Display options
Cite
Farrell K, Kim S, Han N, et al. Genome-wide association study and functional validation implicates JADE1 in tauopathy. Acta Neuropathol. 2021;143(1):33-53doi: 10.1007/s00401-021-02379-z.
Farrell, K., Kim, S., Han, N., Iida, M. A., Gonzalez, E. M., Otero-Garcia, M., Walker, J. M., Richardson, T. E., Renton, A. E., Andrews, S. J., Fulton-Howard, B., Humphrey, J., Vialle, R. A., Bowles, K. R., de Paiva Lopes, K., Whitney, K., Dangoor, D. K., Walsh, H., Marcora, E., Hefti, M. M., Casella, A., Sissoko, C. T., Kapoor, M., Novikova, G., Udine, E., Wong, G., Tang, W., Bhangale, T., Hunkapiller, J., Ayalon, G., Graham, R. R., Cherry, J. D., Cortes, E. P., Borukov, V. Y., McKee, A. C., Stein, T. D., Vonsattel, J. P., Teich, A. F., Gearing, M., Glass, J., Troncoso, J. C., Frosch, M. P., Hyman, B. T., Dickson, D. W., Murray, M. E., Attems, J., Flanagan, M. E., Mao, Q., Mesulam, M. M., Weintraub, S., Woltjer, R. L., Pham, T., Kofler, J., Schneider, J. A., Yu, L., Purohit, D. P., Haroutunian, V., Hof, P. R., Gandy, S., Sano, M., Beach, T. G., Poon, W., Kawas, C. H., Corrada, M. M., Rissman, R. A., Metcalf, J., Shuldberg, S., Salehi, B., Nelson, P. T., Trojanowski, J. Q., Lee, E. B., Wolk, D. A., McMillan, C. T., Keene, C. D., Latimer, C. S., Montine, T. J., Kovacs, G. G., Lutz, M. I., Fischer, P., Perrin, R. J., Cairns, N. J., Franklin, E. E., Cohen, H. T., Raj, T., Cobos, I., Frost, B., Goate, A., White Iii, C. L., & Crary, J. F. (2022). Genome-wide association study and functional validation implicates JADE1 in tauopathy. Acta neuropathologica, 143(1), 33-53. https://doi.org/10.1007/s00401-021-02379-z
Farrell, Kurt, et al. "Genome-wide association study and functional validation implicates JADE1 in tauopathy." Acta neuropathologica vol. 143,1 (2022): 33-53. doi: https://doi.org/10.1007/s00401-021-02379-z
Farrell K, Kim S, Han N, Iida MA, Gonzalez EM, Otero-Garcia M, Walker JM, Richardson TE, Renton AE, Andrews SJ, Fulton-Howard B, Humphrey J, Vialle RA, Bowles KR, de Paiva Lopes K, Whitney K, Dangoor DK, Walsh H, Marcora E, Hefti MM, Casella A, Sissoko CT, Kapoor M, Novikova G, Udine E, Wong G, Tang W, Bhangale T, Hunkapiller J, Ayalon G, Graham RR, Cherry JD, Cortes EP, Borukov VY, McKee AC, Stein TD, Vonsattel JP, Teich AF, Gearing M, Glass J, Troncoso JC, Frosch MP, Hyman BT, Dickson DW, Murray ME, Attems J, Flanagan ME, Mao Q, Mesulam MM, Weintraub S, Woltjer RL, Pham T, Kofler J, Schneider JA, Yu L, Purohit DP, Haroutunian V, Hof PR, Gandy S, Sano M, Beach TG, Poon W, Kawas CH, Corrada MM, Rissman RA, Metcalf J, Shuldberg S, Salehi B, Nelson PT, Trojanowski JQ, Lee EB, Wolk DA, McMillan CT, Keene CD, Latimer CS, Montine TJ, Kovacs GG, Lutz MI, Fischer P, Perrin RJ, Cairns NJ, Franklin EE, Cohen HT, Raj T, Cobos I, Frost B, Goate A, White Iii CL, Crary JF. Genome-wide association study and functional validation implicates JADE1 in tauopathy. Acta Neuropathol. 2022 Jan;143(1):33-53. doi: 10.1007/s00401-021-02379-z. Epub 2021 Nov 01. PMID: 34719765.
Copy Download .nbib Format: NLM
Share it on

Acta Neuropathol. 2022 Jan;143(1):33-53. doi: 10.1007/s00401-021-02379-z. Epub 2021 Nov 01.

Genome-wide association study and functional validation implicates JADE1 in tauopathy.

Acta neuropathologica

Kurt Farrell, SoongHo Kim, Natalia Han, Megan A Iida, Elias M Gonzalez, Marcos Otero-Garcia, Jamie M Walker, Timothy E Richardson, Alan E Renton, Shea J Andrews, Brian Fulton-Howard, Jack Humphrey, Ricardo A Vialle, Kathryn R Bowles, Katia de Paiva Lopes, Kristen Whitney, Diana K Dangoor, Hadley Walsh, Edoardo Marcora, Marco M Hefti, Alicia Casella, Cheick T Sissoko, Manav Kapoor, Gloriia Novikova, Evan Udine, Garrett Wong, Weijing Tang, Tushar Bhangale, Julie Hunkapiller, Gai Ayalon, Robert R Graham, Jonathan D Cherry, Etty P Cortes, Valeriy Y Borukov, Ann C McKee, Thor D Stein, Jean-Paul Vonsattel, Andy F Teich, Marla Gearing, Jonathan Glass, Juan C Troncoso, Matthew P Frosch, Bradley T Hyman, Dennis W Dickson, Melissa E Murray, Johannes Attems, Margaret E Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weintraub, Randy L Woltjer, Thao Pham, Julia Kofler, Julie A Schneider, Lei Yu, Dushyant P Purohit, Vahram Haroutunian, Patrick R Hof, Sam Gandy, Mary Sano, Thomas G Beach, Wayne Poon, Claudia H Kawas, María M Corrada, Robert A Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T Nelson, John Q Trojanowski, Edward B Lee, David A Wolk, Corey T McMillan, C Dirk Keene, Caitlin S Latimer, Thomas J Montine, Gabor G Kovacs, Mirjam I Lutz, Peter Fischer, Richard J Perrin, Nigel J Cairns, Erin E Franklin, Herbert T Cohen, Towfique Raj, Inma Cobos, Bess Frost, Alison Goate, Charles L White Iii, John F Crary

Affiliations

  1. Department of Pathology, Neuropathology Brain Bank and Research CoRE, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place Box 1194, New York, NY, 10029, USA.
  2. Nash Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  3. Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  4. Department of Cell Systems and Anatomy, Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, the Sam and Ann Barshop Institute for Longevity and Aging Studies, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  5. Department of Pathology and Laboratory Medicine, Division of Neuropathology, University of California, Los Angeles, CA, USA.
  6. Department of Pathology and Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, UT Health San Antonio, San Antonio, TX, USA.
  7. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  8. Department of Pathology, University of Iowa, Iowa City, IA, USA.
  9. Department of Pathology, Stanford University, Palo Alto, USA.
  10. Department of Human Genetics, Genentech, South San Francisco, CA, USA.
  11. Neumora Therapeutics, South San Francisco, CA, USA.
  12. Maze Therapeutics, San Francisco, CA, USA.
  13. Department of Pathology (Neuropathology), VA Medical Center, Boston University School of Medicine, Boston, MA, USA.
  14. Department of Pathology and Cell Biology, Department of Neurology, and the Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
  15. Department of Pathology and Laboratory Medicine (Neuropathology) and Neurology, Emory University School of Medicine, Atlanta, GA, USA.
  16. Department of Pathology, Division of Neuropathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  17. Department of Neurology and Pathology, Harvard Medical School and Massachusetts General Hospital, Charlestown, MA, USA.
  18. Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
  19. Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
  20. Department of Pathology (Neuropathology), Northwestern Cognitive Neurology and Alzheimer Disease Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  21. Department of Pathology, Oregon Health Sciences University, Portland, OR, USA.
  22. Department of Pathology (Neuropathology), University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
  23. Departments of Pathology (Neuropathology) and Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
  24. Department of Psychiatry, Alzheimer's Disease Research Center, James J. Peters VA Medical Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  25. Department of Neurology, Center for Cognitive Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  26. Department of Neuropathology, Banner Sun Health Research Institute, Sun City, AZ, USA.
  27. Department of Neurology, Department of Epidemiology, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
  28. Department of Neurology, Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, UC Irvine, Irvine, CA, USA.
  29. Department of Neurosciences University of California and the Veterans Affairs San Diego Healthcare System, La Jolla, San Diego, California, USA.
  30. Department of Pathology (Neuropathology) and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA.
  31. Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  32. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  33. Department of Laboratory Medicine and Pathology, University of f Medicine, Seattle, WA, USA.
  34. Laboratory Medicine Program, Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
  35. Tanz Centre for Research in Neurodegenerative Disease and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
  36. Institute of Neurology, Medical University of Vienna, Vienna, Austria.
  37. Department of Psychiatry, Danube Hospital, Vienna, Austria.
  38. Department of Pathology and Immunology, Department of Neurology, Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA.
  39. College of Medicine and Health, University of Exeter, Exeter, UK.
  40. Departments of Medicine, Pathology, and Pharmacology, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA.
  41. Department of Pathology (Neuropathology), University of Texas Southwestern Medical School, Dallas, TX, USA.
  42. Department of Pathology, Neuropathology Brain Bank and Research CoRE, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place Box 1194, New York, NY, 10029, USA. [email protected].
  43. Nash Department of Neuroscience, Ronald M. Loeb Center for Alzheimer's Disease, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].
  44. Department of Artificial Intelligence and Human Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. [email protected].

PMID: 34719765 DOI: 10.1007/s00401-021-02379-z

Abstract

Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

References

  1. Abner EL, Neltner JH, Jicha GA, Patel E, Anderson SL, Wilcock DM et al (2018) Diffuse amyloid-beta plaques, neurofibrillary tangles, and the impact of APOE in elderly persons’ brains lacking neuritic amyloid plaques. J Alzh Dis 64:1307–1324. https://doi.org/10.3233/Jad-180514 - PubMed
  2. Aldridge GM, Podrebarac DM, Greenough WT, Weiler IJ (2008) The use of total protein stains as loading controls: an alternative to high-abundance single-protein controls in semi-quantitative immunoblotting. J Neurosci Methods 172:250–254. https://doi.org/10.1016/j.jneumeth.2008.05.003 - PubMed
  3. Anderson CA, Pettersson FH, Clarke GM, Cardon LR, Morris AP, Zondervan KT (2010) Data quality control in genetic case-control association studies. Nat Protoc 5:1564–1573. https://doi.org/10.1038/nprot.2010.116 - PubMed
  4. Andrews SJ, Fulton-Howard B, Goate A (2020) Interpretation of risk loci from genome-wide association studies of Alzheimer’s disease. Lancet Neurol 19:326–335. https://doi.org/10.1016/S1474-4422(19)30435-1 - PubMed
  5. Augustinack JC, Schneider A, Mandelkow EM, Hyman BT (2002) Specific tau phosphorylation sites correlate with severity of neuronal cytopathology in Alzheimer’s disease. Acta Neuropathol 103:26–35. https://doi.org/10.1007/s004010100423 - PubMed
  6. Beecham GW, Hamilton K, Naj AC, Martin ER, Huentelman M, Myers AJ et al (2014) Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer’s disease and related dementias. Plos Genet. https://doi.org/10.1371/journal.pgen.1004606 - PubMed
  7. Bell WR, An Y, Kageyama Y, English C, Rudow GL, Pletnikova O et al (2019) Neuropathologic, genetic, and longitudinal cognitive profiles in primary age-related tauopathy (PART) and Alzheimer’s disease. Alzheimers Dement 15:8–16. https://doi.org/10.1016/j.jalz.2018.07.215 - PubMed
  8. Bennett DA, Schneider JA, Arvanitakis Z, Kelly JF, Aggarwal NT, Shah RC et al (2006) Neuropathology of older persons without cognitive impairment from two community-based studies. Neurology 66:1837–1844. https://doi.org/10.1212/01.wnl.0000219668.47116.e6 - PubMed
  9. Besser LM, Crary JF, Mock C, Kukull WA (2017) Comparison of symptomatic and asymptomatic persons with primary age-related tauopathy. Neurology 89:1707–1715. https://doi.org/10.1212/WNL.0000000000004521 - PubMed
  10. Besser LM, Mock C, Teylan MA, Hassenstab J, Kukull WA, Crary JF (2019) Differences in cognitive impairment in primary age-related tauopathy versus alzheimer disease. J Neuropath Exp Neur 78:219–228. https://doi.org/10.1093/jnen/nly132 - PubMed
  11. Boettger LM, Handsaker RE, Zody MC, McCarroll SA (2012) Structural haplotypes and recent evolution of the human 17q21.31 region. Nat Genet 44:881–882. https://doi.org/10.1038/ng.2334 - PubMed
  12. Boone DK, Weisz HA, Bi M, Falduto MT, Torres KEO, Willey HE et al (2017) Evidence linking microRNA suppression of essential prosurvival genes with hippocampal cell death after traumatic brain injury. Sci Rep 7:6645. https://doi.org/10.1038/s41598-017-06341-6 - PubMed
  13. Borgal L, Habbig S, Hatzold J, Liebau MC, Dafinger C, Sacarea I et al (2012) The ciliary protein nephrocystin-4 translocates the canonical Wnt regulator Jade-1 to the nucleus to negatively regulate beta-catenin signaling. J Biol Chem 287:25370–25380. https://doi.org/10.1074/jbc.M112.385658 - PubMed
  14. Braak E, Braak H, Mandelkow EM (1994) A sequence of cytoskeleton changes related to the formation of neurofibrillary tangles and neuropil threads. Acta Neuropathol 87:554–567. https://doi.org/10.1007/BF00293315 - PubMed
  15. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16:271–278. https://doi.org/10.1016/0197-4580(95)00021-6 - PubMed
  16. Braak H, Del Tredici K (2014) Are cases with tau pathology occurring in the absence of A beta deposits part of the AD-related pathological process? Acta Neuropathol 128:767–772. https://doi.org/10.1007/s00401-014-1356-1 - PubMed
  17. Broce I, Karch CM, Wen N, Fan CC, Wang YP, Tan CH et al (2018) Immune-related genetic enrichment in frontotemporal dementia: an analysis of genome-wide association studies. Plos Med. https://doi.org/10.1371/journal.pmed.1002487 - PubMed
  18. Chen JA, Chen Z, Won H, Huang AY, Lowe JK, Wojta K et al (2018) Joint genome-wide association study of progressive supranuclear palsy identifies novel susceptibility loci and genetic correlation to neurodegenerative diseases. Mol Neurodegener 13:41. https://doi.org/10.1186/s13024-018-0270-8 - PubMed
  19. Chitalia VC, Foy RL, Bachschmid MM, Zeng L, Panchenko MV, Zhou MI et al (2008) Jade-1 inhibits Wnt signalling by ubiquitylating beta-catenin and mediates Wnt pathway inhibition by pVHL. Nat Cell Biol 10:1208–1216. https://doi.org/10.1038/ncb1781 - PubMed
  20. Clarke L, Fairley S, Zheng-Bradley XQ, Streeter I, Perry E, Lowy E et al (2017) The international genome sample resource (IGSR): a worldwide collection of genome variation incorporating the 1000 genomes project data. Nucleic Acids Res 45:D854–D859. https://doi.org/10.1093/nar/gkw829 - PubMed
  21. Combs B, Kanaan NM (2017) Exposure of the amino terminus of tau is a pathological event in multiple tauopathies. Am J Pathol 187:1222–1229. https://doi.org/10.1016/j.ajpath.2017.01.019 - PubMed
  22. Congdon EE, Sigurdsson EM (2018) Tau-targeting therapies for Alzheimer disease. Nat Rev Neurol 14:399–415. https://doi.org/10.1038/s41582-018-0013-z - PubMed
  23. Crary JF, Trojanowski JQ, Schneider JA, Abisambra JF, Abner EL, Alafuzoff I et al (2014) Primary age-related tauopathy (PART): a common pathology associated with human aging. Acta Neuropathol 128:755–766. https://doi.org/10.1007/s00401-014-1349-0 - PubMed
  24. Das S, Forer L, Schonherr S, Sidore C, Locke AE, Kwong A et al (2016) Next-generation genotype imputation service and methods. Nat Genet 48:1284–1287. https://doi.org/10.1038/ng.3656 - PubMed
  25. De Jager PL, Ma Y, McCabe C, Xu J, Vardarajan BN, Felsky D et al (2018) A multi-omic atlas of the human frontal cortex for aging and Alzheimer’s disease research. Sci Data 5:180142. https://doi.org/10.1038/sdata.2018.142 - PubMed
  26. Derisbourg M, Leghay C, Chiappetta G, Fernandez-Gomez FJ, Laurent C, Demeyer D et al (2015) Role of the Tau N-terminal region in microtubule stabilization revealed by new endogenous truncated forms. Sci Rep-Uk. https://doi.org/10.1038/srep09659 - PubMed
  27. Dregni AJ, Mandala VS, Wu H, Elkins MR, Wang HK, Hung I et al (2019) In vitro 0N4R tau fibrils contain a monomorphic beta-sheet core enclosed by dynamically heterogeneous fuzzy coat segments. Proc Natl Acad Sci U S A 116:16357–16366. https://doi.org/10.1073/pnas.1906839116 - PubMed
  28. Duyckaerts C, Braak H, Brion JP, Buee L, Del Tredici K, Goedert M et al (2015) PART is part of Alzheimer disease. Acta Neuropathol 129:749–756. https://doi.org/10.1007/s00401-015-1390-7 - PubMed
  29. Efthymiou AG, Goate AM (2017) Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk. Mol Neurodegener 12:43. https://doi.org/10.1186/s13024-017-0184-x - PubMed
  30. Farfel JM, Yu L, De Jager PL, Schneider JA, Bennett DA (2016) Association of APOE with tau-tangle pathology with and without beta-amyloid. Neurobiol Aging 37:19–25. https://doi.org/10.1016/j.neurobiolaging.2015.09.011 - PubMed
  31. Finak G, McDavid A, Yajima M, Deng J, Gersuk V, Shalek AK et al (2015) MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol 16:278. https://doi.org/10.1186/s13059-015-0844-5 - PubMed
  32. Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ et al (2017) Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature 547:185–190. https://doi.org/10.1038/nature23002 - PubMed
  33. Folstein MF, Robins LN, Helzer JE (1983) The mini-mental state examination. Arch Gen Psychiatry 40:812 - PubMed
  34. Frost B, Ollesch J, Wille H, Diamond MI (2009) Conformational diversity of wild-type Tau fibrils specified by templated conformation change. J Biol Chem 284:3546–3551. https://doi.org/10.1074/jbc.M805627200 - PubMed
  35. Hoglinger GU, Melhem NM, Dickson DW, Sleiman PMA, Wang LS, Klei L et al (2011) Identification of common variants influencing risk of the tauopathy progressive supranuclear palsy. Nat Genet 43:699-U125. https://doi.org/10.1038/ng.859 - PubMed
  36. Holmes BB, Devos SL, Kfoury N, Li M, Jacks R, Yanamandra K et al (2013) Heparan sulfate proteoglycans mediate internalization and propagation of specific proteopathic seeds. P Natl Acad Sci USA 110:E3138–E3147. https://doi.org/10.1073/pnas.1301440110 - PubMed
  37. Hong S, Prokopenko D, Dobricic V, Kilpert F, Bos I, Vos SJB et al (2020) Genome-wide association study of Alzheimer’s disease CSF biomarkers in the EMIF-AD multimodal biomarker discovery dataset. Trans Psychiatry 10:403. https://doi.org/10.1038/s41398-020-01074-z - PubMed
  38. Hutton M, Lendon CL, Rizzu P, Baker M, Froelich S, Houlden H et al (1998) Association of missense and 5’-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 393:702–705. https://doi.org/10.1038/31508 - PubMed
  39. Iida MA, Farrell K, Walker JM, Richardson TE, Marx G, Bryce CH et al (2021) Predictors of cognitive impairment in primary age-related tauopathy: an autopsy study. bioRxiv. https://doi.org/10.1101/2021.06.08.447553 - PubMed
  40. Ikeda K, Akiyama H, Arai T, Oda T, Kato M, Iseki E et al (1999) Clinical aspects of “senile dementia of the tangle type” - A subset of dementia in the senium separable from late-onset Alzheimer’s disease. Dement Geriatr Cogn 10:6–11. https://doi.org/10.1159/000017091 - PubMed
  41. Ikeda K, Akiyama H, Arai T, Sahara N, Mori H, Usami M et al (1997) A subset of senile dementia with high incidence of the apolipoprotein E epsilon2 allele. Ann Neurol 41:693–695. https://doi.org/10.1002/ana.410410522 - PubMed
  42. Jabbari E, Koga S, Valentino RR, Reynolds RH, Ferrari R, Tan MMX et al (2021) Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study. Lancet Neurol 20:107–116. https://doi.org/10.1016/S1474-4422(20)30394-X - PubMed
  43. Janocko NJ, Brodersen KA, Soto-Ortolaza AI, Ross OA, Liesinger AM, Duara R et al (2012) Neuropathologically defined subtypes of Alzheimer’s disease differ significantly from neurofibrillary tangle-predominant dementia. Acta Neuropathol 124:681–692. https://doi.org/10.1007/s00401-012-1044-y - PubMed
  44. Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S et al (2019) Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk. Nat Genet 51:404–413. https://doi.org/10.1038/s41588-018-0311-9 - PubMed
  45. Jellinger KA, Attems J (2007) Neurofibrillary tangle-predominant dementia: comparison with classical Alzheimer disease. Acta Neuropathol 113:107–117. https://doi.org/10.1007/s00401-006-0156-7 - PubMed
  46. Jun G, Ibrahim-Verbaas CA, Vronskaya M, Lambert JC, Chung J, Naj AC et al (2016) A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry 21:108–117. https://doi.org/10.1038/mp.2015.23 - PubMed
  47. Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK et al (2017) A unique microglia type associated with restricting development of alzheimer’s disease. Cell 169(1276–1290):e1217. https://doi.org/10.1016/j.cell.2017.05.018 - PubMed
  48. Knopman DS, Parisi JE, Salviati A, Floriach-Robert M, Boeve BF, Ivnik RJ et al (2003) Neuropathology of cognitively normal elderly. J Neuropath Exp Neur 62:1087–1095. https://doi.org/10.1093/jnen/62.11.1087 - PubMed
  49. Kouri N, Ross OA, Dombroski B, Younkin CS, Serie DJ, Soto-Ortolaza A et al (2015) Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nat Commun. https://doi.org/10.1038/ncomms8247 - PubMed
  50. Kovacs GG (2015) Invited review: neuropathology of tauopathies: principles and practice. Neuropathol Appl Neurobiol 41:3–23. https://doi.org/10.1111/nan.12208 - PubMed
  51. Kovacs GG, Ferrer I, Grinberg LT, Alafuzoff I, Attems J, Budka H et al (2016) Aging-related tau astrogliopathy (ARTAG): harmonized evaluation strategy. Acta Neuropathol 131:87–102. https://doi.org/10.1007/s00401-015-1509-x - PubMed
  52. Kunkle BW, Grenier-Boley B, Sims R, Bis JC, Damotte V, Naj AC et al (2019) Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing. Nat Genet 51:414–430. https://doi.org/10.1038/s41588-019-0358-2 - PubMed
  53. Lafirdeen ASM, Cognat E, Sabia S, Hourregue C, Lilamand M, Dugravot A et al (2019) Biomarker profiles of Alzheimer’s disease and dynamic of the association between cerebrospinal fluid levels of beta-amyloid peptide and tau. PLoS ONE 14:e0217026. https://doi.org/10.1371/journal.pone.0217026 - PubMed
  54. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet 45:1452–1458. https://doi.org/10.1038/ng.2802 - PubMed
  55. Larsson M, Duffy DL, Zhu G, Liu JZ, Macgregor S, McRae AF et al (2011) GWAS findings for human iris patterns: associations with variants in genes that influence normal neuronal pattern development. Am J Hum Genet 89:334–343. https://doi.org/10.1016/j.ajhg.2011.07.011 - PubMed
  56. Lee SH, Meilandt WJ, Xie L, Gandham VD, Ngu H, Barck KH et al (2021) Trem2 restrains the enhancement of tau accumulation and neurodegeneration by beta-amyloid pathology. Neuron 109(1283–1301):e1286. https://doi.org/10.1016/j.neuron.2021.02.010 - PubMed
  57. Lisztwan J, Imbert G, Wirbelauer C, Gstaiger M, Krek W (1999) The von Hippel-Lindau tumor suppressor protein is a component of an E3 ubiquitin-protein ligase activity. Gene Dev 13:1822–1833. https://doi.org/10.1101/gad.13.14.1822 - PubMed
  58. Marioni RE, Harris SE, Zhang Q, McRae AF, Hagenaars SP, Hill WD et al (2018) GWAS on family history of Alzheimer’s disease. Transl Psychiatry 8:99. https://doi.org/10.1038/s41398-018-0150-6 - PubMed
  59. Martin L, Latypova X, Wilson CM, Magnaudeix A, Perrin ML, Yardin C et al (2013) Tau protein kinases: involvement in Alzheimer’s disease. Ageing Res Rev 12:289–309. https://doi.org/10.1016/j.arr.2012.06.003 - PubMed
  60. McCarthy S, Das S, Kretzschmar W, Delaneau O, Wood AR, Teumer A et al (2016) A reference panel of 64,976 haplotypes for genotype imputation. Nat Genet 48:1279–1283. https://doi.org/10.1038/ng.3643 - PubMed
  61. McMillan CT, Lee EB, Jefferson-George K, Naj A, Van Deerlin VM, Trojanowski JQ et al (2018) Alzheimer’s genetic risk is reduced in primary age-related tauopathy: a potential model of resistance? Ann Clin Transl Neur 5:927–934. https://doi.org/10.1002/acn3.581 - PubMed
  62. Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM et al (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD). Part II standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486 - PubMed
  63. Mitchell TW, Mufson EJ, Schneider JA, Cochran EJ, Nissanov J, Han LY et al (2002) Parahippocampal tau pathology in healthy aging, mild cognitive impairment, and early Alzheimer’s disease. Ann Neurol 51:182–189. https://doi.org/10.1002/ana.10086 - PubMed
  64. Morris JC (1993) The clinical dementia rating (CDR): current version and scoring rules. Neurology 43:2412–2414 - PubMed
  65. Mungas D, Tractenberg R, Schneider JA, Crane PK, Bennett DA (2014) A 2-process model for neuropathology of Alzheimer’s disease. Neurobiol Aging 35:301–308. https://doi.org/10.1016/j.neurobiolaging.2013.08.007 - PubMed
  66. Myers AJ, Kaleem M, Marlowe L, Pittman AM, Lees AJ, Fung HC et al (2005) The H1c haplotype at the MAPT locus is associated with Alzheimer’s disease. Hum Mol Genet 14:2399–2404. https://doi.org/10.1093/hmg/ddi241 - PubMed
  67. Nagy Z, VatterBittner B, Braak H, Braak E, Yilmazer DM, Schultz C et al (1997) Staging of Alzheimer-type pathology: an interrater-intrarater study. Dement Geriatr Cogn 8:248–251. https://doi.org/10.1159/000106639 - PubMed
  68. Nalls MA, Blauwendraat C, Vallerga CL, Heilbron K, Bandres-Ciga S, Chang D et al (2019) Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol 18:1091–1102. https://doi.org/10.1016/S1474-4422(19)30320-5 - PubMed
  69. Nelson PT, Abner EL, Schmitt FA, Kryscio RJ, Jicha GA, Santacruz K et al (2009) Brains with medial temporal lobe neurofibrillary tangles but no neuritic amyloid plaques are a diagnostic dilemma but may have pathogenetic aspects distinct from Alzheimer disease. J Neuropathol Exp Neurol 68:774–784. https://doi.org/10.1097/NEN.0b013e3181aacbe9 - PubMed
  70. Nelson PT, Alafuzoff I, Bigio EH, Bouras C, Braak H, Cairns NJ et al (2012) Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature. J Neuropathol Exp Neurol 71:362–381. https://doi.org/10.1097/NEN.0b013e31825018f7 - PubMed
  71. Nelson PT, Jicha GA, Schmitt FA, Liu H, Davis DG, Mendiondo MS et al (2007) Clinicopathologic correlations in a large Alzheimer disease center autopsy cohort: neuritic plaques and neurofibrillary tangles “do count” when staging disease severity. J Neuropathol Exp Neurol 66:1136–1146. https://doi.org/10.1097/nen.0b013e31815c5efb - PubMed
  72. Novak M, Jakes R, Edwards PC, Milstein C, Wischik CM (1991) Difference between the tau-protein of alzheimer paired helical filament core and normal tau revealed by epitope analysis of monoclonal antibodies-423 and antibodies-7.51. P Natl Acad Sci USA 88:5837–5841. https://doi.org/10.1073/pnas.88.13.5837 - PubMed
  73. Otero-Garcia M, Xue Y-Q, Shakouri T, Deng Y, Morabito S, Allison T et al (2020) Single-soma transcriptomics of tangle-bearing neurons in Alzheimer’s disease reveals the signatures of tau-associated synaptic dysfunction. bioRxiv. https://doi.org/10.1101/2020.05.11.088591 - PubMed
  74. Panagiotou OA, Ioannidis JPA, Project G-WS (2012) What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. Int J Epidemiol 41:273–286. https://doi.org/10.1093/ije/dyr178 - PubMed
  75. Panchenko MV (2016) Structure, function and regulation of jade family PHD finger 1 (JADE1). Gene 589:1–11. https://doi.org/10.1016/j.gene.2016.05.002 - PubMed
  76. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38:904–909. https://doi.org/10.1038/ng1847 - PubMed
  77. Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP et al (2010) LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26:2336–2337. https://doi.org/10.1093/bioinformatics/btq419 - PubMed
  78. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D et al (2007) PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575. https://doi.org/10.1086/519795 - PubMed
  79. Reiman EM, Arboleda-Velasquez JF, Quiroz YT, Huentelman MJ, Beach TG, Caselli RJ et al (2020) Exceptionally low likelihood of Alzheimer’s dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. https://doi.org/10.1038/s41467-019-14279-8 - PubMed
  80. Robinson JL, Geser F, Corrada MM, Berlau DJ, Arnold SE, Lee VM et al (2011) Neocortical and hippocampal amyloid-beta and tau measures associate with dementia in the oldest-old. Brain 134:3708–3715. https://doi.org/10.1093/brain/awr308 - PubMed
  81. Sanchez-Contreras MY, Kouri N, Cook CN, Serie DJ, Heckman MG, Finch NA et al (2018) Replication of progressive supranuclear palsy genome-wide association study identifies SLCO1A2 and DUSP10 as new susceptibility loci. Mol Neurodegener. https://doi.org/10.1186/s13024-018-0267-3 - PubMed
  82. Sanchez-Juan P, Moreno S, de Rojaso I, Hernandez I, Valero S, Alegret M et al (2019) The MAPT H1 haplotype is a risk factor for Alzheimer’s disease in APOE epsilon 4 non-carriers. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2019.00327 - PubMed
  83. Santa-Maria I, Haggiagi A, Liu XM, Wasserscheid J, Nelson PT, Dewar K et al (2012) The MAPT H1 haplotype is associated with tangle-predominant dementia. Acta Neuropathol 124:693–704. https://doi.org/10.1007/s00401-012-1017-1 - PubMed
  84. Scheres SH, Zhang W, Falcon B, Goedert M (2020) Cryo-EM structures of tau filaments. Curr Opin Struct Biol 64:17–25. https://doi.org/10.1016/j.sbi.2020.05.011 - PubMed
  85. Schneider JA, Aggarwal NT, Barnes L, Boyle P, Bennett DA (2009) The neuropathology of older persons with and without dementia from community versus clinic cohorts. J Alzheimers Dis 18:691–701. https://doi.org/10.3233/Jad-2009-1227 - PubMed
  86. Sealey MA, Vourkou E, Cowan CM, Bossing T, Quraishe S, Grammenoudi S et al (2017) Distinct phenotypes of three-repeat and four-repeat human tau in a transgenic model of tauopathy. Neurobiol Dis 105:74–83. https://doi.org/10.1016/j.nbd.2017.05.003 - PubMed
  87. Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao LZ, Luo WJ et al (2017) ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy. Nature 549:523–524. https://doi.org/10.1038/nature24016 - PubMed
  88. Sieberts SK, Perumal TM, Carrasquillo MM, Allen M, Reddy JS, Hoffman GE et al (2020) Large eQTL meta-analysis reveals differing patterns between cerebral cortical and cerebellar brain regions. Scient Data. https://doi.org/10.1038/s41597-020-00642-8 - PubMed
  89. Silva MC, Ferguson FM, Cai Q, Donovan KA, Nandi G, Patnaik D et al (2019) Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. Elife. https://doi.org/10.7554/eLife.45457 - PubMed
  90. Siriwardana NS, Meyer R, Havasi A, Dominguez I, Panchenko MV (2014) Cell cycle-dependent chromatin shuttling of HBO1-JADE1 histone acetyl transferase (HAT) complex. Cell Cycle 13:1885–1901. https://doi.org/10.4161/cc.28759 - PubMed
  91. Smith HL, Mallucci GR (2016) The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain 139:2113–2121. https://doi.org/10.1093/brain/aww101 - PubMed
  92. Steinberg KM, Antonacci F, Sudmant PH, Kidd JM, Campbell CD, Vives L et al (2012) Structural diversity and African origin of the 17q21.31 inversion polymorphism. Nat Genet 44:872–873. https://doi.org/10.1038/ng.2335 - PubMed
  93. Strickland SL, Reddy JS, Allen M, N’songo A, Burgess JD, Corda MM et al (2020) MAPT haplotype-stratified GWAS reveals differential association for AD risk variants. Alzheimers Dement 16:983–1002. https://doi.org/10.1002/alz.12099 - PubMed
  94. Stutzbach LD, Xie SX, Naj AC, Albin R, Gilman S, Lee VMY et al (2013) The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease. Acta Neuropathol Com. https://doi.org/10.1186/2051-5960-1-31 - PubMed
  95. Van Cauwenberghe C, Van Broeckhoven C, Sleegers K (2016) The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genet Med 18:421–430. https://doi.org/10.1038/gim.2015.117 - PubMed
  96. Voas MG, Rebay I (2003) The novel plant homeodomain protein rhinoceros antagonizes Ras signaling in the Drosophila eye. Genetics 165:1993–2006 - PubMed
  97. Walker JM, Richardson TE, Farrell K, Iida MA, Foong C, Shang P et al (2021) Early selective vulnerability of the CA2 hippocampal subfield in primary age-related tauopathy. J Neuropath Exp Neur 80:102–111. https://doi.org/10.1093/jnen/nlaa153 - PubMed
  98. Wesseling H, Mair W, Kumar M, Schlaffner CN, Tang S, Beerepoot P et al (2020) Tau PTM profiles identify patient heterogeneity and stages of Alzheimer’s disease. Cell 183(1699–1713):e1613. https://doi.org/10.1016/j.cell.2020.10.029 - PubMed
  99. Willer CJ, Li Y, Abecasis GR (2010) METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26:2190–2191. https://doi.org/10.1093/bioinformatics/btq340 - PubMed
  100. Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M et al (2001) Tauopathy in drosophila: neurodegeneration without neurofibrillary tangles. Science 293:711–714. https://doi.org/10.1126/science.1062382 - PubMed
  101. Yamada M (2003) Senile dementia of the neurofibrillary tangle type (tangle-only dementia): neuropathological criteria and clinical guidelines for diagnosis. Neuropathology 23:311–317. https://doi.org/10.1046/j.1440-1789.2003.00522.x - PubMed
  102. Yokoyama JS, Karch CM, Fan CC, Bonham LW, Kouri N, Ross OA et al (2017) Shared genetic risk between corticobasal degeneration, progressive supranuclear palsy, and frontotemporal dementia. Acta Neuropathol 133:825–837. https://doi.org/10.1007/s00401-017-1693-y - PubMed
  103. Yu L, Chibnik LB, Srivastava GP, Pochet N, Yang J, Xu J et al (2015) Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease. JAMA Neurol 72:15–24. https://doi.org/10.1001/jamaneurol.2014.3049 - PubMed
  104. Zeng LL, Bai M, Mittal AK, El-Jouni W, Zhou J, Cohen DM et al (2013) Candidate tumor suppressor and pVHL partner Jade-1 binds and inhibits AKT in renal cell Carcinoma. Cancer Res 73:5371–5380. https://doi.org/10.1158/0008-5472.Can-12-4707 - PubMed
  105. Zhou MI, Foy RL, Chitalia VC, Zhao J, Panchenko MV, Wang HM et al (2005) Jade-1, a candidate renal tumor suppressor that promotes apoptosis. P Natl Acad Sci USA 102:11035–11040. https://doi.org/10.1073/pnas.0500757102 - PubMed
  106. Zhou MI, Wang H, Ross JJ, Kuzmin I, Xu C, Cohen HT (2002) The von Hippel-Lindau tumor suppressor stabilizes novel plant homeodomain protein Jade-1. J Biol Chem 277:39887–39898. https://doi.org/10.1074/jbc.M205040200 - PubMed
  107. Zhou Y, Song WM, Andhey PS, Swain A, Levy T, Miller KR et al (2020) Human and mouse single-nucleus transcriptomics reveal TREM2-dependent and TREM2-independent cellular responses in Alzheimer’s disease. Nat Med 26:131–142. https://doi.org/10.1038/s41591-019-0695-9 - PubMed

Publication Types

Grant support