{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T20:09:35Z","timestamp":1770667775640,"version":"3.49.0"},"posted":{"date-parts":[[2026,2,5]]},"group-title":"Neurology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T00:00:00Z","timestamp":1770249600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,2,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Women face greater vulnerability to dementia and Alzheimer\u2019s disease (AD), potentially due to estrogen fluctuations across the lifespan. However, its role in vascular brain health is unclear. We investigated associations between lifelong estrogen exposure\u2014endogenous (reproductive span) and exogenous (oral contraceptives [OC], menopausal hormone therapy [MHT])\u2014and late-life vascular brain injury, AD-related atrophy, and\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b54 modification.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods and findings<\/jats:title>\n                  <jats:p>\n                    We included 352 cognitively unimpaired 70-years-old women from the Gothenburg H70-1944 Birth Cohort with brain MRI and 5-year follow-up. Reproductive lifespan was calculated as age at menopause or oophorectomy minus age at menarche. OC and MHT use were self-reported. Outcomes included cerebral small vessel disease (SVD), AD-related cortical thickness, and white-matter integrity (fractional anisotropy). Linear and multinomial regression and mixed-effects models were adjusted for confounders and stratified by\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b54.\n                  <\/jats:p>\n                  <jats:p>\n                    Longer reproductive span (OR=0.90 [95%CI 0.83\u20130.98]) and MHT use (OR=0.43 [95% CI 0.20\u20130.92]) were linked to lower SVD burden, particularly fewer perivascular spaces and microbleeds. OC and MHT were associated with greater white matter integrity, with additive use throughout life showing the highest fractional anisotropy (OR=0.45 [95% CI 0.12\u20130.78]). MHT use was associated with greater thickness in areas often affected in AD among\n                    <jats:italic>APOE<\/jats:italic>\n                    -\u03b54 carriers (\u03b2=0.38 [95% CI 0.01\u20130.76]) but not in non-carriers. Longer estrogen exposure was linked to stable cortical thickness and WMH trajectories over time.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Extended estrogen exposure throughout life\u2014both endogenous and exogenous\u2014appear to support late-life cerebrovascular health in women, with potential genotype-specific neuroprotective effects. Given the current absence of sex-specific prevention guidelines for cognitive disorders, future research should clarify estrogen\u2019s long-term impact on brain health and cognition to inform personalized medicine.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.02.04.26345605","type":"posted-content","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T00:15:12Z","timestamp":1770336912000},"source":"Crossref","is-referenced-by-count":0,"title":["Reproductive lifespan and hormonal therapy in relation to later-life neurovascular health: A population-based study of women in the Gothenburg H70-1944 Birth Cohort"],"prefix":"10.64898","author":[{"given":"Giulia","family":"Lorenzon","sequence":"first","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"},{"name":"Department of Neurology, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gemma","family":"Garc\u00eda-Lluch","sequence":"additional","affiliation":[{"name":"C\u00e1tedra DeCo MICOF-CEU UCH, Universidad Cardenal Herrera-CEU, CEU Universities, 46115, Valencia, Spain"},{"name":"Division of Neuroinmunology, Instituto de Investigaci\u00f3n Sanitaria La Fe, Valencia, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian","family":"Coughlan","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shireen","family":"Sindi","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"},{"name":"Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Maioli","sequence":"additional","affiliation":[{"name":"Division of Neurogeriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konstantinos","family":"Poulakis","sequence":"additional","affiliation":[{"name":"Department of Neuropsychiatry, Sahlgrenska University Hospital, Region V\u00e4stra G\u00f6taland, M\u00f6lndal. Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jenna","family":"Najar","sequence":"additional","affiliation":[{"name":"Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Neuropsychiatry, Sahlgrenska University Hospital, Region V\u00e4stra G\u00f6taland, M\u00f6lndal. Sweden"},{"name":"Alzheimer Center, Department of Neurology, Amsterdam UMC, Vrije Universiteit. Amsterdam, Amsterdam Neuroscience, Amsterdam, the Netherlands"},{"name":"Amsterdam Neuroscience, Neurodegeneration, Amsterdam 1081HV, The Netherlands"},{"name":"Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Vrije Universiteit Amsterdam, Amsterdam UMC, RDC building, 1081 BT Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosaleena","family":"Mohanty","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"},{"name":"Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Ryd\u00e9n","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"},{"name":"Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sara","family":"Shams","sequence":"additional","affiliation":[{"name":"Department of Radiology, Stanford University Hospital, USA"},{"name":"Department of Radiology, The Institution for Clinical Neuroscience, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silke","family":"Kern","sequence":"additional","affiliation":[{"name":"Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Neuropsychiatry, Sahlgrenska University Hospital, Region V\u00e4stra G\u00f6taland, M\u00f6lndal. Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel","family":"Buckley","sequence":"additional","affiliation":[{"name":"Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA"},{"name":"Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women\u2019s Hospital, Boston, Massachusetts, USA"},{"name":"Melbourne School of Psychological Science, University of Melbourne, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Westman","sequence":"additional","affiliation":[{"name":"Division of Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden"},{"name":"Ageing Epidemiology Research Unit, School of Public Health, Imperial College London, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ingmar","family":"Skoog","sequence":"additional","affiliation":[{"name":"Neuropsychiatric Epidemiology Unit, Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy, Centre for Ageing and Health (AGECAP) at the University of Gothenburg, Gothenburg, Sweden"},{"name":"Department of Neuropsychiatry, Sahlgrenska University Hospital, Region V\u00e4stra G\u00f6taland, M\u00f6lndal. 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