Advertisement

Acta Neuropathologica

, Volume 136, Issue 6, pp 857–872 | Cite as

Sex-specific genetic predictors of Alzheimer’s disease biomarkers

  • Yuetiva Deming
  • Logan Dumitrescu
  • Lisa L. Barnes
  • Madhav Thambisetty
  • Brian Kunkle
  • Katherine A. Gifford
  • William S. Bush
  • Lori B. Chibnik
  • Shubhabrata Mukherjee
  • Philip L. De Jager
  • Walter Kukull
  • Matt Huentelman
  • Paul K. Crane
  • Susan M. Resnick
  • C. Dirk Keene
  • Thomas J. Montine
  • Gerard D. Schellenberg
  • Jonathan L. Haines
  • Henrik Zetterberg
  • Kaj Blennow
  • Eric B. Larson
  • Sterling C. Johnson
  • Marilyn Albert
  • Abhay Moghekar
  • Jorge L. del Aguila
  • Maria Victoria Fernandez
  • John Budde
  • Jason Hassenstab
  • Anne M. Fagan
  • Matthias Riemenschneider
  • Ronald C. Petersen
  • Lennart Minthon
  • Michael J. Chao
  • Vivianna M. Van Deerlin
  • Virginia M.-Y. Lee
  • Leslie M. Shaw
  • John Q. Trojanowski
  • Elaine R. Peskind
  • Gail Li
  • Lea K. Davis
  • Julia M. Sealock
  • Nancy J. Cox
  • Alzheimer’s Disease Neuroimaging Initiative (ADNI)
  • The Alzheimer Disease Genetics Consortium (ADGC)
  • Alison M. Goate
  • David A. Bennett
  • Julie A. Schneider
  • Angela L. Jefferson
  • Carlos Cruchaga
  • Timothy J. HohmanEmail author
Original Paper

Abstract

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer’s disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = − 0.03, p = 4.25 × 10−8; β = 0.03, p = 3.97 × 10−8) than males (β = − 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10−10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD’s genetic architecture.

Keywords

Alzheimer disease Cerebrospinal fluid biomarkers Neuropathology Sex difference APOE Amyloid Tau 

Notes

Acknowledgements

We thank all the participants and their families, as well as the many institutions and their staff that provided support for all studies involved in this collaboration. We thank the study participants and staff of the Rush Alzheimer’s Disease Center and of the Kaiser Permanente (formerly Group Health)/University of Washington Adult Changes in Thought study. We also thank the Alzheimer Disease Genetic Consortium (ADGC) for genotyping and providing data for the BIOCARD, UPENN, and MAYO cohorts.

ADNI Coinvestigators: Michael W. Weiner, M.D. (University of California San Francisco, ADNI Principal Investigator); Ron Petersen, Ph.D., M.D. (Mayo Clinic, Protocol principal investigator); Paul Aisen, M.D. (University of California San Diego, Clinical Core Director); Clifford Jack, M.D. (Mayo Clinic, MRI Core Director); William Jagust, M.D. (University of California Berkeley, PET Core Director); Leslie M. Shaw, Ph.D. (University of Pennsylvania, Biomarker Core Director); John Trojanowski, Ph.D. (University of Pennsylvania, Biomarker Core Director); Laurel Beckett, Ph.D. (University of California Davis, Biostatistics Core Director); Art Toga, Ph.D. (UCLA, LONI Principal Investigator); Andrew Saykin, Psy.D. (Indiana University Purdue University Indianapolis, Genetics Core Director); John C. Morris, M.D. (Washington University in St. Louis; Neuropathology Core Director); Tom Montine, Ph.D. (University of Washington, Resource Allocation Review Committee); Robert Green, M.D., MPH (Boston University, ADNI Data and Publications Committee).

ADGC Member List: Erin Abner, PhD. University of Kentucky, Perrie Adams, PhD. University of Texas Southwestern Medical Center, Marilyn Albert, PhD. Johns Hopkins University, Roger Albin, MD. University of Michigan, Liana Apostolova, MD. Indiana University, Steven Arnold, MD. University of Pennsylvania Perelman School of Medicine, Sanjay Asthana, MD. University of Wisconsin, Craig Atwood, PhD. University of Wisconsin, Clinton Baldwin, PhD. Boston University, Robert Barber, PhD. University of North Texas Health Science Center, Lisa Barnes, PhD. Rush University Medical Center, Sandra Barral, PhD. Columbia University, Thomas Beach, MD PhD. Banner Sun Health Research Institute, James Becker, PhD. University of Pittsburgh School of Medicine, Gary Beecham, PhD. University of Miami, Duane Beekly, BS. University of Washington, David Bennett, MD. Rush University Medical Center, Eileen Bigio, MD. Northwestern University Feinberg School of Medicine, Thomas Bird, MD. University of Washington, Deborah Blacker, MD. Harvard School of Public Health, Bradley Boeve, MD. Mayo Clinic, James Bowen, MD. Swedish Medical Center, Adam Boxer, MD PhD. University of California San Francisco, James Burke, MD PhD. Duke University, Jeffrey Burns, MD MS. University of Kansas Medical Center, Joseph Buxbaum, PhD. Mount Sinai School of Medicine, Nigel Cairns, PhD FRCPath. Washington University, Laura Cantwell, MPH. University of Pennsylvania Perelman School of Medicine, Chuanhai Cao, PhD. University of South Florida, Chris Carlson, PhD. Fred Hutchinson Cancer Research Center, Cynthia Carlsson, MD. University of Wisconsin, Regina Carney, MD. University of Miami, Minerva Carrasquillo, PhD. Mayo Clinic, Helena Chui, MD. University of Southern California, Paul Crane, MD MPH. University of Washington, David Cribbs, PhD. University of California Irvine, Elizabeth Crocco, MD. University of Miami, Carlos Cruchaga, PhD. Washington University School of Medicine, Philip De Jager, MD PhD. Brigham and Women’s Hospital and Harvard Medical School, Charles DeCarli, MD. University of California Davis, Malcolm Dick, PhD. University of California Irvine, Dennis Dickson, MD. Mayo Clinic, Rachelle Doody, MD PhD. Baylor College of Medicine, Ranjan Duara, MD. Mount Sinai Medical Center, Nilufer Ertekin-Taner, MD PhD. Mayo Clinic, Denis Evans, MD. Rush University Medical Center, Kelley Faber, MS. Indiana University, Thomas Fairchild, PhD. University of North Texas Health Science Center, Kenneth Fallon, MD. University of Alabama at Birmingham, David Fardo, PhD. University of Kentucky, Martin Farlow, MD. Indiana University, Lindsay Farrer, PhD. Boston University, Steven Ferris, PhD. New York University, Tatiana Foroud, PhD. Indiana University, Matthew Frosch, MD PhD. Massachusetts General Hospital, Douglas Galasko, MD. University of California San Diego, Marla Gearing, PhD. Emory University, Daniel Geschwind, MD PhD. University of California Los Angeles, Bernardino Ghetti, MD. Indiana University, John Gilbert, PhD. University of Miami, Alison Goate, D.Phil. Mount Sinai School of Medicine, Neill Graff-Radford, MD. Mayo Clinic, Robert Green, MD MPH. Brigham and Women’s Hospital and Harvard Medical School, John Growdon, MD. Massachusetts General Hospital/Harvard Medical School, Jonathan Haines, PhD. Case Western Reserve University, Hakon Hakonarson, MD PhD. Children’s Hospital of Philadelphia, Ronald Hamilton, MD. University of Pittsburgh, Kara Hamilton-Nelson, MPH. University of Miami, John Hardy, PhD. University College London, Lindy Harrell, MD PhD. University of Alabama at Birmingham, Lawrence Honig, MD PhD. Columbia University, Ryan Huebinger, PhD. University of Texas Southwestern Medical Center, Matthew Huentelman, PhD. Translational Genomics Research Institute, Christine Hulette, MD. Duke University, Bradley Hyman, MD PhD. Massachusetts General Hospital/Harvard Medical School, Gail Jarvik, MD PhD. University of Washington, Lee-Way Jin, MD PhD. University of California Davis, Gyungah Jun, PhD. Boston University, M. Ilyas Kamboh, PhD. University of Pittsburgh, Anna Karydas, BA. University of California San Francisco, Mindy Katz, MPH. Albert Einstein College of Medicine, John Kauwe, PhD. Brigham Young University, Jeffrey Kaye, MD. Oregon Health & Science University, C. Dirk Keene, MD PhD. University of Washington, Ronald Kim, MD. University of California Irvine, Neil Kowall, MD. Boston University, Joel Kramer, PsyD. University of California San Francisco, Walter Kukull, PhD. University of Washington, Brian Kunkle, PHD MPH. University of Miami, Amanda Kuzma, MS. University of Pennsylvania Perelman School of Medicine, Frank LaFerla, PhD. University of California Irvine, James Lah, MD PhD. Emory University, Eric Larson, MD MPH. University of Washington, James Leverenz, MD. Cleveland Clinic, Allan Levey, MD PhD. Emory University, Ge Li, MD PhD. VA Puget Sound Health Care System/GRECC, Andrew Lieberman, MD PhD. University of Michigan, Richard Lipton, MD. Albert Einstein College of Medicine, Oscar Lopez, MD. University of Pittsburgh Alzheimer’s Disease Research Center, Kathryn Lunetta, PhD. Boston University, Constantine Lyketsos, MD MHS. Johns Hopkins University, John Malamon, MSE. University of Pennsylvania Perelman School of Medicine, Daniel Marson, JD PhD. University of Alabama at Birmingham, Eden Martin, PhD. University of Miami, Frank Martiniuk, PhD. New York University, Deborah Mash, PhD. University of Miami, Eliezer Masliah, MD. University of California San Diego, Richard Mayeux, MD. Columbia University , Wayne McCormick, MD MPH. University of Washington, Susan McCurry, PhD. University of Washington, Andrew McDavid, BA. Fred Hutchinson Cancer Research Center, Stefan McDonough, PhD. Pfizer Worldwide Research and Development, Ann McKee, MD. Boston University, Marsel Mesulam, MD. Northwestern University Feinberg School of Medicine, Bruce Miller, MD. University of California San Francisco, Carol Miller, MD. University of Southern California, Joshua Miller, PhD. University of California Davis, Thomas Montine, MD PhD. University of Washington, John Morris, MD. Washington University, Shubhabrata Mukherjee, PhD. University of Washington, Amanda Myers, PhD. University of Miami, Adam Naj, PhD. University of Pennsylvania Perelman School of Medicine, Sid O’Bryant, PhD. University of North Texas Health Science Center, John Olichney, MD. University of California Davis, Joseph Parisi, MD. Mayo Clinic, Henry Paulson, MDPhD. University of Michigan, Margaret Pericak-Vance, PhD. University of Miami, Elaine Peskind, MD. University of Washington School of Medicine, Ronald Petersen, MD PhD. Mayo Clinic, Aimee Pierce, MD. University of California Irvine, Wayne Poon, PhD. University of California Irvine, Huntington Potter, PhD. University of Colorado School of Medicine, Liming Qu, MS. University of Pennsylvania Perelman School of Medicine, Joseph Quinn, MD. Oregon Health & Science University, Ashok Raj, MD. University of South Florida, Murray Raskind, MD. University of Washington School of Medicine, Eric Reiman, MD. Translational Genomics Research Institute, Barry Reisberg, MD. New York University, Joan Reisch, PhD. University of Texas Southwestern Medical Center, Christiane Reitz, MD PhD. Columbia University, John Ringman, MD. University of Southern California, Erik Roberson, MD PhD. University of Alabama at Birmingham, Ekaterina Rogaeva, PhD. University of Toronto, Howard Rosen, MD. University of California San Francisco, Roger Rosenberg, MD. University of Texas Southwestern, Donald Royall, MD. South Texas Veterans Health Administration Geriatric Research Education & Clinical Center (GRECC), UT Health Science Center at San Antonio, Mark Sager, MD. University of Wisconsin, Mary Sano, PhD. Mount Sinai School of Medicine, Andrew Saykin, PsyD. Indiana University, Gerard Schellenberg, PhD. University of Pennsylvania Perelman School of Medicine, Julie Schneider, MD. Rush University Medical Center, Lon Schneider, MD. University of Southern California, William Seeley, MD. University of California San Francisco, Amanda Smith, MD. University of South Florida, Joshua Sonnen, MD. University of Washington, Salvatore Spina, MD. Indiana University, Peter St George-Hyslop, MD FRCP. University of Toronto, Robert Stern, PhD. Boston University, Russell Swerdlow, MD. University of Kansas Medical Center, Rudolph Tanzi, PhD. Massachusetts General Hospital/Harvard Medical School, John Trojanowski, MD PhD. University of Pennsylvania Perelman School of Medicine, Juan Troncoso, MD. Johns Hopkins University, Debby Tsuang, MD. VA Puget Sound Health Care System/GRECC, Otto Valladares, MS. University of Pennsylvania Perelman School of Medicine, Vivianna Van Deerlin, MD PhD. University of Pennsylvania Perelman School of Medicine, Linda Van Eldik, Phd. University of Kentucky, Badri Vardarajan, MS. Columbia University, Harry Vinters, MD. University of California Los Angeles, Jean Paul Vonsattel, MD. Columbia University, Li-San Wang, PhD. University of Pennsylvania Perelman School of Medicine, Sandra Weintraub, PhD. Northwestern University Feinberg School of Medicine, Kathleen Welsh-Bohmer, PhD. Duke University, Kirk Wilhelmsen, MD PhD. University of North Carolina Chapel Hill, Jennifer Williamson, MS. Columbia University, Thomas Wingo, MD. Emory University, Randall Woltjer, MD PhD. Oregon Health & Science University, Clinton Wright, MD MS. University of Miami, Chuang-Kuo Wu, MD PhD. Texas Tech University Health Science Center, Steven Younkin, MD PhD. Mayo Clinic, Chang-En Yu, PhD. University of Washington, Lei Yu, PhD. Rush University Medical Center, Yi Zhao, MS. University of Pennsylvania Perelman School of Medicine.

Author contributions

YD and LD contributed equally to this work: analyzed data, prepared figures and tables, and wrote the manuscript. LLB, MT, BK, KAG, WSB, LBC, SM, PLDJ, WK, MH, PKC, SMR, CDK, TJM, GDS, JLH, EBL, SCJ, MA, AM, ALJ, LKD, JM S, and NJC contributed to the interpretation of data and critical revision of the manuscript for important intellectual content. JLdA, MVF, and JB prepared genetic data: performed imputation, cleaning, and calculated principal components. Also contributed to critical revision of the manuscript for important intellectual content. JH, AMF, MR, RCP, LM, VMVD, VM-YL, LMS, JQT, ERP, GL, LKD, MJC, HZ, ADNI, ADGC, AMG, DAB, and JAS provided data, contributed to analysis and/or interpretation of data, and contributed to critical revision of the manuscript for important intellectual content. CC and TJH contributed equally to this work: conceived and planned the study, analyzed data, prepared the manuscript, and supervised the project. All authors reviewed and approved the final manuscript.

Funding

This research was supported in part by K01 AG049164, K12 HD043483, K24 AG046373, HHSN311201600276P, S10 OD023680, R01 AG034962, R01 HL111516, R01 NS100980, R01 AG056534, P30 AG10161, RF1 AG15819, R01 AG17917, R01 AG30146, R01 AG019085, R01 AG15819, R01 AG30146, R01 AG027161, R01 AG021155, R01 AG037639, U01 AG46152, U01 AG006781, U01 AG032984, U01 HG004610, U01 HG006375, U24 AG021886, U24 AG041689, R01 AG044546, P01 AG003991, RF1 AG053303, R01 AG035083, R01 NS085419, and the Alzheimer’s Association (NIRG-11-200110), further supported in part by the Intramural Research Program, NIA, NIH and the Vanderbilt Memory and Alzheimer’s Center. YD is supported by an NIMH training grant (T32MH014877). Support for PDJ was provided by R01 AG048015. SK received support from NIA R03 AG050856, Alzheimer’s Association, Michael J Fox Foundation, and ARUK Biomarkers Across Neurodegenerative Diseases (BAND). MR received support from the German Federal Ministry of Education and Research (BMBF) National Genome Research Network (NGFN) Grant No. 01GS08125 and through the Helmholtz Alliance for Mental Health in an Aging Society (HELMA) Grant No. Ha-15. HZ is a Wallenberg Academy Fellow and is further supported but the Swedish and European Research Councils and the UK Dementia Research Institute. KB holds the Torsten Söderberg professorship at the Royal Swedish Academy of Sciences. 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), P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P50 AG005134 (PI Bradley Hyman, MD, PhD), P50 AG016574 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Steven Ferris, PhD), P30 AG013854 (PI M. Marsel Mesulam, MD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P50 AG016570 (PI David Teplow, PhD), P50 AG005131 (PI Douglas Galasko, MD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, 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), P50 AG005136 (PI Thomas Grabowski, MD, PhD), P50 AG033514 (PI Sanjay Asthana, MD, FRCP), and P50 AG005681 (PI John Morris, MD). Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. 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; data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Compliance with ethical standards

ADNI

Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research and Development, LLC.; Johnson and Johnson Pharmaceutical Research and Development LLC.; Lumosity; Lundbeck; Merck and Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California.

Conflict of interest

Dr. Larson reports royalties from UpToDate. Dr. Schneider reports personal fees from Avid Radiopharmaceuticals, personal fees from Navidea Biopharmaceuticals, outside the submitted work. Dr. Zetterberg has served at advisory boards of Eli Lilly, Roche Diagnostics and Pharmasum Therapeutics and is one of the founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg. Dr. Blennow has served at advisory boards of Alzheon, BioArctic, Eli Lilly, IBL International, Fujirebio, Merck, and Roche Diagnostics and is one of the founders of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.

Supplementary material

401_2018_1881_MOESM1_ESM.docx (1 mb)
Supplementary material 1 (DOCX 1025 kb)
401_2018_1881_MOESM2_ESM.xlsx (191 kb)
Supplementary material 2 (XLSX 190 kb)

References

  1. 1.
    Altmann A, Tian L, Henderson VW, Greicius MD, Alzheimer’s Disease Neuroimaging Initiative I (2014) Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol 75:563–573.  https://doi.org/10.1002/ana.24135 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Apostolova LG, Dinov ID, Dutton RA, Hayashi KM, Toga AW, Cummings JL, Thompson PM (2006) 3D comparison of hippocampal atrophy in amnestic mild cognitive impairment and Alzheimer’s disease. Brain 129:2867–2873.  https://doi.org/10.1093/brain/awl274 CrossRefPubMedGoogle Scholar
  3. 3.
    Ataman B, Boulting GL, Harmin DA, Yang MG, Baker-Salisbury M, Yap EL, Malik AN, Mei K, Rubin AA, Spiegel I et al (2016) Evolution of Osteocrin as an activity-regulated factor in the primate brain. Nature 539:242–247.  https://doi.org/10.1038/nature20111 CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Barnes LL, Wilson RS, Bienias JL, Schneider JA, Evans DA, Bennett DA (2005) Sex differences in the clinical manifestations of Alzheimer disease pathology. Arch Gen Psychiatry 62:685–691.  https://doi.org/10.1001/archpsyc.62.6.685 CrossRefPubMedGoogle Scholar
  5. 5.
    Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS (2012) Overview and findings from the religious orders study. Curr Alzheimer Res 9:628–645CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Bennett DA, Schneider JA, Buchman AS, Barnes LL, Boyle PA, Wilson RS (2012) Overview and findings from the rush memory and aging project. Curr Alzheimer Res 9:646–663CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Blennow K, Hampel H, Weiner M, Zetterberg H (2010) Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nat Rev Neurol 6:131–144.  https://doi.org/10.1038/nrneurol.2010.4 CrossRefGoogle Scholar
  8. 8.
    Bord S, Ireland DC, Moffatt P, Thomas GP, Compston JE (2005) Characterization of osteocrin expression in human bone. J Histochem Cytochem 53:1181–1187.  https://doi.org/10.1369/jhc.4C6561.2005 CrossRefPubMedGoogle Scholar
  9. 9.
    Chassaing N, Ragge N, Plaisancie J, Patat O, Genevieve D, Rivier F, Malrieu-Eliaou C, Hamel C, Kaplan J, Calvas P (2016) Confirmation of TENM3 involvement in autosomal recessive colobomatous microphthalmia. Am J Med Genet A 170:1895–1898.  https://doi.org/10.1002/ajmg.a.37667 CrossRefPubMedGoogle Scholar
  10. 10.
    Crane PK, Carle A, Gibbons LE, Insel P, Mackin RS, Gross A, Jones RN, Mukherjee S, Curtis SM, Harvey D et al (2012) Development and assessment of a composite score for memory in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Brain Imaging Behav 6:502–516.  https://doi.org/10.1007/s11682-012-9186-z CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM, Benitez BA, Jeng AT, Skorupa T, Carrell D et al (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron 78:256–268.  https://doi.org/10.1016/j.neuron.2013.02.026 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cruchaga C, Kauwe JS, Mayo K, Spiegel N, Bertelsen S, Nowotny P, Shah AR, Abraham R, Hollingworth P, Harold D et al (2010) SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer’s disease. PLoS Genet 6:e1001101.  https://doi.org/10.1371/journal.pgen.1001101 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Dale AM, Fischl B, Sereno MI (1999) Cortical surface-based analysis. I. Segmentation and surface reconstruction. Neuroimage 9:179–194.  https://doi.org/10.1006/nimg.1998.0395 CrossRefGoogle Scholar
  14. 14.
    Deitch EA, Ananthakrishnan P, Cohen DB, Xu DZ, Feketeova E, Hauser CJ (2006) Neutrophil activation is modulated by sex hormones after trauma-hemorrhagic shock and burn injuries. Am J Physiol Heart Circ Physiol 291:H1456–H1465.  https://doi.org/10.1152/ajpheart.00694.2005 CrossRefPubMedGoogle Scholar
  15. 15.
    Deming Y, Li Z, Kapoor M, Harari O, Del-Aguila JL, Black K, Carrell D, Cai Y, Fernandez MV, Budde J et al (2017) Genome-wide association study identifies four novel loci associated with Alzheimer’s endophenotypes and disease modifiers. Acta Neuropathol 133:839–856.  https://doi.org/10.1007/s00401-017-1685-y CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Espuny-Camacho I, Arranz AM, Fiers M, Snellinx A, Ando K, Munck S, Bonnefont J, Lambot L, Corthout N, Omodho L et al (2017) Hallmarks of Alzheimer’s disease in stem-cell-derived human neurons transplanted into mouse brain. Neuron 93(1066–1081):e1068.  https://doi.org/10.1016/j.neuron.2017.02.001 CrossRefGoogle Scholar
  17. 17.
    Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA et al (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59:512–519.  https://doi.org/10.1002/ana.20730 CrossRefGoogle Scholar
  18. 18.
    Farley K, Stolley JM, Zhao P, Cooley J, Remold-O’Donnell E (2012) A serpinB1 regulatory mechanism is essential for restricting neutrophil extracellular trap generation. J Immunol 189:4574–4581.  https://doi.org/10.4049/jimmunol.1201167 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Farrer LA, Cupples L, Haines JL et al (1997) Effects of age, sex, and ethnicity on the association between apolipoprotein e genotype and alzheimer disease: a meta-analysis. JAMA 278:1349–1356.  https://doi.org/10.1001/jama.1997.03550160069041 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fischl B, Sereno MI, Dale AM (1999) Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system. Neuroimage 9:195–207.  https://doi.org/10.1006/nimg.1998.0396 CrossRefGoogle Scholar
  21. 21.
    Fischl B, Sereno MI, Tootell RB, Dale AM (1999) High-resolution intersubject averaging and a coordinate system for the cortical surface. Hum Brain Mapp 8:272–284CrossRefPubMedGoogle Scholar
  22. 22.
    Gibbons LE, Carle AC, Mackin RS, Harvey D, Mukherjee S, Insel P, Curtis SM, Mungas D, Crane PK, Alzheimer’s Disease Neuroimaging I (2012) A composite score for executive functioning, validated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants with baseline mild cognitive impairment. Brain Imaging Behav 6:517–527.  https://doi.org/10.1007/s11682-012-9176-1 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    GTEx Consortium (2017) Genetic effects on gene expression across human tissues. Nature 550:204–213.  https://doi.org/10.1038/nature24277 CrossRefPubMedCentralGoogle Scholar
  24. 24.
    GTEx Consortium (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348:648–660.  https://doi.org/10.1126/science.1262110 CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Henderson VW, Buckwalter JG (1994) Cognitive deficits of men and women with Alzheimer’s disease. Neurology 44:90–96CrossRefPubMedGoogle Scholar
  26. 26.
    Hohman TJ, Dumitrescu L, Barnes LL, Thambisetty M, Beecham G, Kunkle B, Gifford KA, Bush WS, Chibnik LB, Mukherjee S et al (2018) Sex-specific association of apolipoprotein E with cerebrospinal fluid levels of tau. JAMA Neurol.  https://doi.org/10.1001/jamaneurol.2018.0821 CrossRefPubMedGoogle Scholar
  27. 27.
    Hou J, Goodenough DA (2010) Claudin-16 and claudin-19 function in the thick ascending limb. Curr Opin Nephrol Hypertens 19:483–488.  https://doi.org/10.1097/MNH.0b013e32833b7125 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Hua X, Hibar DP, Lee S, Toga AW, Jack CR Jr, Weiner MW, Thompson PM, Alzheimer’s Disease Neuroimaging I (2010) Sex and age differences in atrophic rates: an ADNI study with n = 1368 MRI scans. Neurobiol Aging 31:1463–1480.  https://doi.org/10.1016/j.neurobiolaging.2010.04.033 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Huang KL, Marcora E, Pimenova AA, Di Narzo AF, Kapoor M, Jin SC, Harari O, Bertelsen S, Fairfax BP, Czajkowski J et al (2017) A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer’s disease. Nat Neurosci 20:1052–1061.  https://doi.org/10.1038/nn.4587 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Jack CR Jr, Bennett DA, Blennow K, Carrillo MC, Feldman HH, Frisoni GB, Hampel H, Jagust WJ, Johnson KA, Knopman DS et al (2016) A/T/N: an unbiased descriptive classification scheme for Alzheimer disease biomarkers. Neurology 87:539–547.  https://doi.org/10.1212/WNL.0000000000002923 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Jack CR Jr, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, Shaw LM, Vemuri P, Wiste HJ, Weigand SD et al (2013) Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12:207–216.  https://doi.org/10.1016/S1474-4422(12)70291-0 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Jack CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, Petersen RC, Trojanowski JQ (2010) Hypothetical model of dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurology 9:119–128CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Li G, Millard SP, Peskind ER, Zhang J, Yu CE, Leverenz JB, Mayer C, Shofer JS, Raskind MA, Quinn JF et al (2014) Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span. JAMA Neurol 71:742–751.  https://doi.org/10.1001/jamaneurol.2014.445 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lim AS, Srivastava GP, Yu L, Chibnik LB, Xu J, Buchman AS, Schneider JA, Myers AJ, Bennett DA, De Jager PL (2014) 24-hour rhythms of DNA methylation and their relation with rhythms of RNA expression in the human dorsolateral prefrontal cortex. PLoS Genet 10:e1004792.  https://doi.org/10.1371/journal.pgen.1004792 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Lonsdale J, Thomas J, Salvatore M, Phillips R, Lo E, Shad S, Hasz R, Walters G, Garcia F, Young N et al (2013) The Genotype-Tissue Expression (GTEx) project. Nat Genet 45: 580  https://doi.org/10.1038/ng.2653. https://www.nature.com/articles/ng.2653#supplementary-information
  36. 36.
    Mattsson N, Zetterberg H, Hansson O, Andreasen N, Parnetti L, Jonsson M, Herukka SK, van der Flier WM, Blankenstein MA, Ewers M et al (2009) CSF biomarkers and incipient Alzheimer disease in patients with mild cognitive impairment. JAMA 302:385–393.  https://doi.org/10.1001/jama.2009.1064 CrossRefPubMedGoogle Scholar
  37. 37.
    Mazure CM, Swendsen J (2016) Sex differences in Alzheimer’s disease and other dementias. Lancet Neurol 15:451–452.  https://doi.org/10.1016/S1474-4422(16)00067-3 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Mielke MM, Vemuri P, Rocca WA (2014) Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol 6:37–48.  https://doi.org/10.2147/CLEP.S37929 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Mormino EC, Kluth JT, Madison CM, Rabinovici GD, Baker SL, Miller BL, Koeppe RA, Mathis CA, Weiner MW, Jagust WJ et al (2009) Episodic memory loss is related to hippocampal-mediated beta-amyloid deposition in elderly subjects. Brain 132:1310–1323.  https://doi.org/10.1093/brain/awn320 CrossRefPubMedGoogle Scholar
  40. 40.
    Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, Gallins PJ, Buxbaum JD, Jarvik GP, Crane PK et al (2011) Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43:436–441.  https://doi.org/10.1038/ng.801 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Neu SC, Pa J, Kukull W, Beekly D, Kuzma A, Gangadharan P, Wang LS, Romero K, Arneric SP, Redolfi A et al (2017) Apolipoprotein E genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol 74:1178–1189.  https://doi.org/10.1001/jamaneurol.2017.2188 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Petersen RC, Aisen PS, Beckett LA, Donohue MC, Gamst AC, Harvey DJ, Jack CR, Jagust WJ, Shaw LM, Toga AW et al (2010) Alzheimer’s Disease Neuroimaging Initiative (ADNI) Clinical characterization. Neurology 74:201–209CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Petrone AB, Simpkins JW, Barr TL (2014) 17beta-estradiol and inflammation: implications for ischemic stroke. Aging Dis 5:340–345.  https://doi.org/10.14336/AD.2014.0500340 CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Romanitan MO, Popescu BO, Spulber S, Bajenaru O, Popescu LM, Winblad B, Bogdanovic N (2010) Altered expression of claudin family proteins in Alzheimer’s disease and vascular dementia brains. J Cell Mol Med 14:1088–1100.  https://doi.org/10.1111/j.1582-4934.2009.00999.x CrossRefPubMedGoogle Scholar
  45. 45.
    Sabolic I, Asif AR, Budach WE, Wanke C, Bahn A, Burckhardt G (2007) Gender differences in kidney function. Pflugers Arch 455:397–429.  https://doi.org/10.1007/s00424-007-0308-1 CrossRefPubMedGoogle Scholar
  46. 46.
    Saykin AJ, Shen L, Foroud TM, Potkin SG, Swaminathan S, Kim S, Risacher SL, Nho K, Huentelman MJ, Craig DW et al (2010) Alzheimer’s Disease Neuroimaging Initiative biomarkers as quantitative phenotypes: genetics core aims, progress, and plans. Alzheimers Dementia 6:265–273.  https://doi.org/10.1016/j.jalz.2010.03.013 CrossRefGoogle Scholar
  47. 47.
    Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S, Van der Flier WM (2016) Alzheimer’s disease. Lancet 388:505–517.  https://doi.org/10.1016/S0140-6736(15)01124-1 CrossRefGoogle Scholar
  48. 48.
    Schubert D (1997) Serpins inhibit the toxicity of amyloid peptides. Eur J Neurosci 9:770–777CrossRefPubMedGoogle Scholar
  49. 49.
    Spulber S, Bogdanovic N, Romanitan MO, Bajenaru OA, Popescu BO (2012) Claudin expression profile separates Alzheimer’s disease cases from normal aging and from vascular dementia cases. J Neurol Sci 322:184–186.  https://doi.org/10.1016/j.jns.2012.05.031 CrossRefPubMedGoogle Scholar
  50. 50.
    Voevodskaya O, Simmons A, Nordenskjold R, Kullberg J, Ahlstrom H, Lind L, Wahlund LO, Larsson EM, Westman E, Alzheimer’s Disease Neuroimaging I (2014) The effects of intracranial volume adjustment approaches on multiple regional MRI volumes in healthy aging and Alzheimer’s disease. Front Aging Neurosci 6:264.  https://doi.org/10.3389/fnagi.2014.00264 CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Winkler TW, Kutalik Z, Gorski M, Lottaz C, Kronenberg F, Heid IM (2015) EasyStrata: evaluation and visualization of stratified genome-wide association meta-analysis data. Bioinformatics 31:259–261.  https://doi.org/10.1093/bioinformatics/btu621 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Yuetiva Deming
    • 1
  • Logan Dumitrescu
    • 2
  • Lisa L. Barnes
    • 3
  • Madhav Thambisetty
    • 4
  • Brian Kunkle
    • 5
  • Katherine A. Gifford
    • 2
  • William S. Bush
    • 5
  • Lori B. Chibnik
    • 6
    • 7
  • Shubhabrata Mukherjee
    • 8
  • Philip L. De Jager
    • 9
    • 10
  • Walter Kukull
    • 11
  • Matt Huentelman
    • 12
  • Paul K. Crane
    • 8
  • Susan M. Resnick
    • 4
  • C. Dirk Keene
    • 13
  • Thomas J. Montine
    • 14
  • Gerard D. Schellenberg
    • 15
  • Jonathan L. Haines
    • 5
  • Henrik Zetterberg
    • 16
    • 17
    • 18
    • 19
  • Kaj Blennow
    • 16
    • 17
  • Eric B. Larson
    • 8
    • 20
  • Sterling C. Johnson
    • 21
    • 22
  • Marilyn Albert
    • 23
  • Abhay Moghekar
    • 23
  • Jorge L. del Aguila
    • 1
  • Maria Victoria Fernandez
    • 1
  • John Budde
    • 1
  • Jason Hassenstab
    • 1
  • Anne M. Fagan
    • 24
  • Matthias Riemenschneider
    • 25
  • Ronald C. Petersen
    • 26
  • Lennart Minthon
    • 27
  • Michael J. Chao
    • 28
  • Vivianna M. Van Deerlin
    • 29
  • Virginia M.-Y. Lee
    • 29
  • Leslie M. Shaw
    • 29
  • John Q. Trojanowski
    • 29
  • Elaine R. Peskind
    • 30
  • Gail Li
    • 30
    • 31
  • Lea K. Davis
    • 32
  • Julia M. Sealock
    • 32
  • Nancy J. Cox
    • 32
  • Alzheimer’s Disease Neuroimaging Initiative (ADNI)
  • The Alzheimer Disease Genetics Consortium (ADGC)
  • Alison M. Goate
    • 28
  • David A. Bennett
    • 3
  • Julie A. Schneider
    • 3
  • Angela L. Jefferson
    • 2
  • Carlos Cruchaga
    • 1
  • Timothy J. Hohman
    • 2
    Email author
  1. 1.Department of PsychiatryWashington University School of MedicineSt. LouisUSA
  2. 2.Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical CenterVanderbilt University School of MedicineNashvilleUSA
  3. 3.Rush Alzheimer’s Disease CenterRush University Medical CenterChicagoUSA
  4. 4.Unit of Clinical and Translational Neuroscience, Laboratory of Behavioral NeuroscienceNational Institute on Aging, National Institutes of HealthBaltimoreUSA
  5. 5.Department of Population and Quantitative Health Sciences, Institute for Computational BiologyCase Western Reserve UniversityClevelandUSA
  6. 6.Department of EpidemiologyHarvard T.H. Chan School of Public HealthBostonUSA
  7. 7.Channing Division of Network MedicineBrigham and Women’s HospitalBostonUSA
  8. 8.Department of MedicineUniversity of WashingtonSeattleUSA
  9. 9.Department of Neurology, Center for Translational and Computational NeuroimmunologyColumbia University Medical CenterNew YorkUSA
  10. 10.Cell Circuits Program, Broad InstituteCambridgeUSA
  11. 11.Department of Epidemiology, School of Public HealthUniversity of WashingtonSeattleUSA
  12. 12.Neurogenomics DivisionTranslational Genomics Research InstitutePhoenixUSA
  13. 13.Department of PathologyUniversity of WashingtonSeattleUSA
  14. 14.Department of PathologyStanford UniversityStanfordUSA
  15. 15.Department of Pathology and Laboratory Medicine, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  16. 16.Department of Psychiatry and Neurochemistry, Institute of Neuroscience and PhysiologyThe Sahlgrenska Academy at University of GothenburgMölndalSweden
  17. 17.Clinical Neurochemistry LaboratorySahlgrenska University HospitalMölndalSweden
  18. 18.Department of Molecular NeuroscienceUCL Institute of NeurologyLondonUK
  19. 19.UK Dementia Research Institute at UCLLondonUK
  20. 20.Kaiser Permanente Washington Health Research InstituteSeattleUSA
  21. 21.Alzheimer’s Disease Research CenterUniversity of Wisconsin School of Medicine and Public HealthMadisonUSA
  22. 22.Geriatric Research Education and Clinical Center of the Wm. S. Middleton Memorial VA HospitalMadisonUSA
  23. 23.Department of NeurologyThe Johns Hopkins University School of MedicineBaltimoreUSA
  24. 24.Department of NeurologyWashington University School of MedicineSt. LouisUSA
  25. 25.Clinic of Psychiatry and PsychotherapySaarland UniversityHomburg/SaarGermany
  26. 26.Department of NeurologyMayo ClinicRochesterUSA
  27. 27.Clinical Memory Research Unit, Department of Clinical SciencesLund UniversityLundSweden
  28. 28.Ronald M Loeb Center for Alzheimer’s Disease, Department of NeuroscienceIcahn School of Medicine at Mount SinaiNew YorkUSA
  29. 29.Department of Pathology and Laboratory MedicinePerelman School of Medicine at the University of PennsylvaniaPhiladelphiaUSA
  30. 30.Department of Psychiatry and Behavioral SciencesUniversity of WashingtonSeattleUSA
  31. 31.Geriatric Research, Education, and Clinical CenterVA Puget Sound Health Care SystemSeattleUSA
  32. 32.Department of Medicine, Vanderbilt Genetics InstituteVanderbilt University Medical CenterNashvilleUSA

Personalised recommendations