dataesr/scientific-paragraphs-categorization huggingface dataset:
S6-7 ). This was the result of the low frequency of APOE*4/4 controls and the strong case-control imbalance in APOE*4/4 carriers. Overall, this supported concern for the validity of approach 1. We then used the recently released new ADSP WGS and WES data, which now cover additional subjects that are duplicated on SNP array samples included in our discovery analyses (N = 3644 as determined by identity-by-descent). We assessed the APOE genotype calls from the novel WES/WGS data and observed that three APOE*4/4-rs439401 control subjects (not from the MIRAGE cohort) in the prior discovery samples were in fact APOE*3/3 or APOE*3/4 carriers, which was also the imputed APOE genotype (Table  S8 ). Overall, this again raised concern about the validity of approach 1. In sum, these additional checks for robustness of the findings suggested problems with APOE genotype reliability in subjects with APOE*4-rs439401 haplotypes and APOE*4/4 carriers overall, indicating a limitation to the first (conventional) APOE filtering approach.
APOE filtering approach 2: Rs439401 shows no association with Alzheimer's disease risk In light of the identified APOE reliability limitations, we extended approach 1 to filter out any subjects that did not have WGS/WES APOE and at the same time were discordant for provided and (high-quality) imputed APOE. We also filtered out any discordant APOE calls with regard to the new ADSP WES/WGS data since this information was available (in case of APOE*4-rs439401 carriers, this overlapped with samples where provided and imputed APOE were discordant). We then applied this to the discovery samples and reran analyses. Exclusion of subjects with discordant APOE status with the newly released ASDP WES/WGS data removed 61 (out of 12,367) subjects from the SNP-array samples. Further applying the new APOE filter excluded 632 (out of 12,753 considered) subjects from the discovery SNP-array samples.
Based on our observations, we suggest that future studies consider implementing the methodology that we proposed in approach 2 and subject their assessment of APOE genotypes to extensive scrutiny. The limitations observed for APOE*2/3/4 genotype reliability also emphasize that next-generation sequencing data will be crucial to interrogate the APOE locus with higher confidence and to ensure that putative rare haplotypes are not missed because of the need for sample filtering in SNP array data. Lastly, in order to have higher confidence in local haplotypes, long read sequencing approaches will additionally be crucial to help disentangle the local haplotype structure on APOE with regard to AD.
Sample demographics for association analyses with Alzheimer's disease case-control status Cohort data were available through the National Institute on Aging and Genetics of Alzheimer's Disease Data Storage Site (NIAGADS), the National Alzheimer's Coordinating Center (NACC), Accelerating Medicines Partnership -Alzheimer's Disease (AMP-AD) Knowledge Portal, the Database of Genotypes and Phenotypes (dbGaP), Rush Alzheimer's Disease Center at Rush University, the Image & Data Archive powered by Laboratory of Neuro Imaging (IDA-LONI), the Rotterdam study, the European Alzheimer's Disease Initiative (EADI), and the European Alzheimer & Dementia BioBank (EADB). Cohorts included Adult Changes in Thought (ACT), Alzheimer's Disease Center Datasets (ADC1-7) for which phenotype data is managed by NACC, European collaboration for the discovery of novel biomarkers for Alzheimer's disease (ADDNEURO), the Alzheimer's Disease Neuroimaging Initiative (ADNI), ADNI Department of Defense (ADOD), Alzheimer's Disease Sequencing Project (ADSP) Discovery and Extension Phase, National Institute on Aging Genetics Initiative for Late-Onset Alzheimer's Disease (NIA-LOAD), Oregon Health and Science University study (OHSU), Mayo Clinic Alzheimer's Disease Genetics studies (MAYO), MAYO RNAseq study (MAYO2), Multi Institutional Research on Alzheimer Genetics Epidemiology (MIRAGE), Mount Sinai Brain Bank (MSBB), University of Miami/Texas Alzheimer's Research Care Consortium Wave 2/Case Western Reserve University (MTC), Rush University Religious Orders Study/Memory and Aging Project (ROSMAP), Translational Genomics Research Institute series 2 (TGEN2), University of Miami/Vanderbilt University/Mt.
EADB. We thank the many study participants, researchers, and staff for collecting and contributing to the data, the high-performance computing service at the  University of Lille , and the staff at  CEA-CNRGH  for their help with sample preparation and genotyping, and excellent technical assistance. We thank  Antonio Pardinas  for his help. This research was conducted using the UK Biobank resource (application number:  61054 ). This work was funded by a grant ( European Alzheimer & Dementia BioBank, EADB)  from the  EU Joint Programme -Neurodegenerative Disease Research (JPND). Inserm   UMR1167  is also funded by the  Inserm ,  Institut Pasteur de Lille, Lille Métropole Communauté Urbaine , and the  French government 's  LABEX DISTALZ program  (development of innovative strategies for a transdisciplinary approach to Alzheimer's disease).
Additional support for EADB cohorts. The work for this manuscript was further supported by the  CoSTREAM  project (www. costr eam. eu) and funding from the  European Union 's  Horizon 2020 research and innovation programme  under grant agreement No  667375. This work is also funded by  la fondation pour la recherché médicale (FRM)  ( EQU202003010147 )  Italian Ministry of Health (Ricerca Corrente); Ministero dell'Istruzione, del l'Università e della Ricerca-MIUR  project " Dipartimenti di Eccellenza 2018-2022 " to  Department of Neuroscience "Rita Levi Montalcini, " University of Torino (IR) , and  AIRAlzh Onlus-ANCC-COOP (SB) ; partly supported by  "Ministero della Salute", I. R. C. C. S. Research Program ,  Ricerca Corrente   2018-2020 , Linea n. 2 " Meccanismi genetici, predizione e terapie innovative delle malattie complesse " and by the "5 x 1000" voluntary contribution to the  Fondazione I.
CBAS: Supported by the project no. LQ1605  from the  National Program of Sustainability II  ( MEYS CR ), Supported by  Ministry of Health of the Czech Republic , grant nr. NV19-04-00270  (All rights reserved),  Grant Agency of Charles University  Grants No. 693018  and  654217 ; the  Ministry of Health , Czech Republic-conceptual development of research organization,  University Hospital Motol, Prague ,  Czech Republic  Grant No. 00064203 ; the  Czech Ministry of Health Project AZV  Grant No. 16-27611A ; and  Institutional Support of Excellence 2. LF UK  Grant No. 699012. CNRMAJ-Rouen: This study received fundings from the  Centre National de Référence Malades Alzheimer Jeunes (CNRMAJ). The  Finnish Geriatric Intervention Study for the Prevention of Cognitive Impairment and Disability (FINGER ) data collection was supported by grants from the  Academy of Finland ,  La Carita Foundation ,  Juho Vainio Foundation ,  Novo Nordisk Foundation ,  Finnish Social Insurance Institution, Ministry of Education and Culture Research Grants ,  Yrjö Jahnsson Foundation ,  Finnish Cultural Foundation South Osthrobothnia Regional Fund , and EVO/State Research Funding grants of  University Hospitals of Kuopio, Oulu and Turku, Seinäjoki Central Hospital and Oulu City Hospital ,  Alzheimer's Research & Prevention Foundation USA, AXA Research Fund, Knut and Alice Wallenberg Foundation Sweden, Center for Innovative Medicine (CIMED)  at  Karolinska Institutet Sweden , and  Stiftelsen Stockholms sjukhem Sweden.
FINGER cohort genotyping was funded by  EADB  project in the  JPND CO-FUND  (grant number  301220 ). Research at the Belgian EADB site is funded in part by the  Alzheimer Research Foundation (SAO-FRA) ,  The Research Foundation Flanders (FWO) , and the  University of Antwerp Research Fund. FK is supported by a  BOF DOCPRO fellowship of the University of Antwerp Research Fund. SNAC-K is financially supported by the  Swedish Ministry of Health and Social Affairs , the participating County Councils and Municipalities, and the  Swedish Research Council. BDR Bristol: We would like to thank the  South West Dementia Brain Bank (SWDBB)  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.
Cardiff University  acknowledges the support of the  UK Dementia Research Institute , of which  J. Williams  is an associate director. Cambridge University acknowledges support from the  MRC. Patient recruitment for the  MRC Prion Unit/UCL Department of Neurodegenerative Disease collection  was supported by the  UCLH/UCL Biomedical Centre  and  NIHR Queen Square Dementia Biomedical Research Unit. The University of Southampton  acknowledges support from the  AS. King's College London  was supported by the  NIHR Biomedical Research Centre for Mental Health  and the  Biomedical Research Unit  for Dementia at the  South London and Maudsley NHS Foundation Trust  and by  King's College London  and the  MRC. ARUK  and the  Big Lottery Fund  provided support to  Nottingham University. Alfredo Ramirez: Part of the work was funded by the  JPND   EADB grant  ( German Federal Ministry of Education and Research (BMBF)  grant:  01ED1619A ).
Alfredo Ramirez  is also supported by the  German Research Foundation  (DFG) grants Nr:  RA 1971/6-1 ,  RA1971/7-1 , and  RA 1971/8-1. German Study on Ageing, Cognition and Dementia in Primary Care Patients (AgeCoDe) : This study/publication is part of the  German Research Network on Dementia (KND) , the  German Research Network on Degenerative Dementia (KNDD; German Study on Ageing, Cognition and Dementia in Primary Care Patients; AgeCoDe) , and the  Health Service Research Initiative  (Study on Needs, health service use, costs and health-related quality of life in a large sample of oldestold primary care patients (85+; AgeQualiDe)) and was funded by the  German Federal Ministry of Education and Research  (grants KND:  01GI0102 ,  01GI0420 ,  01GI0422 ,  01GI0423 ,  01GI0429 ,  01GI0431 ,  01GI0433 ,  01GI0434 ; grants KNDD:  01GI0710 ,  01GI0711 ,  01GI0712 ,  01GI0713 ,  01GI0714 ,  01GI0715 ,  01GI0716 ; grants  Health Service Research Initiative :  01GY1322A ,  01GY1322B ,  01GY1322C ,  01GY1322D ,  01GY1322E ,  01GY1322F ,  01GY1322G ).
VITA study: The support of the  Ludwig Boltzmann Society  and the  AFI Germany have  supported the VITA study. The former VITA study group should be acknowledged:  W. Danielczyk ,  G. Gatterer ,  K Jellinger ,  S Jugwirth ,  KH Tragl ,  S Zehetmayer. Vogel Study: This work was financed by a research grant of the " Vogelstiftung Dr. Eckernkamp. " HELIAD  study: This study was supported by the grants:  IIRG-09-133014  from the  Alzheimer's Association ,  189 10276/8/9/2011  from the  ESPA-EU program Excellence Grant (ARISTEIA)  and the ΔΥ2β/οικ. 51657/14. 4. 2009 of the  Ministry for Health and Social Solidarity (Greece). Biobank Department of Psychiatry ,  UMG :  Prof. Jens Wiltfang  is supported by an  Ilídio Pinho professorship and iBiMED  ( UID/BIM/04501/2013 ), and  FCT  project  PTDC/DTP_PIC/5587/2014  at the  University of Aveiro , Portugal.
Lausanne study: This work was supported by grants from the  Swiss National Research Foundation  ( SNF 320030_141179 ). PAGES study:  Harald Hampel  is an employee of  Eisai Inc. During part of this work he was supported by the  AXA Research Fund , the  "Fondation partenariale Sorbonne Université" and the "Fondation pour la Recherche sur Alzheimer", Paris ,  France. Mannheim ,  Germany Biobank :  Department of geriatric Psychiatry, Central Institute for Mental Health, Mannheim, University of Heidelberg, Germany. Genotyping  for the  Swedish Twin Studies of Aging  was supported by  NIH/NIA  grant  R01 AG037985. Genotyping in TwinGene was supported by  NIH/NIDDK   U01 DK066134. WvdF is recipient of  Joint Programming for Neurodegenerative Diseases (JPND)  grants  PERADES  ( ANR-13-JPRF-0001 ) and EADB (733051061).
Funding was awarded from the  Australian National Health and Medical Research Council (NHMRC)   Program Grants  ( 350833 ,  568969 ,  109308 ). AddNeuroMed consortium was led by  Simon Lovestone ,  Bruno Vellas ,  Patrizia Mecocci ,  Magda Tsolaki ,  Iwona Kłoszewska ,  Hilkka Soininen. This work was supported by  InnoMed (Innovative Medicines in Europe) , an integrated project funded by the  European Union  of the  Sixth Framework program  priority ( FP6-2004-LIFESCIHEALTH-5 ). Oviedo: This work was partly supported by Grant from  Fondo de Investigaciones Sanitarias-Fondos FEDER Europe-anUnion  to  Victoria Alvarez   PI15/00878. Project MinE: The ProjectMinE study was supported by the  ALS Foundation Netherlands  and the  MND association (UK)  (Project  MinE , www. proje ctmine. com). The SPIN cohort: We are indebted to patients and their families for their participation in the " Sant Pau Initiative on Neurodegeneration cohort , " at the  Sant Pau Hospital (Barcelona).
This is a multimodal research cohort for biomarker discovery and validation that is partially funded by  Generalitat de Catalunya  ( 2017 SGR 547  to JC), as well as from the  Institute of Health Carlos III-Subdirección General de Evaluación  and the  Fondo Europeo de Desarrollo Regional (FEDER-"Una manera de Hacer Europa")  (grants  PI11/02526 ,  PI14/01126 , and  PI17/01019  to JF;  PI17/01895  to AL), and the  Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas programme (Program 1 ,  Alzheimer Disease  to AL). We would also like to thank the  Fundació Bancària Obra Social La Caixa  ( DABNI  project) to JF and AL; and  Fundación BBVA  (to AL), for their support in funding this follow-up study. Adolfo López de Munain  is supported by  Fundación Salud 2000  ( PI2013156 ),  CIBERNED  and  Diputación Foral de Gipuzkoa (Exp.
114/17 ). Pascual Sánchez-Juan is supported by  CIBERNED  and  Carlos III Institute of Health, Spain  ( PI08/0139 ,  PI12/02288 , and  PI16/01652 ,  PI20/01011 ), jointly funded by  Fondo Europeo de Desarrollo Regional (FEDER) ,  Unión Europea, "Una manera de hacer Europa. " We thank  Biobanco Valdecilla  for their support. Amsterdam dementia Cohort (ADC):  Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program  of  Amsterdam Neuroscience. The AlzheimerCenter Amsterdam is supported by  Stichting Alzheimer Nederland  and  Stichting VUmc  fonds. The clinical database structure was developed with funding from  Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer & Dementia biobank) funded by the  JPco-fuND   FP-829-029  ( ZonMW  project number # 733051061 ).
The DELCODE study was funded by the  German Center for Neurodegenerative Diseases (Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) ), reference number  BN012. Gra@ce. The  Genome Research @ Fundació ACE  project ( GR@ACE ) is supported by  Grifols SA, Fundación bancaria 'La Caixa' , Fundació ACE , and  CIBERNED  ( Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (Program 1 ,  Alzheimer Disease  to MB and AR)). A. R. and M. B. receive support from the  European Union/EFPIA Innovative Medicines Initiative  Joint undertaking ADAPTED and MOPEAD projects (grant numbers  115975  and  115985 , respectively). M. B. and A. R. are also supported by national grants  PI13/02434 ,  PI16/01861 ,  PI17/01474  and  PI19/01240. Acción Estratégica en Salud  is integrated into the  Spanish National R + D + I Plan  and funded by  ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación  and the  Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa').
Some control samples and data from patients included in this study were provided in part by the  National DNA Bank Carlos III  (www. banco adn. org,  University of Salamanca, Spain ) and  Hospital Universitario Virgen de Valme (Sevilla, Spain) ; they were processed following standard operating procedures with the appropriate approval of the Ethical and Scientific Committee. The present work has been performed as part of the  doctoral program  of  I. de Rojas  at the  Universitat de Barcelona (Barcelona, Spain ). EADI. This work has been developed and supported by the  LABEX (laboratory of excellence program  investment for the future)  DISTALZ grant  ( Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease ) including funding from  MEL  ( Metropole européenne de Lille ),  ERDF  ( European Regional Development Fund) , and  Conseil Régional Nord Pas de Calais.
This work was supported by  INSERM , the  National Foundation  for Alzheimer's disease and related disorders, the  Institut Pasteur de Lille  and the  Centre National de Recherche en Génomique Humaine, CEA , the  JPND PERADES , the  Laboratory of Excellence GENMED (Medical Genomics)  grant no. ANR-10-LABX-0013  is managed by the  National Research Agency (ANR)  part of the  Investment for the Future program , and the  FP7 AgedBrainSysBio. The Three-City Study was performed as part of collaboration between the  Institut National de la Santé et de la Recherche Médicale (Inserm) , the  Victor Segalen Bordeaux II University and Sanofi-Synthélabo. The  Fondation pour la Recherche Médicale  funded the preparation and initiation of the study. The 3C Study was also funded by the  Caisse Nationale Maladie des Travailleurs Salariés ,  Direction Générale de la Santé ,  MGEN ,  Institut de la Longévité ,  Agence Française de Sécurité Sanitaire des Produits de Santé , the  Aquitaine and Bourgogne Regional Councils ,  Agence Nationale de la Recherche ,  ANR  supported the  COGINUT  and  COVADIS projects.
of Michigan,  P30 AG053760  and  AG063760 ;  University of Pennsylvania ,  P30 AG010124 ;  University of Pittsburgh ,  P50 AG005133 ,  AG030653 ,  AG041718 ,  AG07562 ,  AG02365 ;  University of Southern California ,  P50 AG005142 ; University of  Texas Southwestern ,  P30 AG012300 ;  University of Miami ,  R01 AG027944 ,  AG010491 ,  AG027944 ,  AG021547 ,  AG019757 ;  University of Washington ,  P50 AG005136 ,  R01 AG042437 ;  University of Wisconsin ,  P50 AG033514 ;  Vanderbilt University ,  R01 AG019085 ; and  Washington University ,  P50 AG005681 ,  P01 AG03991 ,  P01 AG026276. The  Kathleen Price Bryan Brain Bank at Duke University Medical Center  is funded by  NINDS  grant #  NS39764 ,  NIMH MH60451  and by  Glaxo Smith Kline. Genotyping  of the TGEN2 cohort was supported by  Kronos Science.
NACC. The NACC database is funded by  NIA/NIH  Grant  U01 AG016976. NACC data are contributed by the  NIA -funded ADCs:  P30 AG019610  ( PI Eric Reiman, MD ),  P30 AG013846  ( PI Neil Kowall, MD ),  P30 AG062428-01  ( PI James Leverenz, MD )  P50 AG008702  ( PI Scott Small, MD ),  P50 AG025688  ( PI Allan Levey, MD, PhD ),  P50 AG047266  ( PI Todd Golde, MD, PhD ),  P30 AG010133  ( PI Andrew Saykin, PsyD ),  P50 AG005146  ( PI Marilyn Albert, PhD ),  P30 AG062421-01  ( PI Bradley Hyman, MD, PhD ),  P30 AG062422-01  (PI  Ronald Petersen, MD, PhD ),  P50 AG005138  (PI  Mary Sano, PhD ),  P30 AG008051  ( PI Thomas Wisniewski, MD ),  P30 AG013854  (PI  Robert Vassar, PhD ),  P30 AG008017  ( PI Jeffrey Kaye, MD ),  P30 AG010161  ( PI David Bennett, MD ),  P50 AG047366  (PI Victor Henderson, MD, MS),  P30 AG010129  ( PI Charles DeCarli, MD ),  P50 AG016573  ( PI Frank LaFerla, PhD ),  P30 AG062429-01 (PI  James Brewer, MD, PhD ),  P50 AG023501  ( PI Bruce Miller, MD ),  P30 AG035982  ( PI Russell Swerdlow, MD ),  P30 AG028383  ( PI Linda Van Eldik, PhD ),  P30 AG053760  ( PI Henry Paulson, MD, PhD ),  P30 AG010124  ( PI John Trojanowski, MD, PhD ),  P50 AG005133  ( PI Oscar Lopez, MD ),  P50 AG005142  ( PI Helena Chui, MD ),  P30 AG012300  ( PI Roger Rosenberg, MD ),  P30 AG049638  ( PI Suzanne Craft, PhD ),  P50 AG005136  ( PI Thomas Grabowski, MD ),  P30 AG062715-01  ( PI Sanjay Asthana, MD, FRCP ),  P50 AG005681  ( PI John Morris, MD ),  P50 AG047270  ( PI Stephen Strittmatter, MD, PhD ).
GenADA. The genotypic and associated phenotypic data used in the study " Multi-Site Collaborative Study for Genotype-Phenotype Associations in Alzheimer's Disease (GenADA )" were provided by the  GlaxoSmithKline , R&D Limited. ROSMAP. ROSMAP study data were provided by the  Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago. Data collection was supported through funding by  NIA  grants  P30AG10161 ,  R01AG15819 ,  R01AG17917 ,  R01AG30146 ,  R01AG36836 ,  U01AG32984 ,  U01AG46152 , the  Illinois Department of Public Health , and the  Translational Genomics Research Institute. AddNeuroMed. The AddNeuroMed data are from a public-private partnership supported by  EFPIA companies and SMEs as part of InnoMed (Innovative Medicines in Europe) , an  Integrated  Project funded by the  European Union  of the  Sixth Framework program  priority  FP6-2004-LIFESCIHEALTH-5.
Acknowledgements NCRAD. Biological samples used in this study were stored at study investigators' institutions and at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University, which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA). We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. Phenotypic data were provided by principal investigators, the NIA funded Alzheimer's Disease Centers (ADCs), the National Alzheimer's Coordinating Center (NACC, U01AG016976.
LDL receptor gene. The LDLR gene (OMIM-#606945) consists of 18 exons spanning 45 kilobases (kb) at 19p13. 2. It encodes the 860 amino acid LDLr proprotein, which includes a 21-amino acid signal peptide  [25, 26]. The LDLr proprotein is synthesized in the endoplasmic reticulum (ER), its 21 amino acid signal peptide is cleaved, and the protein is glycosylated to form the mature 160 kDa (839 amino acid) glycoprotein. This transmembrane receptor is found on the surface of most cell types and mediates the internalization of LDL into cells via receptor-mediated endocytosis  [9, 25]. To date, thousands of FH variants in the LDLR gene have been reported in the historic locus-specific databases (UMD-LDLR  [27]  and University College London database  [28] ) as well as general databases such as HGMD and ClinVar  [29].
Furthermore, another less frequent variant, [p. (Arg46Leu)], was found in Caucasian subjects from the ARIC study and was associated with a 15% reduction in LDL-C levels and a 47% reduction in the risk of CHD  [108, 109]. Subsequent studies on European Caucasians identified two other hypocholesterolemic variants p. (Gly106Arg) and p. (Arg237Trp), and again notably p. (Arg46Leu). However, their overall effect on total and LDL-C blood levels is smaller than that of the two African LOFs  [110]. To date, almost 1200 nucleotide variants (most of them single nucleotide variants) in PCSK9 are found in The Genome Aggregation Database (gno-mAD)  [111] , the largest public genomic database. Curated variants can be accessed both in Clin-Var  [32]  and the PCSK9 Locus Specific Database  [112]. In these two databases, numerous variants are listed (over 800 for the first and 308 for the second) but both are concordant for pathogenic and likely pathogenic variants numbered between 34 and 36.