Evidence map›Paper›PMID 32844198›Full record

ArticleBrain : a journal of neurology2020

Genetic variants and functional pathways associated with resilience to Alzheimer's disease.

Logan Dumitrescu, Emily R Mahoney, Shubhabrata Mukherjee, Michael L Lee, William S Bush, Corinne D Engelman, Qiongshi Lu, David W Fardo, Emily H Trittschuh, Jesse Mez and 40 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Brain : a journal of neurology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 110 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
110citing papers in PubMed, 4 pooled it
8.0field-weighted citation impact, top 2% of its field
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

110 citing papers in PubMed, 4 syntheses or guidelines pooled it, 139 citations in OpenAlex.

  1. Pooled it
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  5. Article
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  8. From adolescence to Alzheimer's: a neurodevelopmental lifespan model of cognitive vulnerability.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2026
    Review
  9. Association Between the Genetic Risk for Attention-Deficit/Hyperactivity Disorder and Cognitive Function in Older Age: The MYHAT Population-Based Study.The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry · 2026
    Article
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50 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

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

50 authors at 20 institutions in 2 countries.

Logan DumitrescuVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Emily R MahoneyVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Shubhabrata MukherjeeDepartment of Medicine, University of Washington, Seattle, WA, USA.
Michael L LeeDepartment of Medicine, University of Washington, Seattle, WA, USA.
William S BushCleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
Corinne D EngelmanDepartment of Population Health Sciences, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA.
Qiongshi LuDepartment of Statistics, University of Wisconsin-Madison, Madison, WI, USA.
David W FardoDepartment of Biostatistics, College of Public Health, University of Kentucky, Lexington, KY, USA.
Emily H TrittschuhDepartment of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, WA, USA.
Jesse MezDeparment of Neurology, Boston University School of Medicine, Boston, MA, USA.
Catherine KaczorowskiThe Jackson Laboratory, Bar Harbor, ME, USA.
Hector Hernandez SaucedoUC Davis Alzheimer's Disease Research Center, Department of Neurology, University of California Davis Medical Center, Sacramento, CA, USA.
Keith F WidamanUniversity of California at Riverside, Riverside, CA, USA.
Rachel BuckleyDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Michael ProperziDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Elizabeth MorminoDepartment of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Hyun-Sik YangDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Tessa HarrisonHelen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.
Trey HeddenIcahn School of Medicine at Mount Sinai, New York City, NY, USA.
Kwangsik NhoDepartment of Radiology and Imaging Sciences, Indiana Alzheimer Disease Center, Indiana University School of Medicine, Indianapolis, IN, USA.
Shea J AndrewsIcahn School of Medicine at Mount Sinai, New York City, NY, USA.
Doug TommetDepartment of Psychiatry and Human Behavior, Brown University School of Medicine, Providence, RI, USA.
Niran HadadThe Jackson Laboratory, Bar Harbor, ME, USA.
R Elizabeth SandersDepartment of Medicine, University of Washington, Seattle, WA, USA.
Douglas M RuderferVanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Katherine A GiffordVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Annah M MooreVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Francis CambroneroVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Xiaoyuan ZhongDepartment of Statistics, University of Wisconsin-Madison, Madison, WI, USA.
Neha S RaghavanDepartment of Neurology, Columbia University, New York, NY, USA.
Badri VardarajanDepartment of Neurology, Columbia University, New York, NY, USA.
Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Alzheimer’s Disease Genetics Consortium (ADGC), A4 Study Team
Margaret A Pericak-VanceJohn P. Hussman Institute for Human Genomics, University of Miami School of Medicine, Miami, FL, USA.
Lindsay A FarrerDeparment of Neurology, Boston University School of Medicine, Boston, MA, USA.
Li-San WangPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Carlos CruchagaDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
Gerard SchellenbergPenn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Nancy J CoxVanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Jonathan L HainesCleveland Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.
C Dirk KeeneDepartment of Pathology, University of Washington, Seattle, WA, USA.
Andrew J SaykinDepartment of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN, USA.
Eric B LarsonDepartment of Medicine, University of Washington, Seattle, WA, USA.
Reisa A SperlingDepartment of Neurology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA.
Richard MayeuxDepartment of Neurology, Columbia University, New York, NY, USA.
David A BennettRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Julie A SchneiderRush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
Paul K CraneDepartment of Medicine, University of Washington, Seattle, WA, USA.
Angela L JeffersonVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Timothy J HohmanVanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
Vanderbilt University Medical Center · USUniversity of Washington · USBoston University · USNewYork–Presbyterian Hospital · USRush University Medical Center · USUniversity of Wisconsin–Madison · USBrigham and Women's Hospital · USCase Western Reserve University · USHarvard University · USIcahn School of Medicine at Mount Sinai · USJackson Laboratory · USWashington University in St. Louis · USBrown University · USIndiana University School of MedicineKaiser Permanente Washington Health Research Institute · USStanford University · USUniversity of California, Berkeley · USUniversity of California Davis Medical Center · USUniversity of California, Riverside · USUniversity of Kentucky · US

Funding

Alzheimer's Disease Neuroimaging Initiative - SupplementU01AG024904 · NIA · NORTHERN CALIFORNIA INSTITUTE RES &EDUC · PI WEINER, MICHAEL W · 2004 to 2015
$121.0M
National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD)U24AG021886 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI TATIANA M. FOROUD · 2002 to 2026
$119.8M
Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Charles B Hall · 1985 to 2026
$73.9M
Alzheimer's Disease Genetics ConsortiumU01AG032984 · NIA · UNIVERSITY OF PENNSYLVANIA · PI SCHELLENBERG, GERARD DAVID · 2009 to 2024
$60.4M
THERAPEUTIC EFFECTS OF INTRA-NASAL INSULIN DETEMIRP50AG005136 · NIA · UNIVERSITY OF WASHINGTON · PI GRABOWSKI, THOMAS J. · 1985 to 2019
$57.2M
SUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6M
SUPPLEMENT TO RUSH ALZHEIMERS DISEASE CENTER COREP30AG010161 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI LEURGANS, SUE E. · 1991 to 2020
$49.1M
Satellite Diagnostic and Treatment Clinic CoreP50AG008702 · NIA · COLUMBIA UNIV NEW YORK MORNINGSIDE · PI DE JAGER, PHILIP L · 1989 to 2019
$46.3M
EPIDEMIOLOGY OF NEURAL RESERVE AND NEUROBIOLOGY IN AGINGR01AG017917 · NIA · RUSH UNIVERSITY MEDICAL CENTER · PI BENNETT, DAVID ALAN · 2001 to 2023
$43.3M
THE NIA GENETICS OF ALZHEIMER'S DISEASE DATA STORAGE SITEU24AG041689 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LI-SAN WANG · 2012 to 2026
$42.3M
The Vanderbilt Institute for Clinical and Translational Research (VICTR)UL1TR000445 · NCATS · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BERNARD, GORDON RAPHAEL · 2012 to 2016
$41.4M
Furthering scientific understanding of mechanisms underlying resilience to the effects of AD pathology by incorporating state of the art quantification of gliosis, inflammation, & synaptic toxicityU01AG006781 · NIA · UNIVERSITY OF WASHINGTON · PI CRANE, PAUL K, LARSON, ERIC B · 1986 to 2020
$39.3M
Howard Hughes Medical InstituteNCATS NIH HHS UL1 TR000445NIA NIH HHS F31 AG059345NIA NIH HHS K01 AG049164NIA NIH HHS K01 AG051718NIA NIH HHS K23 AG062750NIA NIH HHS K24 AG046373NIA NIH HHS K99 AG061238NIA NIH HHS L30 AG048601NIA NIH HHS P01 AG002219NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG017216NIA NIH HHS P30 AG010161NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG062715NIA NIH HHS P30 AG066462NIA NIH HHS P30 AG066509NIA NIH HHS P50 AG005136NIA NIH HHS P50 AG005138NIA NIH HHS P50 AG008702NIA NIH HHS P50 AG016574NIA NIH HHS P50 AG025711NIA NIH HHS R01 AG015819NIA NIH HHS R01 AG017917NIA NIH HHS R01 AG018023NIA NIH HHS R01 AG032990NIA NIH HHS R01 AG034962NIA NIH HHS R01 AG046171NIA NIH HHS R01 AG054047NIA NIH HHS R01 AG056534NIA NIH HHS R01 AG057914NIA NIH HHS R01 AG059716NIA NIH HHS R01 AG063689NIA NIH HHS R13 AG030995NIA NIH HHS R56 AG057191NIA NIH HHS RF1 AG051550NIA NIH HHS RF1 AG054023NIA NIH HHS U01 AG006781NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG024904NIA NIH HHS U01 AG032984NIA NIH HHS U01 AG046139NIA NIH HHS U01 AG046152NIA NIH HHS U01 AG061356NIA NIH HHS U24 AG021886NIA NIH HHS U24 AG041689NIA NIH HHS U24 AG056270NICHD NIH HHS K12 HD043483NIDA NIH HHS HHSN271201300031CNIH HHS S10 OD023680NIMH NIH HHS P50 MH066392NIMH NIH HHS P50 MH084053NIMH NIH HHS R01 MH075916NIMH NIH HHS R01 MH080405NIMH NIH HHS R01 MH085542NIMH NIH HHS R01 MH093725NIMH NIH HHS R01 MH097276NIMH NIH HHS R01 MH109677NIMH NIH HHS R01 MH109897NIMH NIH HHS R01 MH110921NIMH NIH HHS R37 MH057881NIMH NIH HHS U01 MH103392NINDS NIH HHS R01 NS080820NINDS NIH HHS R01 NS100980NINDS NIH HHS U24 NS072026NLM NIH HHS R01 LM012535
6 · The paper itself

Abstract

Approximately 30% of older adults exhibit the neuropathological features of Alzheimer's disease without signs of cognitive impairment. Yet, little is known about the genetic factors that allow these potentially resilient individuals to remain cognitively unimpaired in the face of substantial neuropathology. We performed a large, genome-wide association study (GWAS) of two previously validated metrics of cognitive resilience quantified using a latent variable modelling approach and representing better-than-predicted cognitive performance for a given level of neuropathology. Data were harmonized across 5108 participants from a clinical trial of Alzheimer's disease and three longitudinal cohort studies of cognitive ageing. All analyses were run across all participants and repeated restricting the sample to individuals with unimpaired cognition to identify variants at the earliest stages of disease. As expected, all resilience metrics were genetically correlated with cognitive performance and education attainment traits (P-values < 2.5 × 10-20), and we observed novel correlations with neuropsychiatric conditions (P-values < 7.9 × 10-4). Notably, neither resilience metric was genetically correlated with clinical Alzheimer's disease (P-values > 0.42) nor associated with APOE (P-values > 0.13). In single variant analyses, we observed a genome-wide significant locus among participants with unimpaired cognition on chromosome 18 upstream of ATP8B1 (index single nucleotide polymorphism rs2571244, minor allele frequency = 0.08, P = 2.3 × 10-8). The top variant at this locus (rs2571244) was significantly associated with methylation in prefrontal cortex tissue at multiple CpG sites, including one just upstream of ATPB81 (cg19596477; P = 2 × 10-13). Overall, this comprehensive genetic analysis of resilience implicates a putative role of vascular risk, metabolism, and mental health in protection from the cognitive consequences of neuropathology, while also providing evidence for a novel resilience gene along the bile acid metabolism pathway. Furthermore, the genetic architecture of resilience appears to be distinct from that of clinical Alzheimer's disease, suggesting that a shift in focus to molecular contributors to resilience may identify novel pathways for therapeutic targets.

Indexed as

Aged, 80 and overAgingAlzheimer DiseaseBrainChromosomes, Human, Pair 18Cognitive DysfunctionCognitive ReserveFemaleGenome-Wide Association StudyGenotypeHumansMalePolymorphism, Single NucleotideAlzheimer’s diseaseamyloidGWASreserveresilience

Identifiers

PMID32844198
PMCPMC7447518
OpenAlexW3081150912

What OpenQuestion holds

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LicenceCC BY-NC
Read underepoch 390

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.