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      Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk

      research-article
      1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 3 , 4 , 3 , 4 , 5 , 6 , 5 , 6 , 7 , 8 , 7 , 8 , 7 , 8 , 9 , 10 , 11 , 11 , 12 , 12 , 12 , 13 , 13 , 14 , 15 , 15 , 16 , 17 , 16 , 18 , 16 , 18 , 16 , 17 , 18 , 19 , 17 , 18 , 20 , 21 , 22 , 3 , 4 , 23 , 24 , on behalf of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), on behalf of the Dominantly Inherited Alzheimer Network (DIAN), 1 , 2 , 23 , * ,
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          Abstract

          Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho ( KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SV HET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VS HET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VS HET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VS HET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55–0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19–0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27–0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60–80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VS HET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.

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          Second-generation PLINK: rising to the challenge of larger and richer datasets

          PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1's primary data format. To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher's exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information. The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.
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            Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.

            The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
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              Global prevalence of dementia: a Delphi consensus study.

              100 years after the first description, Alzheimer's disease is one of the most disabling and burdensome health conditions worldwide. We used the Delphi consensus method to determine dementia prevalence for each world region. 12 international experts were provided with a systematic review of published studies on dementia and were asked to provide prevalence estimates for every WHO world region, for men and women combined, in 5-year age bands from 60 to 84 years, and for those aged 85 years and older. UN population estimates and projections were used to estimate numbers of people with dementia in 2001, 2020, and 2040. We estimated incidence rates from prevalence, remission, and mortality. Evidence from well-planned, representative epidemiological surveys is scarce in many regions. We estimate that 24.3 million people have dementia today, with 4.6 million new cases of dementia every year (one new case every 7 seconds). The number of people affected will double every 20 years to 81.1 million by 2040. Most people with dementia live in developing countries (60% in 2001, rising to 71% by 2040). Rates of increase are not uniform; numbers in developed countries are forecast to increase by 100% between 2001 and 2040, but by more than 300% in India, China, and their south Asian and western Pacific neighbours. We believe that the detailed estimates in this paper constitute the best currently available basis for policymaking, planning, and allocation of health and welfare resources.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Data curation
                Role: Data curation
                Role: Data curation
                Role: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: Funding acquisitionRole: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: Project administrationRole: Writing – review & editing
                Role: ConceptualizationRole: Funding acquisitionRole: SupervisionRole: ValidationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 May 2022
                2022
                : 17
                : 5
                : e0267298
                Affiliations
                [1 ] Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [2 ] Neurogenomics and Informatics Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [3 ] Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [4 ] Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [5 ] Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
                [6 ] Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, University of Gothenburg, Sahlgrenska University Hospital, Mölndal, Sweden
                [7 ] Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
                [8 ] UK Dementia Research Institute at UCL, London, United Kingdom
                [9 ] Department of Anesthesiology and Intensive Care Medicine, Sahlgrenska University Hospital, Mölndal, Sweden
                [10 ] Institute of Clinical Sciences, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
                [11 ] Department of Internal Medicine, Institute of Medicine, The Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden
                [12 ] Neurology Department, Hospital de Sant Pau, Barcelona, Spain
                [13 ] IDIBAPS, Alzheimer´s Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic, Barcelona, Spain
                [14 ] Alzheimer´s Disease and Other Cognitive Disorders Unit, Neurology Service, ICN Hospital Clinic i Universitari, Barcelona, Spain
                [15 ] BarcelonaBeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
                [16 ] Biomedical Center (BMC), Biochemistry, Ludwig‐Maximilians‐Universität München, Munich, Germany
                [17 ] German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
                [18 ] Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
                [19 ] Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München, Munich, Germany
                [20 ] Department of Neurology, Ludwig-Maximilians-Universität München, Munich, Germany
                [21 ] Indiana Alzheimer Disease Research Center, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [22 ] Department of Neurology, Indiana University School of Medicine, Indianapolis, Indiana, United States of America
                [23 ] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri, United States of America
                [24 ] Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America
                Niigata University, JAPAN
                Author notes

                Competing Interests: CC receives research support from: Biogen, EISAI, Alector and GSK. The funders of the study had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the paper for publication. CC is a member of the advisory board of Vivid genetics, Halia Therapeutics, Circular Genomics and ADx Healthcare. HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Alector, Eisai, Denali, Roche, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, CogRx, and Red Abbey Labs, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. KB has served as a consultant, at advisory boards, or at data monitoring committees for Abcam, Axon, Biogen, JOMDD/Shimadzu. Julius Clinical, Lilly, MagQu, Novartis, Prothena, Roche Diagnostics, and Siemens Healthineers, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, all unrelated to the work presented in this paper. JL reports speaker fees from Bayer Vital, Biogen and Roche, consulting fees from Axon Neuroscience and Biogen, author fees from Thieme medical publishers and W. Kohlhammer GmbH medical publishers, non-financial support from Abbvie and compensation for duty as part-time CMO from MODAG, outside the submitted work.

                ¶ Membership of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Dominantly Inherited Alzheimer Network (DIAN) is provided in the Acknowledgments.

                Author information
                https://orcid.org/0000-0002-1399-6631
                https://orcid.org/0000-0002-8021-4070
                https://orcid.org/0000-0002-7677-5406
                https://orcid.org/0000-0002-7290-6405
                https://orcid.org/0000-0003-0073-7654
                https://orcid.org/0000-0002-4487-6405
                https://orcid.org/0000-0002-3819-3245
                https://orcid.org/0000-0002-3443-7716
                https://orcid.org/0000-0002-0276-2899
                Article
                PONE-D-22-05551
                10.1371/journal.pone.0267298
                9135221
                35617280
                3f78835a-0b1b-4c51-82b0-582fffeda2c4
                © 2022 Ali et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 23 February 2022
                : 6 April 2022
                Page count
                Figures: 3, Tables: 2, Pages: 16
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100000957, Alzheimer’s Association;
                Award ID: NIRG-11-200110, BAND-14-338165, AARG-16-441560 and BFG-15-362540
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;
                Award ID: R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100014761, Hope Center for Neurological Disorders;
                Funded by: the Departments of Neurology and Psychiatry at Washington University School of Medicine
                Funded by: NIH
                Award ID: P50 AG05681, P01 AG03991, and P01 AG026276
                Funded by: the Swedish Research Council
                Award ID: #2018-02532
                Award Recipient :
                Funded by: the European Research Council
                Award ID: #681712
                Award Recipient :
                Funded by: Swedish State Support for Clinical Research
                Award ID: #ALFGBG-720931
                Award Recipient :
                Funded by: Alzheimer Drug Discovery Foundation (ADDF), USA
                Award ID: 201809-2016862
                Award Recipient :
                Funded by: AD Strategic Fund and the Alzheimer’s Association
                Award ID: #ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C
                Award Recipient :
                Funded by: Olav Thon Foundation
                Award Recipient :
                Funded by: Erling-Persson Family Foundation
                Award Recipient :
                Funded by: Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden
                Award Recipient :
                Funded by: European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement
                Award ID: 86019
                Award Recipient :
                Funded by: UK Dementia Research Institute at UCL
                Award Recipient :
                Funded by: Swedish Research Council
                Award ID: #2017-00915
                Award Recipient :
                Funded by: the Alzheimer Drug Discovery Foundation (ADDF), USA
                Award ID: #RDAPB-201809-2016615
                Award Recipient :
                Funded by: Hjärnfonden, Sweden
                Award ID: #FO2017-0243
                Award Recipient :
                Funded by: the Swedish state
                Award Recipient :
                Funded by: the ALF-agreement
                Award ID: #ALFGBG-715986
                Award Recipient :
                Funded by: the European Union Joint Program for Neurodegenerative Disorders
                Award ID: JPND2019-466-236
                Award Recipient :
                Funded by: the National Institute of Health (NIH), USA
                Award ID: #1R01AG068398-01
                Award Recipient :
                Funded by: the Alzheimer’s Association 2021 Zenith Award
                Award ID: ZEN-21-848495
                Award Recipient :
                This work was supported by grants from the National Institutes of Health (R01AG044546, P01AG003991, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501 and R01AG057777), the Alzheimer Association (NIRG-11-200110, BAND-14-338165, AARG-16-441560 and BFG-15-362540). This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, and the Departments of Neurology and Psychiatry at Washington University School of Medicine. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB is supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB-201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjärnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG068398-01), and the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495).
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