amyloid plaques may lead to a clinical benefit in patients with early AD.</li>\u0000 \u0000 <li>Aggregated Aβ may play a role in both disease expression and progression.</li>\u0000 \u0000 <li>Anti-amyloid monoclonal antibodies might be clinically meaningful through symptomatic amelioration resulting from disease modification.</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":"2025-01-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11746071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143015974","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}