{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:17:14Z","timestamp":1792606634147,"version":"4.5.0"},"reference-count":77,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Hum. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Cognitive reserve (CR) has been proposed as a key factor explaining inter-individual variability in cognitive performance despite comparable neuropathology. However, its role across the Alzheimer\u2019s disease (AD) continuum remains unclear. This study investigates stage-dependent effects of CR on the relationship between memory performance and brain structural network integrity across healthy subjects (HS), individuals with subjective cognitive decline (SCD), and patients with amnestic mild cognitive impairment (a-MCI), and AD dementia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>A total of 209 participants underwent a comprehensive neuropsychological assessment and 3T MRI. Source-based morphometry identified three grey matter structural covariance networks, involving orbitofrontal-temporal-insular regions (OTIN), precuneus-posterior cingulate cortex (PreCiN), and cingulate-hippocampal regions (CHiN). A composite memory score was derived using factor analysis. Regression and moderation models examined the predictive and moderating effects of CR (operationalized as years of education) and network integrity on cognitive performance within each group.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>OTIN and PreCiN showed progressive structural vulnerability along the AD continuum, whereas CHiN showed no significant between-group differences. Across the sample, OTIN and PreCiN integrity significantly predicted cognitive performance. In HS, CR was positively associated with memory performance independently of structural network integrity, suggesting an additive protective role of cognitive reserve in healthy aging. In the SCD group, CR was not directly associated with memory, and only limited effects emerged, indicating early alterations in reserve-related processes. In a-MCI patients, the significant interaction between CR and OTIN integrity suggested patterns consistent with compensatory mechanisms, with higher reserve supporting memory despite structural decline. In AD patients, CR and its interaction with structural networks no longer predicted cognitive outcomes, suggesting a possible exhaustion of reserve capacity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings support a stage-dependent model of CR, characterized by an additive protective role in healthy aging, patterns consistent with compensatory recruitment in early cognitive decline, and a possible loss of reserve effectiveness beyond a critical neuropathological threshold. Distinct network vulnerabilities and stage-specific CR effects highlight potential windows for reserve-enhancing interventions across the AD continuum.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnhum.2026.1830181","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T06:04:32Z","timestamp":1784095472000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Stage-dependent effects of cognitive reserve on memory and brain structural integrity across the spectrum from healthy aging to Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"20","author":[{"given":"Laura","family":"Serra","sequence":"first","affiliation":[{"name":"Department of Human Sciences, Universit\u00e0 degli Studi Guglielmo Marconi","place":["Rome, Italy"]},{"name":"Neuroimaging Laboratory, Fondazione Santa Lucia IRCCS","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Bonarota","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, Fondazione Santa Lucia IRCCS","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Caruso","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, Fondazione Santa Lucia IRCCS","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Mancini","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, Fondazione Santa Lucia IRCCS","place":["Rome, Italy"]},{"name":"Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia","family":"Sperati","sequence":"additional","affiliation":[{"name":"Neuroimaging Laboratory, Fondazione Santa Lucia IRCCS","place":["Rome, 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Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Bozzali","sequence":"additional","affiliation":[{"name":"Department of Neuroscience \u201cRita Levi Montalcini\u201d, University of Turin","place":["Turin, Italy"]},{"name":"SC Neurologia 2U, AOU Citt\u00e0 della Salute e della Scienza","place":["Turin, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Petrosini","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental and Behavioral Neurophysiology, Fondazione Santa Lucia","place":["Rome, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,15]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.jalz.2011.03.008","article-title":"The diagnosis of mild cognitive impairment due to Alzheimer\u2019s disease: recommendations from the National Institute on Aging\u2013Alzheimer\u2019s 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