Evidence map›Paper›PMID 38631765›Full record

ArticleThe Lancet. Neurology2024

MAPT H2 haplotype and risk of Pick's disease in the Pick's disease International Consortium: a genetic association study.

Rebecca R Valentino, William J Scotton, Shanu F Roemer, Tammaryn Lashley, Michael G Heckman, Maryam Shoai, Alejandro Martinez-Carrasco, Nicole Tamvaka, Ronald L Walton, Matthew C Baker and 46 more

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

Article in The Lancet. Neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.

0numbers the graph read from it
0cells of the map it votes in
18citing papers in PubMed
7.8field-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

18 citing papers in PubMed, 22 citations in OpenAlex.

  1. Emerging directions in tauopathy research.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026
    Review
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  5. Article
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  8. Biomedicines · 2025
    Article
  9. Differences in the soluble and insoluble proteome between primary tauopathies.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
    Article
  10. DNA methylation as a contributor to dysregulation ofbioRxiv : the preprint server for biology · 2025
    Article
  11. Article
  12. Review
  13. Review
  14. Describing the diversity ofNPJ dementia · 2025
    Article
  15. Review
  16. Article
  17. Article
  18. Further validation of the association betweenFrontiers in molecular neuroscience · 2024
    Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

56 authors at 20 institutions in 13 countries.

Rebecca R ValentinoDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
William J ScottonDementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK. Electronic address: w.scotton@ucl.ac.uk.
Shanu F RoemerDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Tammaryn LashleyQueen Square Brain Bank for Neurological Disorders, University College London, Queen Square Institute of Neurology London, UK; Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK.
Michael G HeckmanDivision of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA.
Maryam ShoaiDepartment of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK.
Alejandro Martinez-CarrascoDepartment of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology London, UK.
Nicole TamvakaDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Ronald L WaltonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Matthew C BakerDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Hannah L MacphersonDepartment of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK.
Raquel RealDepartment of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology London, UK.
Alexandra I Soto-BeasleyDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Kin MokDepartment of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK; UK Dementia Research Institute at UCL, London, UK; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China; Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China.
Tamas ReveszQueen Square Brain Bank for Neurological Disorders, University College London, Queen Square Institute of Neurology London, UK; Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK.
Elizabeth A ChristopherDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Michael DeTureDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
William W SeeleyDepartment of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
Edward B LeeDepartment of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Matthew P FroschNeuropathology Service, C S Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Laura Molina-PorcelNeurological Tissue Bank, Biobanc-Hospital Clínic-Fundació de Recerca Clínic Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; Alzheimer's Disease and other Cognitive Disorders Unit, Neurology Department, Hospital Clinic, Barcelona, Spain; Barcelona Clinical Research Foundation-August Pi i Sunyer Biomedical Research Institute, Barcelona, Spain.
Tamar GefenMesulam Center for Cognitive Neurology and Alzheimer's Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Javier Redding-OchoaJohns Hopkins School of Medicine, Baltimore, MD, USA.
Bernardino GhettiDepartment of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Andrew C RobinsonDivision of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK; Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre, Manchester, UK.
Christopher KobyleckiDepartment of Neurology, Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, UK.
James B RoweCambridge University Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK.
Thomas G BeachCivin Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
Andrew F TeichDepartment of Pathology and Cell Biology, Columbia University, New York, NY, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA.
Julia L KeithLaboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Istvan BodiClinical Neuropathology Department, King's College Hospital NHS Foundation Trust, London, UK; London Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Glenda M HallidayUniversity of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences, Camperdown, NSW, Australia.
Marla GearingDepartment of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA; Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA; Goizueta Alzheimer's Disease Center Brain Bank, Emory University School of Medicine, Atlanta, GA, USA.
Thomas ArzbergerDepartment of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
Christopher M MorrisNewcastle Brain Tissue Resource, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Charles L WhiteUniversity of Texas Southwestern Medical Center, Dallas, TX, USA.
Naguib MechawarDouglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
Susana BoludaLaboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Alzheimer Prion Team, L'Institut du Cerveau, Paris, France.
Ian R MacKenzieDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Catriona McLeanDepartment of Anatomical Pathology Alfred Heath, Melbourne, VIC, Australia; Victorian Brain Bank, The Florey Institute of Neuroscience of Mental Health, Parkville, VIC, Australia.
Matthew D CykowskiDepartment of Pathology and Genomic Medicine, Houston Methodist Research Institute and Weill Cornell Medicine, Houston, TX, USA.
Shih-Hsiu J WangDepartment of Neurology, Duke University Medical Center, Durham, NC, USA.
Caroline GraffDivision for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Unit for Hereditary Dementias, Karolinska University Hospital Solna, Stockholm, Sweden.
Rashed M NagraHuman Brain and Spinal Fluid Resource Center, Brentwood Biomedical Research Institute, Los Angeles, CA, USA.
Gabor G KovacsTanz Centre for Research in Neurodegenerative Disease, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
Giorgio GiacconeFondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
Manuela NeumannMolecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany; Department of Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
Lee-Cyn AngDepartment of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
Agostinho CarvalhoLife and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
Huw R MorrisDepartment of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology London, UK.
Rosa RademakersDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Vlaams Instituut voor Biotechnologie-Universiteit Antwerpen, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
John A HardyDepartment of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK; Reta Lila Weston Institute, University College London, Queen Square Institute of Neurology London, UK; UK Dementia Research Institute at UCL, London, UK; Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China.
Dennis W DicksonDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Jonathan D RohrerDementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK.
Owen A RossDepartment of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: ross.owen@mayo.edu.
Pick's disease International Consortium
Mayo Clinic in Florida · USNational Hospital for Neurology and Neurosurgery · GBLudwig-Maximilians-Universität München · DEColumbia University · USGerman Center for Neurodegenerative Diseases · DEHong Kong University of Science and Technology · HKHouston Methodist · USManchester Academic Health Science Centre · GBMRC Cognition and Brain Sciences Unit · GBQueen Mary University of London · GBSunnybrook Health Science Centre · CAThe University of Texas Southwestern Medical Center · USUK Dementia Research Institute · GBAssistance Publique – Hôpitaux de Paris · FRBanner Sun Health Research Institute · USBrentwood Biomedical Research Institute · USDouglas Mental Health University Institute · CADuke Medical Center · USEmory University · USFlorey Institute of Neuroscience and Mental Health · AU

Funding

Technology and Remote Assessment CoreU19AG063911 · NIA · MAYO CLINIC ROCHESTER · PI Bradley F Boeve · 2019 to 2026
$120.9M
Vascular Structure and Function in Cognitive AgingP01AG003949 · NIA · YESHIVA UNIVERSITY · PI Cuiling Wang · 1985 to 2026
$73.9M
Early Onset AD Consortium - the LEAD Study (LEADS)U01AG057195 · NIA · INDIANA UNIVERSITY INDIANAPOLIS · PI APOSTOLOVA, LIANA G, CARRILLO, MARIA C · 2018 to 2023
$70.3M
TDP-43 Loss-of-Function: Biology to BiomarkersP01AG019724 · NIA · UNIVERSITY OF PENNSYLVANIA · PI Jennifer Merrilees · 2002 to 2026
$67.2M
SUPPLEMENT TO ALZHEIMERS DISEASE PATIENT REGISTRYU01AG006786 · NIA · MAYO CLINIC ROCHESTER · PI GRAFF-RADFORD, JONATHAN, JACK, CLIFFORD R. · 1986 to 2023
$49.6M
iPSC Neurodegenerative Diseasses InitiativeZIAAG000535 · NIA · NATIONAL INSTITUTE ON AGING · PI COOKSON, MARK · 2019 to 2025
$48.2M
Project: Predicting PhenoconversionU19AG071754 · NIA · WASHINGTON UNIVERSITY · PI Erik Kent St. Louis · 2021 to 2026
$41.2M
Research Education ComponentP30AG010133 · NIA · INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS · PI SAYKIN, ANDREW J · 1991 to 2020
$37.3M
Transgenic Mouse Models of Tau PathologiesP01AG017586 · NIA · UNIVERSITY OF PENNSYLVANIA · PI LEE, VIRGINIA M · 2000 to 2021
$37.3M
Research Education ComponentP30AG062422 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Gil Dan Rabinovici · 2019 to 2026
$36.9M
Research Education ComponentP30AG062421 · NIA · MASSACHUSETTS GENERAL HOSPITAL · PI STEVEN E ARNOLD · 2019 to 2026
$36.5M
UPenn ADCC Biomarker CoreP30AG010124 · NIA · UNIVERSITY OF PENNSYLVANIA · PI DETRE, JOHN A · 1991 to 2020
$35.1M
Intramural NIH HHS ZIA AG000535NIA NIH HHS K08 AG052648NIA NIH HHS K08 AG065463NIA NIH HHS K24 AG053435NIA NIH HHS P01 AG003949NIA NIH HHS P01 AG017586NIA NIH HHS P01 AG019724NIA NIH HHS P01 AG066597NIA NIH HHS P30 AG010124NIA NIH HHS P30 AG010133NIA NIH HHS P30 AG013854NIA NIH HHS P30 AG019610NIA NIH HHS P30 AG062421NIA NIH HHS P30 AG062422NIA NIH HHS P30 AG062677NIA NIH HHS P30 AG066462NIA NIH HHS P30 AG066511NIA NIH HHS P30 AG072958NIA NIH HHS P30 AG072976NIA NIH HHS P30 AG072977NIA NIH HHS P30 AG072979NIA NIH HHS P30 AG072980NIA NIH HHS P50 AG023501NIA NIH HHS R01 AG037491NIA NIH HHS R01 AG050603NIA NIH HHS R01 AG056258NIA NIH HHS R01 AG060477NIA NIH HHS R01 AG062566NIA NIH HHS R01 AG077444NIA NIH HHS U01 AG006786NIA NIH HHS U01 AG045390NIA NIH HHS U01 AG057195NIA NIH HHS U19 AG062418NIA NIH HHS U19 AG063911NIA NIH HHS U19 AG071754NIDCD NIH HHS R01 DC008552NIDCD NIH HHS R01 DC012519NIDCD NIH HHS R01 DC014942NINDS NIH HHS P01 NS084974NINDS NIH HHS P50 NS072187NINDS NIH HHS R01 NS075075NINDS NIH HHS R01 NS078086NINDS NIH HHS R01 NS089757NINDS NIH HHS R01 NS109260NINDS NIH HHS R01 NS112153NINDS NIH HHS R01 NS120992NINDS NIH HHS RF1 NS112153NINDS NIH HHS RF1 NS118584NINDS NIH HHS RF1 NS120992NINDS NIH HHS U01 NS100620NINDS NIH HHS U24 NS072026NINDS NIH HHS U54 NS100693NINDS NIH HHS U54 NS110435NINDS NIH HHS UG3 NS104095Wellcome Trust
6 · The paper itself

Abstract

backgroundPick's disease is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. Pick's disease is pathologically defined by the presence in the frontal and temporal lobes of Pick bodies, composed of hyperphosphorylated, three-repeat tau protein, encoded by the MAPT gene. MAPT has two distinct haplotypes, H1 and H2; the MAPT H1 haplotype is the major genetic risk factor for four-repeat tauopathies (eg, progressive supranuclear palsy and corticobasal degeneration), and the MAPT H2 haplotype is protective for these disorders. The primary aim of this study was to evaluate the association of MAPT H2 with Pick's disease risk, age at onset, and disease duration.

methodsIn this genetic association study, we used data from the Pick's disease International Consortium, which we established to enable collection of data from individuals with pathologically confirmed Pick's disease worldwide. For this analysis, we collected brain samples from individuals with pathologically confirmed Pick's disease from 35 sites (brainbanks and hospitals) in North America, Europe, and Australia between Jan 1, 2020, and Jan 31, 2023. Neurologically healthy controls were recruited from the Mayo Clinic (FL, USA, or MN, USA between March 1, 1998, and Sept 1, 2019). For the primary analysis, individuals were directly genotyped for the MAPT H1-H2 haplotype-defining variant rs8070723. In a secondary analysis, we genotyped and constructed the six-variant-defined (rs1467967-rs242557-rs3785883-rs2471738-rs8070723-rs7521) MAPT H1 subhaplotypes. Associations of MAPT variants and MAPT haplotypes with Pick's disease risk, age at onset, and disease duration were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele or each additional copy of the given haplotype.

findingsWe obtained brain samples from 338 people with pathologically confirmed Pick's disease (205 [61%] male and 133 [39%] female; 338 [100%] White) and 1312 neurologically healthy controls (611 [47%] male and 701 [53%] female; 1312 [100%] White). The MAPT H2 haplotype was associated with increased risk of Pick's disease compared with the H1 haplotype (OR 1·35 [95% CI 1·12 to 1·64], p=0·0021). MAPT H2 was not associated with age at onset (β -0·54 [95% CI -1·94 to 0·87], p=0·45) or disease duration (β 0·05 [-0·06 to 0·16], p=0·35). Although not significant after correcting for multiple testing, associations were observed at p less than 0·05: with risk of Pick's disease for the H1f subhaplotype (OR 0·11 [0·01 to 0·99], p=0·049); with age at onset for H1b (β 2·66 [0·63 to 4·70], p=0·011), H1i (β -3·66 [-6·83 to -0·48], p=0·025), and H1u (β -5·25 [-10·42 to -0·07], p=0·048); and with disease duration for H1x (β -0·57 [-1·07 to -0·07], p=0·026).

interpretationThe Pick's disease International Consortium provides an opportunity to do large studies to enhance our understanding of the pathobiology of Pick's disease. This study shows that, in contrast to the decreased risk of four-repeat tauopathies, the MAPT H2 haplotype is associated with an increased risk of Pick's disease in people of European ancestry. This finding could inform development of isoform-related therapeutics for tauopathies.

fundingWellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health, and the Mayo Clinic Foundation.

Indexed as

Pick Disease of the BrainTauopathiesFemaleGenetic Association StudiesHaplotypesHumansMaletau ProteinsMAPT protein, humantau Proteins

Identifiers

PMID38631765
PMCPMC11877577
OpenAlexW4394800621

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