Evidence map›Paper›PMID 41950468›Full record

ArticleNeurology2026

Effect of Cognitive Reserve on Age at Symptom Onset and Cognitive Decline in Individuals With Dominantly Inherited Alzheimer Disease.

Jorge J Llibre-Guerra, Ruijin Lu, Ma Florencia Clarens, Ian Liu, Alan Renton, Natalie S Ryan, Alison M Goate, David Aguillón, Ricardo Francisco Allegri, Tammie L S Benzinger and 30 more

Abstract read
In one paragraph

Article in Neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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0citing papers in PubMed
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1 · What the graph read from it

What it found

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2 · The registry

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3 · Its place in the literature

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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

40 authors.

Jorge J Llibre-GuerraDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-2137-7750
Ruijin LuInstitute for Informatics, Data Science and Biostatistics, Washington University School of Medicine, St. Louis, MO.
Ma Florencia ClarensDepartment of Cognitive Neurology, Instituto Neurológico Fleni, Buenos Aires, Argentina.
Ian LiuDepartment of Biostatistics, Brown University School of Public Health, Providence, RI.
Alan RentonRonald M. Loeb Center for Alzheimer's Disease, Dept of Genetics and Genomic Sciences, Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York.
Natalie S RyanDepartment of Neurodegenerative Disease and UK Dementia Research Institute at Queen Square Institute of Neurology, University College London, United Kingdom.
Alison M GoateRonald M. Loeb Center for Alzheimer's Disease, Dept of Genetics and Genomic Sciences, Nash Family Dept of Neuroscience, Icahn School of Medicine at Mount Sinai, New York.ORCID 0000-0002-0576-2472
David AguillónGroup of Neuroscience of Antioquia, GNA, Medical School, University of Antioquia, Medellin, Colombia.ORCID 0000-0003-2283-536X
Ricardo Francisco AllegriDepartment of Cognitive Neurology, Instituto Neurológico Fleni, Buenos Aires, Argentina.
Tammie L S BenzingerDepartment of Radiology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-8114-0552
Sarah BermanDepartment of Neurology and Clinical and Translational Science, University of Pittsburgh, PA.ORCID 0000-0002-5096-4962
Jasmeer P ChhatwalMassachusetts General Hospital, Brigham and Women's Hospital, Harvard Medical School, Boston.ORCID 0000-0002-7792-1698
Patricio Chrem MendezDepartment of Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina.ORCID 0000-0002-6790-6566
Gabriela VigoDepartment of Neurology, Institute for Neurological Research Fleni, Buenos Aires, Argentina.ORCID 0009-0000-5980-9603
Carlos CruchagaDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-0276-2899
Gregory S DayDepartment of Neurology, Mayo Clinic in Florida, Jacksonville.ORCID 0000-0001-5133-5538
Martin R FarlowDepartment of Neurology, Indiana University School of Medicine, Indianapolis.
Nick C FoxDepartment of Neurodegenerative Disease and UK Dementia Research Institute at Queen Square Institute of Neurology, University College London, United Kingdom.ORCID 0000-0002-6660-657X
Brian Andrew GordonDepartment of Radiology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0003-2109-2955
Jason HassenstabDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-7802-3371
Edward D HueyDepartment of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Providence, RI.ORCID 0000-0002-8295-5884
Laura IbanezDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0003-2381-7059
Takeshi IkeuchiBrain Research Institute, Niigata University, Japan.ORCID 0000-0001-8828-8085
Mathias JuckerGerman Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.ORCID 0000-0001-9045-1072
Jae-Hong LeeAsian Medical Center, Seoul, South Korea.ORCID 0000-0001-7368-4560
Allan I LeveyGoizueta Alzheimer's Disease Research Center, Emory University, Atlanta, GA.ORCID 0000-0002-3153-502X
Johannes LevinDepartment of Neurology, LMU University Hospital, LMU Munich, Germany.ORCID 0000-0001-5092-4306
Yoshiki NiimiUnit for Early and Exploratory Clinical Development, University of Tokyo Hospital, Japan.ORCID 0000-0002-2556-8167
Richard J PerrinDepartment of Pathology and Immunology, School of Medicine, Washington University, St. Louis, MO.ORCID 0000-0002-3443-7716
Pedro Rosa-NetoMcGill University Research Centre for Studies in Aging, Department of Neurology and Neurosurgery, Psychiatry and Pharmacology and Therapeutics, McGill University, Montreal, Canada.ORCID 0000-0001-9116-1376
Raquel Sánchez-ValleAlzheimer's and Other Cognitive Disorders Unit, Hospital Clínic de Barcelona, FRCB-IDIBAPS, University of Barcelona, Spain.ORCID 0000-0001-7750-896X
Peter R SchofieldDiscipline of Psychiatry and Mental Health, University of New South Wales, Sydney, Australia; and.ORCID 0000-0003-2967-9662
Guoqiao WangDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.
Yan LiDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.
Chengjie XiongInstitute for Informatics, Data Science and Biostatistics, Washington University School of Medicine, St. Louis, MO.
John C MorrisDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0001-9820-5618
Celeste KarchDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-6854-5547
Alisha J DanielsDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.ORCID 0009-0001-1464-6465
Eric McDadeDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-6764-3866
Randall J BatemanDepartment of Neurology, Washington University School of Medicine, St. Louis, MO.ORCID 0000-0002-7729-1702

Funding

Smartphone-Based "Burst" Cognitive AssessmentsP01AG003991 · NIA · WASHINGTON UNIVERSITY · PI JOHN MORRIS · 1985 to 2026
$69.5M
The natural history of AB accumulation in preclinical ADP01AG026276 · NIA · WASHINGTON UNIVERSITY · PI MORRIS, JOHN · 2005 to 2025
$49.5M
Research Education ComponentP30AG066444 · NIA · WASHINGTON UNIVERSITY · PI Susan Lynn Stark · 2020 to 2026
$28.7M
Understanding Alzheimer disease heterogeneity in Hispanic populations.K01AG073526 · NIA · WASHINGTON UNIVERSITY · PI Jorge Jesus Llibre-Guerra · 2022 to 2026
$511k
NIA NIH HHS K01 AG073526NIA NIH HHS P01 AG003991NIA NIH HHS P01 AG026276NIA NIH HHS P30 AG066444
6 · The paper itself

Abstract

BACKGROUND AND

objectivesCognitive reserve has been shown to modulate the onset and progression of Alzheimer disease (AD) symptoms. Although its role in sporadic AD is well-studied, how cognitive reserve influences the timing and progression of symptoms in dominantly inherited AD (DIAD) remains unclear. This study aimed to quantify cognitive reserve in DIAD carriers and test whether higher cognitive reserve is associated with later symptom onset and slower functional decline.

methodsWe analyzed data from the Dominantly Inherited Alzheimer's Network study. Cognitive reserve was modeled using a residual-based latent variable approach, decomposing cognitive performance into demographic (CogD), biomarker (CogB), and reserve or residual (CogR) components. Primary outcomes were age at clinical symptom onset (CDR >0) and longitudinal change in the Clinical Dementia Rating-Sum of Boxes (CDR-SBs). Data were analyzed using Cox proportional hazards models and linear mixed-effects models, adjusting for estimated years from onset (EYO).

resultA total of 710 Dominantly Inherited Alzheimer Network (DIAN) participants were included in the analysis, comprising 271 non-DIAD carriers (nMC), 284 asymptomatic DIAD carriers (aMC), and 155 symptomatic DIAD carriers. In asymptomatic carriers, using a zero-inflation model adjusted for EYO showed that a 1 SD increase in the reserve component (CogR) was associated with a 4.06-fold increase in the odds of being clinically unimpaired (CDR-SB = 0; 95% CI 1.84-8.95). Similarly, a 1 SD increase in the demographic (CogD) and biomarker (CogB) components increased the odds of being CDR-SB = 0 by 2.60 (95% CI 1.10-6.16) and 5.16 (95% CI 2.00-13.33), respectively. Among symptomatic carriers, only the reserve and the biomarker components were significant. A 1 SD increase in CogR was associated with a 0.81-fold reduction in baseline CDR-SB score (95% CI 0.72-0.92), and a 1 SD increase in CogB was associated with a 0.60-fold reduction in CDR-SB (95% CI 0.50-0.71). DISCUSSION: Our findings indicate that higher cognitive reserve values are associated with delayed conversion to mild cognitive impairment and slower progression on clinical dementia rating scales. These findings suggest that cognitive reserve plays a protective role in modifying the clinical trajectory of genetically determined AD.

Indexed as

Alzheimer DiseaseCognitive DysfunctionCognitive ReserveAgedAge of OnsetDisease ProgressionFemaleHumansLongitudinal StudiesMaleMiddle Aged

Identifiers

PMID41950468
PMCPMC13067375

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