. 2024 May;23(5):487-499.

doi: 10.1016/S1474-4422(24)00083-8.

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

Rebecca R Valentino¹, William J Scotton², Shanu F Roemer¹, Tammaryn Lashley³, Michael G Heckman⁴, Maryam Shoai⁵, Alejandro Martinez-Carrasco⁶, Nicole Tamvaka¹, Ronald L Walton¹, Matthew C Baker¹, Hannah L Macpherson⁵, Raquel Real⁶, Alexandra I Soto-Beasley¹, Kin Mok⁷, Tamas Revesz³, Elizabeth A Christopher¹, Michael DeTure¹, William W Seeley⁸, Edward B Lee⁹, Matthew P Frosch¹⁰, Laura Molina-Porcel¹¹, Tamar Gefen¹², Javier Redding-Ochoa¹³, Bernardino Ghetti¹⁴, Andrew C Robinson¹⁵, Christopher Kobylecki¹⁶, James B Rowe¹⁷, Thomas G Beach¹⁸, Andrew F Teich¹⁹, Julia L Keith²⁰, Istvan Bodi²¹, Glenda M Halliday²², Marla Gearing²³, Thomas Arzberger²⁴, Christopher M Morris²⁵, Charles L White 3rd²⁶, Naguib Mechawar²⁷, Susana Boluda²⁸, Ian R MacKenzie²⁹, Catriona McLean³⁰, Matthew D Cykowski³¹, Shih-Hsiu J Wang³², Caroline Graff³³, Rashed M Nagra³⁴, Gabor G Kovacs³⁵, Giorgio Giaccone³⁶, Manuela Neumann³⁷, Lee-Cyn Ang³⁸, Agostinho Carvalho³⁹, Huw R Morris⁶, Rosa Rademakers⁴⁰, John A Hardy⁴¹, Dennis W Dickson¹, Jonathan D Rohrer⁴², Owen A Ross⁴³; Pick's disease International Consortium

Collaborators, Affiliations

Collaborators

Pick's disease International Consortium:
Thomas T Warner, Zane Jaunmuktane, Bradley F Boeve, Ranjan Duara, Neill R Graff-Radford, Keith A Josephs, David S Knopman, Shunsuke Koga, Melissa E Murray, Kelly E Lyons, Rajesh Pahwa, Ronald C Petersen, Jennifer L Whitwell, Lea T Grinberg, Bruce Miller, Athena Schlereth, Salvatore Spina, Murray Grossman, David J Irwin, EunRan Suh, John Q Trojanowski, Vivianna M Van Deerlin, David A Wolk, Theresa R Connors, Patrick M Dooley, Derek H Oakley, Iban Aldecoa, Mircea Balasa, Ellen Gelpi, Sergi Borrego-Écija, Jordi Gascon-Bayarri, Raquel Sánchez-Valle, Pilar Sanz-Cartagena, Gerard Piñol-Ripoll, Eileen H Bigio, Margaret E Flanagan, Emily J Rogalski, Sandra Weintraub, Julie A Schneider, Lihua Peng, Xiongwei Zhu, Koping Chang, Juan C Troncoso, Stefan Prokop, Kathy L Newell, Matthew Jones, Anna Richardson, Federico Roncaroli, Julie Snowden, Kieren Allinson, Poonam Singh, Geidy E Serrano, Xena E Flowers, James E Goldman, Allison C Heaps, Sandra P Leskinen, Sandra E Black, Mario Masellis, Andrew King, Safa Al-Sarraj, Claire Troakes, John R Hodges, Jillian J Kril, John B Kwok, Olivier Piguet, Sigrun Roeber, Johannes Attems, Alan J Thomas, Bret M Evers, Kevin F Bieniek, Anne A Sieben, Patrick P Cras, Bart B De Vil, Thomas Bird, Rudolph J Castellani, Ann Chaffee, Erin Franklin, Vahram Haroutunian, Max Jacobsen, Dirk Keene, Caitlin S Latimer, Jeff Metcalf, Richard J Perrin, Dushyant P Purohit, Robert A Rissman, Aimee Schantz, Jamie Walker, Peter P De Deyn, Charles Duyckaerts, Isabelle Le Ber, Danielle Seilhean, Sabrina Turbant-Leclere, John F Ervin, Inger Nennesmo, James Riehl, Benedetta Nacmias, Elizabeth C Finger, Cornelis Blauwendraat, Mike A Nalls, Andrew B Singleton, Dan Vitale, Cristina Cunha, Zbigniew K Wszolek

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
² Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK. Electronic address: w.scotton@ucl.ac.uk.
³ Queen 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.
⁴ Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA.
⁵ Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK.
⁶ Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology London, UK.
⁷ Department 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.
⁸ Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Neuropathology Service, C S Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Neurological 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.
¹² Mesulam 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.
¹³ Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Division 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.
¹⁶ Department 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.
¹⁷ Cambridge University Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK.
¹⁸ Civin Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
¹⁹ Department 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.
²⁰ Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
²¹ Clinical 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.
²² University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences, Camperdown, NSW, Australia.
²³ Department 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.
²⁴ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
²⁵ Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁶ University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁷ Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
²⁸ Laboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Alzheimer Prion Team, L'Institut du Cerveau, Paris, France.
²⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³⁰ Department of Anatomical Pathology Alfred Heath, Melbourne, VIC, Australia; Victorian Brain Bank, The Florey Institute of Neuroscience of Mental Health, Parkville, VIC, Australia.
³¹ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Weill Cornell Medicine, Houston, TX, USA.
³² Department of Neurology, Duke University Medical Center, Durham, NC, USA.
³³ Division 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.
³⁴ Human Brain and Spinal Fluid Resource Center, Brentwood Biomedical Research Institute, Los Angeles, CA, USA.
³⁵ Tanz 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.
³⁶ Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
³⁷ Molecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany; Department of Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
³⁸ Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³⁹ Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
⁴⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Vlaams Instituut voor Biotechnologie-Universiteit Antwerpen, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
⁴¹ Department 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.
⁴² Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK.
⁴³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: ross.owen@mayo.edu.

PMID: 38631765
PMCID: PMC11877577
DOI: 10.1016/S1474-4422(24)00083-8

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

Rebecca R Valentino et al. Lancet Neurol. 2024 May.

. 2024 May;23(5):487-499.

doi: 10.1016/S1474-4422(24)00083-8.

Authors

Collaborators

Pick's disease International Consortium:
Thomas T Warner, Zane Jaunmuktane, Bradley F Boeve, Ranjan Duara, Neill R Graff-Radford, Keith A Josephs, David S Knopman, Shunsuke Koga, Melissa E Murray, Kelly E Lyons, Rajesh Pahwa, Ronald C Petersen, Jennifer L Whitwell, Lea T Grinberg, Bruce Miller, Athena Schlereth, Salvatore Spina, Murray Grossman, David J Irwin, EunRan Suh, John Q Trojanowski, Vivianna M Van Deerlin, David A Wolk, Theresa R Connors, Patrick M Dooley, Derek H Oakley, Iban Aldecoa, Mircea Balasa, Ellen Gelpi, Sergi Borrego-Écija, Jordi Gascon-Bayarri, Raquel Sánchez-Valle, Pilar Sanz-Cartagena, Gerard Piñol-Ripoll, Eileen H Bigio, Margaret E Flanagan, Emily J Rogalski, Sandra Weintraub, Julie A Schneider, Lihua Peng, Xiongwei Zhu, Koping Chang, Juan C Troncoso, Stefan Prokop, Kathy L Newell, Matthew Jones, Anna Richardson, Federico Roncaroli, Julie Snowden, Kieren Allinson, Poonam Singh, Geidy E Serrano, Xena E Flowers, James E Goldman, Allison C Heaps, Sandra P Leskinen, Sandra E Black, Mario Masellis, Andrew King, Safa Al-Sarraj, Claire Troakes, John R Hodges, Jillian J Kril, John B Kwok, Olivier Piguet, Sigrun Roeber, Johannes Attems, Alan J Thomas, Bret M Evers, Kevin F Bieniek, Anne A Sieben, Patrick P Cras, Bart B De Vil, Thomas Bird, Rudolph J Castellani, Ann Chaffee, Erin Franklin, Vahram Haroutunian, Max Jacobsen, Dirk Keene, Caitlin S Latimer, Jeff Metcalf, Richard J Perrin, Dushyant P Purohit, Robert A Rissman, Aimee Schantz, Jamie Walker, Peter P De Deyn, Charles Duyckaerts, Isabelle Le Ber, Danielle Seilhean, Sabrina Turbant-Leclere, John F Ervin, Inger Nennesmo, James Riehl, Benedetta Nacmias, Elizabeth C Finger, Cornelis Blauwendraat, Mike A Nalls, Andrew B Singleton, Dan Vitale, Cristina Cunha, Zbigniew K Wszolek

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
² Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK. Electronic address: w.scotton@ucl.ac.uk.
³ Queen 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.
⁴ Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL, USA.
⁵ Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology London, UK.
⁶ Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology London, UK.
⁷ Department 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.
⁸ Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
⁹ Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹⁰ Neuropathology Service, C S Kubik Laboratory for Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹¹ Neurological 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.
¹² Mesulam 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.
¹³ Johns Hopkins School of Medicine, Baltimore, MD, USA.
¹⁴ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
¹⁵ Division 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.
¹⁶ Department 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.
¹⁷ Cambridge University Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK; Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK.
¹⁸ Civin Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
¹⁹ Department 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.
²⁰ Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
²¹ Clinical 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.
²² University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences, Camperdown, NSW, Australia.
²³ Department 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.
²⁴ Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
²⁵ Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
²⁶ University of Texas Southwestern Medical Center, Dallas, TX, USA.
²⁷ Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada.
²⁸ Laboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Alzheimer Prion Team, L'Institut du Cerveau, Paris, France.
²⁹ Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³⁰ Department of Anatomical Pathology Alfred Heath, Melbourne, VIC, Australia; Victorian Brain Bank, The Florey Institute of Neuroscience of Mental Health, Parkville, VIC, Australia.
³¹ Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Weill Cornell Medicine, Houston, TX, USA.
³² Department of Neurology, Duke University Medical Center, Durham, NC, USA.
³³ Division 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.
³⁴ Human Brain and Spinal Fluid Resource Center, Brentwood Biomedical Research Institute, Los Angeles, CA, USA.
³⁵ Tanz 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.
³⁶ Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy.
³⁷ Molecular Neuropathology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases, Tübingen, Germany; Department of Neuropathology, University Hospital of Tübingen, Tübingen, Germany.
³⁸ Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
³⁹ Life and Health Sciences Research Institute, School of Medicine, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
⁴⁰ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Vlaams Instituut voor Biotechnologie-Universiteit Antwerpen, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
⁴¹ Department 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.
⁴² Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK.
⁴³ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, USA. Electronic address: ross.owen@mayo.edu.

PMID: 38631765
PMCID: PMC11877577
DOI: 10.1016/S1474-4422(24)00083-8

Abstract

Background: Pick'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.

Methods: In 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.

Findings: We 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).

Interpretation: The 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.

Funding: Wellcome 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.

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Conflict of interest statement

Declarations of interest WJS declares funding from a Wellcome Trust Clinical PhD Fellowship (220582/Z/20/Z) and from the Rotha Abraham Trust; and has received conference travel funding from the Guarantors of Brain. NT declares funding from the 2023 Diana Jacobs Kalman-American Federation for Aging Research Scholarship for Pre-Doctoral Research on the biology of aging. KM declares funding from the Michael J Fox Foundation, Innovation and Technology Commission, Hong Kong Government, and the Chow Tai Fook Charity Foundation; affiliations with the Hong Kong University of Science and Technology and University College London; employment with the Hong Kong Center for Neurodegenerative Diseases; and support for speaker and educational activity from the National Taiwan University, Yonsei University, and the Movement Disorder Society. WWS declares funding from the National Institutes of Health (NIH), Tau Consortium, Bluefield Project to Cure Frontotemporal Dementia, and the Chan-Zuckerberg Initiative. EBL declares funding from the NIH and personal honorarium from University of Toronto, Mayo Clinic, St Louis University, Haverford, University of Oslo, NIH, and the Association of Frontotemporal Dementia. LM-P declares personal honorarium from the Galician Society of Neurology and the Spanish Society of Neurology. JBR declares funding from the NIH Research Biomedical Research Centre, the Medical Research Council, Wellcome Trust, Cambridge Centre for Parkinson-plus, PSP association, and Alzheimer's UK; and has received consulting fees from Asceneuron, Astronautx, Astex, Curasen, CumulusNeuro, Wave, Prevail, and SVHealth. TGB declares funding from the NIH, Michael J Fox Foundation, and Life Molecular Imaging; personal consulting fees from Aprinoia Therapeutics; and stock options in Vivid Genomics. S-HJW declares funding from NIH and personal honorarium from the American Society of Clinical Pathology. CG declares funding from the Swedish Frontotemporal Dementia Inititative-Schörling Foundation, EU Joint Programme-Neurodegenerative Disease Research-Prefrontals, EU Joint Programme-Neurodegenerative Disease Research-Genetic Frontotemporal Dementia Initiative-Proximity, the Alzheimer Foundation, Brain Foundation, Dementia Foundation, Region Karolinska Institutet-StratNeuro Strategiska forskningsområden, Centre for Innovative Medicine, and Karolinska Institutet-Region Stockholm Core facility; personal honoraria from Demensdagarna Örebro, Diakonia Ersta sjukhus, and Göteborgsregionen. GGK declares funding from Edmond J Safra Philanthropic Foundation, Michael J Fox Foundation, Parkinson Canada, Canada, Canada Foundation for Innovation, MSA Coalition, and the NIH; and royalties from a patent for 5G4 synuclein antibody (DE102011008153B4); and personal honoraria from the Movement Disorders Society. MN declares funding from Deutsche Forschungsgemeinschaft and Alzheimer Forschungsinitiative. HRM declares funding from the PSP Association, CBD Solutions, the Drake Foundation, the Cure Parkinson's Trust, the Michael J Fox Foundation, and Parkinson's UK; consulting fees from Roche, Amylyx, and Aprinoia; personal honoraria from Kyowa-Kirin, BMJ, and the Movement Disorders Society; travel support from the Michael J Fox Foundation; is a co-applicant on a patent application related to C9ORF72 method for diagnosing a neurodegenerative disease (PCT/GB2012/052140); and serves on the Cure PSP Association Advisory Board, the Association of British Neurologists Movement Disorders Special Interest Group, and the Association of British Neurologists Neurogenetics Advisory Group. RRa declares consulting fees from Arkuda Therapeutics and is on the advisory board for the Kissick Family Foundation. JAH declares funding from the Dolby Charities, and consulting fees from Eli Lilly and Eisai. JDR declares funding from the Bluefied project and the Alzheimer's Associaton; and consulting fees from Novartis, Wave Life Sciences, Prevail, Alector, Aviado Bio, Takeda, Arkuda Therapeutics, and Denali Therapeutics. OAR declares internal funding from the Mayo Clinic Foundation. All other authors declare no competing interests.

Figures

**Figure 1:. Global map (A) and table reporting countries and recruitment sites (B) that have contributed Pick’s disease tissues to the Pick’s disease International Consortium (PIC) to date.**
Dark red = countries that have collected and donated Pick’s disease tissues.

**Figure 2:. Pathological assessments of Pick’s disease brains at Mayo Clinic Brain Bank for Neurodegenerative Diseases in Jacksonville, FL, USA.**
[A] The superior and dorsolateral surfaces of the frontal cortex and temporal lobe often show severe circumscribed ‘knife-edge’ edge atrophy. [B] Coronal sections of the brain show markedly dilated ventricles, cortical atrophy, and hippocampal affection. [C] Enlarged, amorphous ballooned neurons. [D] In regions with severe astrogliosis and neuronal loss, staining against αβ-crystallin may highlight ballooned neurons. [E] Phosphorylated tau antibodies highlight spherical cytoplasmic neuronal inclusions and may also show marked neuropil staining, especially in individuals with concomitant Alzheimer’s type pathology. [F] Gallyas silver stains may stain isolated glial lesions or neurofibrillary tangles; however, Pick bodies do not show any significant degree of silver staining. [G] 3R tau staining of the dentate fascia of the hippocampus show strong immunoreactivity of spherical inclusions. [H] 4R tau staining of the dentate fascia show negative spherical inclusion, although isolated neurofibrillary tangles may stain positive. Images are from individuals with Pick’s disease submitted to Mayo Clinic.

**Figure 3:. Pathological assessments of Pick’s disease brains at Queen Square Brain Bank for Neurological Disorders (QSBB), UCL Queen Square Institute of Neurology, London, UK.**
The top row shows a Pick’s disease case that was positive for AT8 and 3R-tau immunoreactive Pick bodies. The bottom row shows a non-Pick’s disease case (that was originally pathologically diagnosed with Pick’s disease) that was positive for AT8 and 4R-tau but negative for 3R tau immunoreactive Pick bodies. Images are from individuals with Pick’s disease submitted to UCL.

See this image and copyright information in PMC

Update of

Creating the Pick's disease International Consortium: Association study of MAPT H2 haplotype with risk of Pick's disease.
Valentino RR, Scotton WJ, Roemer SF, Lashley T, Heckman MG, Shoai M, Martinez-Carrasco A, Tamvaka N, Walton RL, Baker MC, Macpherson HL, Real R, Soto-Beasley AI, Mok K, Revesz T, Warner TT, Jaunmuktane Z, Boeve BF, Christopher EA, DeTure M, Duara R, Graff-Radford NR, Josephs KA, Knopman DS, Koga S, Murray ME, Lyons KE, Pahwa R, Parisi JE, Petersen RC, Whitwell J, Grinberg LT, Miller B, Schlereth A, Seeley WW, Spina S, Grossman M, Irwin DJ, Lee EB, Suh E, Trojanowski JQ, Van Deerlin VM, Wolk DA, Connors TR, Dooley PM, Frosch MP, Oakley DH, Aldecoa I, Balasa M, Gelpi E, Borrego-Écija S, de Eugenio Huélamo RM, Gascon-Bayarri J, Sánchez-Valle R, Sanz-Cartagena P, Piñol-Ripoll G, Molina-Porcel L, Bigio EH, Flanagan ME, Gefen T, Rogalski EJ, Weintraub S, Redding-Ochoa J, Chang K, Troncoso JC, Prokop S, Newell KL, Ghetti B, Jones M, Richardson A, Robinson AC, Roncaroli F, Snowden J, Allinson K, Green O, Rowe JB, Singh P, Beach TG, Serrano GE, Flowers XE, Goldman JE, Heaps AC, Leskinen SP, Teich AF, Black SE, Keith JL, Masellis M, Bodi I, King A, Sarraj SA, Troakes C, Halliday GM, Hodges JR, Kril JJ, Kwok JB, Piguet O, Gearing M, Arzberger T, Roeber S, Attems J, Morris CM, Thomas AJ, Ever… See abstract for full author list ➔ Valentino RR, et al. medRxiv [Preprint]. 2023 Apr 24:2023.04.17.23288471. doi: 10.1101/2023.04.17.23288471. medRxiv. 2023. Update in: Lancet Neurol. 2024 May;23(5):487-499. doi: 10.1016/S1474-4422(24)00083-8. PMID: 37163045 Free PMC article. Updated. Preprint.

References

1. Choudhury P, Scharf EL, Paolini MA, Graff-Radford J, Alden EC, Machulda MM, et al. Pick’s disease: clinicopathologic characterization of 21 cases. J Neurol. 2020;267(9):2697–704. - PubMed
1. Irwin DJ, Brettschneider J, McMillan CT, Cooper F, Olm C, Arnold SE, et al. Deep clinical and neuropathological phenotyping of Pick disease. Ann Neurol. 2016;79(2):272–87. - PMC - PubMed
1. Piguet O, Halliday GM, Reid WGJ, Casey B, Carman R, Huang Y, et al. Clinical phenotypes in autopsy-confirmed pick disease. Neurology. 2011;76(3):253–9. - PubMed
1. Rohrer JD, Lashley T, Schott JM, Warren JE, Mead S, Isaacs AM, et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain. 2011;134(9):2565–81. - PMC - PubMed
1. Whitwell JL, Tosakulwong N, Schwarz CC, Senjem ML, Spychalla AJ, Duffy JR, et al. Longitudinal anatomic, functional, and molecular characterization of Pick disease phenotypes. Neurology. 2020;95(24):e3190–202. - PMC - PubMed

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

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

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