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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 487-499 |
| Number of pages | 13 |
| Journal | The Lancet Neurology |
| Volume | 23 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 2024 |
Funding
This paper is dedicated to the memory of John Q Trojanowski, who was an inspirational researcher and neuropathologist at the University of Pennsylvania and pioneered discoveries in tauopathies that resulted in improvements to diagnosis and treatment. John was a leader in neuroscience and his presence and insights will be thoroughly missed by scientists worldwide. We would also like to acknowledge our dear colleagues Charles Duyckaerts and Murray Grossman, eminent neuropathologists at Sorbonne University, Paris, and University of Pennsylvania, USA, who also sadly passed away during our manuscript writing. We sincerely thank all those who contributed towards our research, particularly the patients and families who donated brain and blood tissues. Without their generous donations the Pick's disease International Consortium would not exist, and this study would not have been possible. Direct funding for the current genetic study was provided by the Wellcome Trust, Rotha Abraham Trust, Brain Research UK, the Dolby Fund, Dementia Research Institute (Medical Research Council), US National Institutes of Health (NIH), and the Mayo Clinic Foundation. SK receives funding from CurePSP and the Rainwater Charitable Foundation, the State of Florida Ed, and Ethel Moore Alzheimer's Disease Research Program (22A05), and Mayo Clinic Alzheimer's Disease Research Center (ADRC). MEM receives funding from the State of Florida (20A22), Longitudinal Early-onset Alzheimer's Disease Study Neuropathology Core (U01AG057195), and the Chan Zuckerberg Initiative Collaborative Pairs Grant, which are paid directly to the institute. KAJ is supported by NIH grants (R01 DC014942, R01, R01-AG37491, R01-NS89757, RF1-NS112153, and RF1-NS120992). BFB is supported by NIH grants (P30 AG62677, U19 AG063911, U01 NS100620, and U19 AG071754), the Robert H and Clarice Smith and Abigail Van Buren Alzheimers Disease Research Program of the Mayo Foundation, the Lewy Body Dementia Association, the Mayo Clinic Dorothy and Harry T Mangurian Jr Lewy Body Dementia Program, the Little Family Foundation, and the Turner Family Foundation. ZKW is partially supported by the NIH-National Institute on Aging (NIA) and NIH-National Institute of Neurological Disorders and Stroke (NINDS; 1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, gifts from the Donald G and Jodi P Heeringa Family, the Haworth Family Professorship in Neurodegenerative Diseases fund, and The Albertson Parkinson's Research Foundation; serves as principal investigator or co-principal investigator on Biohaven Pharmaceuticals (BHV4157-206), Neuraly (NLY01-PD-1), and Vigil Neuroscience (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and Csf1r biomarker and repository project) grants; serves as co-principal investigator of the Mayo Clinic APDA Center for Advanced Research; and as an external advisory board member for Vigil Neuroscience. OAR and DWD are both supported by NINDS Tau Center without Walls Program (U54-NS100693) and the NIH (UG3-NS104095). DWD receives research support from the NIH (P30 AG062677, U54-NS100693, and P01-AG003949), CurePSP, the Tau Consortium, and the Robert E Jacoby Professorship. OAR is supported by NIH (P50-NS072187, R01- NS078086, U54-NS100693, and U54-NS110435), Department of Defence (W81XWH-17-1-0249), the Michael J Fox Foundation, The Little Family Foundation, the Mangurian Foundation Lewy Body Dementia Program at Mayo Clinic, the Turner Family Foundation, Mayo Clinic Foundation, and the Center for Individualized Medicine. Mayo Clinic is also an LBD Center without Walls (U54-NS110435). KAJ and JLW receive research support from the NIH (R01-DC12519, R01-NS89757, R01-AG50603, R01-DC14942, R01-AG37491, RF1-NS112153, and RF1-NS120992). Samples included in this study were clinical controls from Mayo Clinic Rochester and Mayo Clinic Jacksonville as part of the Alzheimer's Disease Research Center (P30 AG062677), and the Mayo Clinic Study of Aging (U01 AG006786) or tissue donations to the Mayo Clinic Brain Bank in Jacksonville, which is supported by CurePSP and Mayo Clinic funding. Human tissue samples were provided by the Neurodegenerative Disease Brain Bank at the University of California, San Francisco, which receives funding support from NIH grants P01AG019724 and P50AG023501, the Consortium for Frontotemporal Dementia Research, and the Tau Consortium. LTG and SS receive funding from NIH grants K24053435 and K08AG052648, respectively. ES, JQT, MG, VMVD, DJI, DAW, and EBL all receive funding through NIH (ES P01-AG017586, P01-AG066597, P30-AG010124, and P30-AG072979; JQT P01-AG017586, P30-AG010124, and P30-AG072979; MG P01-AG017586, P01-AG066597, P30-AG010124, and P30-AG072979; VMVD P01-AG017586, P01-AG066597, P30-AG010124, and P30-AG072979; DJI R01-NS109260, P30-AG010124, P01-AG066597; DAW: P30-AG010124, and P30-AG072979; and EBL P01-AG066597, P30-AG072979 and U19AG062418). ER, TG, SW, EHB, and MEF receive support from NIA under award numbers R01 AG062566, R01 AG077444, P30 AG13854, P30 AG072977; the National Institute of Deafness and Other Communication Disorders (NIDCD) under award number R01 DC008552; and the NINDS under award number R01 NS075075. MEF also receives support from NIA grant K08 AG065463. We are grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, Arizona for the provision of human biological materials. The Brain and Body Donation Program has been supported by the NINDS (U24 NS072026 National Brain and Tissue Resource for Parkinson's Disease and Related Disorders), the NIA (P30 AG19610 Arizona Alzheimer's Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer's Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson's Disease Consortium), and the Michael J Fox Foundation for Parkinson's Research. MG is supported by NIH grant P30 AG066511. MDC receives funding from NIH grant RF1 NS118584. We thank the Columbia University ADRC, funded by NIH grant P30AG066462. The ADRC is supported by the NIH, through grant number P30AG066462. ACH receives NIH support through P30AG066462. The Bryan Brain Bank and Biorepository of the Duke-UNC ADRC and SJW are supported by the NIA grant P30AG072958. Brain samples were provided by Neuropathology Core of the Massachusetts Alzheimer Disease Research Center, which receives funding support from NIH grant P30 AG062421, which also supported TRC, PMD, MPF, and DHO. DHO was also received support from the Dr and Mrs E P Richardson, Jr, Fellowship in Neuropathology. BG is supported by the US NIH (grant P30 AG072976). Curation and provision of control data was supported in part by the Intramural Research Program of the NIH, NIA, Department of Health and Human Services; project number ZO1 AG000535; and the National Institute of Neurological Disorders and Stroke. This work used the computational resources of the NIH high performance computing Biowulf cluster. We also acknowledge the Dale E Creighton Brain and Biobank. GGK receives funding from The Rossy Foundation and Edmond J Safra Philanthropic Foundation. The Douglas-Bell Canada Brain Bank is funded by Healthy Brains for Healthy Lives (CFREF), the R\u00E9seau Qu\u00E9b\u00E9cois sur le suicide, le troubles de l'humeur et les troubles associ\u00E9s (FRQ-S), and by Brain Canada. NM is funded by a Canadian Institutes of Health Research project grant. WJS receives a Wellcome Trust Clinical PhD Fellowship (220582/Z/20/Z). JDR receives a Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). TL receives an Alzheimer's Research UK senior fellowship. HRM is supported by research grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council, and the Michael J Fox Foundation. RRe is funded by Aligning Science Across Parkinson's. The London Neurodegenerative Diseases Brain Bank, KCL, receives funding from the MRC and as part of the Brains for Dementia Research project (jointly funded by the Alzheimer's Society and Alzheimer's Research UK). Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. JBR receives support from Wellcome Trust (220258) and NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR, the Department of Health and Social Care, PSP Association and Evelyn Trust, or the Medical Research Council (SUAG051 R101400). We would like to thank the Southwest Dementia Brain Bank (SWDBB), their donors and donor's families for providing brain tissue for this study. The SWDBB is part of the Brains for Dementia Research programme, jointly funded by Alzheimer's Research UK and Alzheimer's Society and is supported by Bristol Research into Alzheimer's and Care of the Elderly and the Medical Research Council. We acknowledge the Oxford Brain Bank, supported by the Medical Research Council, Brains for Dementia Research (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Centre. Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK Medical Research Council (G0400074), by NIHR Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and as part of the Brains for Dementia Research Programme jointly funded by Alzheimer's Research UK and Alzheimer's Society. Tissue samples were supplied by The Manchester Brain Bank, which is part of the Brains for Dementia Research programme, jointly funded by Alzheimer's Research UK and Alzheimer's Society. We are indebted to the Fundaci\u00F3 de Recerca Cl\u00EDnic Barcelona-Institut d'Investigacions Biom\u00E8diques August Pi i Sunyer Biobank, integrated in the Spanish National Biobanks Network, for the biological human samples and data procurement. GP-R acknowledges the support from the Department of Health (PERIS 2019 SLT008/18/00050). SB-\u00C9 is funded by the Joan Rod\u00E9s-Josep Baselga grant from the Fundamentos Banco Bilbao Vizcaya Argentaria. Brain tissues were obtained from The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam. The Brain bank at Karolinska Institutet receives Centrum f\u00F6r Innovativ Medicin funding. The NeuroCEB Neuropathology network includes: Franck Letournel (Centre Hospitalier Universitaire [CHU] Angers), Marie-Laure Martin-N\u00E9grier (CHU Bordeaux), Maxime Faisant (CHU Caen), Claude-Alain Maurage (CHU Lille), Vincent Deramecourt (CHU Lille), David Meyronnet (CHU Lyon), Delteil Clemence (CHU Marseille), Val\u00E9rie Rigau (CHU Montpellier), Danielle Seilhean (CHU PS, Paris), Susana Boluda (CHU PS, Paris), Isabelle Plu (CHU PS, Paris), Dan Christian Chiforeanu (CHU Rennes), Florent Marguet (CHU Rouen), and B\u00E9atrice Lannes (CHU Strasbourg). Brain tissues were received from the Victorian Brain Bank, supported by The Florey, The Alfred, Victorian Institute of Forensic Medicine and Coroners Court of Victoria and funded in part by Parkinson's Victoria, MND Victoria, FightMND, Yulgilbar Foundation and Ian and Maria Cootes. JBK is supported by NHMRC Dementia Team 1095127. GMH receives funding from NHMRC program grants 1037746 and 1132524, NHMRC Dementia Team 1095127, and NHMRC Fellowships 1079679 and 1176607. OP receives funding from by NHMRC program grant 1132524 and NHMRC Dementia Team 1095127, and NHMRC Fellowships 1103258 and 2008020. JJK and JRH both receive funding from NHMRC program grants 1037746 and 1132524, and NHMRC Dementia Team 1095127. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations.
ASJC Scopus subject areas
- Clinical Neurology