Resilience in Alzheimer's disease: Impact of operationalization and methodological choices

Article Article scientifique Article Resilience in Alzheimer's disease: Impact of operationalization and methodological choices eng 2025-04-28 2025-04 author Mutel Sophie 0000-0003-2683-2465 Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 843705 author Quattrocchi Lara Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 886013 author Altomare Daniele Competence Centre on Ageing (CCA) Department of Business Economics Health and Social Care (DEASS) University of Applied Sciences and Arts of Southern Switzerland (SUPSI) Manno Switzerland 917820 author Chicherio Christian Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 85466 author Scheffler Max 0000-0003-2274-5129 Division of Radiology Geneva University Hospitals Thonex Switzerland 686304 Département de radiologie et informatique médicale (RADIO) author Lövblad Karl-Olof Neurodiagnostic and Neurointerventional Division Diagnostic Department Geneva University Hospitals Geneva Switzerland 135154 Département de radiologie et informatique médicale (RADIO) author Blennow Kaj Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Göteborg Sweden author Ashton Nicholas J. Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Göteborg Sweden author Zetterberg Henrik Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Göteborg Sweden author Abramowicz Marc Genetic Medicine Division University Hospitals and University of Geneva Geneva Switzerland 884432 Département de médecine génétique et développement (GEDEV) author Blouin Jean-Louis Genetic Medicine Division University Hospitals and University of Geneva Geneva Switzerland 513663 Département de médecine génétique et développement (GEDEV) author Wang Chen Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 894272 author Wyss Dominguez Carine Genetic Medicine Division University Hospitals and University of Geneva Geneva Switzerland 94933 author Martins Mendes Augusto José Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 405544 dept de réadaptation et gériatrie (MIGRG) author Garibotto Valentina 0000-0003-2422-698X Laboratory of Neuroimaging and Innovative Molecular Tracers (NIMTlab) Geneva University Neurocentre and Faculty of Medicine, University of Geneva Geneva Switzerland 704817 Département de radiologie et informatique médicale (RADIO) author Frisoni Giovanni Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 810190 dept de réadaptation et gériatrie (MIGRG) author Ribaldi Federica 0000-0001-9208-4472 Laboratory of Neuroimaging of Aging (LANVIE) University of Geneva Geneva Switzerland 920118 dept de réadaptation et gériatrie (MIGRG) e70185 10.1002/alz.70185 40289834 1552-5260 PMC12035551 https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.70185 INTRODUCTION : Resilience, the ability to maintain cognition or brain integrity despite Alzheimer's disease (AD) pathology, is often quantified using the residual approach. However, the variability in methodology and correction methods for this approach raises concerns about the interpretability of findings across studies. METHODS : We assessed brain resilience (BR) and cognitive resilience (CR) in a memory clinic population using the residual approach. We compared non‐corrected and corrected residuals’ associations with risk factors using linear regression models, and their impact on longitudinal cognition using linear mixed‐effects models. RESULTS : Corrected versus non‐corrected BR yielded distinct, often opposing, associations. For example, glial fibrillary acidic protein (GFAP) was negatively associated with non‐corrected BR (β = –0.33; p < 0.01) but positively with corrected BR (β = 0.5, p < 0.001). Only corrected CR measures yielded significant associations. Only corrected residuals predicted cognitive decline. DISCUSSION : The observed discrepancies raise questions about the reliability of the residual approach in accurately capturing resilience. HIGHLIGHTS : Corrected and non‐corrected residuals show distinct associations with risk factors. Corrected and non‐corrected residuals show different predictions of cognitive decline. These approaches may reflect general brain health rather than true resilience mechanisms. Alzheimer's disease resilience Brain resilience Cognitive decline Cognitive resilience Residual approach Residual correction methods Risk factors Dewey 616.8 Dewey 616.0757 Dewey 618.97 Dewey 576.5 Swiss National Science Foundation Biomarkers for risk profiling of persons with subjective cognitive decline (bioSCODE) 220269 CH Projects European Commission Common mechanisms and pathways in Stroke and Alzheimer's disease. 667375 CoSTREAM EU H2020 Swiss National Science Foundation Individual cognitive risk profiling in aging according to Amyloid, Tau and Neurodegeneration imaging biomarkers 185028 CH Projects Swiss National Science Foundation Brain connectivity and metacognition in persons with subjective cognitive decline (COSCODE): correlation with clinical features and in vivo neuropathology 182772 CH Projects Swiss National Science Foundation The Biological Basis of Cognitive Impairment due to Suspected Non-Alzheimer’s Pathology (SNAP) : Studying the interplay between amyloidosis and tau-related neurodegeneration 169876 CH Projects European Commission Fluid Biomarkers for Neurodegenerative Dementias 101053962 FLUBIODEM EU HE European Commission Multi-omics Interdisciplinary Research Integration to Address DEmentia diagnosis 860197 MIRIADE EU H2020 62 Département de radiologie et informatique médicale 227 16 Centre interfacultaire de neurosciences 0D9 65 Département de réadaptation et gériatrie 22B 14 Centre interfacultaire de gérontologie et d'études des vulnérabilités 0D6 135 Département de médecine génétique et développement 21D false 470 Ischémie cérébrale et connectivité 801 926 Imagerie per-opératoire multi-modalité en radiologie interventionnelle 949 1222 Laboratoire de neuroimagerie et de traceurs moléculaires innovants 984 853 Troubles de mémoire et maladie d'Alzeimer 935 259 BLOUIN JEAN-LOUIS 505 1297 Abramowicz Lab 1013 Alzheimer's & dementia 21 4 ceee7522-32fc-4c1f-9e81-044a6f62194c Article (Published version) Public Alzheimer_s_Dementia_-_2025_-_Mutel.pdf 921391 application/pdf CC BY-4.0 96e1f5ca21120ee6ddf3e9005457396cde8a50b01277be3e77bcd09b2b964d87 3c5bf356-28b5-48fc-9b45-8c2ae66518ab Supplemental data Public alz70185-sup-0001-icmje.pdf 3532406 application/pdf e7faad540137182bbb47e99ae98774b9ba54d27e2207a2274d043e2ed87bd4c7 3e7671a4-bb98-47dc-9e0e-67cd061225f1 Supplemental data Public alz70185-sup-0002-tables.docx 33519 application/vnd.openxmlformats-officedocument.wordprocessingml.document 73475fe6e7531872b824912a11176fac7d3d46ea78d8e852e141c15c90ec3640 openAccess Faculté de médecine / Section de médecine clinique / Département de radiologie et informatique médicale Centres et instituts / Centre interfacultaire de neurosciences Faculté de médecine / Section de médecine clinique / Département de réadaptation et gériatrie Centres et instituts / Centre interfacultaire de gérontologie et d'études des vulnérabilités Faculté de médecine / Section de médecine fondamentale / Département de médecine génétique et développement

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Wyss Dominguez, Carine