Rethinking the residual approach: leveraging statistical learning to operationalize cognitive resilience in Alzheimer's disease.
Colin Birkenbihl, Madison Cuppels, Rory T Boyle, Hannah M Klinger, Oliver Langford, Gillian T Coughlan, Michael J Properzi, Jasmeer Chhatwal, Julie C Price, Aaron P Schultz, Dorene M Rentz, Rebecca E Amariglio, Keith A Johnson, Rebecca F Gottesman, Shubhabrata Mukherjee, Paul Maruff, Yen Ying Lim, Colin L Masters, Alexa Beiser, Susan M Resnick, Timothy M Hughes, Samantha Burnham, Ilke Tunali, Susan Landau, Ann D Cohen, Sterling C Johnson, Tobey J Betthauser, Sudha Seshadri, Samuel N Lockhart, Sid E O'Bryant, Prashanthi Vemuri, Reisa A Sperling, Timothy J Hohman, Michael C Donohue, Rachel F Buckley
Author Information
Colin Birkenbihl: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Madison Cuppels: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Rory T Boyle: Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA.
Hannah M Klinger: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Oliver Langford: Alzheimer Therapeutic Research Institute, University of Southern California, San Diego, USA.
Gillian T Coughlan: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Michael J Properzi: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Jasmeer Chhatwal: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Julie C Price: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Aaron P Schultz: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Dorene M Rentz: Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Rebecca E Amariglio: Department of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Keith A Johnson: Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Rebecca F Gottesman: National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Shubhabrata Mukherjee: Division of General Internal Medicine, Department of Medicine, University of Washington, Seattle, USA.
Paul Maruff: Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, Australia.
Yen Ying Lim: Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, Australia.
Colin L Masters: Florey Institute, University of Melbourne, Parkville, VIC, Australia.
Alexa Beiser: Department of Neurology, Chobanian and Avedisian School of Medicine, Boston University School of Medicine, Boston, MA, USA.
Susan M Resnick: Laboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
Timothy M Hughes: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Samantha Burnham: Eli Lilly and Company, Indianapolis, USA.
Ilke Tunali: Eli Lilly and Company, Indianapolis, USA.
Susan Landau: Neuroscience Department, University of California, Berkeley, Berkeley, CA, USA.
Ann D Cohen: Department of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA.
Sterling C Johnson: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Tobey J Betthauser: Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Sudha Seshadri: Department of Neurology, Chobanian and Avedisian School of Medicine, Boston University School of Medicine, Boston, MA, USA.
Samuel N Lockhart: Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Sid E O'Bryant: Institute for Translational Research, Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA.
Prashanthi Vemuri: Department of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
Reisa A Sperling: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Timothy J Hohman: Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Michael C Donohue: Alzheimer Therapeutic Research Institute, University of Southern California, San Diego, USA.
Rachel F Buckley: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. rfbuckley@mgh.harvard.edu.
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.
