Fei Tian, Jinde Zhao, Lan Chen, Shengtao Wei, Hualiang Lin
Objective
Various modifiable risk factors have been identified for dementia, but it remains unclear whether these associations and importance vary according to genetic predisposition.
Methods
We included 182,473 dementia-free individuals from United Kingdom (UK) Biobank cohort. We calculated the hazard ratios (HRs) and population-attributable fractions (PAF) of 11 modifiable risk factors (smoking status, drinking status, diet, physical activity, hypertension, diabetes, waist-to-hip ratio, education, depression, social contact, and air pollution) for dementia in general population and across various genetic groups based on APOE genotypes and a weighted polygenic-risk score (PRS).
Results
During 12.42-year follow-up, a total of 2,065 incident all-cause dementia (ACD) cases were documented. Low social contact, diabetes, and abdominal obesity were top 3 modifiable risk factors associated with an increased risk of dementia, especially in low APOE risk (ε2ε2 or ε2ε3) group. The HRs associated with low social contact, diabetes, and abdominal obesity were 3.86 (95% CI: 2.08–7.17), 2.18 (95% CI: 1.43–3.32) and 1.29 (95% CI: 0.88–1.89) for dementia in the low APOE risk. The same patterns were also observed in PRS groups. In terms of PAFs, abdominal obesity contributed the most in low genetic risk groups (PAF: 13.68 to 15.73%). In contrast, less education was the largest contributor in high APOE and high PRS groups (PAF: 11.35% [95% CI: 5.32–17.38%] and 11.24% [95% CI: 4.40–18.07%], respectively), followed by hypertension (PAF: 9.09% [95% CI: 2.01–16.17%] and 5.29% [95% CI: −2.72 to 13.29%], respectively). Overall, the total PAF decreased with increasing genetic risk, particularly for metabolic risk factors.
Interpretation
Our findings highlight the importance of personalized risk assessments and the development of tailored interventions based on genetic background to prevent dementia more effectively. ANN NEUROL 2025;98:1210–1221
{"title":"Prioritizing Modifiable Risk Factors for Dementia Prevention across the Spectrum of Genetic Susceptibility: A Prospective Cohort Study","authors":"Fei Tian, Jinde Zhao, Lan Chen, Shengtao Wei, Hualiang Lin","doi":"10.1002/ana.78060","DOIUrl":"10.1002/ana.78060","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Various modifiable risk factors have been identified for dementia, but it remains unclear whether these associations and importance vary according to genetic predisposition.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included 182,473 dementia-free individuals from United Kingdom (UK) Biobank cohort. We calculated the hazard ratios (HRs) and population-attributable fractions (PAF) of 11 modifiable risk factors (smoking status, drinking status, diet, physical activity, hypertension, diabetes, waist-to-hip ratio, education, depression, social contact, and air pollution) for dementia in general population and across various genetic groups based on <i>APOE</i> genotypes and a weighted polygenic-risk score (PRS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>During 12.42-year follow-up, a total of 2,065 incident all-cause dementia (ACD) cases were documented. Low social contact, diabetes, and abdominal obesity were top 3 modifiable risk factors associated with an increased risk of dementia, especially in low <i>APOE</i> risk (ε2ε2 or ε2ε3) group. The HRs associated with low social contact, diabetes, and abdominal obesity were 3.86 (95% CI: 2.08–7.17), 2.18 (95% CI: 1.43–3.32) and 1.29 (95% CI: 0.88–1.89) for dementia in the low <i>APOE</i> risk. The same patterns were also observed in PRS groups. In terms of PAFs, abdominal obesity contributed the most in low genetic risk groups (PAF: 13.68 to 15.73%). In contrast, less education was the largest contributor in high <i>APOE</i> and high PRS groups (PAF: 11.35% [95% CI: 5.32–17.38%] and 11.24% [95% CI: 4.40–18.07%], respectively), followed by hypertension (PAF: 9.09% [95% CI: 2.01–16.17%] and 5.29% [95% CI: −2.72 to 13.29%], respectively). Overall, the total PAF decreased with increasing genetic risk, particularly for metabolic risk factors.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our findings highlight the importance of personalized risk assessments and the development of tailored interventions based on genetic background to prevent dementia more effectively. ANN NEUROL 2025;98:1210–1221</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1210-1221"},"PeriodicalIF":7.7,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285206","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":"Reconsidering Central and Peripheral Contributions to Propranolol's Anti Tremor Effects in Parkinson's Disease","authors":"Sijia Zhu, Wenqin Jin","doi":"10.1002/ana.70019","DOIUrl":"10.1002/ana.70019","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 5","pages":"1150-1151"},"PeriodicalIF":7.7,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290431","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":"Reply to Letter to the Editor: “Disease Characteristics and Treatments Associated with Outcome in Primary Angiitis of the Central Nervous System—A Multicenter Cohort Study in 163 Patients”","authors":"Carolin Beuker MD, Jens Minnerup MD","doi":"10.1002/ana.70026","DOIUrl":"10.1002/ana.70026","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 5","pages":"1153-1154"},"PeriodicalIF":7.7,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145290441","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":"Comment on Clinical, Prognostic, and Longitudinal Functional and Neuropsychological Features of West Nile Virus Neuroinvasive Disease in the United States: A Systematic Review and Meta-Analysis","authors":"Yechao Yin, Pengyu Miao","doi":"10.1002/ana.78069","DOIUrl":"10.1002/ana.78069","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1403-1404"},"PeriodicalIF":7.7,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278499","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}
Steve Simpson-Yap, Ellen Morwitch, Samuel A Tanner, Sarah M Thomson, Alex Eisner, Rod A Lea, Trevor J Kilpatrick, Jeannette Lechner-Scott, Rodney J Scott, Alexandre Xavier, Vicki E Maltby, Robyn M Lucas, Bruce V Taylor, Brett A Lidbury, Simon A Broadley, Ingrid van der Mei, Mehari Woldemariam Merid, Boris Novakovic, Richard Saffery, Anna Karin Hedström, Pernilla Stridh, Tomas Olsson, Maja Jagodic, Lars Alfredsson, Anne-Louise Ponsonby
Objectives: Multiple sclerosis (MS) onset risk factors include Epstein-Barr virus (EBV) indices (including host response), lower serum 25-vitamin D (25(OH)D) levels, low sun exposure, and HLA-DRB1*1501. The underlying molecular mechanisms are unclear. Here, we examined mediation through differential DNA methylation (DNAm) to better understand possible epigenetic programming.
Methods: Two case-control studies (Ausimmune Study, Australia = 206 cases + 348 controls; and Epidemiologic Investigations of MS [EIMS], Sweden = 140 cases + 139 controls). DNAm was measured using Illumina arrays. Dimension-reduction methods generated MS-associated DNAm modules. Pathway enrichment analyses were used to describe DNAm modules' system-level biological characteristics. Individual and joint associations with MS risk were assessed using logistic regression. DNAm module mediation of risk factor-outcome associations were assessed using mediation analysis. A range of temporality analyses were used.
Results: EBV indices (infectious mononucleosis history and anti-EBNA IgG titer), lower 25(OH)D, low sun exposure, and HLA-DRB1*1501 risk variant were individually and jointly associated with MS risk. In each study, 2 DNAm modules were found which mediated multiple exposure-MS associations. Proportions mediated ranged from 21 to 47% in Ausimmune and 25 to 53% in EIMS. Results were robust to sensitivity analyses. Top-ranked genomewide association study (GWAS) MS risk-associated genes were over-represented in both Ausimmune DNAm modules, A1 3.5-fold (p = 0.004) and A2 3-fold (p = 0.015). Reactome pathways enriched for DNAm had cross-study overlap - 45% of pathways enriched in Ausimmune DNAm modules were also enriched in EIMS (4.82-fold, p < 0.001).
Interpretation: EBV, lower vitamin D, low sun exposure, and HLA-DRB1*1501 risk variant act in concert and through common epigenetic pathways to impact MS onset risk. ANN NEUROL 2025.
{"title":"Epstein-Barr Virus, Lower Vitamin D, Low Sun Exposure, and HLA-DRB1*1501 Risk Variant Share Common Epigenetic Pathways Leading to Multiple Sclerosis Onset.","authors":"Steve Simpson-Yap, Ellen Morwitch, Samuel A Tanner, Sarah M Thomson, Alex Eisner, Rod A Lea, Trevor J Kilpatrick, Jeannette Lechner-Scott, Rodney J Scott, Alexandre Xavier, Vicki E Maltby, Robyn M Lucas, Bruce V Taylor, Brett A Lidbury, Simon A Broadley, Ingrid van der Mei, Mehari Woldemariam Merid, Boris Novakovic, Richard Saffery, Anna Karin Hedström, Pernilla Stridh, Tomas Olsson, Maja Jagodic, Lars Alfredsson, Anne-Louise Ponsonby","doi":"10.1002/ana.78043","DOIUrl":"https://doi.org/10.1002/ana.78043","url":null,"abstract":"<p><strong>Objectives: </strong>Multiple sclerosis (MS) onset risk factors include Epstein-Barr virus (EBV) indices (including host response), lower serum 25-vitamin D (25(OH)D) levels, low sun exposure, and HLA-DRB1*1501. The underlying molecular mechanisms are unclear. Here, we examined mediation through differential DNA methylation (DNAm) to better understand possible epigenetic programming.</p><p><strong>Methods: </strong>Two case-control studies (Ausimmune Study, Australia = 206 cases + 348 controls; and Epidemiologic Investigations of MS [EIMS], Sweden = 140 cases + 139 controls). DNAm was measured using Illumina arrays. Dimension-reduction methods generated MS-associated DNAm modules. Pathway enrichment analyses were used to describe DNAm modules' system-level biological characteristics. Individual and joint associations with MS risk were assessed using logistic regression. DNAm module mediation of risk factor-outcome associations were assessed using mediation analysis. A range of temporality analyses were used.</p><p><strong>Results: </strong>EBV indices (infectious mononucleosis history and anti-EBNA IgG titer), lower 25(OH)D, low sun exposure, and HLA-DRB1*1501 risk variant were individually and jointly associated with MS risk. In each study, 2 DNAm modules were found which mediated multiple exposure-MS associations. Proportions mediated ranged from 21 to 47% in Ausimmune and 25 to 53% in EIMS. Results were robust to sensitivity analyses. Top-ranked genomewide association study (GWAS) MS risk-associated genes were over-represented in both Ausimmune DNAm modules, A1 3.5-fold (p = 0.004) and A2 3-fold (p = 0.015). Reactome pathways enriched for DNAm had cross-study overlap - 45% of pathways enriched in Ausimmune DNAm modules were also enriched in EIMS (4.82-fold, p < 0.001).</p><p><strong>Interpretation: </strong>EBV, lower vitamin D, low sun exposure, and HLA-DRB1*1501 risk variant act in concert and through common epigenetic pathways to impact MS onset risk. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273282","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}
Kai Michael Schubert MD, PhD, Vineet Punia MD, Carla Bentes MD, PhD, Marian Galovic MD, PhD, for the SeLECT Consortium
{"title":"Reply to “The Role of EEG in Predicting Post-Stroke Seizures and an Updated Prognostic Model (SeLECT-EEG)”","authors":"Kai Michael Schubert MD, PhD, Vineet Punia MD, Carla Bentes MD, PhD, Marian Galovic MD, PhD, for the SeLECT Consortium","doi":"10.1002/ana.78053","DOIUrl":"10.1002/ana.78053","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1396-1397"},"PeriodicalIF":7.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273222","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}
Guicheng Kuang MD, Zhenghaonan Qiu MD, Lingxiao Li MD, Yi Liu MD
{"title":"Letter on the Role of Electroencephalography in Predicting Post-Stroke Seizures and an Updated Prognostic Model (SeLECT-EEG)","authors":"Guicheng Kuang MD, Zhenghaonan Qiu MD, Lingxiao Li MD, Yi Liu MD","doi":"10.1002/ana.78054","DOIUrl":"10.1002/ana.78054","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1395-1396"},"PeriodicalIF":7.7,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145273271","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":"Risk-Based EEG Allocation: The Next Step for SeLECT-EEG","authors":"Shenglong Li, Longfei You","doi":"10.1002/ana.78062","DOIUrl":"10.1002/ana.78062","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1399-1400"},"PeriodicalIF":7.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249024","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}
Kai Michael Schubert MD, PhD, Vineet Punia MD, Carla Bentes MD, PhD, Marian Galovic MD, PhD, for the SeLECT Consortium
{"title":"Reply to “Risk-Based EEG Allocation: The Next Step for SeLECT-EEG”","authors":"Kai Michael Schubert MD, PhD, Vineet Punia MD, Carla Bentes MD, PhD, Marian Galovic MD, PhD, for the SeLECT Consortium","doi":"10.1002/ana.78061","DOIUrl":"10.1002/ana.78061","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 6","pages":"1400-1401"},"PeriodicalIF":7.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145249015","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}
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