{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T23:29:30Z","timestamp":1784762970305,"version":"3.55.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T00:00:00Z","timestamp":1763942400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006473","name":"Ministerio de Ciencia, Innovaci\u00f3n, Tecnolog\u00eda y Telecomunicaciones","doi-asserted-by":"publisher","award":["PID2021-123087OB-I00"],"award-info":[{"award-number":["PID2021-123087OB-I00"]}],"id":[{"id":"10.13039\/501100006473","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003086","name":"Eusko Jaurlaritza","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003086","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100019124","name":"Diputaci\u00f3n Foral de Gipuzkoa","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100019124","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"publisher","award":["n115736"],"award-info":[{"award-number":["n115736"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The aging global population underscores the need to understand brain aging and its links to neurodegenerative diseases. While most brain aging studies use cognitive impairment as exclusion criteria, preclinical biomarkers may influence results, potentially masking early pathological effects. This study evaluates how preclinical AD and vascular biomarkers impact brain aging models in cognitively normal subjects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Using baseline data from the European Prevention of Alzheimer's Dementia Longitudinal Cohort Study (EPAD LCS), we analyzed 1,380 cognitively unimpaired participants (50+ years) stratified into five groups based on cerebrospinal fluid biomarkers (A\u03b242, t-tau, p-tau) and vascular pathology (Fazekas scale, microbleeds). Structural MRI volumes of cortical\/subcortical regions were normalized and compared using Nadaraya-Watson kernel regression. Bootstrapping and Bonferroni-corrected statistical tests assessed differences in the relationship between age and brain volume between groups.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Significant differences emerged in the relationship between age and brain volume in biomarker-negative and biomarker-positive groups, particularly in the entorhinal cortex, amygdalas, and basal forebrain (\n                      <jats:italic>p<\/jats:italic>\n                      &amp;lt; 0.01). The AD and mixed AD\/vascular groups showed the largest deviations. Gender-specific analyses revealed stronger effects in males. Vascular pathology alone affected distinct regions (e.g., left entorhinal cortex) without amygdala involvement, suggesting disease-specific atrophy patterns.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Preclinical AD and vascular biomarkers significantly alter brain aging in cognitively normal individuals. These findings highlight the importance of biomarker stratification in brain age studies to avoid biased estimates. Entorhinal cortex and amygdala volumes may serve as sensitive early indicators of neurodegeneration, supporting their use in targeted interventions and personalized monitoring.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnagi.2025.1653074","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T06:29:55Z","timestamp":1763965795000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Preclinical Alzheimer's and vascular biomarkers alter brain aging in cognitively normal adults: a MRI-based study"],"prefix":"10.3389","volume":"17","author":[{"given":"Unai","family":"Torres","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bernal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ibai","family":"Gurrutxaga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ainara","family":"Estanga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Mart\u00ednez-Lage","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olatz","family":"Arbelaitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e230009","DOI":"10.1148\/rg.230009","article-title":"Amyloid-related imaging abnormalities in Alzheimer disease treated with anti\u2013amyloid- therapy","volume":"43","author":"Agarwal","year":"2023","journal-title":"Radiographics"},{"key":"B2","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1016\/S1474-4422(16)30029-1","article-title":"Relation of cerebral vessel disease to Alzheimer's disease dementia and cognitive function in elderly people: a cross-sectional study","volume":"15","author":"Arvanitakis","year":"2016","journal-title":"Lancet Neurol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1186\/s13195-024-01606-5","article-title":"Longitudinal evidence for a mutually reinforcing relationship between white matter hyperintensities and cortical thickness in cognitively unimpaired older adults","volume":"16","author":"Bernal","year":"2024","journal-title":"Alzheimer's Res. Ther"},{"key":"B4","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological stageing of Alzheimer-related changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathologica"},{"key":"B5","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/0197-4580(95)00021-6","article-title":"Staging of Alzheimer's disease-related neurofibrillary changes","volume":"16","author":"Braak","year":"1995","journal-title":"Neurobiol. Aging"},{"key":"B6","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1212\/WNL.0b013e318246d67a","article-title":"Accelerated cortical atrophy in cognitively normal elderly with high -amyloid deposition","volume":"78","author":"Ch\u00e9telat","year":"2012","journal-title":"Neurology"},{"key":"B7","doi-asserted-by":"publisher","first-page":"e276","DOI":"10.1016\/S2666-7568(24)00025-4","article-title":"The mediating role of neuroimaging-derived biological brain age in the association between risk factors for dementia and cognitive decline in middle-aged and older individuals without cognitive impairment: a cohort study","volume":"5","author":"Cumplido-Mayoral","year":"2024","journal-title":"Lancet Healthy Longevity"},{"key":"B8","doi-asserted-by":"publisher","first-page":"e81067","DOI":"10.7554\/eLife.81067","article-title":"Biological brain age prediction using machine learning on structural neuroimaging data: multi-cohort validation against biomarkers of Alzheimer's disease and neurodegeneration stratified by sex","volume":"12","author":"Cumplido-Mayoral","year":"","journal-title":"Elife"},{"key":"B9","doi-asserted-by":"publisher","first-page":"e078194","DOI":"10.1002\/alz.078194","article-title":"Brain-age prediction and its associations with glial and synaptic csf markers","volume":"19","author":"Cumplido-Mayoral","year":"","journal-title":"Alzheimer's Dement"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1303036","DOI":"10.3389\/fnagi.2023.1303036","article-title":"A deep learning model for brain age prediction using minimally preprocessed T1w images as input","volume":"15","author":"Dartora","year":"2024","journal-title":"Front. Aging Neurosci"},{"key":"B11","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1001\/jamaneurol.2018.3122","article-title":"Clinical significance of magnetic resonance imaging markers of vascular brain injury: a systematic review and meta-analysis","volume":"76","author":"Debette","year":"2019","journal-title":"JAMA Neurol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1001\/jamaneurol.2013.1062","article-title":"Cross-sectional and longitudinal analysis of the relationship between a deposition, cortical thickness, and memory in cognitively unimpaired individuals and in Alzheimer disease","volume":"70","author":"Dor\u00e9","year":"2013","journal-title":"JAMA Neurol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"6139","DOI":"10.1002\/hbm.26502","article-title":"Prediction of brain age using structural magnetic resonance imaging: a comparison of accuracy and test\u2013retest reliability of publicly available software packages","volume":"44","author":"D\u00f6rfel","year":"2023","journal-title":"Hum. Brain Mapp"},{"key":"B14","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.neurobiolaging.2005.03.021","article-title":"Age effects on atrophy rates of entorhinal cortex and hippocampus","volume":"27","author":"Du","year":"2006","journal-title":"Neurobiol. Aging"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1001\/jamaneurol.2024.3770","article-title":"Alzheimer disease as a clinical-biological construct\u2013an international working group recommendation","volume":"81","author":"Dubois","year":"2024","journal-title":"JAMA Neurol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1016\/S1474-4422(23)00131-X","article-title":"Neuroimaging standards for research into small vessel disease-advances since 2013","volume":"22","author":"Duering","year":"2023","journal-title":"Lancet Neurol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"120469","DOI":"10.1016\/j.neuroimage.2023.120469","article-title":"Base: brain age standardized evaluation","volume":"285","author":"Dular","year":"2024","journal-title":"Neuroimage"},{"key":"B18","doi-asserted-by":"publisher","first-page":"101075","DOI":"10.1016\/j.arr.2020.101075","article-title":"MRI-based biomarkers of accelerated aging and dementia risk in midlife: how close are we?","volume":"61","author":"Elliott","year":"2020","journal-title":"Ageing Res. Rev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e0234255","DOI":"10.1371\/journal.pone.0234255","article-title":"Brain regions vulnerable and resistant to aging without Alzheimer's disease","volume":"15","author":"Feng","year":"2020","journal-title":"PLoS ONE"},{"key":"B20","doi-asserted-by":"publisher","first-page":"4491","DOI":"10.1523\/JNEUROSCI.16-14-04491.1996","article-title":"Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer disease","volume":"16","author":"G\u00f3mez-Isla","year":"1996","journal-title":"J. Neurosci"},{"key":"B21","doi-asserted-by":"publisher","first-page":"2411","DOI":"10.1093\/cercor\/bhv062","article-title":"Cognitive correlates of basal forebrain atrophy and associated cortical hypometabolism in mild cognitive impairment","volume":"26","author":"Grothe","year":"2015","journal-title":"Cereb. Cortex"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s11357-023-00924-0","article-title":"Brain age prediction across the human lifespan using multimodal mri data","volume":"46","author":"Guan","year":"2024","journal-title":"GeroScience"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1164","DOI":"10.1093\/brain\/aww008","article-title":"White matter hyperintensities and imaging patterns of brain ageing in the general population","volume":"139","author":"Habes","year":"2016","journal-title":"Brain"},{"key":"B24","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1111\/jon.12297","article-title":"Entorhinal cortex thickness across the human lifespan","volume":"26","author":"Hasan","year":"2015","journal-title":"J. Neuroimag"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e0289619","DOI":"10.1371\/journal.pone.0289619","article-title":"Determining the statistical significance of the difference between arbitrary curves: a spreadsheet method","volume":"18","author":"Hristova","year":"2023","journal-title":"PLoS ONE"},{"key":"B26","doi-asserted-by":"publisher","first-page":"fcac117","DOI":"10.1093\/braincomms\/fcac117","article-title":"Disentangling Alzheimer's disease neurodegeneration from typical brain ageing using machine learning","volume":"4","author":"Hwang","year":"2022","journal-title":"Brain Commun"},{"key":"B27","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.tins.2022.11.006","article-title":"Entorhinal cortex dysfunction in Alzheimer's disease","volume":"46","author":"Igarashi","year":"2023","journal-title":"Trends Neurosci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5143","DOI":"10.1002\/alz.13859","article-title":"Revised criteria for diagnosis and staging of Alzheimer's disease: Alzheimer's association workgroup","volume":"20","author":"Jack","year":"2024","journal-title":"Alzheimer's Dement"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1517","DOI":"10.1093\/brain\/awy059","article-title":"Longitudinal tau PET in ageing and Alzheimer's disease","volume":"141","author":"Jack","year":"2018","journal-title":"Brain"},{"key":"B30","doi-asserted-by":"publisher","first-page":"3600","DOI":"10.1161\/STROKEAHA.119.028487","article-title":"Strictly lobar microbleeds reflect amyloid angiopathy regardless of cerebral and cerebellar compartments","volume":"51","author":"Jung","year":"2020","journal-title":"Stroke"},{"key":"B31","doi-asserted-by":"publisher","first-page":"1402573","DOI":"10.3389\/fnagi.2024.1402573","article-title":"Impairment of entorhinal cortex network activity in Alzheimer's disease","volume":"16","author":"Karimani","year":"2024","journal-title":"Front. Aging Neurosci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1038\/nn.3606","article-title":"Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease","volume":"17","author":"Khan","year":"2014","journal-title":"Nat. Neurosci"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1093\/brain\/awz025","article-title":"Entorhinal cortex tau, amyloid-, cortical thickness and memory performance in non-demented subjects","volume":"142","author":"Knopman","year":"2019","journal-title":"Brain"},{"key":"B34","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.neurobiolaging.2021.09.010","article-title":"Regional age-related atrophy after screening for preclinical Alzheimer disease","volume":"109","author":"Koenig","year":"2022","journal-title":"Neurobiol. Aging"},{"key":"B35","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1007\/s00401-020-02215-w","article-title":"Cerebral blood flow decrease as an early pathological mechanism in Alzheimer's disease","volume":"140","author":"Korte","year":"2020","journal-title":"Acta Neuropathol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"304","DOI":"10.1212\/WNL.0000000000000612","article-title":"Structural network efficiency is associated with cognitive impairment in small-vessel disease","volume":"83","author":"Lawrence","year":"2014","journal-title":"Neurology"},{"key":"B37","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1016\/j.neurobiolaging.2019.11.005","article-title":"Improving brain age prediction models: incorporation of amyloid status in Alzheimer's disease","volume":"87","author":"Ly","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"B38","doi-asserted-by":"publisher","first-page":"e14435","DOI":"10.1002\/alz.14435","article-title":"Biological brain age and resilience in cognitively unimpaired 70-year-old individuals","volume":"21","author":"Marseglia","year":"2025","journal-title":"Alzheimer's Dement"},{"key":"B39","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1137\/1109020","article-title":"On estimating regression","volume":"9","author":"Nadaraya","year":"1964","journal-title":"Theory Probab. Appl"},{"key":"B40","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1016\/j.neurobiolaging.2014.08.031","article-title":"Greater cortical thinning in normal older adults predicts later cognitive impairment","volume":"36","author":"Pacheco","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"B41","doi-asserted-by":"publisher","first-page":"e12436","DOI":"10.1002\/trc2.12436","article-title":"Atrophy of specific amygdala subfields in subjects converting to mild cognitive impairment","volume":"9","author":"Padulo","year":"2023","journal-title":"Alzheimer's Dement"},{"key":"B42","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.pscychresns.2011.06.014","article-title":"Amygdala atrophy is prominent in early Alzheimer's disease and relates to symptom severity","volume":"194","author":"Poulin","year":"2011","journal-title":"Psychiat. Res.: Neuroimag"},{"key":"B43","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s13195-024-01525-5","article-title":"Can white matter hyperintensities based fazekas visual assessment scales inform about Alzheimer's disease pathology in the population?","volume":"16","author":"Pradeep","year":"2024","journal-title":"Alzheimer's Res. Therapy"},{"key":"B44","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1038\/nrneurol.2015.10","article-title":"White matter hyperintensities, cognitive impairment and dementia: an update","volume":"11","author":"Prins","year":"2015","journal-title":"Nature Rev. Neurol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1016\/S2215-0366(15)00454-X","article-title":"Development of interventions for the secondary prevention of Alzheimer's dementia: the European Prevention of Alzheimer's Dementia (EPAD) project","volume":"3","author":"Ritchie","year":"2016","journal-title":"Lancet Psychiatry"},{"key":"B46","doi-asserted-by":"publisher","first-page":"7205","DOI":"10.1002\/alz.14235","article-title":"Amygdala atrophies in specific subnuclei in preclinical Alzheimer's disease","volume":"20","author":"Salman","year":"2024","journal-title":"Alzheimer's Dement"},{"key":"B47","doi-asserted-by":"publisher","first-page":"13249","DOI":"10.1038\/ncomms13249","article-title":"Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology","volume":"7","author":"Schmitz","year":"2016","journal-title":"Nat. Commun"},{"key":"B48","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.seizure.2024.11.015","article-title":"Mri in older patients-a focused review","volume":"128","author":"Seiler","year":"2025","journal-title":"Seizure: Eur. J. Epilepsy"},{"key":"B49","doi-asserted-by":"publisher","first-page":"e021017","DOI":"10.1136\/bmjopen-2017-021017","article-title":"European prevention of Alzheimer's dementia longitudinal cohort study (EPAD LCS): study protocol","volume":"8","author":"Solomon","year":"2018","journal-title":"BMJ Open"},{"key":"B50","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.pscychresns.2012.06.002","article-title":"Hippocampal and entorhinal cortex volume decline in cognitively intact elderly","volume":"211","author":"Thomann","year":"2013","journal-title":"Psychiat. Res.: Neuroimag"},{"key":"B51","article-title":"\u201cWorld population prospects 2024: summary of results,\u201d","year":"2024","journal-title":"Technical Report, United Nations"},{"key":"B52","doi-asserted-by":"publisher","first-page":"18003","DOI":"10.1038\/nrdp.2018.3","article-title":"Vascular cognitive impairment","volume":"4","author":"van der Flier","year":"2018","journal-title":"Nat. Rev. Dis. Primers"},{"key":"B53","doi-asserted-by":"publisher","first-page":"755","DOI":"10.3233\/JAD-2012-121408","article-title":"Entorhinal cortex thickness predicts cognitive decline in Alzheimer's disease","volume":"33","author":"Velayudhan","year":"2013","journal-title":"J. Alzheimer's Dis"},{"key":"B54","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/S1474-4422(13)70124-8","article-title":"Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration","volume":"12","author":"Wardlaw","year":"2013","journal-title":"Lancet Neurol"},{"key":"B55","first-page":"359","article-title":"Smooth regression analysis","volume":"26","author":"Watson","year":"1964","journal-title":"Sankhy"},{"key":"B56","doi-asserted-by":"publisher","first-page":"272","DOI":"10.1186\/s13195-024-01491-y","article-title":"Brain age as a biomarker for pathological versus healthy ageing \u2013 a remember study","volume":"16","author":"Wittens","year":"2024","journal-title":"Alzheimer's Res. Ther"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2024.1390574","article-title":"The relationship between hippocampal changes in healthy aging and Alzheimer's disease: a systematic literature review","author":"Woodward","year":"2024","journal-title":"Front. Aging Neurosci"},{"key":"B58","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1097\/WCO.0000000000000913","article-title":"Cerebral small vessel disease and vascular cognitive impairment: from diagnosis to management","volume":"34","author":"Zanon Zotin","year":"2021","journal-title":"Curr. Opin. Neurol"}],"container-title":["Frontiers in Aging Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1653074\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T06:29:56Z","timestamp":1763965796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnagi.2025.1653074\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,24]]},"references-count":58,"alternative-id":["10.3389\/fnagi.2025.1653074"],"URL":"https:\/\/doi.org\/10.3389\/fnagi.2025.1653074","relation":{},"ISSN":["1663-4365"],"issn-type":[{"value":"1663-4365","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,24]]},"article-number":"1653074"}}