Rethinking the residual approach: leveraging statistical learning to operationalize cognitive resilience in Alzheimer’s disease
Cognitive resilience (CR) describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. This is especially true when information about CR is contained in the data the linear model was fitted to, either through inclusion of CR-associated variables or due to correlation. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and CR and achieves better estimation accuracy on simulated ground-truth data.
Authors
- Susan M. Resnick (ORCID: https://orcid.org/0000-0003-1115-7145)
- Oliver Langford (ORCID: https://orcid.org/0009-0006-8951-1326)
- Aaron P. Schultz (ORCID: https://orcid.org/0000-0002-0418-0999)
- Timothy J. Hohman (ORCID: https://orcid.org/0000-0002-3377-7014)
- Sudha S. Seshadri (ORCID: https://orcid.org/0000-0001-6135-2622)
- Tobey J. Betthauser (ORCID: https://orcid.org/0000-0001-8856-1352)
- Keith A. Johnson (ORCID: https://orcid.org/0000-0002-4685-5173)
- Ann D. Cohen (ORCID: https://orcid.org/0000-0001-7395-9624)
- Michael Donohue (ORCID: https://orcid.org/0000-0001-6026-2238)
- Rachel F. Buckley (ORCID: https://orcid.org/0000-0002-5356-5537)
- Yen Ying Lim (ORCID: https://orcid.org/0000-0002-0308-5156)
- Rebecca F. Gottesman (ORCID: https://orcid.org/0000-0002-9504-1256)
- Prashanthi Vemuri (ORCID: https://orcid.org/0000-0003-4286-0589)
- Colin L. Masters (ORCID: https://orcid.org/0000-0003-3072-7940)
- Sid E. O’Bryant (ORCID: https://orcid.org/0000-0003-0582-5266)
- Alexa S. Beiser (ORCID: https://orcid.org/0000-0001-8551-7778)
- Timothy M. Hughes (ORCID: https://orcid.org/0000-0002-2919-7199)
- Paul Maruff (ORCID: https://orcid.org/0000-0002-6947-9537)
- Gillian Coughlan (ORCID: https://orcid.org/0000-0003-1806-702X)
- Samuel N. Lockhart (ORCID: https://orcid.org/0000-0002-0893-5420)
- Dorene M. Rentz
- Colin Birkenbihl (ORCID: https://orcid.org/0000-0002-7212-7700)
- Julie C. Price
- Ilke Tunali
- Samantha C. Burnham (ORCID: https://orcid.org/0000-0003-4805-5193)
- Rory Boyle (ORCID: https://orcid.org/0000-0003-0787-6892)
- Shubhabrata Mukherjee (ORCID: https://orcid.org/0000-0002-9093-539X)
- Rebecca England Amariglio (ORCID: https://orcid.org/0009-0009-5878-8930)
- Michael J Properzi (ORCID: https://orcid.org/0000-0001-7855-2372)
- Susan Landau (ORCID: https://orcid.org/0000-0003-4826-6134)
- Jasmeer P. Chhatwal (ORCID: https://orcid.org/0000-0002-7792-1698)
- Hannah M Klinger
- Madison Cuppels
- Sterling C. Johnson
- Reisa A. Sperling
Institutions
- Boston University (US)
- University of Southern California (US)
- University of North Texas (US)
- Brigham and Women's Hospital (US)
- University of Wisconsin–Madison (US)
- Harvard University (US)
- University of North Texas Health Science Center (US)
- The University of Melbourne (AU)
- The University of Texas at San Antonio Health Science Center (US)
- Eli Lilly (United States) (US)
- University of Pittsburgh (US)
- Vanderbilt University (US)
- University of Washington (US)
- Florey Institute of Neuroscience and Mental Health (AU)
- Massachusetts General Hospital (US)
- National Institute of Neurological Disorders and Stroke (US)
- Mayo Clinic in Arizona (US)
- Athinoula A. Martinos Center for Biomedical Imaging (US)
- National Institute on Aging (US)
- Wake Forest University (US)
- Monash University (AU)
- Seattle University (US)
- University of Pennsylvania (US)
- Vanderbilt University Medical Center (US)
- University of California, Berkeley (US)
Publication Details
- Journal
- Brain Informatics
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1186/s40708-024-00249-4
- Citations
- 3
- Primary Topic
- Dementia and Cognitive Impairment Research
- Type
- article
- Field-Weighted Citation Impact
- 4.41
Funders
- Alzheimer's Association
- National Institutes of Health