{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T10:34:14Z","timestamp":1792233254143,"version":"4.4.0"},"reference-count":37,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"crossref","award":["202208330062"],"award-info":[{"award-number":["202208330062"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Type 2 diabetes (T2D) is a recognized risk factor for dementia and stroke, but whether risks begin during prediabetes remains unclear. We aimed to determine the risks of these neurological conditions among individuals with prediabetes and the glycaemic thresholds at which risks emerge.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>We studied 432 887 adults (mean age, 57 years; 55% women) from the UK Biobank who were free of dementia or stroke at baseline, categorized by glycaemic status (normoglycaemia, prediabetes, and T2D). Incident dementia, stroke, and magnetic resonance imaging (MRI)\u2013derived brain markers, including brain volumes and white matter hyperintensity volumes, were assessed for these conditions. HbA1c was modelled continuously using natural cubic splines to assess linear and non-linear effects. Outcomes were estimated using Cox proportional hazards and linear regression models, adjusted for demographic, lifestyle, and clinical factors. Two-sample Mendelian randomization (MR) was used to test causality. During a median 13.7 years of follow-up, prediabetes (n = 52 693) was associated with higher risks of vascular dementia [hazard ratio (HR): 1.36; 95% confidence interval (CI): 1.14\u20131.61], stroke (HR:1.09; 95% CI: 1.01\u20131.16), ischaemic stroke (HR:1.10; 95% CI: 1.02\u20131.19), and intracerebral haemorrhage (HR:1.19; 95% CI: 1.01\u20131.39) compared with normoglycaemia, after adjustment for major confounding factors and across extensive sensitivity analyses. In the brain MRI cohort (n = 39 996), grey matter volumes (\u03b2 = \u22120.04, 95% CI \u22120.07 to \u22120.01) and hippocampal volumes (\u03b2 = \u22120.03, 95% CI \u22120.06\u20130.00) were smaller, and log-transformed white matter hyperintensity volume (\u03b2 = 0.04, 95% CI 0.01\u20130.07) was larger in prediabetes. Spline models indicated that adverse outcomes were associated with higher HbA1c levels, even before the diagnostic threshold for T2D was reached. Risks were further elevated in T2D. Mendelian randomization analyses supported causal effects of glycaemia on dementia, stroke, and hippocampal atrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Prediabetes is not a benign state: even modest HbA1c elevations are linked to vascular dementia, stroke, and brain structural decline. These risks emerge below current diagnostic glycaemic thresholds, underscoring prediabetes as a critical stage for early intervention to preserve brain health.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/eurjpc\/zwag278","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T07:41:06Z","timestamp":1779176466000},"source":"Crossref","is-referenced-by-count":3,"title":["Prediabetes as a critical stage for risk of dementia and stroke: evidence from the UK Biobank and Mendelian randomization"],"prefix":"10.1093","author":[{"given":"Si","family":"Han","sequence":"first","affiliation":[{"name":"Department of Data Science and Biostatistics, Julius Global Health, University Medical Centre Utrecht , Universiteitsweg 100, 3584 CG Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elnaz","family":"Naderi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, University Medical Centre Groningen, University of Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]},{"name":"National Clinical Research Centre for Metabolic Diseases (Shanghai), Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission, National Research Centre for Translational Medicine, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Harvard T.H. Chan School of Public Health , Boston, Massachusetts ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geert Jan","family":"Biessels","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brain Centre, University Medical Centre Utrecht , Utrecht ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6261-9445","authenticated-orcid":false,"given":"Fariba","family":"Ahmadizar","sequence":"additional","affiliation":[{"name":"Department of Data Science and Biostatistics, Julius Global Health, University Medical Centre Utrecht , Universiteitsweg 100, 3584 CG Utrecht ,","place":["The Netherlands"]},{"name":"Department of General Practice, Amsterdam University Medical Center , Meibergdreef 9, 1105 AZ Amsterdam ,","place":["The 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