{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T20:58:54Z","timestamp":1775941134325,"version":"3.50.1"},"reference-count":95,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,18]],"date-time":"2025-11-18T00:00:00Z","timestamp":1763424000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Chronological age is an imprecise proxy for cognitive aging. The Cognitive Age Delta (CAD)\u2014the difference between predicted cognitive age and chronological age\u2014offers a scalable, individualized marker of functional brain aging. We examined determinants of CAD in cognitively unimpaired (CU) adults stratified by Alzheimer\u2019s disease (AD) and vascular biomarkers. Methods: We analyzed 177 CU participants from the Gipuzkoa Alzheimer Project (Basque Country, Northern Spain) classified as amyloid-negative\/vascular-negative (CUA\u2212V\u2212, n = 140), amyloid-positive (CUA+, n = 23), or vascular-positive (CUV+, n = 14) using CSF and MRI criteria; vascular burden was defined as Fazekas \u2265 2 on T2-FLAIR or \u22654 microbleeds on SWI, excluding non-traumatic superficial siderosis and established ischemic lesions. MRI was used solely for vascular classification. Associations with demographic, genetic, lifestyle, and reserve measures were tested with General Linear Models. Results: CAD did not differ across biomarker groups (Kruskal\u2013Wallis H(2) = 0.17, p = 0.91). Median (IQR) CAD values were 0.28 (\u22124.13, 4.69) for CUA\u2212V\u2212, \u22120.14 (\u22123.15, 2.87) for CUA+, and 0.77 (\u22122.22, 3.76) for CUV+, indicating comparable distributions. Higher vocabulary scores (proxy of cognitive reserve) related to a younger cognitive age in CUA\u2212V\u2212 (\u03b2 = \u22121.39, p &lt; 0.001) and CUA+ (\u03b2 = \u22122.08, p = 0.054). In CUA+, greater sedentary time\u2014particularly computer-based sitting\u2014was also associated with lower CAD (daily sitting \u03b2 = \u22122.13, p = 0.009; workday computer sitting \u03b2 = \u22122.32, p = 0.015). CAD showed no associations with CSF A\u03b242, p-tau or t-tau, APOE \u03b54 load, or vascular risk factors (all p &gt; 0.05). Conclusions: CAD captures interindividual resilience-related variability beyond classical AD biomarkers. Vocabulary, a marker of lifelong enrichment, emerged as a robust determinant of a younger cognitive age, while amyloid and vascular pathology exerted limited influence at preclinical stages. These findings support CAD as a sensitive, scalable endpoint for identifying protective factors and guiding personalized prevention in early Aging.<\/jats:p>","DOI":"10.3390\/jcm14228176","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T12:55:31Z","timestamp":1763556931000},"page":"8176","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Cognitive Age Delta as a Marker of Healthy and Pathological Cognitive Aging: The Role of Lifestyle, Cognitive Reserve, and Vascular Risk"],"prefix":"10.3390","volume":"14","author":[{"given":"Ainara","family":"Estanga","sequence":"first","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1832-5183","authenticated-orcid":false,"given":"I\u00f1igo","family":"Tellaetxe-Elorriaga","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Laboratory, Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"},{"name":"Biomedical Research Doctorate Program, Universidad Del Pa\u00eds Vasco (EHU), 48940 Leioa, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7170-6180","authenticated-orcid":false,"given":"Mirian","family":"Ecay-Torres","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Garc\u00eda Condado","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Laboratory, Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"},{"name":"Biomedical Research Doctorate Program, Universidad Del Pa\u00eds Vasco (EHU), 48940 Leioa, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3480-6056","authenticated-orcid":false,"given":"Maite","family":"Garc\u00eda-Sebasti\u00e1n","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Arriba","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6662-8676","authenticated-orcid":false,"given":"Naia","family":"Ros","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"},{"name":"Department of Clinical and Health Psychology and Research Methods, University of the Basque Country UPV\/EHU, 20018 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ane","family":"Iriondo","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5427-8214","authenticated-orcid":false,"given":"Imanol","family":"Reparaz-Escudero","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"},{"name":"Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad P\u00fablica de Navarra (UPNA), IdiSNA, 31008 Pamplona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9402-2184","authenticated-orcid":false,"given":"Asier","family":"Erramuzpe","sequence":"additional","affiliation":[{"name":"Computational Neuroimaging Laboratory, Biobizkaia Health Research Institute, 48903 Barakaldo, Spain"},{"name":"Ikerbasque, the Basque Foundation for Science, 48009 Bilbao, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-9967","authenticated-orcid":false,"given":"Pablo","family":"Mart\u00ednez-Lage","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9709-5314","authenticated-orcid":false,"given":"Miren","family":"Altuna","sequence":"additional","affiliation":[{"name":"Center for Research and Memory Clinic, CITA-Alzheimer Foundation, 20009 Donostia-San Sebasti\u00e1n, Spain"},{"name":"Department of Neurology, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, 01009 Vitoria-Gasteiz, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/S0140-6736(24)01296-0","article-title":"Dementia Prevention, Intervention, and Care: 2024 Report of the Lancet Standing Commission","volume":"404","author":"Livingston","year":"2024","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Safiri, S., Ghaffari Jolfayi, A., Fazlollahi, 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