Evidence map›Paper›PMID 39871006›Full record

ArticleBrain informatics2025

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 and 25 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain informatics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Sex specificity of resistance to caTAUstrophe.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Article
  2. Review
  3. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

35 authors.

Colin BirkenbihlDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Madison CuppelsDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Rory T BoylePenn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Pennsylvania, USA.
Hannah M KlingerDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Oliver LangfordAlzheimer Therapeutic Research Institute, University of Southern California, San Diego, USA.
Gillian T CoughlanDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Michael J ProperziDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Jasmeer ChhatwalDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Julie C PriceDepartment of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Aaron P SchultzDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Dorene M RentzDepartment of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Rebecca E AmariglioDepartment of Neurology, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
Keith A JohnsonDepartment of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Rebecca F GottesmanNational Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.
Shubhabrata MukherjeeDivision of General Internal Medicine, Department of Medicine, University of Washington, Seattle, USA.
Paul MaruffTurner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, Australia.
Yen Ying LimTurner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC, Australia.
Colin L MastersFlorey Institute, University of Melbourne, Parkville, VIC, Australia.
Alexa BeiserDepartment of Neurology, Chobanian and Avedisian School of Medicine, Boston University School of Medicine, Boston, MA, USA.
Susan M ResnickLaboratory of Behavioral Neuroscience, National Institute on Aging, Baltimore, MD, USA.
Timothy M HughesDepartment of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Samantha BurnhamEli Lilly and Company, Indianapolis, USA.
Ilke TunaliEli Lilly and Company, Indianapolis, USA.
Susan LandauNeuroscience Department, University of California, Berkeley, Berkeley, CA, USA.
Ann D CohenDepartment of Psychiatry, School of Medicine, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA, 15213, USA.
Sterling C JohnsonDepartment of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Tobey J BetthauserDepartment of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Sudha SeshadriDepartment of Neurology, Chobanian and Avedisian School of Medicine, Boston University School of Medicine, Boston, MA, USA.
Samuel N LockhartDepartment of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
Sid E O'BryantInstitute for Translational Research, Department of Family Medicine, University of North Texas Health Science Center, Fort Worth, TX, USA.
Prashanthi VemuriDepartment of Radiology, Mayo Clinic, Rochester, MN, 55905, USA.
Reisa A SperlingDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
Timothy J HohmanVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Michael C DonohueAlzheimer Therapeutic Research Institute, University of Southern California, San Diego, USA.
Rachel F BuckleyDepartment of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA. rfbuckley@mgh.harvard.edu.

Funding

Research Education ComponentP30AG066507 · NIA · JOHNS HOPKINS UNIVERSITY · PI JUAN TRONCOSO · 2020 to 2026
$29.3M
Building predictive algorithms to identify resilience and resistance to Alzheimer's diseaseR01AG079142 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI Rachel Frances Buckley, Michael C Donohue · 2023 to 2026
$4.0M
Menopause, hormone therapy and Alzheimer's disease clinicopathology: An in vivo perspectiveK99AG083063 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI COUGHLAN, GILLIAN THERESA · 2024 to 2025
$269k
Alzheimer's Association AARF-23-1151259NIA NIH HHS K99 AG083063NIA NIH HHS P30 AG066507NIH HHS K99AG083063NIH HHS R01AG079142
6 · The paper itself

Abstract

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.

Indexed as

Alzheimer’s diseaseArtificial intelligenceCognitive declineCognitive reserveCognitive resilienceDementiaMachine learningPathology resistance

Identifiers

PMID39871006
PMCPMC11772644

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.