Effect of CLU genetic variants on cerebrospinal fluid and neuroimaging markers in healthy, mild cognitive impairment and Alzheimer’s disease cohorts

• DOI: 10.1038/srep26027
• Publication Date: 2016-05-27T09:38:19Z
• Authors: Lin Tan; Hui-Fu Wang; Meng-Shan Tan; Chen-Chen Tan; Xi-Chen Zhu; Dan Miao; Wan-Jiang Yu; Teng Jiang; Lan Tan; Jin-Tai Yu; ; Michael W. Weiner; Paul Aisen; Ronald Petersen; Clifford R. Jack; William Jagust; John Q. Trojanowki; Arthur W. Toga; Laurel Beckett; Robert C. Green; Andrew J. Saykin; John Morris; Leslie M. Shaw; Jeffrey Kaye; Joseph Quinn; Lisa Silbert; Betty Lind; Raina Carter; Sara Dolen; Lon S. Schneider; Sonia Pawluczyk; Mauricio Beccera; Liberty Teodoro; Bryan M. Spann; James Brewer; Helen Vanderswag; Adam Fleisher; Judith L. Heidebrink; Joanne L. Lord; Sara S. Mason; Colleen S. Albers; David Knopman; Kris Johnson; Rachelle S. Doody; Javier Villanueva...; Munir Chowdhury; Susan Rountree; Mimi Dang; Yaakov Stern; Lawrence S. Honig; Karen L. Bell; Beau Ances; John C. Morris; Maria Carroll; Mary L. Creech; Erin Franklin; Mark A. Mintun; Stacy Schneider; Angela Oliver; Daniel Marson; Randall Griffith; David Clark; David Geldmacher; John Brockington; Erik Roberson; Marissa Natelson ...; Hillel Grossman; Effie Mitsis; Raj C. Shah; Leyla deToledo-Mo...; Ranjan Duara; Daniel Varon; Maria T. Greig; Peggy Roberts; Marilyn Albert; Chiadi Onyike; Daniel D’Agostino; Stephanie Kielb; James E. Galvin; Brittany Cerbone; Christina A. Michel; Dana M. Pogorelec; Henry Rusinek; Mony J. de Leon; Lidia Glodzik; Susan De Santi; P. Murali Doraiswamy; Jeffrey R. Petrella; Salvador Borges-Neto; Terence Z. Wong; Edward Coleman; Charles D. Smith; Greg Jicha; Peter Hardy; Partha Sinha; Elizabeth Oates; Gary Conrad; Anton P. Porstein...; Bonnie S. Goldstein; Kim Martin; Kelly M. Makino; M. Saleem Ismail; Connie Brand; Ruth A. Mulnard; Gaby Thai; Catherine Mc-Adam...; Kyle Womack; Dana Mathews; Mary Quiceno; Allan I. Levey; James J. Lah; Janet S. Cellar; Jeffrey M. Burns; Russell H. Swerdlow; William M. Brooks; Liana Apostolova; Kathleen Tingus; Ellen Woo; Daniel H. S. Silv...; Po H. Lu; George Bartzokis; Neill R. Graff-Ra...; Francine Parfitt; Tracy Kendall; Heather Johnson; Martin R. Farlow; Ann Marie Hake; Brandy R. Matthews; Jared R. Brosch; Scott Herring; Cynthia Hunt; Christopher H. va...; Richard E. Carson; Martha G. MacAvoy; Pradeep Varma; Howard Chertkow; Howard Bergman; Chris Hosein; Sandra Black; Bojana Stefanovic; Curtis Caldwell; Ging-Yuek Robin H...; Howard Feldman; Benita Mudge; Michele Assaly; Elizabeth Finger; Stephen Pasternack; Irina Rachisky; Dick Trost; Andrew Kertesz; Charles Bernick; Donna Munic; Marek-Marsel Mesulam; Kristine Lipowski; Sandra Weintraub; Borna Bonakdarpour; Diana Kerwin; Chuang-Kuo Wu; Nancy Johnson; Carl Sadowsky; Teresa Villena; Raymond Scott Turner; Kathleen Johnson; Brigid Reynolds; Reisa A. Sperling; Keith A. Johnson; Gad Marshall; Jerome Yesavage; Joy L. Taylor; Barton Lane; Allyson Rosen; Jared Tinklenberg; Marwan N. Sabbagh; Christine M. Belden; Sandra A. Jacobson; Sherye A. Sirrel; Neil Kowall; Ronald Killiany; Andrew E. Budson; Alexander Norbash; Patricia Lynn Joh...; Thomas O. Obisesan; Saba Wolday; Joanne Allard; Alan Lerner; Paula Ogrocki; Curtis Tatsuoka; Parianne Fatica; Evan Fletcher; Pauline Maillard; John Olichney; Charles DeCarli; Owen Carmichael; Smita Kittur; Michael Borrie; T -Y Lee; Rob Bartha; Sterling Johnson; Sanjay Asthana; Cynthia M. Carlsson; Steven G. Potkin; Adrian Preda; Dana Nguyen; Pierre Tariot; Anna Burke; Nadira Trncic; Adam Fleisher; Stephanie Reeder; Vernice Bates; Horacio Capote; Michelle Rainka; Douglas W. Scharre; Maria Kataki; Anahita Adeli; Earl A. Zimmerman; Dzintra Celmins; Alice D. Brown; Godfrey D. Pearlson; Karen Blank; Karen Anderson; Laura A. Flashman; Marc Seltzer; Mary L. Hynes; Robert B. Santulli; Kaycee M. Sink; Leslie Gordineer; Jeff D. Williamson; Pradeep Garg; Franklin Watkins; Brian R. Ott; Henry Querfurth; Geoffrey Tremont; Stephen Salloway; Paul Malloy; Stephen Correia; Howard J. Rosen; Bruce L. Miller; David Perry; Jacobo Mintzer; Kenneth Spicer; David Bachman; Nunzio Pomara; Raymundo Hernando; Antero Sarrael; Norman Relkin; Gloria Chaing; Michael Lin; Lisa Ravdin; Amanda Smith; Balebail Ashok Raj; Kristin Fargher
• Keywords: Male; Risk; 570; Aging; Neuroimaging; Neurodegenerative; Alzheimer's Disease; Hippocampus; Polymorphism, Single Nucleotide; 630; Article; 03 medical and health sciences; 0302 clinical medicine; Clinical Research; Alzheimer Disease; Health Sciences; Genetics; Acquired Cognitive Impairment; 80 and over; 2.1 Biological and endogenous factors; Humans; Genetic Predisposition to Disease; Polymorphism; Aged; Cerebrospinal Fluid; Aged, 80 and over; Amyloid beta-Peptides; Neurosciences; Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD); Single Nucleotide; Alzheimer’s Disease Neuroimaging Initiative; Organ Size; Biological Sciences; Brain Disorders; 4.1 Discovery and preclinical testing of markers and technologies; 3. Good health; Clusterin; Glucose; Neurological; Unfolded Protein Response; Dementia; Female; Biomarkers

AbstractThe Clusterin (CLU) gene, also known as apolipoprotein J (ApoJ), is currently the third most associated late-onset Alzheimer’s disease (LOAD) risk gene. However, little was known about the possible effect of CLU genetic variants on AD pathology in brain. Here, we evaluated the interaction between 7 CLU SNPs (covering 95% of genetic variations) and the role of CLU in β-amyloid (Aβ) deposition, AD-related structure atrophy, abnormal glucose metabolism on neuroimaging and CSF markers to clarify the possible approach by that CLU impacts AD. Finally, four loci (rs11136000, rs1532278, rs2279590, rs7982) showed significant associations with the Aβ deposition at the baseline level while genotypes of rs9331888 (P = 0.042) increased Aβ deposition. Besides, rs9331888 was significantly associated with baseline volume of left hippocampus (P = 0.014). We then further validated the association with Aβ deposition in the AD, mild cognitive impairment (MCI), normal control (NC) sub-groups. The results in sub-groups confirmed the association between CLU genotypes and Aβ deposition further. Our findings revealed that CLU genotypes could probably modulate the cerebral the Aβ loads on imaging and volume of hippocampus. These findings raise the possibility that the biological effects of CLU may be relatively confined to neuroimaging trait and hence may offer clues to AD.