Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring最新文献

{"title":"Exploring the association between mild behavioral impairment and plasma p-tau217: Implications for early detection of Alzheimer's disease.","authors":"Maryam Ghahremani, Rebeca Leon, Eric E Smith, Zahinoor Ismail","doi":"10.1002/dad2.70119","DOIUrl":"10.1002/dad2.70119","url":null,"abstract":"<p><strong>Introduction: </strong>Mild behavioral impairment (MBI), marked by late-onset persistent neuropsychiatric symptoms (NPS), may signal early dementia risk. While MBI is linked to previously established amyloid-beta (Aβ) and tau biomarkers, its association with plasma p-tau217, a promising blood-based biomarker for Alzheimer's disease (AD), remains unexplored. Here, we investigated the association between MBI and plasma p-tau217 in dementia-free individuals from the Alzheimer's Disease Neuroimaging Initiative.</p><p><strong>Methods: </strong>MBI was defined using the Neuropsychiatric Inventory (NPI) data. Linear regression assessed the association between NPS status and continuous p-tau217 levels, while logistic regression modeled the association between NPS status and p-tau217 positivity, using a study-specific cutoff. Models adjusted for age, sex, education, and cognitive diagnosis.</p><p><strong>Results: </strong>Among 101 participants (mean age = 72.0 ± 6.5; 44.6% female), those with MBI had higher plasma p-tau217 levels (<i>β</i> = 36.4%; 95% confidence interval [CI]: 2.2-82.0, <i>p </i>= 0.04) and higher odds of being p-tau217 positive (odds ratio [OR] = 3.06, 95% CI: 1.14-8.70, <i>p</i> = 0.03) than MBI- participants.</p><p><strong>Discussion: </strong>Findings support the role of MBI in AD risk stratification.</p><p><strong>Highlights: </strong>Mild behavioral impairment (MBI) is linked to elevated plasma p-tau217, a specific Alzheimer's disease biomarker.MBI increases the odds of plasma p-tau217 positivity in dementia-free individuals.Findings support MBI as an early indicator for Alzheimer's disease risk.MBI assessment can improve biomarker-based screening and clinical trial efficiency.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70119"},"PeriodicalIF":4.0,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12094880/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144129081","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":"Relationship between language features extracted through NLP and clinically diagnosed Alzheimer's disease and mild cognitive impairment in Slovak.","authors":"Nataliia Casnochova Zozuk, Dasa Munkova, Livia Kelebercova, Michal Munk","doi":"10.1002/dad2.70122","DOIUrl":"10.1002/dad2.70122","url":null,"abstract":"<p><strong>Background: </strong>Dementia, particularly Alzheimer's disease (AD), affects language, especially lexical-semantic processing. Discourse analysis using NLP methods can aid early detection, but research in inflectional languages like Slovak is limited.</p><p><strong>Methods: </strong>Speech samples from 216 Slovak-speaking participants (64 AD, 44 MCI, 108 HC) were collected using a picture description task and analyzed for lexical complexity using 15 NLP-based measures.</p><p><strong>Results: </strong>Several lexical complexity measures, including GTTR, UBER, SICHEL, MTLD, HDD and others, significantly differentiated AD or MCI from healthy controls. Some measures (UBER, YULEI, HONORE) also distinguished between AD and MCI.</p><p><strong>Conclusion: </strong>Lexical complexity metrics can serve as non-invasive linguistic indicators of neurodegenerative diseases, demonstrating diagnostic relevance for early detection of AD and MCI in Slovak.</p><p><strong>Highlights: </strong>Lexical complexity metrics effectively differentiate between healthy controls, MCI, and AD in Slovak speakers.Measures such as GTTR, UBER, and HONOR exhibit strong diagnostic potential for neurodegenerative diseases.Education significantly influences linguistic deficits, with higher education correlating to reduced cognitive decline.Findings underscore the importance of studying minority languages for advancing AD and MCI diagnostics.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70122"},"PeriodicalIF":4.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12089133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144112614","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":"Cognitive decline and carotid intima-media thickness: The presumed association of two vaguely defined clinical \"entities\".","authors":"Christian Saleh","doi":"10.1002/dad2.70124","DOIUrl":"https://doi.org/10.1002/dad2.70124","url":null,"abstract":"","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70124"},"PeriodicalIF":4.0,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12078751/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144082055","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":"Fully automated MRI-based analysis of the locus coeruleus in aging and Alzheimer's disease dementia using ELSI-Net.","authors":"Max Dünnwald, Friedrich Krohn, Alessandro Sciarra, Mousumi Sarkar, Anja Schneider, Klaus Fliessbach, Okka Kimmich, Frank Jessen, Ayda Rostamzadeh, Wenzel Glanz, Enise I Incesoy, Stefan Teipel, Ingo Kilimann, Doreen Goerss, Annika Spottke, Johanna Brustkern, Michael T Heneka, Frederic Brosseron, Falk Lüsebrink, Dorothea Hämmerer, Emrah Düzel, Klaus Tönnies, Steffen Oeltze-Jafra, Matthew J Betts","doi":"10.1002/dad2.70118","DOIUrl":"10.1002/dad2.70118","url":null,"abstract":"<p><strong>Introduction: </strong>The locus coeruleus (LC) is linked to the development and pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD). Magnetic resonance imaging-based LC features have shown potential to assess LC integrity in vivo.</p><p><strong>Methods: </strong>We present a deep learning-based LC segmentation and feature extraction method called Ensemble-based Locus Coeruleus Segmentation Network (ELSI-Net) and apply it to healthy aging and AD dementia datasets. Agreement to expert raters and previously published LC atlases were assessed. We aimed to reproduce previously reported differences in LC integrity in aging and AD dementia and correlate extracted features to cerebrospinal fluid (CSF) biomarkers of AD pathology.</p><p><strong>Results: </strong>ELSI-Net demonstrated high agreement to expert raters and published atlases. Previously reported group differences in LC integrity were detected and correlations to CSF biomarkers were found.</p><p><strong>Discussion: </strong>Although we found excellent performance, further evaluations on more diverse datasets from clinical cohorts are required for a conclusive assessment of ELSI-Net's general applicability.</p><p><strong>Highlights: </strong>We provide a thorough evaluation of a fully automatic locus coeruleus (LC) segmentation method termed Ensemble-based Locus Coeruleus Segmentation Network (ELSI-Net) in aging and Alzheimer's disease (AD) dementia.ELSI-Net outperforms previous work and shows high agreement with manual ratings and previously published LC atlases.ELSI-Net replicates previously shown LC group differences in aging and AD.ELSI-Net's LC mask volume correlates with cerebrospinal fluid biomarkers of AD pathology.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70118"},"PeriodicalIF":4.0,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12069022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143991856","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":"The two cut-offs approach for plasma p-tau217 in detecting Alzheimer's disease in subjective cognitive decline and mild cognitive impairment.","authors":"Giulia Giacomucci, Chiara Crucitti, Assunta Ingannato, Valentina Moschini, Silvia Bagnoli, Federico Emanuele Pozzi, Elisa Marcantelli, Sonia Padiglioni, Carmen Morinelli, Salvatore Mazzeo, Sandro Sorbi, Valentina Berti, Benedetta Nacmias, Valentina Bessi","doi":"10.1002/dad2.70116","DOIUrl":"https://doi.org/10.1002/dad2.70116","url":null,"abstract":"<p><strong>Background: </strong>The study aimed to explore the applicability of plasma phosphorylated tau (p-tau)217 in identifying patients with subjective cognitive decline (SCD) and mild cognitive impairment (MCI) carrying Alzheimer's disease (AD) pathology in real-world settings.</p><p><strong>Methods: </strong>Fifty SCD, 87 MCI, and 50 AD-demented patients underwent blood collection to dose plasma p-tau217 with a fully automated Lumipulse G600II assay. Patients were classified according to the Revised Criteria of the Alzheimer's Association Workgroup as Core1+ or Core1- (based on amyloid positron emission tomography, cerebrospinal fluid [CSF] amyloid beta [Aβ]42/Aβ40, CSF p-tau181/Aβ42).</p><p><strong>Results: </strong>Plasma p-tau217 was accurate for discriminating between Core1+ and Core1- patients (area under the curve = 0.92) with an optimal cut-off value of 0.274 pg/mL, revealing good accuracy (86.29%), positive predictive value (PPV; 88.18%), and negative predictive value (NPV; 83.09%). The two cut-offs approach (0.229-0.516 pg/mL) showed higher accuracy (91.11%), a PPV of 96.25% and a NPV of 83.63%.</p><p><strong>Conclusion: </strong>The two cut-offs approach provides for stronger accuracy, PPV, and NPV than a single cut-off, making reliable the clinical application of plasma p-tau217 for early detection of AD in real-world settings.</p><p><strong>Highlights: </strong>Plasma phosphorylated tau (p-tau)217 was highly accurate in detecting Alzheimer's disease (AD) pathology.The two cut-offs approach increased plasma p-tau217 accuracy for AD diagnosis.Even when measured with immunoassay, p-tau217 is a good biomarker for AD diagnosis.Transition of p-tau217 from research setting to clinical practice seems feasible.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70116"},"PeriodicalIF":4.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994980","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":"Can annual wellness visits reduce disparity in early dementia diagnosis?","authors":"Yong-Fang Kuo, Huey-Ming Tzeng, Yong Shan, Mukaila A Raji","doi":"10.1002/dad2.70114","DOIUrl":"https://doi.org/10.1002/dad2.70114","url":null,"abstract":"<p><strong>Introduction: </strong>Disparity exists in early dementia diagnoses by race/ethnicity, sex, education, and rural/urban residence. No data exist on whether Medicare Annual Wellness Visits (AWVs) can reduce these disparities.</p><p><strong>Methods: </strong>Nested case-control studies included 100% Medicare beneficiaries with a new diagnosis of mild cognitive impairment (MCI) or Alzheimer's disease and related dementias (ADRD) in 2017 to 2020. We examined the association between AWV receipt and MCI diagnosis versus ADRD.</p><p><strong>Results: </strong>Medicare beneficiaries who received an AWV were 13% to 21% more likely than those without an AWV to be diagnosed at MCI stage versus ADRD stage. The interaction effect of AWV, sex, and race/ethnicity on MCI diagnosis was significant. The likelihood of MCI diagnosis versus ADRD was similar between females and males among those who received AWVs. Receiving an AWV reduced, but did not eliminate, racial/ethnic differences in MCI diagnosis.</p><p><strong>Discussion: </strong>AWVs had modest but significant effects in reducing disparity in the diagnosis of early cognitive impairment.</p><p><strong>Highlights: </strong>Data from analyses of Medicare beneficiaries newly diagnosed with mild cognitive impairment/Alzheimer's disease and related dementias suggested a positive association between Annual Wellness Visit (AWV) use and early diagnosis of cognitive impairment (CI).AWVs had modest but significant effects in reducing the sex and racial/ethnic disparity in early CI diagnosis.Further studies, including on cognition assessment, caregivers' preferences for AWVs, and the ways in which providers deliver AWVs, will help us better understand the effect of AWVs on reducing disparities in early dementia diagnosis.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70114"},"PeriodicalIF":4.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994832","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":"Standardization of criteria in MacCAT-T and MacCAT-CR for monoclonal anti-beta-amyloid antibodies: A Delphi study.","authors":"Jonas Karneboge, Ferdinand von Boehn, Julia Haberstroh","doi":"10.1002/dad2.70112","DOIUrl":"https://doi.org/10.1002/dad2.70112","url":null,"abstract":"<p><strong>Introduction: </strong>Assessing capacity to consent to treatment and participation in clinical research with monoclonal anti-beta-amyloid antibodies is critical, especially given the frequent uncertainty in the eligible population. Capacity tends to be underestimated in Alzheimer's patients and overestimated in those with mild cognitive impairment (MCI).</p><p><strong>Methods: </strong>Using the Delphi method, an international expert panel (<i>N</i> = 21) was surveyed in two waves.</p><p><strong>Results: </strong>The participants reached consensus on 85 % of identified features, 90 % of benefits, and 88 % of risks.</p><p><strong>Discussion: </strong>The resulting standard emphasizes the understanding subscale of the MacArthur competence assessment tools (MacCAT) for both treatment and research, supporting use across clinical and research settings. Despite proven utility, only 4 % of psychiatrists currently use tools like MacArthur Competence Assessment Tool for Treatment (MacCAT-T). This consensus aims to promote wider adoption of capacity assessments, integrating them routinely into clinical practice to balance patient autonomy with beneficence.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70112"},"PeriodicalIF":4.0,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12066392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144040592","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":"Cerebrospinal fluid YKL-40 relates to white matter hyperintensity progression in females but not males over a 6-year period.","authors":"Amalia J Peterson, Yunyi Sun, Derek B Archer, Hailey A Adegboye, Elizabeth E Moore, Isabella Deberghes, Kimberly R Pechman, Niranjana Shashikumar, W Hudson Robb, Abigail W Workmeister, T Bryan Jackson, Dandan Liu, Logan Dumitrescu, L Taylor Davis, Bennett A Landman, Kaj Blennow, Henrik Zetterberg, Timothy J Hohman, Angela L Jefferson","doi":"10.1002/dad2.70110","DOIUrl":"https://doi.org/10.1002/dad2.70110","url":null,"abstract":"<p><strong>Introduction: </strong>Neuroinflammation may have sex-specific effects on white matter injury and impact the development of dementia.</p><p><strong>Methods: </strong>Human chitinase-3-like protein-1 (YKL-40) concentrations at baseline were related to white matter hyperintensity (WMH) volume, free water (FW), and FW-corrected fractional anisotropy using linear effects models (for cross-sectional outcomes) and linear mixed-effects models (for longitudinal outcomes), adjusting for demographic and medical risk factors. Models were repeated with a sex-interaction term and then stratified by sex.</p><p><strong>Results: </strong>In stratified analyses, greater baseline YKL-40 concentrations were associated with increased WMHs in females but not males in the parietal (females <i>p</i> = 0.04; males <i>p</i> = .34) and temporal lobes (females <i>p</i> = 0.005; males = <i>p</i> = 0.71) longitudinally. YKL-40 associations with FW and FW-corrected fractional anisotropy were null.</p><p><strong>Discussion: </strong>Results suggest that neuroinflammation is a sex-specific driver of WMHs (but not FW) in females. Differential sequelae of neuroinflammation may be one reason that females have a greater burden of WMHs.</p><p><strong>Highlights: </strong>·Cerebrospinal fluid YKL-40 is associated with white matter hyperintensities in females but not males cross-sectionally and longitudinally.·Longitudinally, cerebrospinal fluid YKL-40 is associated with white matter hyperintensities in the parietal and temporal lobes, regions that exhibit early pathological changes in Alzheimer's disease .·Cerebrospinal fluid YKL-40 is not associated with white matter microstructural measures.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70110"},"PeriodicalIF":4.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064334/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144048996","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":"Association of RDoC dimensions with <i>post mortem</i> brain transcriptional profiles in Alzheimer's disease.","authors":"Weiqian Jiang, Jonathan Vogelgsang, Shu Dan, Peter Durning, Thomas H McCoy, Sabina Berretta, Torsten Klengel","doi":"10.1002/dad2.70103","DOIUrl":"10.1002/dad2.70103","url":null,"abstract":"<p><strong>Introduction: </strong>Neuropsychiatric symptoms are common in people with Alzheimer's disease (AD) across all severity stages. Their heterogeneous presentation and variable temporal association with cognitive decline suggest shared and distinct biological mechanisms. We hypothesized that specific patterns of gene expression associate with distinct National Institute of Mental Health Research Domain Criteria (RDoC) domains in AD.</p><p><strong>Methods: </strong>Post-mortem bulk RNA sequencing of the insula and anterior cingulate cortex from 60 brain donors, representing the spectrum of canonical Alzheimer's disease neuropathology, was combined with natural language processing approaches based on the RDoC Clinical Domains to uncover transcriptomic patterns linked to disease progression.</p><p><strong>Results: </strong>Distinct sets of >100 genes (<i>P</i> _{false discovery rate}< 0.05) were specifically associated with at least one clinical domain (cognitive, social, negative, positive, arousal). In addition, dysregulation of immune response pathways was shared across domains and brain regions.</p><p><strong>Discussion: </strong>Our findings provide evidence for distinct transcriptional profiles associated with RDoC domains suggesting that each dimension is characterized by sets of genes providing insight into the underlying mechanisms.</p><p><strong>Highlights: </strong><i>Post mortem</i> brain tissue investigations are critically important for Alzheimer's disease (AD) research.Neuropsychiatric symptoms in AD are common and an important aspect of AD.Categorical phenotypes are commonly used, but insufficiently describe the heterogenous presentation of AD.Using natural language processing (NLP) of <i>post mortem</i> brain donor health records provides insight into dimensional phenotypes of AD.We provide evidence for distinct RNA expression profiles associated with NLP-derived Research Domain Criteria clinical domain scores.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70103"},"PeriodicalIF":4.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064340/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144008245","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":"Disentangling the effects of sex and gender on <i>APOE</i> ɛ4-related neurocognitive impairment.","authors":"Tatiana Dessy, Amina Barhdadi, Marie-Christyne Cyr, Johanna Sandoval, Louis Bherer, Joëlle Rouleau, Sylvie Provost, Louis-Philippe Lemieux Perreault, Marie-Pierre Sylvestre, Sarah A Gagliano Taliun, Marie-Pierre Dubé","doi":"10.1002/dad2.70111","DOIUrl":"https://doi.org/10.1002/dad2.70111","url":null,"abstract":"<p><strong>Introduction: </strong>The apolipoprotein E (<i>APOE</i>) ɛ4 allele is a well-established risk factor for neurocognitive impairment (NCI), with varying impacts between men and women. This study investigates the distinct roles of sex and gender in modifying <i>APOE</i> ɛ4-related NCI.</p><p><strong>Methods: </strong>Biological sex was inferred from sex chromosomes, and a femininity score (FS) was used as a proxy for gender. We analyzed 276,596 UK Biobank participants without prior NCI to assess whether sex and FS modified the effect of <i>APOE</i> ɛ4 on NCI.</p><p><strong>Results: </strong>NCI risk was higher in <i>APOE</i> ɛ4 carriers compared to non-carriers (hazard ratio [HR] = 2.48 in females; HR = 1.96 in males) with significant interaction by sex (<i>P</i> < 0.0001). FS was associated with an increased NCI risk after accounting for sex (HR = 1.07, 95% confidence interval: 1.04-1.10, <i>P</i> < 0.0001) with no significant differences by sex or <i>APOE</i> ɛ4 carrier status.</p><p><strong>Discussion: </strong>Our findings show that <i>APOE</i> ɛ4 increases NCI risk more in females, while FS independently elevates risk across sexes.</p><p><strong>Highlights: </strong>Apolipoprotein E (<i>APOE</i>) ɛ4 increases neurocognitive impairment (NCI) risk, with a greater impact in females (hazard ratio [HR] = 2.48) than males (HR = 1.96).Sex significantly modifies the effect of <i>APOE</i> ɛ4 on NCI (<i>P</i> < 0.0001f).Femininity score increases NCI risk (HR = 1.07) independently of sex and <i>APOE</i> ɛ4.Understanding the distinct sex and gender contributions to <i>APOE</i> ɛ4-related NCI can improve interventions.</p>","PeriodicalId":53226,"journal":{"name":"Alzheimer''s and Dementia: Diagnosis, Assessment and Disease Monitoring","volume":"17 2","pages":"e70111"},"PeriodicalIF":4.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12064333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144065005","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}