Alzheimer's & Dementia最新文献

{"title":"Developing and validating a prediction tool for cerebral amyloid angiopathy neuropathological severity","authors":"Chenyin Chu,&nbsp;Yihan Wang,&nbsp;Liwei Ma,&nbsp;Chloe A. Mutimer,&nbsp;Guangyan Ji,&nbsp;Huiyu Shi,&nbsp;Nawaf Yassi,&nbsp;Colin L. Masters,&nbsp;Benjamin Goudey,&nbsp;Liang Jin,&nbsp;Yijun Pan","doi":"10.1002/alz.14583","DOIUrl":"10.1002/alz.14583","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Cerebral amyloid angiopathy (CAA) is a cerebrovascular condition, the severity of which can only be determined <i>post mortem</i>. Here, we developed machine learning models, the Florey CAA Score (FCAAS), to predict CAA severity (none/mild/moderate/severe).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Building on an auto-score-ordinal algorithm, the FCAAS models were developed and validated using data collected by three cohort studies of aging and dementia. The developed FCAAS models were digitized as a web-based tool. A pilot trial was conducted using this web-based tool.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>The FCAAS-4 achieved a mean area under the receiver operating characteristic curve (AUC-ROC) of 0.74 (95% confidence interval: 0.71–0.77) and a Harrell generalized c-index of 0.72 (0.70–0.75). Pilot trial results obtained a mean AUC-ROC of 0.82 (0.71–0.85) and Harrell generalized c-index 0.79 (0.73–0.82).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>The FCAAS models demonstrate a promising performance in predicting CAA severity. This framework holds the potential for predicting development of amyloid-related imaging abnormalities (ARIAs), given the CAA–ARIAs link.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>The severity of cerebral amyloid angiopathy (CAA) can only be determined <i>post mortem</i>.</li>\u0000 \u0000 <li>A web tool, the Florey CAA Score (FCAAS), was developed to predict CAA severity.</li>\u0000 \u0000 <li>The FCAAS holds the potential to be used for CAA risk stratification in clinics.</li>\u0000 \u0000 <li>CAA is linked to increased risk of amyloid-related imaging abnormalities (ARIAs).</li>\u0000 \u0000 <li>The framework used by FCAAS can possibly be adapted to predict ARIAs risk.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14583","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating proteomic biomarkers for cerebral amyloid angiopathy screening and risk stratification","authors":"Jiajie Xu,&nbsp;Ya Su,&nbsp;Yuhui Sha,&nbsp;Jiayu Fu,&nbsp;Tingmeng Yan,&nbsp;Feifan Xu,&nbsp;Han Tang,&nbsp;Yunqing Ying,&nbsp;Yiwei Xia,&nbsp;Qiang Dong,&nbsp;M. Edip Gurol,&nbsp;Jun Ni,&nbsp;Xin Cheng","doi":"10.1002/alz.70044","DOIUrl":"10.1002/alz.70044","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>We systematically characterized plasma protein profiles in cerebral amyloid angiopathy (CAA) using proteomics and identified a hub protein panel for disease diagnosis and risk stratification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>A total of 146 patients with probable CAA and 128 community-dwelling controls were prospectively enrolled. Plasma samples underwent proteomic analysis, and the hub proteins were validated in two validation cohorts. Machine learning algorithms were applied to construct and validate the performance of the circulating panel.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>We identified 166 differentially expressed proteins in patients with CAA. Six hub proteins were selected to form the circulating panel, demonstrating excellent performance to distinguish patients from controls in all cohorts. Additionally, the risk stratification system derived from the hub protein panel accurately identified patients at high risk for new-onset lobar intracerebral hemorrhage.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Our findings revealed distinctive circulating protein signatures in CAA and established a validated hub protein panel aiding in CAA screening and risk stratification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We identified plasma protein signatures in CAA using proteomics.</li>\u0000 \u0000 <li>A circulating hub protein panel was developed and validated, demonstrating high accuracy for disease screening.</li>\u0000 \u0000 <li>The hub protein panel effectively stratified CAA patients according to risk of future intracerebral hemorrhage.</li>\u0000 \u0000 <li>The circulating panel offers potential for CAA screening and risk stratification.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70044","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring public perceptions of dementia on Twitter (X): a cross-cultural analysis","authors":"Saowaluk Srikajornlarp,&nbsp;Tassanee Lerksuthirat,&nbsp;Pattama Patpong,&nbsp;Boonsong Ongphiphadhanakul,&nbsp;Tanchanok Chattaris","doi":"10.1002/alz.70042","DOIUrl":"10.1002/alz.70042","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Twitter (X) is widely used to reflect individual perspectives. We wished to study social insight regarding dementia using this digital platform.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We conducted a cross-sectional study retrieving tweets containing “dementia” or “#dementia” and their Thai equivalents. English tweets were randomly selected, while all Thai tweets were collected. We identified user types, topics, and sentiments.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Of 10,062 English and 9511 Thai tweets, general users were the most prevalent in both languages. “Dementia” was used accurately in 39.0% of English tweets and as misinformation in 49.2% of Thai tweets. Stigma was significantly more common in English (38.9%) than in Thai (22.6%) tweets (<i>p</i>-value &lt; 0.001), and negative perceptions were expressed in 44.2% and 81.3% of English and Thai tweets, respectively (<i>p</i>-value &lt; 0.001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Different inappropriate uses of “dementia” were observed. To alleviate negative perceptions, reducing stigmatization is urgently needed in English-speaking communities, whereas in Thailand, appropriate dementia education should be undertaken immediately.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We found differences in the perceptions of “dementia” between English and Thai tweets.</li>\u0000 \u0000 <li>Using “dementia” to attack individuals was common among English Twitter (X) users.</li>\u0000 \u0000 <li>“Misinformation” regarding the term “dementia” was observed among Thai users.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70042","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic stress, social support, and Alzheimer's blood-based biomarkers in the HABS-HD study","authors":"Jillian K. Lee,&nbsp;Leigh Johnson,&nbsp;James R. Hall,&nbsp;James R. Bateman,&nbsp;Lisa L. Barnes,&nbsp;Sid O'Bryant,&nbsp;Michelle M. Mielke","doi":"10.1002/alz.70043","DOIUrl":"10.1002/alz.70043","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>High levels of chronic stress and low social support have been associated with worse cognition among older adults, but the underlying mechanisms remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We included 2117 older adults (mean age 65.5 years) enrolled in the Health and Aging Brain Study – Health Disparities (HABS-HD). Linear regression models evaluated the associations between social support or chronic stress and Alzheimer's-related blood-based biomarkers (BBMs), including amyloid beta (Aβ) 42/40 ratio, neurofilament light chain (NfL), phosphorylated tau (p-tau)181, and total tau (t-tau). Interactions between chronic stress or social support and gender or race/ethnicity in relation to BBMs were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Higher chronic stress was associated with higher levels of t-tau. Higher social support was associated with lower levels of NfL. Neither gender nor race/ethnicity modified the associations between chronic stress or social support and BBM levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Chronic stress and social support are associated with BBMs of neurodegeneration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Higher chronic stress was associated with higher levels of plasma total tau.</li>\u0000 \u0000 <li>Higher social support was associated with lower levels of plasma neurofilament light chain.</li>\u0000 \u0000 <li>Neither gender nor race/ethnicity modified the associations between chronic stress or social support and levels of blood-based biomarkers.</li>\u0000 \u0000 <li>Chronic stress and social support affect pathways related to neurodegeneration.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70043","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicted natural progression as an Alzheimer's prognostic covariate improves the precision of lecanemab efficacy assessments and clinical trial efficiency","authors":"Viswanath Devanarayan,&nbsp;Yuanqing Ye,&nbsp;Liang Zhu,&nbsp;Lu Tian,&nbsp;Lynn Kramer,&nbsp;Michael Irizarry,&nbsp;Shobha Dhadda","doi":"10.1002/alz.70045","DOIUrl":"10.1002/alz.70045","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> BACKGROUND</h3>\u0000 \u0000 <p>Heterogeneity in Alzheimer's disease (AD) progression introduces variability in treatment effect assessments. Using predicted future progression as an AD prognostic covariate (APC) may reduce this variability. This study evaluates this strategy in lecanemab trials and its implications for AD trial design.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Two APCs were derived at baseline for each trial participant from published models with historical controls: one with clinical features, the other adding structural MRI features. Their impact on estimating the difference in cognitive decline between the treatment and placebo arms and the time saved from delayed progression (TSDP) was assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Incorporating either APC reduced variance estimates by up to 19.1% across phase II and phase III trials, increased power to 90.2%, and reduced sample size by 27.2%. These APCs improved treatment effect estimates and TSDP, demonstrating broad applicability across endpoints.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>APCs enhance treatment effect evaluation, improve statistical power, and reduce required sample sizes in Alzheimer's trials.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> CLINICAL TRIALS.GOV IDENTIFIERS</h3>\u0000 \u0000 <p>NCT01767311 (Lecanemab Study 201), NCT03887455 (Lecanemab Study 301; ClarityAD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Baseline prediction of future progression can serve as an APC for treatment effect assessments.</li>\u0000 \u0000 <li>These predictions can be derived from progression models developed using external controls.</li>\u0000 \u0000 <li>APC accounts for heterogeneity in progression among trial participants, improving treatment effect estimates.</li>\u0000 \u0000 <li>Enhanced accuracy and precision were observed across lecanemab phase II and phase III trials for various endpoints.</li>\u0000 \u0000 <li>This approach results in substantial increase in statistical power and reduced sample size for future AD trials.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545930","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Scam susceptibility is associated with a markedly accelerated onset of Alzheimer's disease dementia","authors":"Patricia A. Boyle,&nbsp;Tianhao Wang,&nbsp;Gary Mottola,&nbsp;Chris Stewart,&nbsp;Robert S. Wilson,&nbsp;David A. Bennett,&nbsp;Lei Yu","doi":"10.1002/alz.14544","DOIUrl":"10.1002/alz.14544","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>The association of scam susceptibility with the timing of Alzheimer's disease (AD) dementia onset is unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>One thousand ninety-two older adults without dementia underwent assessments of scam susceptibility and annual clinical evaluations to document incident AD dementia. Accelerated failure time models examined the relation of scam susceptibility with dementia onset.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>During a mean of 5 years of follow-up (standard deviation = 3.1), 188 individuals (17%) were diagnosed with incident AD dementia. A higher level of scam susceptibility was associated with a considerably earlier dementia onset (<span></span><math>\u0000 <semantics>\u0000 <mi>β</mi>\u0000 <annotation>$beta $</annotation>\u0000 </semantics></math> = −0.039; 95% confidence interval: −0.061, −0.017); those with a high level of susceptibility developed AD dementia at a mean age of 90.9 years compared to 98.2 for those with a low level. Results persisted after controlling for global cognition, sex, and education.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Scam susceptibility is associated with a markedly earlier onset of AD dementia. Assessment of susceptibility may facilitate early identification of individuals at risk of developing dementia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>We examined whether scam susceptibility among older adults is associated with an accelerated onset of Alzheimer's disease dementia.</li>\u0000 \u0000 <li>Participants came from a large ongoing cohort study of aging.</li>\u0000 \u0000 <li>Scam susceptibility was assessed using a validated measure.</li>\u0000 \u0000 <li>Scam susceptibility was associated with a marked acceleration in dementia onset.</li>\u0000 \u0000 <li>Assessment of susceptibility may facilitate early identification of dementia.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 3","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14544","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The tau isoform 1N4R confers vulnerability of MAPT knockout human iPSC-derived neurons to amyloid beta and phosphorylated tau-induced neuronal dysfunction","authors":"Sarah Buchholz, Mohamed Aghyad Al Kabbani, Michael Bell-Simons, Lena Kluge, Cagla Cagmak, Jennifer Klimek, Natja Haag, Lukas C. Iohan, Audrey Coulon, Marcos R. Costa, Devrim Kilinc, Hans Zempel","doi":"10.1002/alz.14403","DOIUrl":"https://doi.org/10.1002/alz.14403","url":null,"abstract":"Human tau protein, composed of six brain-specific isoforms, is a major driver of Alzheimer's disease (AD). The role of its isoforms however remains unclear and human AD models are scarce.","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"7 1","pages":""},"PeriodicalIF":14.0,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143517976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Independent associations of high-density lipoprotein cholesterol and triglyceride levels with Alzheimer's disease and related dementias","authors":"Erin L. Ferguson,&nbsp;Scott C. Zimmerman,&nbsp;Chen Jiang,&nbsp;Minhyuk Choi,&nbsp;Travis J. Meyers,&nbsp;Thomas J. Hoffmann,&nbsp;Paola Gilsanz,&nbsp;Akinyemi Oni-Orisan,&nbsp;Jingxuan Wang,&nbsp;Rachel A. Whitmer,&nbsp;Neil Risch,&nbsp;Ronald M. Krauss,&nbsp;Catherine A. Schaefer,&nbsp;M. Maria Glymour","doi":"10.1002/alz.14575","DOIUrl":"https://doi.org/10.1002/alz.14575","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>We evaluated the independent associations between high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels with Alzheimer's disease and related dementias (ADRD).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>Among 177,680 members of Kaiser Permanente Northern California who completed a survey on health risks, we residualized TGs and HDL-C conditional on age, sex, and body mass index. We included these residuals individually and concurrently in Cox models predicting ADRD incidence.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Low (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02–1.10) and high quintiles (HR 1.07, 95% CI 1.03–1.12) of HDL-C residuals were associated with an increased risk of ADRD compared to the middle quintile. Additional adjustment for TGs attenuated the association with high HDL-C (HR 1.03, 95% CI 0.99–1.08). Low TG residuals were associated with an increased ADRD risk (HR 1.10, 95% CI 1.06–1.15); high TG residuals were protective (HR 0.92, 95% CI 0.88–0.96). These estimates were unaffected by HDL-C adjustment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>Low HDL-C and TG levels are independently associated with increased ADRD risk. The correlation with low TG level explains the association of high HDL-C with ADRD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>Strong correlations between lipid levels are important considerations when investigating lipids as late-life risk factors for Alzheimer's disease and related dementias (ADRD).</li>\u0000 \u0000 <li>Low levels of high-density lipoprotein cholesterol (HDL-C) and triglycerides (TGs) were independently associated with an increased risk of ADRD.</li>\u0000 \u0000 <li>We found no evidence for an association between high HDL-C and increased ADRD risk after adjustment for TGs.</li>\u0000 \u0000 <li>High levels of TGs were consistently associated with a decreased risk of ADRD.</li>\u0000 \u0000 <li>There may be interaction between TG and HDL-C levels, where both low HDL-C and TG levels increase the risk of ADRD compared to average levels of both.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.14575","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Posterior cingulate cortex microRNA dysregulation differentiates cognitive resilience, mild cognitive impairment, and Alzheimer's disease","authors":"Scott E. Counts,&nbsp;John S. Beck,&nbsp;Bryan Maloney,&nbsp;Michael Malek-Ahmadi,&nbsp;Stephen D. Ginsberg,&nbsp;Elliott J. Mufson,&nbsp;Debomoy K. Lahiri","doi":"10.1002/alz.70019","DOIUrl":"https://doi.org/10.1002/alz.70019","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>MicroRNA (miRNA) activity is increasingly appreciated as a key regulator of pathophysiologic pathways in Alzheimer's disease (AD). However, the role of miRNAs during the progression of AD, including resilience and prodromal syndromes such as mild cognitive impairment (MCI), remains underexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We performed miRNA-sequencing on samples of posterior cingulate cortex (PCC) obtained <i>post mortem</i> from Rush Religious Orders Study participants diagnosed <i>ante mortem</i> with no cognitive impairment (NCI), MCI, or AD. NCI subjects were subdivided as low pathology (Braak stage I/II) or high pathology (Braak stage III/IV), suggestive of resilience. Bioinformatics approaches included differential expression, messenger RNA (mRNA) target prediction, interactome modeling, functional enrichment, and AD risk modeling.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>We identified specific miRNA groups, mRNA targets, and signaling pathways distinguishing AD, MCI, resilience, <i>ante mortem</i> neuropsychological test performance, <i>post mortem</i> neuropathological burden, and AD risk.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>These findings highlight the potential of harnessing miRNA activity to manipulate disease-modifying pathways in AD, with implications for precision medicine.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>MicroRNA (MiRNA) dysregulation is a well-established feature of Alzheimer's disease (AD).</li>\u0000 \u0000 <li>Novel miRNAs also distinguish subjects with mild cognitive impairment and putative resilience.</li>\u0000 \u0000 <li>MiRNAs correlate with cognitive performance and neuropathological burden.</li>\u0000 \u0000 <li>Select miRNAs are associated with AD risk with age as a significant covariate.</li>\u0000 \u0000 <li>MiRNA pathways include insulin, prolactin, kinases, and neurite plasticity.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparing Alzheimer's genes in African, European, and Amerindian induced pluripotent stem cell–derived microglia","authors":"Sofia Moura,&nbsp;Luciana Bertholim Nasciben,&nbsp;Aura M. Ramirez,&nbsp;Lauren Coombs,&nbsp;Joe Rivero,&nbsp;Derek J. Van Booven,&nbsp;Brooke A. DeRosa,&nbsp;Kara L. Hamilton-Nelson,&nbsp;Patrice L. Whitehead,&nbsp;Larry D. Adams,&nbsp;Takiyah D. Starks,&nbsp;Pedro R. Mena,&nbsp;Maryenela Illanes-Manrique,&nbsp;Sergio Tejada,&nbsp;Goldie S. Byrd,&nbsp;Mario R. Cornejo-Olivas,&nbsp;Briseida E. Feliciano-Astacio,&nbsp;Karen Nuytemans,&nbsp;Liyong Wang,&nbsp;Margaret A. Pericak-Vance,&nbsp;Derek M. Dykxhoorn,&nbsp;Farid Rajabli,&nbsp;Anthony J. Griswold,&nbsp;Juan I. Young,&nbsp;Jeffery M. Vance","doi":"10.1002/alz.70031","DOIUrl":"https://doi.org/10.1002/alz.70031","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> INTRODUCTION</h3>\u0000 \u0000 <p>Genome-wide association studies (GWAS) studies in Alzheimer's disease (AD) demonstrate ancestry-specific loci. Previous studies in the regulatory architecture have only been conducted in Europeans (EUs), thus studies in additional ancestries are needed. Given the prevalence of AD genes expressed in microglia, we initiated our studies in induced pluripotent stem cell (iPSC) -derived microglia.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> METHODS</h3>\u0000 \u0000 <p>We created iPSC-derived microglia from 13 individuals of either high Amerindian (AI), African (AF), or EU global ancestry, including both AD and controls. RNA-seq, ATAC-seq, and pathway analyses were compared between ancestries in both AD and non-AD genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> RESULTS</h3>\u0000 \u0000 <p>Twelve AD genes were differentially expressed genes (DEGs) and/or accessible between ancestries, including <i>ABI3</i>, <i>CTSB</i>, and <i>MS4A6A</i>. A total of 5% of all genes had differential ancestral expression, but differences in accessibility were less than 1%. The DEGs were enriched in known AD pathways.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> DISCUSSION</h3>\u0000 \u0000 <p>This resource will be valuable in evaluating AD in admixed populations and other neurological disorders and understanding the AD risk differences between populations.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Highlights</h3>\u0000 \u0000 <div>\u0000 <ul>\u0000 \u0000 <li>First comparison of the genomics of AI, AF, and EU microglia.</li>\u0000 \u0000 <li>Report differences in expression and accessibility of AD genes between ancestries.</li>\u0000 \u0000 <li>Ancestral expression differences are greater than differences in accessibility.</li>\u0000 \u0000 <li>Good transcriptome correlation was seen between brain and iPSC-derived microglia.</li>\u0000 \u0000 <li>Differentially expressed AD genes were in known AD pathways.</li>\u0000 </ul>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":"21 2","pages":""},"PeriodicalIF":13.0,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/alz.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490051","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}