Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer's Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reaching moderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

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Journal
Nature Communications
Published
2025-11-21
DOI
https://doi.org/10.1038/s41467-025-66354-y
Citations
1
Primary Topic
Dementia and Cognitive Impairment Research
Type
article
Field-Weighted Citation Impact
1.47

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article

Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change

Didac Vidal‐Piñeiro, Katherine J. Bangen, Marie Strømstad, James M. Roe et al.
1 citations
Nature Communications
Dementia and Cognitive Impairment Research
1.47
article

Vulnerability to memory decline in aging revealed by a mega-analysis of structural brain change

Didac Vidal‐Piñeiro, Katherine J. Bangen, Marie Strømstad, James M. Roe, Thomas Wolfers, Sally P. Mendoza, G. Levine, Tyler Bell, Christine Fennema‐Notestine, Divya S. Bolar, Corwin Boake, Thomas Liu, Jeremy A. Elman, Wesley K. Thompson, Larry J. Seidman, Robert A. Rissman, Lisa T. Eyler, Andreas M. Brandmaier, William S. Kremen, Claire Murphy, Bruce Fischl, Anders M. Fjell, Xin Tu, Alice Cronin‐Golomb, Mark W. Logue, Richard N. Henson, Seth A. Eisen, Amy J. Jak, Linda K. McEvoy, Chandra A. Reynolds, Ming T. Tsuang, Inge K. Amlien, Nathan A. Gillespie, Eric Granholm, Øystein Sørensen, Brinda K. Rana, Randy L. Buckner, Kristen C. Jacobson, Diane M. Jacobs, Richard L. Hauger, David Bartrés‐Faz, Athanasia M. Mowinckel, Paolo Ghisletta, Ruth McKenzie, Álvaro Pascual‐Leone, Terry L. Jernigan, Rosemary Toomey, Kristine B. Walhovd, Michael J. Lyons, Leiv Otto Watne, William F.C. Baaré, Cristina Solé‐Padullés, Donald J. Hagler, Hong Xian, Lars Nyberg, Simone Kühn, Carol E. Franz, Sonia Lupien, Rongxiang Tang, Matthew S. Panizzon, Nicholas J. Schork, Warner Schaie, Stephen M Dorros, Dirk H. Hellhammer, Ulman Lindenberger, Gabriele Cattaneo, Anders M. Dale, Javier Solana Sánchez, Nicholas L. Smith, Michael C. Neale, Lindon J. Eaves, Daniel E. Gustavson, Sandra Düzel, Art Wingfield
article en
1 citations

Abstract

Brain atrophy is a key factor behind episodic memory loss in aging, but the nature and ubiquity of this relationship remains poorly understood. This study leverages 13 longitudinal datasets, including 3737 cognitively healthy adults (10,343 MRI scans; 13,460 memory assessments), to determine whether brain change-memory change associations are more pronounced with age and genetic risk for Alzheimer's Disease. Both factors are associated with accelerated brain decline, yet it remains unclear whether memory loss is exacerbated beyond what atrophy alone would predict. Additionally, we assess whether memory decline aligns with a global pattern of atrophy or stems from distinct regional contributions. Our mega-analysis reveals a nonlinear relationship between memory decline and brain atrophy, primarily affecting individuals with above-average brain structural decline. The associations are stronger in the hippocampus but also spread across diverse cortical and subcortical regions. The associations strengthen with age, reaching moderate associations in participants in their eighties. While APOE ε4 carriers exhibit steeper brain and memory loss, genetic risk has no effect on the change-change associations. These findings support the presence of common biological macrostructural substrates underlying memory function in older age which are vulnerable to multiple age-related factors, even in the absence of overt pathological changes.

Nature CommunicationsVol. 16(1)
University of California, Riverside (US), University of Geneva (CH), Oslo University Hospital (NO), Translational Genomics Research Institute (US), Harvard University (US), Universität Hamburg (DE), Baylor College of Medicine (US), Virginia Commonwealth University (US), University of Oslo (NO), University of Colorado Boulder (US), MRC Cognition and Brain Sciences Unit (GB), University of Washington (US), University of Cambridge (GB), San Diego State University (US), Akershus University Hospital (NO), Amager Hospital (DK), Massachusetts Mental Health Center (US), Harvard University Press (US), Hvidovre Hospital (DK), Copenhagen University Hospital (DK), University of California San Diego (US), University of Illinois Chicago (US), University of Chicago (US), Merrimack College (US), Massachusetts General Hospital (US), MSB Medical School Berlin (DE), Seattle Epidemiologic Information and Research Center (US), St. Louis VA Medical Center (US), University Medical Center Hamburg-Eppendorf (DE), Prostate Cancer Research (GB), Institut Guttmann (ES), Max Planck Institute for Human Development (DE), Hebrew SeniorLife (US), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), VA St. Louis Health Care System (US), Department of Veterans Affairs (AU), Laureate Institute for Brain Research (US), Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES), University College London (GB), Saint Louis University (US), Brandeis University (US), Université de Montréal (CA), Universitat de Barcelona (ES), University of Tübingen (DE), University of California, Davis (US), Universität Trier (DE), Massachusetts Department of Mental Health (US), Umeå University (SE), Texas A&M University (US), Stanford University (US)
Alzheimer's Association, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, Biogen, University of Southern California, BrightFocus Foundation, Meso Scale Diagnostics, Alzheimer's Disease Neuroimaging Initiative, BioClinica, Novartis Pharmaceuticals Corporation, Northern California Institute for Research and Education, Ministerio de Ciencia, Innovación y Universidades, Centres de Recerca de Catalunya, Commonwealth Scientific and Industrial Research Organisation, Bundesministerium für Bildung und Forschung, Generalitat de Catalunya, Institució Catalana de Recerca i Estudis Avançats, Eisai, Ministerio de Ciencia e Innovación, Universitetet i Oslo, Norges Forskningsråd, Universitat de Barcelona, Servier, Nasjonalforeningen for Folkehelsen, H. Lundbeck A/S, IXICO, Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona, National Institutes of Health, Genentech, Canadian Institutes of Health Research, Medical Research Council, European Regional Development Fund, Livsvitenskap, Universitetet i Oslo, National Institute on Aging
Openalex Percentile: Top 13%
Dementia and Cognitive Impairment Research
1.47
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