Creating the Pick’s disease International Consortium: Genetic association study of the MAPT H2 haplotype with risk of Pick’s disease

Rebecca R Valentino; William J Scotton; Shanu F Roemer; Professor Tammaryn Lashley; Michael G Heckman; Maryam Shoai; Alejandro Martinez-Carrasco; Nicole Tamvaka; Ronald L Walton; Matthew C Baker; Hannah L Macpherson; Raquel Real; Alexandra I Soto-Beasley; Kin Mok; Professor Huw R Morris; Professor Rosa Rademakers; Professor John A Hardy; Professor Dennis W Dickson; Professor Jonathan D Rohrer; Professor Owen A Ross

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

. Author manuscript; available in PMC: 2025 May 1.

Published in final edited form as: Lancet Neurol. 2024 May;23(5):487–499. doi: 10.1016/S1474-4422(24)00083-8

Creating the Pick’s disease International Consortium: Genetic association study of the MAPT H2 haplotype with risk of Pick’s disease

Rebecca R Valentino ^1,^*, William J Scotton ^2,^*, Shanu F Roemer ¹, Tammaryn Lashley ^3,⁴, Michael G Heckman ⁵, Maryam Shoai ⁴, Alejandro Martinez-Carrasco ⁶, Nicole Tamvaka ¹, Ronald L Walton ¹, Matthew C Baker ¹, Hannah L Macpherson ⁴, Raquel Real ⁶, Alexandra I Soto-Beasley ¹, Kin Mok ^4,^7,^8,⁹, Huw R Morris ⁶, Rosa Rademakers ^10,¹, John A Hardy ^7,^11,^4,¹², Dennis W Dickson ¹, Jonathan D Rohrer ^2,^*, Owen A Ross ^1,^13,^*, on behalf of the Pick’s disease International Consortium (PIC)

¹Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA

²Dementia Research Centre, Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK

³Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square Institute of Neurology London, UK

⁴Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK

⁵Division of Clinical Trials and Biostatistics, Mayo Clinic, Jacksonville, FL 32224, USA

⁶Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology, London, UK

⁷UK Dementia Research Institute at UCL, London, UK

⁸Division 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

⁹Hong Kong Center for Neurodegenerative Diseases, Hong Kong Science Park, Hong Kong, China

¹⁰VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp 2610, Belgium

¹¹Reta Lila Weston Institute, University College London, Queen Square Institute of Neurology, London, UK

¹²Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong, China

¹³Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL 32224, USA

denotes joint authorship

^†

Deceased

Author Contributions

RRV and WJS - Equal contribution first author, writing – conceptualisation, original draft, formal analysis, investigation, project administration, visualisation, writing – review & editing. SFR and TL - original draft, investigation, writing – review & editing. MGH - original draft, formal analysis, methodology, visualisation, writing – review & editing. MS and AMC- investigation, methodology, writing – review & editing. NT - project administration, investigation, writing – review & editing. RLW, MCB, HLM, RR, AISB and KM - investigation, writing – review & editing. HRM and RR - conceptualisation, resources, writing – review & editing. JAH, DWD and JDR - original draft, conceptualisation, funding acquisition, supervision, resources, writing – review & editing. OAR - writing – conceptualisation, original draft, funding acquisition, supervision, resources, writing – review & editing. All authors including those in PIC were involved in funding acquisition, resources, validation, critically reviewing and approving final version of manuscript.

^✉

Corresponding author’s contact information: Owen A. Ross, Ph.D., Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, Fax: (904)-953-7370, ross.owen@mayo.edu

PMCID: PMC11877577 NIHMSID: NIHMS2056186 PMID: 38631765

Abstract

Background:

Pick’s disease (PiD) is a rare and predominantly sporadic form of frontotemporal dementia that is classified as a primary tauopathy. PiD is pathologically defined by the presence of Pick bodies in the frontal and temporal lobes, composed of hyperphosphorylated, 3-repeat tau protein, encoded by the MAPT gene. The MAPT H1 haplotype is the major genetic risk factor for 4-repeat tauopathies, progressive supranuclear palsy and corticobasal degeneration, and is the priority genetic target for PiD. Thus, the primary aim of this study was to evaluate the specific association of MAPT H1-H2 with risk of PiD, age of onset (AAO), and disease duration (DD).

Methods:

We established the Pick’s disease International Consortium (PIC) and collected 338 (60.7% male) pathologically confirmed PiD brains from 35 sites in North America, Europe, and Australia. 1,312 neurologically healthy clinical controls were recruited from Mayo Clinic FL (N=881) or MN (N=431). For the primary analysis, individuals were directly genotyped for MAPT H1-H2 haplotype-defining variant rs8070723. In secondary analysis, we genotyped and constructed the six-variant MAPT H1 subhaplotypes. Associations of individual MAPT variants with risk of PiD, AAO, and DD were examined using logistic and linear regression models; odds ratios (ORs) and β coefficients were estimated and correspond to each additional minor allele. Regarding haplotype analysis, associations between six-variant MAPT haplotypes were evaluated using score tests for association under a logistic or linear regression framework.

Findings:

Our primary analysis found that the MAPT H2 haplotype was associated with increased risk of PiD (OR: 1.35, P=0.002). MAPT H2 was not associated with AAO (β: −0.54, P=0.45) or DD (β: 0.25, P=0.50) or DD (β: 0.25, 95% CI: −0.46 to 0.96, P=0.50) In secondary analysis involving H1 subhaplotypes, nominally significant (P<0.05) associations were observed with PiD for the H1f haplotype (OR: 0.11, P=0.049), with AAO for H1b (β: 2.66, P=0.011), H1i (β: −3.66, P=0.025) and H1u (β: −5.25, P=0.048), and with DD for H1x (β: −0.57, P=0.026).

Interpretation:

The PIC represents the first opportunity to perform relatively large-scale studies to enhance our understanding of the pathobiology of PiD. This study demonstrates that in contrast to the decreased risk in 4R tauopathies, the MAPT H2 haplotype is associated with an increased risk of PiD. This finding is critical in directing isoform-related therapeutics for tauopathies.

Funding:

There have been many funding sources acquired by the brain banks over decades to support the collection and characterization of the individuals that facilitated the creation of PIC (see acknowledgments), direct funding for the current genetic study was supported by Dolby grant, DRI (MRC), NIH and the Mayo Clinic Foundation.

Keywords: Pick’s disease, MAPT, haplotype, genetics, tau, frontotemporal dementia

Introduction

Pick’s disease (PiD) is a rare and predominantly sporadic subtype of frontotemporal lobar degeneration (FTLD) which represents approximately 5% of all dementias worldwide. Although there are no clinical diagnostic criteria for PiD, it develops in individuals at a mean age 57.0 years ±12.5 years and presents with behavioral change, impaired cognition and occasionally motor difficulties (1–7). PiD is a relatively rapidly progressive disease and patients die approximately 10 years after disease onset (1–6). Symptomatic treatments are available, but currently no treatments exist that can delay disease onset or progression. A definite diagnosis of PiD requires autopsy confirmation.

Neuropathologically, PiD is classified by severe frontotemporal, knife-edge like cortical atrophy macroscopically, and microscopically the presence of ballooned neurons and argyrophilic, tau-immunoreactive inclusion “Pick bodies” in frontal and temporal regions (1). Characteristic Pick bodies consist of hyperphosphorylated 3-repeat (3R) tau aggregate proteins which are encoded by the MAPT gene on chromosome 17 (7,8), and therefore PiD is classified as a 3R tauopathy. MAPT encodes six major tau protein isoforms in the adult human brain, and these are generated by alternative splicing of exons 2, 3, and 10 influencing the number of repeat domains across the tau protein (9). More specifically, alternative splicing leading to exon 10 exclusion results in 3-repeat units in the microtubule binding C-terminal domain, generating 3R tau proteins (10).

Rare missense and gene duplication mutations of MAPT have been identified in a handful of individuals with PiD or with PiD-like pathology (11–14); however, these data require replication, and to date independent cohorts of individuals with PiD do not report common missense MAPT mutations (15). The MAPT gene also has two well characterized common haplotypes, H1 and H2, which developed from a 900kb ancestral genetic inversion event (16). Not only has MAPT H1 consistently been associated with an increased risk of 4-repeat (4R) primary tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), but the H1 haplotype is also the strongest genetic risk factor for both diseases (17,18). To date, this observation has not been replicated in 3R tauopathy of PiD which may be due to the limited available sample size (19,20), and thus a targeted analysis is warranted.

Due to its rare prevalence and the inability to diagnose it clinically in life, PiD is an understudied neurodegenerative disease, and its genetic etiology is unknown. As previously mentioned, the few studies of MAPT haplotype in PiD that have been conducted were small and underpowered. Moreover, limited access to 3R tauopathy samples has stalled research advancement in understanding how MAPT haplotypes and isoforms influence disease risk/pathology and has prevented progress in developing isoform-specific therapies. To address this, we established the Pick’s disease International Consortium (PIC) and are collecting data from pathologically confirmed individuals with PiD from sites worldwide, with current sites from North America, Europe, and Australia. Whilst also developing an in-depth consortium database of clinical, pathological, and demographic information, the primary aim of the PIC was to evaluate the association of the MAPT H1/H2 haplotype with disease risk, age of onset (AAO), and disease duration (DD) in PiD.

Methods

Pick’s disease International Consortium (PIC)

Given Pick’s disease cannot currently be diagnosed in life, due to the heterogeneity of clinical presentation and the absence of a specific in-vivo biomarker, the incidence and prevalence of Pick’s disease is currently unknown. Brain bank studies suggest that could account for up to 30% of FTLD-Tau individuals at autopsy, and 10% of all instances cases of FTLD overall(22). The prevalence and incidence of the FTLD syndromes has been estimated at 10.2/100,000 and 1.61/100,000 person-years(23) respectively, suggesting that the prevalence of Pick’s disease could around 1/100,000 with an incidence of around 0.2/100,000 person years.

Due to the rare and understudied landscape of PiD, researchers at Mayo Clinic Brain Bank in Jacksonville, FL, USA (MC) and the UK Dementia Research Institute at University College London Queen Square Institute of Neurology (UCL) led efforts to establish the world’s first international consortium for Pick’s disease (PIC). MC led the effort for identifying and sourcing individuals with PiD from North American regions and UCL was responsible for collecting individuals with PiD from European and Australasian territories. Inclusion criteria were a neuropathologic diagnosis of PiD with Pick bodies and available frozen brain tissue. Exclusion criteria were frontotemporal dementia due to etiology other than a 3R predominant tauopathy or lack of frozen specimens. Institutional Review Board (IRB) approval was obtained for the studies at both collection hubs (MC and UCL) and each individual brain bank had institutional IRB approval for collection and sharing of specimens.

Study Participants

In the current study, 338 neuropathologically confirmed individuals with PiD were recruited from 35 sites in North America, Europe, and Australia (Figure 1). Frozen brain tissue from cerebellum or prefrontal cortex were obtained from each case and sent to two major collection hubs in North America (MC) and Europe (UCL). All individuals were self-reported unrelated and Caucasian, non-Hispanic (genetically confirmed by array data in individuals with PiD). Baseline demographic information was collected for all individuals (AAO and age at death (AAD) for individuals with PiD, age at blood collection for controls, and sex). DD was calculated from the difference between AAD and AAO for a subset of 309 individuals with PiD. In addition to basic demographic information, the PIC also collected information related to clinical characteristics (e.g. clinical diagnosis, behavioral and language impairments, and presence/absence of parkinsonism), and pathological information (e.g. Thal phase, Braak stage, and brain weight,) for each individual with PiD, as well as noting whether other tissues and brain imaging data were available. Individuals were removed if a rare MAPT missense mutation was identified by Sanger exon sequencing (primers on request). Peripheral blood-derived DNA was provided from 1,312 controls from Mayo Clinic in Jacksonville, FL (N=881) or Rochester, MN (N=431). Controls were deemed neurologically healthy by neurologists at Mayo Clinic.

Figure 1: — Dark red = countries that have collected and donated Pick’s disease tissues.

Neuropathological diagnosis of Pick’s disease

Established methods for the neuropathological diagnosis of Pick’s disease

Currently, diagnostic consensus criteria for the neuropathologic diagnosis of PiD do not exist. In many diagnostic centers a neuropathological diagnosis of PiD relies on the presence of argyrophilic, spherical neuronal inclusions using traditional silver staining methods, such as Bielschowsky’s or Gallyas-Braak silver staining methods. Both silver staining methods stain Alzheimer’s disease (AD) neurofibrillary tangles, yet spherical inclusions in PiD are positive with Bielschowsky and negative on the Gallyas-Braak silver staining method (24). This differentiation in silver staining methods is helpful especially for centers that do rely on immunohistochemistry against phosphorylated tau (p-tau) and do not have isotype specific tau antibodies incorporated in the diagnostic work-up as AD and PiD neuropathologic changes may co-exist in the same patient. Immunohistochemistry against epitope-specific tau antibodies further helps to distinguish between AD and PiD features. Since both spherical inclusions and neurofibrillary tangles stain positive with antibodies against phosphorylated tau (p-tau), epitope-specific antibodies highlight selective 3R tau spherical inclusions in PiD, which is further validated by antibodies to 4R tau where these spherical inclusions stain negative. This distinction is particularly obvious in the granule cell neurons of the hippocampal dentate fascia, which may be used solely to diagnose PiD.

PIC diagnostic study selection criteria for pathology confirmed Pick’s disease

Since a harmonized neuropathologic diagnostic scheme does not exist it became pivotal to the PIC aims to establish a defined set of operational diagnostic criteria within PIC that would ensure that submitted individuals with PiD reflect a 3R-predominant tauopathy. All individuals with PiD submitted to the PIC had an archival neuropathologic diagnosis of PiD (i.e. the presence of argyrophilic or p-tau positive spherical inclusions) and underwent neuropathological assessments at their respective brain banks. Due to the multi-site nature of the PIC, each participating center were requested to submit and report respective 3R and 4R tau staining results for each individual PiD case to the PIC. To fulfill PIC criteria all individuals had to confirm the presence of Pick bodies and must have had 3R tau positive and 4R tau negative inclusions. The additional presence of ballooned neurons and negative Gallyas staining of inclusions was preferred to confirm diagnosis. If 3R/4R tau immunohistochemistry had not been performed at their respective brain banks, centers submitted routinely cut sections (up to seven microns) of unstained, formalin fixed paraffin embedded tissue from hippocampal, frontal or temporal lobe regions for 3R and 4R tau immunohistochemistry assessments (Figure 2). Individuals with PiD submitted to Mayo Clinic Brain Bank for Neurodegenerative Diseases were evaluated by two PIC neuropathologists (DWD, SFR) and individuals with PiD submitted to UCL were examined by two PIC investigators (WS, TL) which included a PIC neuropathologist (TL), all using the PIC diagnostic study selection criteria. All sections were stained using standard immunohistochemical methods (25) (Figure 3).

Figure 2: — [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: — 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.

DNA Preparation

DNA was extracted from each subject at either the Mayo Clinic (North American PiD series and all controls) or the Queen Square Brank Bank (European/Australasian PiD series) for Neurological Disorders. At the Mayo Clinic, genomic DNA was extracted from frozen brain tissue from individuals with PiD and from peripheral blood lymphocytes from controls using an automated or manual method. Automated DNA extractions were carried out using Autogen Tissue Kit reagents according to manufacturer protocols and were processed on the Autogen FlexSTAR+ (both Autogen, Holliston, MA, USA). At the Queen Square Brain Bank for Neurological Disorders, total genomic DNA was extracted from frozen brain tissue using the Kleargene XL Nucleic Acid Purification kit (LGC, Hoddesdon, Herts, UK). DNA quality was assessed with a NanoDrop 8000 spectrophotometer (ThermoFisher Scientific, USA) and absorbance ratios for 260/280 and 260/230 were between 1.7-2.2 and 2.0-2.2, respectively.

SNP Genotyping

The MAPT H2 haplotype-tagging variant rs8070723 was genotyped in all individuals with PiD and controls. In addition, the five common MAPT variants (rs1467967, rs242557 [the H1C haplotype-tagging variant], rs3785883, rs2471738, and rs7521) which along with rs8070723 define H1-subhaplotypes were genotyped to assess MAPT subhaplotype structure (26,27). North American individuals with PiD and all controls were genotyped using TaqMan SNP genotyping assays on an ABI 7900HT Fast Real-Time PCR system (Applied Bio-systems, Foster City, CA, USA), as previously described (28). MAPT variants were genotyped according to manufacturer instructions (primer sequences available upon request). Genotypes were called using TaqMan Genotyper Software v1.3 (Applied Bio-systems, Foster City, CA, USA). European and Australasian individuals with PiD were genotyped using KASP^™ SNP genotyping assays on the Hydrocyler2 system (LGC Genomics, Hoddesdon, Herts, UK) according to manufacturer instructions, and were read on a PHERAStar FSX plate reader (BMG Labtech, Cary, NC, USA). Genotypes were called using Kraken KlusterKaller^™ software (LGC Genomics, Hoddesdon, Herts, UK). Genotype call rates for all individuals were 100% for each variant. There was no evidence of a departure from Hardy-Weinberg equilibrium in controls for any of the six variants (all P >0.01 after Bonferroni correction). All individuals with PiD were assessed for European ancestry using available genome wide SNP genotyping data. After standard genotyping data quality control steps, we performed a principal components analysis (PCA), merged all individuals with PiD with the European (CEU) HapMap reference dataset, and identified any individuals with non-white European ancestry (individuals with PiD who deviated more than six standard deviations from the mean of the first 10 principal components of the HapMap3 CEU population) which were excluded from further analysis. For clarity, individuals with known Hispanic or non-European ancestry were excluded as the frequencies of genetic variants can vary quite substantially based on ethnic background, and there were not enough non-European individuals in our study to analyze such individuals separately or adjust for this factor in regression models. For controls where whole-genome data was not available to confirm the aforementioned self-reported Caucasian/non-Hispanic ethnicity, we also compared the control allele frequencies with the population level frequencies on GnomAD (http://gnomad.broadinstitute.org/), as well as the frequencies of a subset of controls (n=980) from the Global Parkinson’s Genetics Program (GP2) (29). Allele and genotype frequencies for each variant are detailed in Supplementary Tabble 1.

Statistical Analysis

Statistical analyses were performed using R Statistical Software (version 4.1.2; R Foundation for Statistical Computing, Vienna, Austria). Associations between individual MAPT variants and risk of PiD were evaluated using logistic regression models that were adjusted for age (age at death in PiD and age at blood draw in controls) and sex; each variant was assessed as number of minor alleles (i.e., under an additive model) in all regression analysis. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated and correspond to each additional minor allele. In PiD individuals, associations of individual variants with AAO were examined using linear regression models that were adjusted for sex and cohort (Europe/Australia or North America), while associations between individual variants with DD were assessed using linear regression models that were adjusted for sex, AAO, and cohort in DD analysis. DD was considered on the square root scale in all regression analyses owing to its skewed distribution. Regression coefficients (referred to as β) and 95% CIs were estimated and are interpreted as the increase in the mean AAO or DD (on the square root scale for DD) corresponding to each additional copy of the minor allele. For all associations between individual MAPT variants and outcomes, analysis involving rs8070723 (the H2-tagging variant) was considered as the primary analysis, with results for the five remaining variants considered as secondary and presented for completeness. In more exploratory analysis, associations of rs8070723 with other clinical and neuropathological factors were also assessed; these analyses are described in the Supplemental Information.

Associations between six-variant MAPT haplotypes and risk of PiD were assessed using the R haplo.stats package(30). Specifically, based on estimated haplotype probabilities, the expected number of copies of the given haplotype was first estimated for each individual, and subsequently logistic regression models that were adjusted for age (age at death in PiD and age at blood draw in controls) and sex were utilized to assess the association between the expected number of copies of the given haplotype and risk of PiD (30). ORs and 95% CIs were estimated and correspond to each additional copy of the given haplotype. In analysis of individuals with PiD, associations of six-variant MAPT haplotypes with AAO were assessed in the same way based on the expected number of copies of the given haplotype (30) , except that linear regression models that were adjusted for sex and cohort were employed. Finally, associations of six-variant MAPT haplotypes with DD were evaluated in this same manner(30) here linear regression models that were adjusted for sex, AAO, and cohort were utilized. β-coefficients and 95% CIs were estimated and are interpreted as the increase in the mean AAO or DD (on the square root scale for DD) corresponding to each additional copy of the given haplotype. Haplotypes occurring in <1% of individuals in a specific analysis were excluded from that analysis.

We adjusted for multiple testing separately for each outcome measure that was examined (presence of PiD, AAO, or DD). P-values <0.05 were considered as statistically significant in the primary analysis involving the MAPT rs8070723 variant. In secondary analysis assessing associations between MAPT haplotypes and outcomes, p-values < 0.0028 (18 tests, corresponding to 18 different haplotypes with ≥1% frequency in this specific analysis) were considered as statistically significant after Bonferroni correction in the disease-association analysis, and p-values < 0.0031 (16 tests, corresponding to 16 different haplotypes with ≥1% frequency in this specific analysis) were considered as statistically significant in the AAO and DD analyses. P-values ≤ 0.05 were considered as significant in all remaining analysis. All statistical tests were two-sided. Examples of R code for the association analysis involving individual variants as well as 6-variant haplotypes are provided in the Supplementary Information.

Role of the funding source

Study sponsors (for individual brain bank collections) had no such involvement with this study design, in the collection, analysis, and interpretation of data, in the writing of the report, or in the decision to submit the paper for publication. All authors confirm that they had full access to all the data in this study and accept responsibility of publication submission.

Results

A total of 338 pathologic-defined individuals with PiD were identified across 35 independent recruitment sites to establish the first PiD consortium (PIC). Characteristics of the 338 individuals with PiD and the 1,312 controls are summarized in Table 1. There was a significant association between the MAPT rs8070723 H2 allele and an increased risk of PiD in the overall series (OR: 1.35, 95% CI: 1.12-1.64, P=0.0021), with minor allele frequencies of 29.0% in the 338 individuals with PiD and 23.0% in the 1,312 controls. MAPT rs8070723 was not associated with AAO (β: −0.54, 95% CI: −1.94 to 0.87, P=0.45) or DD (β: 0.25, 95% CI: −0.46 to 0.96, P=0.50). Single-variant associations with PiD, AAO and DD are shown for all six MAPT variants used to define MAPT haplotypes in Supplementary Tables 2 and 3. Of note, there was not a notable association between rs242557 and risk of PiD (OR: 0.94, 95% CI: 0.79-1.12, P=0.51, Supplementary Table 2). We further analyzed the association of MAPT H2 with the available clinical and neuropathological data and observed no significant associations (Supplementary Table 4).

Table 1:

Summary of characteristics of the Pick’s disease series and controls.

Variable	N	Median (25^th percentile, 75^th percentile) or No. (%) (N=338)
Pick’s disease series
Age at death (years)		69 (65, 74)
Age of disease onset (years)		58 (54, 65)
Disease duration (years)		10 (8, 13)
Sex
Male		205 (60.7%)
Female		133 (39.3%)
Clinical diagnosis	328
FTD		262 (79.9%)
AD		40 (12.2%)
CBS		15 (4.6%)
PSP		2 (0.6%)
Dementia not otherwise specified		8 (2.4%)
Vascular dementia		1 (0.3%)
Behavioral impairment during illness	232	188 (81.0%)
Language impairment during illness	221	153 (69.2%)
Parkinsonism during illness	206	56 (27.2%)
Braak NFT stage	176
0		87 (49.4%)
I		29 (16.5%)
II		28 (15.9%)
III		11 (6.3%)
IV		10 (5.7%)
V		4 (2.3%)
VI		7 (4.0%)
Thal amyloid phase	177
0		100 (56.5%)
1		32 (18.1%)
2		18 (10.2%)
3		15 (8.5%)
4		7 (4.0%)
5		5 (2.8%)
Brain weight (g)	296	980 (880, 1083)
Controls
Age at blood draw (years)		69 (61, 75)
Sex
Male		611 (46.6%)
Female		701 (53.4%)

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FTD=frontotemporal dementia; bvFTD=behavioral variant FTD; PPA=primary progressive aphasia; AD=Alzheimer’s disease; CBS=corticobasal syndrome; PSP=progressive supranuclear palsy; VaD=vascular dementia; NFT=neurofibrillary tangle.

Age at disease onset and disease duration information was not available for 29 individuals in the Pick’s disease series.

In secondary analysis, an evaluation of associations between six-variant MAPT haplotypes and risk of PiD is displayed in Table 2. As with the single-variant analysis, the H2 haplotype was associated with an increased risk of PiD (OR: 1.34, 95% CI:1.11-1.63, P=0.0028); the slight difference between the two numerical estimates is due to the two different analysis approaches. Additionally, a nominally significant (P<0.05) association was noted for the rare H1f haplotype (OR: 0.11, 95% CI: 0.01-0.99, P=0.049), with a slightly weaker finding noted for H1b (OR: 0.76, 95% CI: 0.58-1.00, P=0.051). There were no other notable associations between MAPT haplotypes and risk of PiD (all P≥0.15, Table 2).

Table 2:

Associations between MAPT haplotypes and risk of Pick’s disease.

	MAPT variant						Haplotype frequency (%)		Association with Pick’s disease

Haplotype	rs1467967	rs242557	rs3785883	rs2471738	rs8070723	rs7521	Pick’s disease patients (N=338)	Controls (N=1312)	OR (95% CI)	P-value
H1b	G	G	G	C	A	A	13.1	16.0	0.76 (0.58, 1.00)	0.051
H1c	A	A	G	T	A	G	10.2	11.3	0.93 (0.70, 1.25)	0.65
H1d	A	A	G	C	A	A	7.4	7.1	0.99 (0.68, 1.42)	0.94
H1e	A	G	G	C	A	A	9.8	9.0	1.03 (0.74, 1.42)	0.87
H1f	G	G	A	C	A	A	0.0	1.2	0.11 (0.01, 0.99)	0.049
H1g	G	A	A	C	A	A	0.7	1.1	0.43 (0.11, 1.65)	0.22
H1h	A	G	A	C	A	A	4.0	4.1	0.95 (0.57, 1.57)	0.85
H1i	G	A	G	C	A	A	3.9	4.4	0.98 (0.60, 1.61)	0.95
H1l	A	G	A	C	A	G	3.6	3.0	1.11 (0.67, 1.84)	0.69
H1m	G	A	G	C	A	G	2.9	2.9	1.00 (0.56, 1.78)	0.99
H1o	A	A	A	C	A	A	1.1	2.3	0.53 (0.23, 1.26)	0.15
H1p	G	G	G	T	A	G	1.1	1.5	0.82 (0.33, 2.04)	0.66
H1r	A	G	G	T	A	G	0.7	1.1	0.63 (0.20, 2.01)	0.44
H1u	A	A	G	C	A	G	2.4	2.4	1.11 (0.58, 2.11)	0.75
H1v	G	G	A	T	A	G	2.2	1.2	1.50 (0.70, 3.21)	0.30
H1x	G	A	A	T	A	G	1.3	1.3	1.06 (0.44, 2.56)	0.91
H1y	A	A	A	T	A	G	1.4	1.6	0.85 (0.34, 2.07)	0.71
H2	A	G	G	C	G	G	28.5	22.7	1.34 (1.11, 1.63)	0.0028

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ORs, 95% CIs, and p-values result were calculated using the R haplo.stats package; based on estimated haplotype probabilities, the expected number of copies of the given haplotype was first estimated for each individual. Subsequently, logistic regression models that were adjusted for age (age at death in PiD and age at blood draw in controls) and sex were utilized to assess the association between the expected number of copies of the given haplotype and risk of PiD. ORs and 95% CIs correspond to each additional copy of the given haplotype. P-values <0.0028 are considered as statistically significant after applying a Bonferroni correction for multiple testing for the 18 different haplotypes that were assessed for association with risk of Pick’s disease.

OR=odds ratio; CI=confidence interval.

Associations of MAPT haplotypes with AAO and DD in individuals with PiD are shown in Table 3. None of the six-variant MAPT haplotypes were significantly associated with AAO or DD after correcting for multiple testing (P<0.0031 considered significant). However, nominally significant associations were observed with AAO for H1b (β: 2.66, 95% CI: 0.63 to 4.70, P=0.011), H1i (β: −3.66, 95% CI: −6.83 to −0.48, P=0.025) and H1u (β: −5.25, 95% CI: −10.42 to −0.07, P=0.048), and with a shorter DD for H1x (β: −0.57, 95% CI: −1.07 to −0.07, P=0.026).

Table 3:

Associations of MAPT haplotype with age of disease onset and disease duration in individuals with Pick’s disease.

		Association with age of disease onset		Association with disease duration

Haplotype	Haplotype frequency (%), N=309	β (95% CI)	P-value	β (95% CI)	P-value
H1b	13.3%	2.66 (0.63, 4.70)	0.011	−0.01 (−0.17, 0.15)	0.91
H1c	10.0%	1.63 (−0.61, 3.86)	0.15	0.01 (−0.16, 0.19)	0.89
H1d	7.2%	0.79 (−1.79, 3.38)	0.55	−0.15 (−0.35, 0.05)	0.15
H1e	9.3%	0.52 (−1.94, 2.98)	0.68	0.05 (−0.14, 0.24)	0.60
H1h	4.0%	2.03 (−1.57, 5.64)	0.27	−0.10 (−0.38, 0.18)	0.50
H1i	4.1%	−3.66 (−6.83, −0.48)	0.025	−0.12 (−0.37, 0.13)	0.36
H1l	3.5%	−1.75 (−5.42, 1.92)	0.35	0.07 (−0.22, 0.35)	0.65
H1m	3.1%	−1.25 (−5.33, 2.84)	0.55	0.14 (−0.18, 0.46)	0.38
H1o	1.2%	0.05 (−6.91, 7.00)	0.99	0.01 (−0.52, 0.55)	0.96
H1p	1.0%	−5.65 (−12.60, 1.30)	0.11	0.01 (−0.53, 0.55)	0.96
H1u	2.2%	−5.25 (−10.42, −0.07)	0.048	−0.38 (−0.78, 0.02)	0.066
H1v	2.1%	−1.74 (−6.61, 3.13)	0.48	0.30 (−0.07, 0.68)	0.11
H1x	1.4%	−5.39 (−11.84, 1.07)	0.10	−0.57 (−1.07, −0.07)	0.026
H1y	1.5%	−0.70 (−6.93, 5.54)	0.83	0.31 (−0.17, 0.79)	0.21
H1z	1.6%	−1.81 (−8.02, 4.40)	0.57	−0.01 (−0.49, 0.47)	0.98
H2	29.4%	−0.62 (−2.03, 0.79)	0.39	0.05 (−0.06, 0.16)	0.39

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β values, 95% CIs, and p-values were calculated using the R haplo.stats package; based on estimated haplotype probabilities, the expected number of copies of the given haplotype was first estimated for each individual. Subsequently linear regression models that were adjusted for sex and cohort (Europe/Australia or North America) were utilized to assess the association between the expected number of copies of the given haplotype and age of disease onset, while linear regression models that were adjusted for sex, age of disease onset, and cohort were used to examine the association between the expected number of copies of the given haplotype and disease duration. β values are interpreted as the change in the mean value of the given outcome (age of disease onset or disease duration) corresponding to each additional copy of the given haplotype. P-values <0.0031 are considered as statistically significant after applying a Bonferroni correction for multiple testing for the 16 different haplotypes that were assessed for association with age of disease onset and disease duration.

β=regression coefficient; CI=confidence interval.

Discussion

PiD is a rare, predominantly sporadic 3R tauopathy that presents primarily as a behavioral or language variant of frontotemporal dementia (1–6). Little is known regarding the etiology or underlying pathobiology of the disease. To date, no genetic variation has been shown to associate with disease risk, although a small number of individuals with PiD or PiD-like pathology have been suggested to be caused by rare MAPT mutations (11–14). Thus, given the rare nature of PiD, a comprehensive screening of rare variants across tau-related genes including copy number changes is warranted and the creation of PIC will facilitate these important studies. It is likely that rare MAPT mutations that strongly promote the expression of 3R specific isoforms of tau will influence the PiD phenotype. In the present study we have shown that the common MAPT H2 haplotype, with a strongly protective OR in 4R-tauopathy, is associated with an increased risk of PiD (3R tauopathy). This was only possible by establishing and creating a global consortium (PIC) to increase the number of available pathologically defined individuals with PiD. Previous early genetic studies were underpowered with only 34 and 33 individuals with PiD respectively (19,20); a ten-fold increase in sample size was needed to establish MAPT H2 as a risk factor for in PiD.

Previous research in frontotemporal dementia linked to chromosome 17 with tau pathology (FTDP17t) has clearly demonstrated that mutations in the 5′ splice site of MAPT exon 10 can increase the expression of the 4R tau isoform, emphasizing how important exon 10 splicing regulation is in tangle formation and neurodegeneration (16,31). Given the association of MAPT H2 with a 3R-tauopathy, and its protection in 4R-tauopathy, it is possible that the MAPT H1 and H2 haplotypes increase the expression of 4R and 3R tau respectively. Previous studies have attempted to investigate the haplotype risk in related neurodegenerative disorders (e.g. PSP and CBD Supplementary Table 5) and the subsequent influence on MAPT/tau expression although results have been inconclusive; given the presence of six different isoforms in human brain defining specific isoform expression remains complex (32–34). The genetic predisposition herein described would appear to support the hypothesis that the pathologic effects of the H1-H2 haplotypes is via isoform specific expression differences. This may have implications in the determination of therapeutic strategies that have focused on either overall lowering of tau expression or specifically targeting the lowering of 4R-tau or increasing 3R-tau isoforms. The overall balance of the 3R and 4R forms of tau would appear to be important for the primary tauopathies but does not in itself explain the mixed pathology observed in AD, although it is tempting to suggest an overall increased expression of total tau may be underlying the mixed pathology. Studies on haplotype/isoform-specific MAPT expression are critically needed.

In addition to providing evidence that the MAPT-H2 haplotype is associated with an increased risk of PiD, we observed nominally significant associations of H1 subhaplotypes with risk of PiD, AAO, and DD, however these will require validation. This study has strengths in the assembled large PiD series of patients and the direct genotyping of the H1-H2 haplotype, but there still remains several limitations which are important to note. Our study did not include a replication series, as generation of such a series does not currently exist given the nature of the PIC; future replication of our reported risk association between MAPT H2 and PiD will be important. The possibility of a type II error (i.e. false-negative finding) is important to consider, and we cannot conclude that there is no true association between a given haplotype and risk of PiD simply due to a non-significant p-value in this study. It is for this reason that our p-value of 0.002 (and OR of 1.35) for H2 regarding association with risk of PiD is of notable interest when considering the importance and prior knowledge of the MAPT gene in tauopathies, even though this p-value does not approach the threshold of 5 x 10-8 that would be considered statistically significant in a GWAS. Additionally, without available genome-wide SNP data for controls, we were unable to regress out genetic principal components or genetically confirm the self-reported Caucasian/non-Hispanic ethnicity, and so it is possible that population stratification could have had an influence on our results. However, we used the case genetic principal components to exclude any individuals with non-European ancestry and our control MAPT H1-H2 frequencies (rs8070723 minor allele frequency 23%) were in keeping with published data (35,36) and the general population frequency (19.7% in non-Finnish Europeans on GnomAD). The highest population frequency on gnomAD is 23.8% which is very similar to the control frequency of 23% in this study. In addition we checked the allele frequency for rs8070723 in a subset of 980 neurologically healthy European controls from the GP2 cohort: again this demonstrated a frequency of 23% giving further confidence that population stratification was not confounding our results. Related to ethnicity, as our study included only individuals of European descent, we cannot extrapolate our findings to individuals of other racial and ethnic backgrounds, indeed we hope that we can establish further collaboration to create a truly worldwide PIC to address this. Finally, although ideally we would have included age- and sex-matched controls from each site to allow for site-specific adjustment in our analysis, unfortunately this was not currently possible in this large collaborative effort of brain banks.

In summary, PiD is a rare and understudied disease with a devastating impact on both patients and their families. Through collaboration and building of the PIC, we have for the first time a rare opportunity to engage in studies that may tease out the underlying pathobiology in PiD. As a primary tauopathy, there is the possibility that the identification of genetic variants, such as MAPT H2, involved in PiD pathology will inform on other more common tau-related disorders, PSP, CBD, and potentially AD. Larger scale unbiased studies to explore genome-wide or structural genetic variation in PiD are now warranted. Furthermore, resolving the genetic determinants of PiD may help in establishing diagnostic criteria and elucidating the dysfunctional pathways may direct future therapeutic intervention strategies.

Supplementary Material

supplementary

NIHMS2056186-supplement-supplementary.docx^{(34.4KB, docx)}

Research in context.

Evidence before this study: We searched original research articles on PubMed written in English between January 1^st 1980 and January 1^st 2023. We assessed the quality of evidence using the GRADE approach(21). Pick’s disease is recognized as a rare frontotemporal dementia that presents with a heterogenous clinical phenotype and no therapeutic management approach is available. It is a primary 3R-tauopathy and is diagnosed post-mortem. Given the rarity of the disorder only a handful of genetic studies have been performed on individuals with Pick’s disease and an association with MAPT H1 (observed for other primary tauopathies) or H2 haplotypes was unclear. We searched PubMed using the terms: ((Pick’s disease) or (Pick disease)) and ((genetic*) or (genome wide association study) or (GWAS))

Added value of this study: Understanding the genetic etiology of the susceptibility and progression of Pick’s disease is crucial to nominate therapeutic intervention strategies. The current study established the Pick’s disease international consortium (PIC), identifying 338 pathologically defined individuals with Pick’s disease across 35 brain banks. With this unique series we were able to identify a disease risk association with the MAPT H2 haplotype, which has been nominated as protective in primary 4R tauopathies.

Implications of all the evidence available: The establishment of the PIC opens up opportunities to gain further insight into the underlying pathogenesis and etiology of Pick’s disease. Collection of these individuals will facilitate future studies not only on genetics but also provide a resource for clinicopathologic, epigenetic, transcriptomic, and proteomics studies. The observation of Pick’s disease risk association with MAPT H2 suggests that the haplotype status may influence tau 3R-4R ratio isoform expression and may inform future therapeutic strategies targeting MAPT/tau expression (e.g. antisense oligonucleotide or immunotherapy approaches).

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Acknowledgements

This paper is dedicated to the memory of John Q. Trojanowski, M.D. Ph.D., who was an inspirational researcher and neuropathologist at the University of Pennsylvania and pioneered discoveries in tauopathies that resulted in improvements of diagnosis and available treatments. 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 PIC would not exist, and this study would not have been possible.

Funding statement

Mayo Clinic: 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), LEADS Neuropathology Core (U01AG057195), and the Chan Zuckerberg Initiative Collaborative Pairs Grant, which are paid directly to the institute. KAJ is supported by National Institutes of Health (NIH) grants (R01 DC014942, R01, R01-AG37491, R01-NS89757, RF1-NS112153 and RF1-NS120992). BFB is supported by National Institutes of Health (NIH) grants (P30 AG62677, U19 AG063911, U01 NS100620, U19 AG071754); the Robert H. and Clarice Smith and Abigail Van Buren Alzheimer s 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; the Turner Family Foundation. ZKW is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), Mayo Clinic Center for Regenerative Medicine, the 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. He serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206), Neuraly, Inc. (NLY01-PD-1), and Vigil Neuroscience, Inc. (VGL101-01.002, VGL101-01.201, PET tracer development protocol, and Csf1r biomarker and repository project) grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc. OAR and DWD are both supported by National Institute of Neurological Disorders and Stroke (NINDS) Tau Center without Walls Program (U54-NS100693) and NIH (UG3-NS104095). DWD receives research support from the NIH (P30 AG062677; U54-NS100693; P01-AG003949), CurePSP, the Tau Consortium, and the Robert E. Jacoby Professorship. OAR is supported by NIH (P50-NS072187; R01- NS078086; U54-NS100693; U54- NS110435), Department of Defence (DOD) (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.

UCSF: 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.

UPenn: ES, JQT, MG, VMVD, DJI, DAW, and EBL all receive funding through NIH - ES: P01-AG017586, P01-AG066597, P30-AG010124, P30-AG072979; JQT: P01-AG017586, P30-AG010124, P30-AG072979; MG: P01-AG017586, P01-AG066597, P30-AG010124, P30-AG072979; VMVD: P01-AG017586, P01-AG066597, P30-AG010124, P30-AG072979; DJI: R01-NS109260, P30-AG010124, P01-AG066597; DAW: P30-AG010124, P30-AG072979; and EBL: P01-AG017586, P01-AG066597, P30-AG010124, P30-AG072979.

Northwestern: ER, TG, SW, EHB, 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 National Institute of Neurological Disorders and Stroke (NINDS) under award number R01 NS075075. MEF also receives support from NIA grant K08 AG065463.

Banner: 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.

Emory: MG is supported by NIH grant P30 AG066511. MDC receives funding from NIH grant RF1 NS118584.

Columbia: We thank the Columbia University Alzheimer’s Disease Research Center (ADRC), funded by NIH grant P30AG066462, to S.A. Small (P.I.), and A. Teich from New York Brain Bank for providing biological samples and associated information. The ADRC is supported by the National Institutes of Health, through grant number P30AG066462. ACH receives NIH support through P30AG066462.

Duke: The Bryan Brain Bank and Biorepository of the Duke-UNC ADRC and SJW are supported by the NIA grant P30AG072958

MGH: 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.

Indiana: BG is supported by the US National Institutes of Health (grant P30-AG010133).

NIH: This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA), National Institutes of Health, Department of Health and Human Services; project number ZO1 AG000535, as well as the National Institute of Neurological Disorders and Stroke. This work utilized the computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov).

Western University: We also acknowledge the DEC Brain & Biobank.

Krembil: GGK receives funding from The Rossy Foundation and Edmond J. Safra Philanthropic Foundation.

McGill: The Douglas-Bell Canada Brain Bank is funded by Healthy Brains for Healthy Lives (CFREF), the Réseau Québécois sur le suicide, le troubles de l’humeur et les troubles associés (FRQ-S), and by Brain Canada. NM is funded by a CIHR project grant.

UCL: 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 Michael J Fox Foundation. RR is funded by ASAP.

KCL: 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: 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 or the Department of Health and Social Care; PSP Association and Evelyn Trust; Medical Research Council (SUAG051 R101400).

Bristol: 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 BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the Medical Research Council.

Oxford: We acknowledge the Oxford Brain Bank, supported by the Medical Research Council (MRC), Brains for Dementia Research (BDR) (Alzheimer Society and Alzheimer Research UK), Autistica UK, and the NIHR Oxford Biomedical Research Centre.

Newcastle: 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.

Manchester: 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.

Barcelona: We are indebted to the HCB-IDIBAPS Biobank, integrated in the Spanish National Biobanks Network, for the biological human samples and data procurement. Gerard Piñol-Ripoll acknowledges the support from the Department of Health (PERIS 2019 SLT008/18/00050). Sergi Borrego-Écija is funded by the Joan Rodés - Josep Baselga grant from the FBBVA.

Amsterdam: Brain tissues were obtained from The Netherlands Brain Bank (NBB), Netherlands Institute for Neuroscience, Amsterdam (open access: www.brainbank.nl). All Material has been collected from donors for or from whom a written informed consent for a brain autopsy and the use of the material and clinical information for research purposes had been obtained by the NBB.

Stockholm: The Brain bank at Karolinska Institutet receives CIMED-funding.

Paris: The NeuroCEB Neuropathology network includes: Dr Franck Letournel (CHU Angers), Dr Marie-Laure Martin-Négrier (CHU Bordeaux), Dr Maxime Faisant (CHU Caen), Pr Catherine Godfraind (CHU Clermont-Ferrand), Pr Claude-Alain Maurage (CHU Lille), Dr Vincent Deramecourt (CHU Lille), Dr David Meyronnet (CHU Lyon), Dr André Maues de Paula (CHU Marseille), Pr Valérie Rigau (CHU Montpellier), Pr Danielle Seilhean (CHU PS, Paris), Dr Susana Boluda (CHU PS, Paris), Dr Isabelle Plu (CHU PS, Paris), Dr Dan Christian Chiforeanu (CHU Rennes), Dr Florent Marguet(CHU Rouen), Dr Béatrice Lannes (CHU Strasbourg).

Victoria: 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.

Sydney: 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.

Declarations of Interest

RRV, SFM, TL, MH, MS, AMC, RLW, MCB, HLB, RR, AISB and DWD declare no competing interests. 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/AFAR 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, 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, Movement Disorder Society. 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. HRM also declares 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 is on the following boards; 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. RR 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.

Appendix – Pick’s disease International Consortium (PIC) members

Professor Tamas Revesz Ph.D., FRCPath^1,2; Professor Thomas T Warner Ph.D., FRCP^1,3; Professor Zane Jaunmuktane M.D., FRCPath^1,3; Professor Bradley F Boeve M.D.⁴; Elizabeth A Christopher M.B.A.⁵; Michael DeTure Ph.D.⁵; Professor Ranjan Duara M.D.⁶; Professor Neill R Graff-Radford M.D.⁷; Professor Keith A Josephs M.D., MST, MSc.⁴; Professor David S Knopman M.D.⁴; Shunsuke Koga M.D., Ph.D.⁵; Professor Melissa E Murray Ph.D.⁵; Professor Kelly E Lyons Ph.D.⁸; Professor Rajesh Pahwa M.D.⁸; Professor Joseph E Parisi M.D.⁹; Professor Ronald C Petersen M.D., Ph.D.⁴; Professor Jennifer L Whitwell Ph.D.¹⁰; Professor Lea T Grinberg M.D., Ph.D.¹¹; Professor Bruce Miller M.D.¹¹; Athena Schlereth¹¹; Professor William W Seeley M.D.¹¹; Professor Salvatore Spina M.D., Ph.D.¹¹; Professor Murray Grossman M.D., Ph.D.^12†; Professor David J Irwin M.D.¹²; Professor Edward B Lee M.D., Ph.D.¹³; EunRan Suh Ph.D.¹³; Professor John Q Trojanowski M.D., Ph.D.^13†; Professor Vivianna M Van Deerlin M.D., Ph.D.¹³; Professor David A Wolk M.D.¹²; Theresa R Connors B.S.¹⁴; Patrick M Dooley B.A.¹⁴; Professor Matthew P Frosch M.D., Ph.D.¹⁴; Derek H Oakley M.D.¹⁴; Iban Aldecoa M.D., Ph.D.^15,16,17; Mircea Balasa M.D., Ph.D.^18,19; Professor Ellen Gelpi M.D., Ph.D.²⁰; Sergi Borrego-Écija M.D.^18,19,16; Rosa Maria de Eugenio Huélamo M.D.²¹; Jordi Gascon-Bayarri M.D.²²; Professor Raquel Sánchez-Valle M.D., Ph.D.^18,19,16; Pilar Sanz-Cartagena M.D., Ph.D.²³; Gerard Piñol-Ripoll M.D., Ph.D.²⁴; Laura Molina-Porcel M.D., Ph.D.^17,18,19; Professor Eileen H Bigio M.D.^25,26; Margaret E Flanagan M.D.^25,26; Tamar Gefen Ph.D.^25,27; Emily J Rogalski Ph.D.^25,27; Professor Sandra Weintraub Ph.D.^25,27; Professor Julie A Schneider M.D., M.S.²⁸; Lihua Peng M.Sc.²⁹; Professor Xiongwei Zhu, Ph.D.²⁹; Javier Redding-Ochoa M.D.³⁰; Koping Chang M.D.³⁰; Professor Juan C Troncoso M.D.³⁰; Stefan Prokop M.D.³¹; Professor Kathy L Newell M.D.³²; Professor Bernardino Ghetti M.D.³²; Matthew Jones M.D., FRCP^33,34; Anna Richardson B.Sc., FRCP^33,34; Andrew C Robinson Ph.D.^35,36; Professor Federico Roncaroli M.D.^35,37; Julie Snowden Ph.D.^33,34; Christopher Kobylecki Ph.D., FRCP^38,34; Kieren Allinson FRCPath.³⁹; Oliver Green B.Sc.³⁹; Professor James B Rowe Ph.D.^40,41; Poonam Singh M.Phil.³⁹; Professor Thomas G Beach M.D., Ph.D.⁴²; Geidy E Serrano Ph.D.⁴²; Xena E Flowers B.S.⁴³; Professor James E Goldman M.D., Ph.D.⁴⁴; Allison C Heaps M.Sc.⁴³; Sandra P Leskinen M.A.⁴³; Andrew F Teich M.D., Ph.D.^45,43; Professor Sandra E Black M.D., FRCPC.⁴⁶; Julia L Keith M.D., FRCPC.⁴⁷; Mario Masellis M.D., Ph.D., FRCPC⁴⁶; Istvan Bodi FRCPath.^48,49; Andrew King FRCPath.^48,49; Professor Safa-Al Sarraj FRCPath.^48,49; Claire Troakes Ph.D.⁴⁹; Professor Glenda M Halliday Ph.D.⁵⁰; Professor John R Hodges M.D.⁵⁰; Professor Jillian J Kril Ph.D.⁵¹; Professor John B Kwok Ph.D.⁵⁰; Professor Olivier Piguet Ph.D.⁵²; Marla Gearing Ph.D.⁵³; Thomas Arzberger M.D.⁵⁴; Sigrun Roeber M.D.⁵⁵; Professor Johannes Attems M.D.⁵⁶; Christopher M Morris Ph.D.⁵⁶; Professor Alan J Thomas Ph.D.⁵⁶; Bret M. Evers M.D., Ph.D.⁵⁷; Professor Charles L White, 3rd M.D.⁵⁷; Kevin F Bieniek Ph.D.^58,59; Professor Naguib Mechawar Ph.D.⁶⁰; Anne A Sieben MD, Ph.D.^61,62,63,64; Professor Patrick P Cras MD., Ph.D.^61,62,65; Bart B De Vil M.Sc. Eng.^61,62,65; Professor Peter P De Deyn M.D., Ph.D.⁶⁶; Professor Charles Duyckaerts M.D., Ph.D.^67†; Professor Isabelle Le Ber M.D., Ph.D.^68,69; Professor Danielle Seilhean M.D., Ph.D.⁶⁷; Susana Boluda M.D.⁶⁷; Sabrina Turbant-Leclere Ph.D.⁷⁰; Professor Ian R MacKenzie M.D.⁷¹; Professor Catriona McLean M.D., Ph.D.^72,73; Matthew D Cykowski M.D.⁷⁴; John F Ervin⁷⁵; Shih-Hsiu J Wang M.D., Ph.D.⁷⁵; Caroline Graff Ph.D.^76,77; Inger Nennesmo M.D.^78,79; Rashed M Nagra Ph.D.⁸⁰; James Riehl B.S.⁸¹; Professor Gabor G Kovacs M.D., Ph.D.^82,83; Giorgio Giaccone M.D.⁸⁴; Benedetta Nacmias Ph.D.^85,86; Professor Manuela Neumann M.D.^87,88; Professor Lee-Cyn Ang M.D.^89,90; Elizabeth C Finger M.D.^91,92; Cornelis Blauwendraat Ph.D.⁹³; Mike A Nalls Ph.D.^93,94,95; Professor Andrew B Singleton Ph.D.⁹³; Dan Vitale M.Sc.^93,94,95; Cristina Cunha Ph.D.⁹⁶; Agostinho Carvalho Ph.D.^96,97; Professor Zbigniew K Wszolek M.D.⁷

^†Deceased

¹Queen Square Brain Bank for Neurological Disorders, University College London, Queen Square Institute of Neurology London, UK; ²Department of Neurodegenerative Disease, University College London, Queen Square Institute of Neurology, London, UK; ³Department of Clinical and Movement Neurosciences, University College London, Queen Square Institute of Neurology, London, UK; ⁴Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA; ⁵Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; ⁶Wien Center for Alzheimer’s Disease and Memory Disorders, Mount Sinai Medical Center Miami Beach, FL; ⁷Department of Neurology, Mayo Clinic, Jacksonville, FL 32224, USA; ⁸University of Kansas Medical Center, Parkinson’s Disease & Movement Disorder Division, Kansas City, KS. 66160; ⁹Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA; ¹⁰Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA; ¹¹Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA; ¹²Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; ¹³Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; ¹⁴Neuropathology Service, C.S. Kubik Laboratory for Neuropathology, Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA; ¹⁵Pathology, BDC, Hospital Clinic de Barcelona, Barcelona, Spain; ¹⁶University of Barcelona, Barcelona, Spain; ¹⁷Neurological Tissue Bank, Biobanc-Hospital Clínic-FRCB-IDIBAPS, Barcelona, Spain; ¹⁸Alzheimer’s Disease and other Cognitive Disorders Unit, Neurology Department, Hospital Clinic, Barcelona, Spain; ¹⁹Barcelona Clinical Research Foundation-August Pi i Sunyer Biomedical Research Institute (FRCB-IDIBAPS), Barcelona, Spain; ²⁰Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, Vienna, Austria; ²¹Hospital de Palamós, Carrer Hospital, 36, 17230 Palamós, Girona, Spain; ²²Servei de Neurologia, Hospital Universitari de Bellvitge. Institut d’Investigació Biomèdica de Bellvitge (Idibell). L’Hospitalet de Llobregat, Spain; ²³Hospital de Mataro, Carr. de Cirera, 230, 08304 Mataró, Barcelona, Spain; ²⁴Unitat Trastorns Cognitius (Cognitive Disorders Unit), Clinical Neuroscience Research, IRBLleida, Santa Maria University Hospital, Lleida, Spain; ²⁵Mesulam Center for Cognitive Neurology & Alzheimer’s Disease, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; ²⁶Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; ²⁷Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; ²⁸Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA; ²⁹Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH, 44106, USA; ³⁰Johns Hopkins School of Medicine, Baltimore, MD, USA; ³¹Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL, USA; ³²Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA; ³³Cerebral Function Unit, Manchester Centre for Clinical Neurosciences, Salford Royal NHS Foundation Trust, UK; ³⁴Division of Neuroscience, School of Biological Sciences, University of Manchester, UK; ³⁵Division of Neuroscience, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, M6 8HD, UK; ³⁶Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.; ³⁷Geoffrey Jefferson Brain Research Centre, Manchester Academic Health Science Centre (MAHSC), Manchester, UK; ³⁸Department of Neurology, Manchester Centre for Clinical Neurosciences, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK; ³⁹Histopathology Box 235 Cambridge University Hospital NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ; ⁴⁰Cambridge University Department of Clinical Neurosciences and Cambridge University Hospitals NHS Trust, Cambridge, UK; ⁴¹Medical Research Council Cognition and Brain Sciences Unit, Cambridge, UK; ⁴²Civin Laboratory of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ 85351, USA; ⁴³Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University, New York, NY, USA; ⁴⁴Department of Pathology and Cell Biology, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; ⁴⁵Department of Pathology and Cell Biology, Columbia University, New York, NY, USA; ⁴⁶Department of Medicine, Division of Neurology, Sunnybrook Health Sciences Centre and University of Toronto, Hurvitz Brain Sciences Research Program, Sunnybrook Research Institute; ⁴⁷Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, and Laboratory Medicine and Pathobiology, University of Toronto; ⁴⁸Clinical Neuropathology Department, King’s College Hospital NHS Foundation Trust, London, UK; ⁴⁹London Neurodegenerative Diseases Brain Bank, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK; ⁵⁰University of Sydney Brain and Mind Centre and Faculty of Medicine and Health School of Medical Sciences; ⁵¹University of Sydney Faculty of Medicine and Health School of Medical Sciences; ⁵²University of Sydney Brain and Mind Centre and Faculty of Science School of Psychology; ⁵³Dept. of Pathology and Laboratory Medicine, Dept. of Neurology, and Goizueta Alzheimer’s Disease Center Brain Bank; Emory University School of Medicine, Atlanta, GA USA; ⁵⁴Department of Psychiatry and Psychotherapy, University Hospital, Ludwig-Maximilians-University Munich, Germany; ⁵⁵Center for Neuropathology and Prion Research, Ludwig-Maximilians-University Munich, Germany; ⁵⁶Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE4 5PL, UK; ⁵⁷University of Texas Southwestern Medical Center, Dallas, TX 75390; ⁵⁸Glenn Biggs Institute for Alzheimer’s and Neurodegenerative Diseases, San Antonio, TX, USA; ⁵⁹University of Texas Health San Antonio, San Antonio, TX, USA; ⁶⁰Douglas Hospital Research Centre, McGill University, Montreal, QC, Canada; ⁶¹Laboratory of Neurology, Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; ⁶²IBB-NeuroBiobank BB190113, Born Bunge Institute, Antwerp, Belgium; ⁶³Department of Pathology, Antwerp University Hospital, Antwerp, Belgium; ⁶⁴Department of Neurology, Ghent University Hospital , Ghent University, Belgium; ⁶⁵Department of Neurology, Antwerp University Hospital - UZA, Antwerp, Belgium; ⁶⁶Laboratory of Neurochemistry and Behavior, Experimental Neurobiology Unit, University of Antwerp, Universiteitsplein 1, 2610 Antwerpen, Belgium; ⁶⁷Laboratoire de Neuropathologie Escourolle, Hôpital de la Salpêtrière, AP-HP, & Alzheimer Prion Team, ICM, 47 Bd de l’Hôpital, 75651 CEDEX 13 Paris, France; ⁶⁸Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris Brain Institute (ICM), Hôpital Pitié-Salpêtrière, Paris, France; ⁶⁹Centre de référence des démences rares ou précoces, Hôpital Pitié-Salpêtrière, Paris, France; ⁷⁰Inserm U1127, CNRS UMR 7225, Sorbonne Université, Paris Brain Institute (ICM) Hôpital Pitié-Salpêtrière, Paris, France; ⁷¹Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC Canada V6T 2B5; ⁷²Department of Anatomical Pathology Alfred Heath, Melbourne, Victoria, 3004, Australia; ⁷³Victorian Brain Bank, The Florey Institute of Neuroscience of Mental Health, Parkville, Victoria, 3052, Australia; ⁷⁴Department of Pathology and Genomic Medicine, Houston Methodist Research Institute and Weill Cornell Medicine, Houston, TX; ⁷⁵Department of Neurology, Duke University Medical Center, Durham, USA; ⁷⁶Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; ⁷⁷Unit for Hereditary Dementias, Karolinska University Hospital Solna, Stockholm, Sweden; ⁷⁸Dept of laboratory Medicine Huddinge Karolinska Institutet, Stockholm Sweden; ⁷⁹Dept of Pathology, Karolinska University Hospital Solna, Stockholm, Sweden; ⁸⁰Human Brain and Spinal Fluid Resource Center, Brentwood Biomedical Research Institute, Los Angeles, CA, United States; ⁸¹UCLA - Sepulveda, Los Angeles, CA; ⁸²Tanz Centre for Research in Neurodegenerative Disease (CRND) and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; ⁸³Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada; ⁸⁴Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy; ⁸⁵Department of Neuroscience, Psychology, Drug Research and Child Health University of Florence, Florence, Italy; ⁸⁶IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy; ⁸⁷Molecular Neuropathology of Neurodegenerative Diseases,German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; ⁸⁸Department of Neuropathology, University Hospital of Tübingen, Tübingen, Germany; ⁸⁹Department of Pathology and Laboratory Medicine, London Health Sciences Centre, London, ON, Canada; ⁹⁰Schulich School of Medicine and Dentistry, Western University, London. ON, Canada; ⁹¹Department of Clinical Neurological Sciences, Western University, London, ON, Canada; ⁹²Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; ⁹³Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA; ⁹⁴Center for Alzheimer’s and Related Dementias, National Institutes of Health, Bethesda, MD, USA; ⁹⁵Data Tecnica International LLC, Washington, DC, USA; ⁹⁶Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal; ⁹⁷ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal

Data sharing

The PIC have built a database that contains detailed demographic, clinical, and pathological information for deidentified participants with Pick’s disease. Basic demographic information (e.g. age at onset, age at death, disease duration, sex, and ethnicity), family history, clinical history (e.g. behavioral and language impairments, presence of parkinsonism, and upper and lower motor deficits), and pathological observations (e.g. immunohistochemical staining records, Thal phase, Braak stage, TDP-43 type, post-mortem intervals, brain weight, and vascular pathology), other available tissues, genetic data and clinical imaging data are available for each subject upon request. All requests must be submitted to Owen A. Ross (ross.owen@mayo.edu) or Jonathan Rohrer (j.rohrer@ucl.ac.uk).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

supplementary

NIHMS2056186-supplement-supplementary.docx^{(34.4KB, docx)}

Data Availability Statement

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PERMALINK

Creating the Pick’s disease International Consortium: Genetic association study of the MAPT H2 haplotype with risk of Pick’s disease

Rebecca R Valentino, Ph.D.

William J Scotton, Ph.D., MBioch, MRCP

Shanu F Roemer, M.D.

Professor Tammaryn Lashley, Ph.D.

Michael G Heckman, M.Sc.

Maryam Shoai, Ph.D.

Alejandro Martinez-Carrasco, M.Sc.

Nicole Tamvaka, B.Sc.

Ronald L Walton, B.Sc.

Matthew C Baker, B.Sc.

Hannah L Macpherson, M.Sc.

Raquel Real, Ph.D.

Alexandra I Soto-Beasley, M.Sc.

Kin Mok, Ph.D., FRCP

Professor Huw R Morris, Ph.D., FRCP

Professor Rosa Rademakers, Ph.D.

Professor John A Hardy, Ph.D.

Professor Dennis W Dickson, M.D.

Professor Jonathan D Rohrer, Ph.D., FRCP

Professor Owen A Ross, Ph.D.

Abstract

Background:

Methods:

Findings:

Interpretation:

Funding:

Introduction

Methods

Pick’s disease International Consortium (PIC)

Study Participants

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.

Neuropathological diagnosis of Pick’s disease

Established methods for the neuropathological diagnosis of Pick’s disease

PIC diagnostic study selection criteria for pathology confirmed Pick’s disease

Figure 2: Pathological assessments of Pick’s disease brains at Mayo Clinic Brain Bank for Neurodegenerative Diseases in Jacksonville, FL, USA.

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.

DNA Preparation

SNP Genotyping

Statistical Analysis

Role of the funding source

Results

Table 1:

Table 2:

Table 3:

Discussion

Supplementary Material

Research in context.

Acknowledgements

Funding statement

Declarations of Interest

Appendix – Pick’s disease International Consortium (PIC) members

Data sharing

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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