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Reisberg, Barry

reisbb01
NYU School of Medicine,  1978-current

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1.

"Neuropsychological and Neuropsychiatric Prediction of Global Cognitive Status Among Older Spanish-Speaking Hispanics and English-Speaking Whites"

Guerrero-Berroa, Elizabeth; Kluger, Alan; Schmeidler, James; Sailor, Kevin; Lizardi, Humberto; Golomb, James; Ferris, Steven; REISBERG, BARRY
Journal of geriatric psychiatry & neurology 2014 Apr;:1452-1458
MEDL:24759088  #948142  10.1177/0891988714532020

BACKGROUND: Neuropsychological and depression measures have been found to predict cognitive functioning. We compared these associations among whites and Spanish-speaking Hispanics. METHODS: Fifty-two pairs of whites and Hispanics were matched demographically and clinically in a cross-sectional study. Hierarchical regression analyses predicted Global Deterioration Scale (GDS) rating by baseline neuropsychological tests and depression symptoms. RESULTS: Neuropsychological tests predicted GDS better in whites; depression symptoms-specifically retardation-predicted well in Hispanics but not whites. Immediate recall of the New York University (NYU)-Paragraph Test and the Retardation item of the Hamilton Depression Rating Scale were associated with GDS in Hispanics and delayed recall of the NYU-Paragraph Test and Wechsler Adult Intelligence Scale-Digit Symbol in whites. Neuropsychological tests and depression symptoms predicted GDS differently in Hispanics and whites. DISCUSSION: These results suggest that other measures should be considered to increase the predictive accuracy of neuropsychological tests when assessing cognitive status in Spanish-speaking Hispanics. Additional studies of specific ethnic/racial and sociodemographic subgroups are warranted..


2.

"A conceptual framework for research on subjective cognitive decline in preclinical Alzheimer's disease"

Jessen, Frank; Amariglio, Rebecca E; van Boxtel, Martin; Breteler, Monique; Ceccaldi, Mathieu; Chetelat, Gael; Dubois, Bruno; Dufouil, Carole; Ellis, Kathryn A; van der Flier, Wiesje M; Glodzik, Lidia; van Harten, Argonde C; de Leon, Mony J; McHugh, Pauline; Mielke, Michelle M; Molinuevo, Jose Luis; Mosconi, Lisa; Osorio, Ricardo S; Perrotin, Audrey; Petersen, Ronald C; Rabin, Laura A; Rami, Lorena; REISBERG, BARRY; Rentz, Dorene M; Sachdev, Perminder S; de la Sayette, Vincent; Saykin, Andrew J; Scheltens, Philip; Shulman, Melanie B; Slavin, Melissa J; Sperling, Reisa A; Stewart, Robert; Uspenskaya, Olga; Vellas, Bruno; Visser, Pieter Jelle; Wagner, Michael
Alzheimer's and dementia 2014 May;:1119-1127
MEDL:24798886  #956732  10.1016/j.jalz.2014.01.001

GRANTS:P30 AG008051/AG/NIA NIH HHS/United States

There is increasing evidence that subjective cognitive decline (SCD) in individuals with unimpaired performance on cognitive tests may represent the first symptomatic manifestation of Alzheimer's disease (AD). The research on SCD in early AD, however, is limited by the absence of common standards. The working group of the Subjective Cognitive Decline Initiative (SCD-I) addressed this deficiency by reaching consensus on terminology and on a conceptual framework for research on SCD in AD. In this publication, research criteria for SCD in pre-mild cognitive impairment (MCI) are presented. In addition, a list of core features proposed for reporting in SCD studies is provided, which will enable comparability of research across different settings. Finally, a set of features is presented, which in accordance with current knowledge, increases the likelihood of the presence of preclinical AD in individuals with SCD. This list is referred to as SCD plus..


3.

"The BEHAVE-AD Assessment System: A Perspective, A Commentary on New Findings, and A Historical Review"

REISBERG, BARRY; Monteiro, Isabel; Torossian, Carol; Auer, Stefanie; Shulman, Melanie B; Ghimire, Santosh; Boksay, Istvan; Guillo Benarous, Francoise; Osorio, Ricardo; Vengassery, Aninditha; Imran, Sheema; Shaker, Hussam; Noor, Sadaf; Naqvi, Shazia; Kenowsky, Sunnie; Xu, Jinfeng
Dementia geriatric & cognitive disorders 2014 Apr;38(1-2):89-146
MEDL:24714384  #886392  Click here for full text  10.1159/000357839

GRANTS:P30 AG008051/AG/NIA NIH HHS/United States;P50 MH043486/MH/NIMH NIH HHS/United States

Background: Behavioral and psychological symptoms of dementia (BPSD) and associated disturbances in Alzheimer's disease (AD) are a source of distress and burden for spouses, professional caregivers, and others with responsibilities for the care of individuals with AD. BPSD with behavioral disturbances are also associated with more rapid institutionalization and increased morbidity and mortality for persons with AD. Objectives: In this review and commentary, we discuss the history of the development of BPSD and behavioral disturbance assessments, which are distinct from those evaluating cognitive and functional symptoms of AD. In particular, we review the informant-based Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD), the related, potentially more sensitive, BEHAVE-AD Frequency-Weighted Severity Scale (BEHAVE-AD-FW), and the direct subject evaluation-based Empirical BEHAVE-AD Rating Scale (E-BEHAVE-AD). The kinds of medications that alleviate behavioral symptoms on these measures as well as the problems and possibilities for further advances with these medications are discussed. Finally, the importance of distinguishing BPSD and behavioral disturbance remediation in AD from the treatment of cognitive decline and other aspects of AD is emphasized in the context of appropriate assessment methodology. The objective of this paper is to provide a framework for further advances in the treatment of BPSD and associated behavioral disturbances in AD and, consequently, a framework for continuing improvements in the lives of individuals with AD and those who share the burden of the disease with the AD person. (c) 2014 S. Karger AG, Basel..


4.

"Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease"

Alperovitch, Annick; Boland, Anne; Delepoine, Marc; Dubois, Bruno; Duron, Emmanuelle; Epelbaum, Jacques; Van Cauwenberghe, Caroline; Engelborghs, Sebastiaan; Vandenberghe, Rik; De Deyn, Peter P; Ferri, Raffaele; Romano, Camelo; Caltagirone, Carlo; Orfei, Maria Donata; Ciaramella, Antonio; Scarpini, Elio; Fenoglio, Chiara; Siciliano, Gabriele; Bonuccelli, Ubaldo; Bagnoli, Silvia; Bracco, Laura; Bessi, Valentina; Cecchetti, Roberta; Bastiani, Patrizia; Squassina, Alessio; Seripa, Davide; Frank-Garcia, Ana; Sastre, Isabel; Blesa, Rafael; Alcolea, Daniel; Suarez-Clavet, Marc; Sanchez-Juan, Pascual; Munoz Fernandez, Carmen; Aladro Benito, Yolanda; Thonberg, Hakan; Forshell, Charlotte; Lilius, Lena; Kinhult-Stahlbom, Anne; Giedraitis, Vilmantas; Kilander, Lena; Brundin, Rose Marie; Concari, Letizia; Helisalmi, Seppo; Koivisto, Anne Maria; Haapasalo, Annakaisa; Solfrizzi, Vincenzo; Frisardi, Vincenza; Ott, Jurg; Carney, Regina M; Mash, Deborah C; Albert, Marilyn S; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Barmada, Michael M; Barnes, Lisa L; Beach, Thomas G; Bigio, Eileen H; Bird, Thomas D; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Burk, James R; Cairns, Nigel J; Cao, Chuanhai; Carlson, Chris S; Carroll, Steven L; Chibnik, Lori B; Chui, Helena C; Clark, David G; Corneveaux, Jason; Cribbs, David G; DeCarli, Charles; DeKosky, Steven T; Demirci, F Yesim; Dick, Malcolm; Dickson, Dennis W; Duara, Ranjan; Ertekin-Taner, Nilufer; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilman, Sid; Glass, Jonathan D; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jarvik, Gail P; Jicha, Gregory A; Jin, Lee-Way; Karydas, Anna; Kauwe, John S K; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Kramer, Joel H; Kramer, Patricia; LaFerla, Frank M; Lah, James J; Levernez, James B; Levey, Allan I; Li, Ge; Lieberman, Andrew P; Lyketsos, Constantine G; Mack, Wendy J; Marson, Daniel C; Martiniuk, Frank; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Morris, John C; Murrell, Jill R; Olichney, John M; Pankratz, Vernon S; Parasi, Joseph E; Peskind, Elaine; Peterson, Ronald C; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reiman, Eric M; REISBERG, BARRY; Ringman, John M; Roberson, Erik D; Rosen, Howard J; Rosenberg, Roger N; Sano, Mary; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Trojanowski, John Q; Troncoso, Juan C; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Woltjer, Randall L; Yu, Chang-En; Barber, Robert; Au, Rhoda; Wolf, Philip A; Beiser, Alexa; Debette, Stephanie; Yang, Qiong; Weinstein, Galit; Johnson, Andrew D; Wang, Jing; Uitterlinden, Andre G; Rivadeneira, Fernando; Koudstgaal, Peter J; Longstreth, William T Jr; Becker, James T; Kuller, Lewis H; Lumley, Thomas; Rice, Kenneth; Garcia, Melissa; Aspelund, Thor; Marksteiner, Josef J M; Dal-Bianco, Peter; Toglhofer, Anna Maria; Freudenberger, Paul; Ransmayr, Gerhard; Benke, Thomas; Toeglhofer, Anna M; Bressler, Jan; Breteler, Monique M B; Fornage, Myriam; Hernandez, Isabel; Rosende Roca, Maitee; Ana Mauleon, Maitee; Alegrat, Montserrat; Ramirez-Lorca, Reposo; Gonzalez-Perez, Antonio; Chapman, Jade; Stretton, Alexandra; Morgan, Angharad; Kehoe, Patrick G; Medway, Christopher; Lord, Jenny; Turton, James; Hooper, Nigel M; Vardy, Emma; Warren, Jason D; Schott, Jonathan M; Uphill, James; Ryan, Natalie; Rossor, Martin; Ben-Shlomo, Yoav; Makrina, Daniilidou; Gkatzima, Olymbia; Lupton, Michelle; Koutroumani, Maria; Avramidou, Despoina; Germanou, Antonia; Jessen, Frank; Riedel-Heller, Steff; Dichgans, Martin; Heun, Reiner; Kolsch, Heike; Schurmann, Britta; Herold, Christine; Lacour, Andre; Drichel, Dmitriy; Hoffman, Per; Kornhuber, Johannes; Gu, Wei; Feulner, Thomas; van den Bussche, Hendrik; Lawlor, Brian; Lynch, Aoibhinn; Mann, David; Smith, A David; Warden, Donald; Wilcock, Gordon; Heuser, Isabella; Wiltgang, Jens; Frolich, Lutz; Hull, Michael; Mayo, Kevin; Livingston, Gill; Bass, Nicholas J; Gurling, Hugh; McQuillin, Andrew; Gwilliam, Rhian; Deloukas, Panagiotis; Al-Chalabi, Ammar; Shaw, Christoher E; Singleton, Andrew B; Guerreiro, Rita; Jockel, Karl-Heinz; Klopp, Norman; Wichmann, H-Erich; Dickson, Dennis W; Graff-Radford, Neill R; Ma, Li; Bisceglio, Gina; Fisher, Elizabeth; Warner, Nick; Pickering-Brown, Stuart
Nature genetics 2013 Dec;45(12):1452-1458
MEDL:24162737  #948132  Click here for full text  10.1038/ng.2802

GRANTS:089703/Wellcome Trust/United Kingdom;100140/Wellcome Trust/United Kingdom;G0601846/Medical Research Council/United Kingdom;G0801306/Medical Research Council/United Kingdom;MC_U123160657/Medical Research Council/United Kingdom;P30 AG010161/AG/NIA NIH HHS/United States;P30 DK063491/DK/NIDDK NIH HHS/United States;P50 AG008702/AG/NIA NIH HHS/United States;P50 AG016573/AG/NIA NIH HHS/United States;R01 AG008122/AG/NIA NIH HHS/United States;R01 AG016495/AG/NIA NIH HHS/United States;R01 AG023629/AG/NIA NIH HHS/United States;R01 AG033193/AG/NIA NIH HHS/United States;R01 AG033193/AG/NIA NIH HHS/United States;R01 AG041232/AG/NIA NIH HHS/United States;R01 HL105756/HL/NHLBI NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U24 AG021886/AG/NIA NIH HHS/United States;UL1 TR000124/TR/NCATS NIH HHS/United States;Arthritis Research UK/United Kingdom;Medical Research Council/United Kingdom;Wellcome Trust/United Kingdom

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease..


5.

"Dementia service centres in Austria: A comprehensive support and early detection model for persons with dementia and their caregivers - theoretical foundations and model description"

Auer, Stefanie R; Span, Edith; REISBERG, BARRY
Dementia 2013 Oct;:?-?
MEDL:24339114  #895862  Click here for full text  10.1177/1471301213502214

GRANTS:P30 AG008051/AG/NIA NIH HHS/United States

Despite the highly developed social services in Austria, the County of Upper Austria, one of the nine counties of Austria had only very limited specialized services for persons with dementia and their caregivers in 2001. Support groups existed in which the desire for more specialized services was voiced. In response to this situation, funding was received to develop a new structure for early disease detection and long term support for both the person with dementia and their caregivers. This article describes the development of the model of the Dementia Service Centres (DSCs) and the successes and difficulties encountered in the process of implementing the model in six different rural regions of Upper Austria. The DSC was described in the First Austrian Dementia Report as one of the potential service models for the future..


6.

"Initial assessment of the pathogenic mechanisms of the recently identified Alzheimer risk Loci"

Holton, Patrick; Ryten, Mina; Nalls, Michael; Trabzuni, Daniah; Weale, Michael E; Hernandez, Dena; Crehan, Helen; Gibbs, J Raphael; Mayeux, Richard; Haines, Jonathan L; Farrer, Lindsay A; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Ramirez-Restrepo, Manuel; Engel, Anzhelika; Myers, Amanda J; Corneveaux, Jason J; Huentelman, Matthew J; Dillman, Allissa; Cookson, Mark R; Reiman, Eric M; Singleton, Andrew; Hardy, John; Guerreiro, Rita; Apostolova, Liana G; Arnold, Steven E; Baldwin, Clinton T; Barber, Robert; Barmada, Michael M; Beach, Thomas G; Beecham, Gary W; Beekly, Duane; Bennett, David A; Bigio, Eileen H; Bird, Thomas D; Blacker, Deborah; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Burke, James R; Buros, Jacqueline; Buxbaum, Joseph D; Cairns, Nigel J; Cantwell, Laura B; Cao, Chuanhai; Carlson, Chris S; Carney, Regina M; Carrasquillo, Minerva M; Carroll, Steven L; Chui, Helena C; Clark, David G; Cotman, Carl W; Crane, Paul K; Crocco, Elizabeth A; Cruchaga, Carlos; Cummings, Jeffrey L; De Jager, Philip L; DeCarli, Charles; DeKosky, Steven T; Demirci, F Yesim; Diaz-Arrastia, Ramon; Dick, Malcolm; Dickson, Dennis W; Duara, Ranjan; Ellis, William G; Ertekin-Taner, Nilufer; Evans, Denis; Faber, Kelley M; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Foroud, Tatiana M; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Gilman, Sid; Giordani, Bruno; Glass, Jonathan D; Goate, Alison M; Graff-Radford, Neill R; Green, Robert C; Growdon, John H; Hakonarson, Hakon; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jarvik, Gail P; Jicha, Gregory A; Jin, Lee-Way; Jun, Gyungah; Kamboh, M Ilyas; Karlawish, Jason; Karydas, Anna; Kauwe, John S K; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Kramer, Patricia; Kukull, Walter A; Lah, James J; Larson, Eric B; Levey, Allan I; Lieberman, Andrew P; Lopez, Oscar L; Lunetta, Kathryn L; Mack, Wendy J; Marson, Daniel C; Martin, Eden R; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Montine, Thomas J; Morris, John C; Naj, Adam C; Nowotny, Petra; Parisi, Joseph E; Peskind, Elaine; Petersen, Ronald C; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Rajbhandary, Ruchita A; Raskind, Murray; REISBERG, BARRY; Reitz, Christiane; Ringman, John M; Roberson, Erik D; Rogaeva, Ekaterina; Rosenberg, Roger N; Sano, Mary; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Shelanski, Michael L; Smith, Charles D; Sonnen, Joshua A; Spina, Salvatore; St George-Hyslop, Peter; Stern, Robert A; Tanzi, Rudolph E; Trojanowski, John Q; Troncoso, Juan C; Tsuang, Debby W; Valladares, Otto; Van Deerlin, Vivianna M; Vardarajan, Badri N; Vinters, Harry V; Vonsattel, Jean Paul; Wang, Li-San; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Woltjer, Randall L; Wright, Clinton B; Younkin, Steven G
Annals of human genetics 2013 Mar;77(2):85-105
MEDL:23360175  #335882  Click here for full text  10.1111/ahg.12000

GRANTS:AG010491/AG/NIA NIH HHS/United States;AG019757/AG/NIA NIH HHS/United States;AG021547/AG/NIA NIH HHS/United States;AG025688/AG/NIA NIH HHS/United States;AG027944/AG/NIA NIH HHS/United States;AG030653/AG/NIA NIH HHS/United States;AG05128/AG/NIA NIH HHS/United States;AG05144/AG/NIA NIH HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;M01RR00096/RR/NCRR NIH HHS/United States;MH60451/MH/NIMH NIH HHS/United States;NS39764/NS/NINDS NIH HHS/United States;P01 AG002219/AG/NIA NIH HHS/United States;P01 AG019724/AG/NIA NIH HHS/United States;P01 AG03991/AG/NIA NIH HHS/United States;P30 AG008017/AG/NIA NIH HHS/United States;P30 AG010124/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG010161/AG/NIA NIH HHS/United States;P30 AG012300/AG/NIA NIH HHS/United States;P30 AG013846/AG/NIA NIH HHS/United States;P30 AG013854/AG/NIA NIH HHS/United States;P30 AG019610/AG/NIA NIH HHS/United States;P30 AG028377/AG/NIA NIH HHS/United States;P30 AG028383/AG/NIA NIH HHS/United States;P30 AG08051/AG/NIA NIH HHS/United States;P30 AG10133/AG/NIA NIH HHS/United States;P30 AG19610/AG/NIA NIH HHS/United States;P30AG10161/AG/NIA NIH HHS/United States;P50 AG005131/AG/NIA NIH HHS/United States;P50 AG005133/AG/NIA NIH HHS/United States;P50 AG005134/AG/NIA NIH HHS/United States;P50 AG005136/AG/NIA NIH HHS/United States;P50 AG005138/AG/NIA NIH HHS/United States;P50 AG005142/AG/NIA NIH HHS/United States;P50 AG005146/AG/NIA NIH HHS/United States;P50 AG005681/AG/NIA NIH HHS/United States;P50 AG008671/AG/NIA NIH HHS/United States;P50 AG008702/AG/NIA NIH HHS/United States;P50 AG016570/AG/NIA NIH HHS/United States;P50 AG016573/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG016575/AG/NIA NIH HHS/United States;P50 AG016576/AG/NIA NIH HHS/United States;P50 AG016577/AG/NIA NIH HHS/United States;P50 AG016582/AG/NIA NIH HHS/United States;P50 AG023501/AG/NIA NIH HHS/United States;P50-AG08671/AG/NIA NIH HHS/United States;R01 AG015819/AG/NIA NIH HHS/United States;R01 AG017173/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG020688/AG/NIA NIH HHS/United States;R01 AG025259/AG/NIA NIH HHS/United States;R01 AG026916/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG031581/AG/NIA NIH HHS/United States;R01 AG034504/AG/NIA NIH HHS/United States;R01 AG15819/AG/NIA NIH HHS/United States;R01 AG17917/AG/NIA NIH HHS/United States;R01 AG30146/AG/NIA NIH HHS/United States;R01 CA129769/CA/NCI NIH HHS/United States;R01 MH080295/MH/NIMH NIH HHS/United States;R01 NS059873/NS/NINDS NIH HHS/United States;R01 NS059873]/NS/NINDS NIH HHS/United States;R01AG15819/AG/NIA NIH HHS/United States;R01AG33193/AG/NIA NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;RC2 AG036528/AG/NIA NIH HHS/United States;RC2 AG036535/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG06781/AG/NIA NIH HHS/United States;U01 AG10483/AG/NIA NIH HHS/United States;U01 HG004610/HG/NHGRI NIH HHS/United States;U24 AG021886/AG/NIA NIH HHS/United States;U24 AG026390/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;UL1RR02777/RR/NCRR NIH HHS/United States;Z01 AG000950-06/AG/NIA NIH HHS/United States;Z01-AG000950-10/AG/NIA NIH HHS/United States;Canadian Institutes of Health Research/Canada;Howard Hughes Medical Institute/United States;Medical Research Council/United Kingdom;Wellcome Trust/United Kingdom

Recent genome wide association studies have identified CLU, CR1, ABCA7 BIN1, PICALM and MS4A6A/MS4A6E in addition to the long established APOE, as loci for Alzheimer's disease. We have systematically examined each of these loci to assess whether common coding variability contributes to the risk of disease. We have also assessed the regional expression of all the genes in the brain and whether there is evidence of an eQTL explaining the risk. In agreement with other studies we find that coding variability may explain the ABCA7 association, but common coding variability does not explain any of the other loci. We were not able to show that any of the loci had eQTLs within the power of this study. Furthermore the regional expression of each of the loci did not match the pattern of brain regional distribution in Alzheimer pathology. Although these results are mainly negative, they allow us to start defining more realistic alternative approaches to determine the role of all the genetic loci involved in Alzheimer's disease..


7.

"SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians"

Miyashita, Akinori; Koike, Asako; Jun, Gyungah; Wang, Li-San; Takahashi, Satoshi; Matsubara, Etsuro; Kawarabayashi, Takeshi; Shoji, Mikio; Tomita, Naoki; Arai, Hiroyuki; Asada, Takashi; Harigaya, Yasuo; Ikeda, Masaki; Amari, Masakuni; Hanyu, Haruo; Higuchi, Susumu; Ikeuchi, Takeshi; Nishizawa, Masatoyo; Suga, Masaichi; Kawase, Yasuhiro; Akatsu, Hiroyasu; Kosaka, Kenji; Yamamoto, Takayuki; Imagawa, Masaki; Hamaguchi, Tsuyoshi; Yamada, Masahito; Moriaha, Takashi; Takeda, Masatoshi; Takao, Takeo; Nakata, Kenji; Fujisawa, Yoshikatsu; Sasaki, Ken; Watanabe, Ken; Nakashima, Kenji; Urakami, Katsuya; Ooya, Terumi; Takahashi, Mitsuo; Yuzuriha, Takefumi; Serikawa, Kayoko; Yoshimoto, Seishi; Nakagawa, Ryuji; Kim, Jong-Won; Ki, Chang-Seok; Won, Hong-Hee; Na, Duk L; Seo, Sang Won; Mook-Jung, Inhee; St George-Hyslop, Peter; Mayeux, Richard; Haines, Jonathan L; Pericak-Vance, Margaret A; Yoshida, Makiko; Nishida, Nao; Tokunaga, Katsushi; Yamamoto, Ken; Tsuji, Shoji; Kanazawa, Ichiro; Ihara, Yasuo; Schellenberg, Gerard D; Farrer, Lindsay A; Kuwano, Ryozo; Ferris, Steven; REISBERG, BARRY; Martiniuk, Frank
PLoS one 2013 ;8(4):e58618-e58618 e58618
MEDL:23565137  #627162  Click here for full text  10.1371/journal.pone.0058618

GRANTS:AG010491/AG/NIA NIH HHS/United States;AG019757/AG/NIA NIH HHS/United States;AG021547/AG/NIA NIH HHS/United States;AG025688/AG/NIA NIH HHS/United States;AG027944/AG/NIA NIH HHS/United States;AG030653/AG/NIA NIH HHS/United States;AG034504/AG/NIA NIH HHS/United States;AG05128/AG/NIA NIH HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;M01RR00096/RR/NCRR NIH HHS/United States;MH60451/MH/NIMH NIH HHS/United States;NS39764/NS/NINDS NIH HHS/United States;P01 AG002219/AG/NIA NIH HHS/United States;P01 AG019724/AG/NIA NIH HHS/United States;P01 AG03991/AG/NIA NIH HHS/United States;P30 AG008017/AG/NIA NIH HHS/United States;P30 AG010124/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG010161/AG/NIA NIH HHS/United States;P30 AG012300/AG/NIA NIH HHS/United States;P30 AG013846/AG/NIA NIH HHS/United States;P30 AG013854/AG/NIA NIH HHS/United States;P30 AG019610/AG/NIA NIH HHS/United States;P30 AG028377/AG/NIA NIH HHS/United States;P30 AG028383/AG/NIA NIH HHS/United States;P30 AG08051/AG/NIA NIH HHS/United States;P30 AG10133/AG/NIA NIH HHS/United States;P50 AG005131/AG/NIA NIH HHS/United States;P50 AG005133/AG/NIA NIH HHS/United States;P50 AG005134/AG/NIA NIH HHS/United States;P50 AG005136/AG/NIA NIH HHS/United States;P50 AG005138/AG/NIA NIH HHS/United States;P50 AG005142/AG/NIA NIH HHS/United States;P50 AG005146/AG/NIA NIH HHS/United States;P50 AG005681/AG/NIA NIH HHS/United States;P50 AG008671/AG/NIA NIH HHS/United States;P50 AG008702/AG/NIA NIH HHS/United States;P50 AG016570/AG/NIA NIH HHS/United States;P50 AG016573/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG016575/AG/NIA NIH HHS/United States;P50 AG016576/AG/NIA NIH HHS/United States;P50 AG016577/AG/NIA NIH HHS/United States;P50 AG016582/AG/NIA NIH HHS/United States;P50 AG023501/AG/NIA NIH HHS/United States;R01 AG017173/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG020688/AG/NIA NIH HHS/United States;R01 AG025259/AG/NIA NIH HHS/United States;R01 AG026916/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG031581/AG/NIA NIH HHS/United States;R01 AG15819/AG/NIA NIH HHS/United States;R01 AG17917/AG/NIA NIH HHS/United States;R01 AG30146/AG/NIA NIH HHS/United States;R01 CA129769/CA/NCI NIH HHS/United States;R01 MH080295/MH/NIMH NIH HHS/United States;R01 NS059873/NS/NINDS NIH HHS/United States;R01AG33193/AG/NIA NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;RC2 AG036528/AG/NIA NIH HHS/United States;RC2 AG036535/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG06781/AG/NIA NIH HHS/United States;U01 AG10483/AG/NIA NIH HHS/United States;U01 HG004610/HG/NHGRI NIH HHS/United States;U24 AG021886/AG/NIA NIH HHS/United States;U24 AG026390/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;UL1RR02777/RR/NCRR NIH HHS/United States;Canadian Institutes of Health Research/Canada;Howard Hughes Medical Institute/United States;Medical Research Council/United Kingdom;Wellcome Trust/United Kingdom

To discover susceptibility genes of late-onset Alzheimer's disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values <2x10(-5) were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P = 7.33x10(-7) in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P = 1.77x10(-9)) and rs3781834 (P = 1.04x10(-8)). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P = 1.71x10(-5)) and rs744373 near BIN1 (P = 1.39x10(-4)). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations..


8.

"Memantine and comprehensive, individualized, person-centered management (CI-PCM) of Alzheimer's disease: A randomized controlled trial" [Meeting Abstract]

REISBERG, B; Kenowsky, S; Boksay, I; Golomb, J; Heller, S; Ghimire, S; Salam, M; Qureshi, S; Kumar, M; Torossian, C; Vedvyas, A
Alzheimer's and dementia 2013 July 2013;9(4):P295-P296
EMBASE:71416480  #953762  Click here for full text  

Background: Demonstration of efficacy of memantine treatment for persons with moderate to severe Alzheimer's disease (AD) over 28 weeks (Reisberg, et al., N. Engl. J. Med., 2003) highlighted both treatment possibilities and treatment needs of persons with advanced AD. In prior work, we developed a science of AD management (Reisberg, et al., Am. J. Alzheimers Dis., 2002), based upon scientific observations of the retrogenesis process and other pathologic AD processes (Reisberg, et al., Eur. Arch. Psych. Clin. Neurosci., 1999; Souren, et al., J. Am. Geriatr. Soc., 1995; Franssen, et al., Arch Neurol., 1993). Herein, we investigated the hypothesis that application of this AD management science would result in improved outcomes beyond those with pharmacologic treatment alone. Methods: The same subject selection procedures were applied as in our published, double-blind, memantine trial. These included: community residence, age > 50, probable AD, a Global Deterioration Scale stage of 5 or 6, a Functional Assessment Staging (FAST) level of > 6a, and an MMSE score of 3 to 14. All subjects were titrated to a maintenance dose of memantine, 10 mg bid, as tolerated. Twenty participants were randomized to one of two groups, each comprised of 10 subjects. The intervention group received the CI-PCM program; the control group received financial compensation upon completion of study landmarks. Results: The first results of this study, presented herein, examined the primary outcome measure, the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) global scores (New York University version) (Reisberg,Int. Psychogeriatr., 2007). This assessment comprehensively evaluates change in terms of cognition, function and behavior. The results indicated significant improvement in CIBIC-Plus scores in the subjects in the management program versus the subjects receiving financial compensation (p < 0.01 at weeks 4 and 12 and p < 0.001 at week 28), with enhanced benefits throughout the 28 week stud!.


9.

"Addition of a comprehensive, individualized, person centered management program, to memantine alone produces a 900% increment in a pivotal trial global measure over medication treatment alone in advanced alzheimer's disease" [Meeting Abstract]

REISBERG, B; Kenowsky, S; Heller, S; Boksay, I; Golomb, J; Ghimire, S; Torossian, C; Lobach, I
Neuropsychopharmacology 2013 December 2013;38:S423-S424
EMBASE:71278551  #752862  Click here for full text  

Background: A decade ago, the senior author and colleagues published a multicenter study which demonstrated the efficacy of memantine in the treatment of moderate to severe Alzheimer's disease (AD) (Reisberg, et al, N Engl J Med., 2003). This study served as a pivotal trial which supported the US and EU approvals of memantine as the first treatment for advanced AD. The advent of pharmacologic treatment of advanced AD served to highlight the continuing needs of these persons. Therefore, we simulta- neously developed a science of AD management (Reisberg, et al, Int Psychogeriatr, 1999; Reisberg, et al, Am J Alzheimers Dis Other Demen, 2002). After the U.S. approval of memantine treatment we embarked upon a study comparing a Comprehensive, Individualized, Person Centered Management Program (CI-PCM) in persons receiving memantine treatment, with memantine treatment alone. The inclusion criteria, outcome measures and study design were based on our 2003 NEJM memantine study. Subjects were randomized to CIPCM plus memantine treatment (n=10), or memantine treatment alone (controls, n=10). A primary pivotal, outcome measure was the NYU CIBIC-Plus, a global primary outcome used in the 2003 pivotal memantine trial. We recently reported that the CI-PCM+memantine treatment subjects showed significant improvement over the controls on this global outcome measure at all time periods examined (ie, 4, 12 and 28 weeks, p<0.01) (Reisberg, et al, Alzheimer's & Dementia, in press). Herein we describe the source and the meaning of the observed differences. Methods: The NYU CIBIC-Plus (Clinician's Interview Based Impression of Change, Plus Caregiver Input) assessment is comprised of 2 parts: Part 1. A subject interview, and Part 2: A caregiver interview. Part 1 has a cognitive component, a behavioral component total score, and a behavioral global score. Part 2 has a functional disability stage, a behavioral component total score, and a behavioral global score. Differences between the CI-PCM treatment group and the con!.


10.

"Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)"

Reitz, C; Tosto, G; Vardarajan, B; Rogaeva, E; Ghani, M; Rogers, R S; Conrad, C; Haines, J L; Pericak-Vance, M A; Fallin, M D; Foroud, T; Farrer, L A; Schellenberg, G D; George-Hyslop, P S; Mayeux, R; Ferris, Steven; REISBERG, BARRY; Martiniuk, Frank
Translational psychiatry 2013 ;3:e256-e256 e256
MEDL:23673467  #627142  Click here for full text  10.1038/tp.2013.13

GRANTS:AG010491/AG/NIA NIH HHS/United States;AG019757/AG/NIA NIH HHS/United States;AG021547/AG/NIA NIH HHS/United States;AG025688/AG/NIA NIH HHS/United States;AG027944/AG/NIA NIH HHS/United States;AG030653/AG/NIA NIH HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;K23AG034550/AG/NIA NIH HHS/United States;K24 AG027841/AG/NIA NIH HHS/United States;MO1RR00096/RR/NCRR NIH HHS/United States;P01 AG002219/AG/NIA NIH HHS/United States;P01 AG03991/AG/NIA NIH HHS/United States;P01AG019724/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG013846/AG/NIA NIH HHS/United States;P30 AG019610/AG/NIA NIH HHS/United States;P30 AG028377/AG/NIA NIH HHS/United States;P30 AG08051/AG/NIA NIH HHS/United States;P30 AG10133/AG/NIA NIH HHS/United States;P30AG008017/AG/NIA NIH HHS/United States;P30AG010124/AG/NIA NIH HHS/United States;P30AG010161/AG/NIA NIH HHS/United States;P30AG012300/AG/NIA NIH HHS/United States;P30AG013854/AG/NIA NIH HHS/United States;P30AG028383/AG/NIA NIH HHS/United States;P50 AG005134/AG/NIA NIH HHS/United States;P50 AG005136/AG/NIA NIH HHS/United States;P50 AG005138/AG/NIA NIH HHS/United States;P50 AG005146/AG/NIA NIH HHS/United States;P50 AG005681/AG/NIA NIH HHS/United States;P50 AG008702/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG016582/AG/NIA NIH HHS/United States;P50AG005131/AG/NIA NIH HHS/United States;P50AG005133/AG/NIA NIH HHS/United States;P50AG005142/AG/NIA NIH HHS/United States;P50AG008671/AG/NIA NIH HHS/United States;P50AG016570/AG/NIA NIH HHS/United States;P50AG016573/AG/NIA NIH HHS/United States;P50AG016575/AG/NIA NIH HHS/United States;P50AG016576/AG/NIA NIH HHS/United States;P50AG016577/AG/NIA NIH HHS/United States;P50AG023501/AG/NIA NIH HHS/United States;R01 AG009029/AG/NIA NIH HHS/United States;R01 AG017173/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG020688/AG/NIA NIH HHS/United States;R01 AG025259/AG/NIA NIH HHS/United States;R01 AG026916/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG031581/AG/NIA NIH HHS/United States;R01 CA129769/CA/NCI NIH HHS/United States;R01 HG002213/HG/NHGRI NIH HHS/United States;R01 HG02213/HG/NHGRI NIH HHS/United States;R01 MH080295/MH/NIMH NIH HHS/United States;R01 NS059873/NS/NINDS NIH HHS/United States;R01AG019085/AG/NIA NIH HHS/United States;R01AG15819/AG/NIA NIH HHS/United States;R01AG17917/AG/NIA NIH HHS/United States;R01AG30146/AG/NIA NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;RC2 AG036535/AG/NIA NIH HHS/United States;RC2AG036528/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG06781/AG/NIA NIH HHS/United States;U01 AG10483/AG/NIA NIH HHS/United States;U01 HG004610/HG/NHGRI NIH HHS/United States;U01AG016976/AG/NIA NIH HHS/United States;U01AG032984/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;U24AG021886/AG/NIA NIH HHS/United States;U24AG026390/AG/NIA NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;UL1RR02777/RR/NCRR NIH HHS/United States;Canadian Institutes of Health Research/Canada;Howard Hughes Medical Institute/United States;Wellcome Trust/United Kingdom

Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on gamma-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P

11.

"Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4,and the risk of late-onset Alzheimer disease in African Americans"

Reitz, Christiane; Jun, Gyungah; Naj, Adam; Rajbhandary, Ruchita; Vardarajan, Badri Narayan; Wang, Li-San; Valladares, Otto; Lin, Chiao-Feng; Larson, Eric B; Graff-Radford, Neill R; Evans, Denis; De Jager, Philip L; Crane, Paul K; Buxbaum, Joseph D; Murrell, Jill R; Raj, Towfique; Ertekin-Taner, Nilufer; Logue, Mark; Baldwin, Clinton T; Green, Robert C; Barnes, Lisa L; Cantwell, Laura B; Fallin, M Daniele; Go, Rodney C P; Griffith, Patrick; Obisesan, Thomas O; Manly, Jennifer J; Lunetta, Kathryn L; Kamboh, M Ilyas; Lopez, Oscar L; Bennett, David A; Hendrie, Hugh; Hall, Kathleen S; Goate, Alison M; Byrd, Goldie S; Kukull, Walter A; Foroud, Tatiana M; Haines, Jonathan L; Farrer, Lindsay A; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Mayeux, Richard; Ferris, Steven; REISBERG, BARRY; Martiniuk, Frank
JAMA 2013 Apr;309(14):1483-1492
MEDL:23571587  #627152  Click here for full text  10.1001/jama.2013.2973

GRANTS:5R01AG20688/AG/NIA NIH HHS/United States;AG005138/AG/NIA NIH HHS/United States;AG010491/AG/NIA NIH HHS/United States;AG019757/AG/NIA NIH HHS/United States;AG021547/AG/NIA NIH HHS/United States;AG025688/AG/NIA NIH HHS/United States;AG027944/AG/NIA NIH HHS/United States;AG030653/AG/NIA NIH HHS/United States;AG05128/AG/NIA NIH HHS/United States;K23 AG034550/AG/NIA NIH HHS/United States;K23AG034550/AG/NIA NIH HHS/United States;KL2 RR024151/RR/NCRR NIH HHS/United States;MH60451/MH/NIMH NIH HHS/United States;MO1RR00096/RR/NCRR NIH HHS/United States;NS39764/NS/NINDS NIH HHS/United States;P01 AG003991/AG/NIA NIH HHS/United States;P01 AG007232/AG/NIA NIH HHS/United States;P01 AG026276/AG/NIA NIH HHS/United States;P01 AG03991/AG/NIA NIH HHS/United States;P01AG002219/AG/NIA NIH HHS/United States;P20 MD000546/MD/NIMHD NIH HHS/United States;P30 AG010133/AG/NIA NIH HHS/United States;P30 AG010161/AG/NIA NIH HHS/United States;P30AG008017/AG/NIA NIH HHS/United States;P30AG010124/AG/NIA NIH HHS/United States;P30AG010129/AG/NIA NIH HHS/United States;P30AG012300/AG/NIA NIH HHS/United States;P30AG013854/AG/NIA NIH HHS/United States;P30AG019610/AG/NIA NIH HHS/United States;P30AG028377/AG/NIA NIH HHS/United States;P30AG028383/AG/NIA NIH HHS/United States;P30AG08051/AG/NIA NIH HHS/United States;P30AG10133/AG/NIA NIH HHS/United States;P30AG10161/AG/NIA NIH HHS/United States;P30AG13846/AG/NIA NIH HHS/United States;P50 AG005133/AG/NIA NIH HHS/United States;P50 AG005133/AG/NIA NIH HHS/United States;P50 AG005138/AG/NIA NIH HHS/United States;P50 AG005681/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG05681/AG/NIA NIH HHS/United States;P50AG005131/AG/NIA NIH HHS/United States;P50AG005134/AG/NIA NIH HHS/United States;P50AG005136/AG/NIA NIH HHS/United States;P50AG005142/AG/NIA NIH HHS/United States;P50AG005146/AG/NIA NIH HHS/United States;P50AG008671/AG/NIA NIH HHS/United States;P50AG008702/AG/NIA NIH HHS/United States;P50AG016570/AG/NIA NIH HHS/United States;P50AG016573/AG/NIA NIH HHS/United States;P50AG016575/AG/NIA NIH HHS/United States;P50AG016576/AG/NIA NIH HHS/United States;P50AG016577/AG/NIA NIH HHS/United States;P50AG016582/AG/NIA NIH HHS/United States;P50AG019724/AG/NIA NIH HHS/United States;P50AG023501/AG/NIA NIH HHS/United States;P50AG16574/AG/NIA NIH HHS/United States;R01 AG009029/AG/NIA NIH HHS/United States;R01 AG009029/AG/NIA NIH HHS/United States;R01 AG009956/AG/NIA NIH HHS/United States;R01 AG011101/AG/NIA NIH HHS/United States;R01 AG015473/AG/NIA NIH HHS/United States;R01 AG015819/AG/NIA NIH HHS/United States;R01 AG017917/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG020688/AG/NIA NIH HHS/United States;R01 AG022018/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG028786/AG/NIA NIH HHS/United States;R01 AG028786/AG/NIA NIH HHS/United States;R01 AG030146/AG/NIA NIH HHS/United States;R01 AG030146/AG/NIA NIH HHS/United States;R01 AG030653/AG/NIA NIH HHS/United States;R01 AG032990/AG/NIA NIH HHS/United States;R01 AG032990/AG/NIA NIH HHS/United States;R01 AG036040/AG/NIA NIH HHS/United States;R01 AG037212/AG/NIA NIH HHS/United States;R01 AG1101/AG/NIA NIH HHS/United States;R01 AG28786-01A1/AG/NIA NIH HHS/United States;R01 NS036768/NS/NINDS NIH HHS/United States;R01AG009956/AG/NIA NIH HHS/United States;R01AG017173/AG/NIA NIH HHS/United States;R01AG019085/AG/NIA NIH HHS/United States;R01AG025259/AG/NIA NIH HHS/United States;R01AG026916/AG/NIA NIH HHS/United States;R01AG028786/AG/NIA NIH HHS/United States;R01AG031581/AG/NIA NIH HHS/United States;R01AG037212/AG/NIA NIH HHS/United States;R01AG15819/AG/NIA NIH HHS/United States;R01AG17917/AG/NIA NIH HHS/United States;R01AG22018/AG/NIA NIH HHS/United States;R01AG30146/AG/NIA NIH HHS/United States;R01AG33193/AG/NIA NIH HHS/United States;R01CA129769/CA/NCI NIH HHS/United States;R01MH080295/MH/NIMH NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;RC2 AG036650/AG/NIA NIH HHS/United States;RC2 AG036650/AG/NIA NIH HHS/United States;RC2-AG036528/AG/NIA NIH HHS/United States;U01 AG006781/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG06781/AG/NIA NIH HHS/United States;U01 HG004610/HG/NHGRI NIH HHS/United States;U01 HG004610/HG/NHGRI NIH HHS/United States;U01-AG016976/AG/NIA NIH HHS/United States;U01-AG032984/AG/NIA NIH HHS/United States;U01-AG10483/AG/NIA NIH HHS/United States;U24 AG021886/AG/NIA NIH HHS/United States;U24 AG026390/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;U24-AG021886/AG/NIA NIH HHS/United States;UL1RR02777/RR/NCRR NIH HHS/United States;UL1RR029893/RR/NCRR NIH HHS/United States

IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 x 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE 4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 x 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings..


12.

"Comprehensive search for Alzheimer disease susceptibility loci in the APOE region"

Jun, Gyungah; Vardarajan, Badri N; Buros, Jacqueline; Yu, Chang-En; Hawk, Michele V; Dombroski, Beth A; Crane, Paul K; Larson, Eric B; Mayeux, Richard; Haines, Jonathan L; Lunetta, Kathryn L; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Farrer, Lindsay A; Ferris, Steven; REISBERG, BARRY; Martiniuk, Frank
Archives of neurology 2012 Oct;69(10):1270-1279
MEDL:22869155  #627172  Click here for full text  10.1001/archneurol.2012.2052

GRANTS:AG010491/AG/NIA NIH HHS/United States;AG019757/AG/NIA NIH HHS/United States;AG021547/AG/NIA NIH HHS/United States;AG025688/AG/NIA NIH HHS/United States;AG027944/AG/NIA NIH HHS/United States;AG030653/AG/NIA NIH HHS/United States;AG05144/AG/NIA NIH HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;K23 AG034550/AG/NIA NIH HHS/United States;M01 RR00096/RR/NCRR NIH HHS/United States;P01 AG002219/AG/NIA NIH HHS/United States;P01 AG019724/AG/NIA NIH HHS/United States;P01 AG03991/AG/NIA NIH HHS/United States;P30 AG008017/AG/NIA NIH HHS/United States;P30 AG010124/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG010161/AG/NIA NIH HHS/United States;P30 AG012300/AG/NIA NIH HHS/United States;P30 AG013846/AG/NIA NIH HHS/United States;P30 AG013846/AG/NIA NIH HHS/United States;P30 AG013854/AG/NIA NIH HHS/United States;P30 AG019610/AG/NIA NIH HHS/United States;P30 AG028377/AG/NIA NIH HHS/United States;P30 AG028383/AG/NIA NIH HHS/United States;P30 AG08051/AG/NIA NIH HHS/United States;P30 AG10133/AG/NIA NIH HHS/United States;P50 AG005131/AG/NIA NIH HHS/United States;P50 AG005131/AG/NIA NIH HHS/United States;P50 AG005133/AG/NIA NIH HHS/United States;P50 AG005134/AG/NIA NIH HHS/United States;P50 AG005136/AG/NIA NIH HHS/United States;P50 AG005138/AG/NIA NIH HHS/United States;P50 AG005142/AG/NIA NIH HHS/United States;P50 AG005146/AG/NIA NIH HHS/United States;P50 AG005681/AG/NIA NIH HHS/United States;P50 AG008671/AG/NIA NIH HHS/United States;P50 AG008702/AG/NIA NIH HHS/United States;P50 AG016570/AG/NIA NIH HHS/United States;P50 AG016573/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG016575/AG/NIA NIH HHS/United States;P50 AG016576/AG/NIA NIH HHS/United States;P50 AG016577/AG/NIA NIH HHS/United States;P50 AG016582/AG/NIA NIH HHS/United States;P50 AG023501/AG/NIA NIH HHS/United States;R01 AG017173/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG020688/AG/NIA NIH HHS/United States;R01 AG025259/AG/NIA NIH HHS/United States;R01 AG025259/AG/NIA NIH HHS/United States;R01 AG026916/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG031581/AG/NIA NIH HHS/United States;R01 AG034504/AG/NIA NIH HHS/United States;R01 AG05128/AG/NIA NIH HHS/United States;R01 AG15819/AG/NIA NIH HHS/United States;R01 AG17917/AG/NIA NIH HHS/United States;R01 AG30146/AG/NIA NIH HHS/United States;R01 AG33193/AG/NIA NIH HHS/United States;R01 CA129769/CA/NCI NIH HHS/United States;R01 MH080295/MH/NIMH NIH HHS/United States;R01 MH60451/MH/NIMH NIH HHS/United States;R01 NS059873/NS/NINDS NIH HHS/United States;R01 NS059873/NS/NINDS NIH HHS/United States;R01 NS39764/NS/NINDS NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;RC2 AG036528/AG/NIA NIH HHS/United States;RC2 AG036535/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG06781/AG/NIA NIH HHS/United States;U01 AG10483/AG/NIA NIH HHS/United States;U01 HG004610/HG/NHGRI NIH HHS/United States;U24 AG021886/AG/NIA NIH HHS/United States;U24 AG026390/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;U24 AG21886/AG/NIA NIH HHS/United States;UL1 RR02777/RR/NCRR NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;Canadian Institutes of Health Research/Canada;Howard Hughes Medical Institute/United States;Medical Research Council/United Kingdom;Wellcome Trust/United Kingdom

OBJECTIVE: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523). DESIGN: Conditional logistic regression models and survival analysis. SETTING: Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium. PARTICIPANTS: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls. MAIN OUTCOME MEASURES: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls. RESULTS: In models adjusting for APOE epsilon4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of epsilon3/epsilon3 subjects. CONCLUSIONS: APOE alleles epsilon2, epsilon3, and epsilon4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci..


13.

"Remission of pre-mild cognitive impairment (MCI), subjective cognitive impairment (SCI): A two-year prospective study of demographic and behavioral markers " [Meeting Abstract]

REISBERG, BARRY; Osorio, Ricardo; Khan, Asif; Torossian, Carol; Roy, Kamalika; Boksay, Istvan; Thwin, Ohnmar; Khanzada, Naveen; Kumar, Pawan; Shulman, Melanie; Lobach, Iryna
Alzheimer's and dementia 2012 ;8(4, Suppl 2):P121-P122
ORIGINAL:0007565  #174416  Click here for full text  

14.

"Relating Memory to Functional Performance in Normal Aging to Dementia Using Hierarchical Bayesian Cognitive Processing Models"

Shankle, WR; Pooley, JP; Steyvers, M; Hara, J; Mangrola, T; REISBERG, B; Lee, MD
Alzheimer disease & associated disorders 2012 Mar;:16-22 e35414
MEDL:22407225  #166780  Click here for full text  10.1097/WAD.0b013e31824d5668

GRANTS:AG03051/AG/NIA NIH HHS/United States;AG08051/AG/NIA NIH HHS/United States

Determining how cognition affects functional abilities is important in Alzheimer disease and related disorders. A total of 280 patients (normal or Alzheimer disease and related disorders) received a total of 1514 assessments using the functional assessment staging test (FAST) procedure and the MCI Screen. A hierarchical Bayesian cognitive processing model was created by embedding a signal detection theory model of the MCI Screen-delayed recognition memory task into a hierarchical Bayesian framework. The signal detection theory model used latent parameters of discriminability (memory process) and response bias (executive function) to predict, simultaneously, recognition memory performance for each patient and each FAST severity group. The observed recognition memory data did not distinguish the 6 FAST severity stages, but the latent parameters completely separated them. The latent parameters were also used successfully to transform the ordinal FAST measure into a continuous measure reflecting the underlying continuum of functional severity. Hierarchical Bayesian cognitive processing models applied to recognition memory data from clinical practice settings accurately translated a latent measure of cognition into a continuous measure of functional severity for both individuals and FAST groups. Such a translation links 2 levels of brain information processing and may enable more accurate correlations with other levels, such as those characterized by biomarkers..


15.

"Abnormal Intracellular Accumulation and Extracellular Abeta Deposition in Idiopathic and Dup15q11.2-q13 Autism Spectrum Disorders"

Wegiel, Jerzy; Frackowiak, Janusz; Mazur-Kolecka, Bozena; Schanen, N Carolyn; Cook, Edwin H Jr; Sigman, Marian; Brown, W Ted; Kuchna, Izabela; Wegiel, Jarek; Nowicki, Krzysztof; Imaki, Humi; Ma, Shuang Yong; Chauhan, Abha; Chauhan, Ved; Miller, David L; Mehta, Pankaj D; Flory, Michael; Cohen, Ira L; London, Eric; REISBERG, BARRY; de Leon, Mony J; Wisniewski, Thomas
PLoS one 2012 ;7(5):e35414-e35414 e35414
MEDL:22567102  #166779  Click here for full text  10.1371/journal.pone.0035414

GRANTS:R01 AG012101/AG/NIA NIH HHS/United States;R01 AG022374/AG/NIA NIH HHS/United States;R01 HD43960/HD/NICHD NIH HHS/United States;R24-MH 068855/MH/NIMH NIH HHS/United States;U19 HD35470/HD/NICHD NIH HHS/United States

BACKGROUND: It has been shown that amyloid ss (Abeta), a product of proteolytic cleavage of the amyloid beta precursor protein (APP), accumulates in neuronal cytoplasm in non-affected individuals in a cell type-specific amount. METHODOLOGY/PRINCIPAL FINDINGS: In the present study, we found that the percentage of amyloid-positive neurons increases in subjects diagnosed with idiopathic autism and subjects diagnosed with duplication 15q11.2-q13 (dup15) and autism spectrum disorder (ASD). In spite of interindividual differences within each examined group, levels of intraneuronal Abeta load were significantly greater in the dup(15) autism group than in either the control or the idiopathic autism group in 11 of 12 examined regions (p<0.0001 for all comparisons; Kruskall-Wallis test). In eight regions, intraneuronal Abeta load differed significantly between idiopathic autism and control groups (p<0.0001). The intraneuronal Abeta was mainly N-terminally truncated. Increased intraneuronal accumulation of Abeta(17-40/42) in children and adults suggests a life-long enhancement of APP processing with alpha-secretase in autistic subjects. Abeta accumulation in neuronal endosomes, autophagic vacuoles, Lamp1-positive lysosomes and lipofuscin, as revealed by confocal microscopy, indicates that products of enhanced alpha-secretase processing accumulate in organelles involved in proteolysis and storage of metabolic remnants. Diffuse plaques containing Abeta(1-40/42) detected in three subjects with ASD, 39 to 52 years of age, suggest that there is an age-associated risk of alterations of APP processing with an intraneuronal accumulation of a short form of Abeta and an extracellular deposition of full-length Abeta in nonfibrillar plaques. CONCLUSIONS/SIGNIFICANCE: The higher prevalence of excessive Abeta accumulation in neurons in individuals with early onset of intractable seizures, and with a high risk of sudden unexpected death in epilepsy in autistic subjects with dup(15) compared to subjects with idiopathic ASD, supports the concept of mechanistic and functional links between autism, epilepsy and alterations of APP processing leading to neuronal and astrocytic Abeta accumulation and diffuse plaque formation..


16.

"Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis"

Whitcomb, David C; Larusch, Jessica; Krasinskas, Alyssa M; Klei, Lambertus; Smith, Jill P; Brand, Randall E; Neoptolemos, John P; Lerch, Markus M; Tector, Matt; Sandhu, Bimaljit S; Guda, Nalini M; Orlichenko, Lidiya; Albert, Marilyn S; Albin, Roger L; Apostolova, Liana G; Arnold, Steven E; Baldwin, Clinton T; Barber, Robert; Barnes, Lisa L; Beach, Thomas G; Beecham, Gary W; Beekly, Duane; Bennett, David A; Bigio, Eileen H; Bird, Thomas D; Blacker, Deborah; Boxer, Adam; Burke, James R; Buxbaum, Joseph D; Cairns, Nigel J; Cantwell, Laura B; Cao, Chuanhai; Carney, Regina M; Carroll, Steven L; Chui, Helena C; Clark, David G; Cribbs, David H; Crocco, Elizabeth A; Cruchaga, Carlos; Decarli, Charles; Demirci, F Yesim; Dick, Malcolm; Dickson, Dennis W; Duara, Ranjan; Ertekin-Taner, Nilufer; Faber, Kelley M; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Foroud, Tatiana M; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Gilman, Sid; Glass, Jonathan D; Goate, Alison M; Graff-Radford, Neill R; Green, Robert C; Growdon, John H; Hakonarson, Hakon; Hamilton-Nelson, Kara L; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jicha, Gregory A; Jin, Lee-Way; Jun, Gyungah; Kamboh, M Ilyas; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Kramer, Joel H; Kramer, Patricia; Kukull, Walter A; Laferla, Frank M; Lah, James J; Leverenz, James B; Levey, Allan I; Li, Ge; Lin, Chiao-Feng; Lieberman, Andrew P; Lopez, Oscar L; Lunetta, Kathryn L; Lyketsos, Constantine G; Mack, Wendy J; Marson, Daniel C; Martin, Eden R; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Montine, Thomas J; Morris, John C; Murrell, Jill R; Naj, Adam C; Olichney, John M; Parisi, Joseph E; Peskind, Elaine; Petersen, Ronald C; Pierce, Aimee; Poon, Wayne W; Potter, Huntington; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reiman, Eric M; REISBERG, BARRY; Reitz, Christiane; Ringman, John M; Roberson, Erik D; Rosen, Howard J; Rosenberg, Roger N; Sano, Mary; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Trojanowski, John Q; Troncoso, Juan C; Tsuang, Debby W; Valladares, Otto; Van Deerlin, Vivianna M; Van Eldik, Linda J; Vardarajan, Badri N; Vinters, Harry V; Vonsattel, Jean Paul; Wang, Li-San; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Woltjer, Randall L; Wright, Clinton B; Younkin, Steven G; Yu, Chang-En; Yu, Lei; Alkaade, Samer; Amann, Stephen T; Anderson, Michelle A; Baillie, John; Banks, Peter A; Conwell, Darwin; Cote, Gregory A; Cotton, Peter B; Disario, James; Farrer, Lindsay A; Forsmark, Chris E; Johnstone, Marianne; Gardner, Timothy B; Gelrud, Andres; Greenhalf, William; Haines, Jonathan L; Hartman, Douglas J; Hawes, Robert A; Lawrence, Christopher; Lewis, Michele; Mayerle, Julia; Mayeux, Richard; Melhem, Nadine M; Money, Mary E; Muniraj, Thiruvengadam; Papachristou, Georgios I; Pericak-Vance, Margaret A; Romagnuolo, Joseph; Schellenberg, Gerard D; Sherman, Stuart; Simon, Peter; Singh, Vijay P; Slivka, Adam; Stolz, Donna; Sutton, Robert; Weiss, Frank Ulrich; Wilcox, C Mel; Zarnescu, Narcis Octavian; Wisniewski, Stephen R; O'Connell, Michael R; Kienholz, Michelle L; Roeder, Kathryn; Barmada, M Michael; Yadav, Dhiraj; Devlin, Bernie
Nature genetics 2012 Nov;44(12):1349-1354
MEDL:23143602  #205272  Click here for full text  10.1038/ng.2466

GRANTS:P30 AG010124/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;R01 AG032990/AG/NIA NIH HHS/United States;R01 MH057881/MH/NIMH NIH HHS/United States

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR and SPINK1 variants were associated with pancreatitis risk. We now report two associations at genome-wide significance identified and replicated at PRSS1-PRSS2 (P < 1 x 10(-12)) and X-linked CLDN2 (P < 1 x 10(-21)) through a two-stage genome-wide study (stage 1: 676 cases and 4,507 controls; stage 2: 910 cases and 4,170 controls). The PRSS1 variant likely affects disease susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous in males) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men (male hemizygote frequency is 0.26, whereas female homozygote frequency is 0.07)..


17.

"Brain expression genome-wide association study (eGWAS) identifies human disease-associated variants"

Zou, Fanggeng; Chai, High Seng; Younkin, Curtis S; Allen, Mariet; Crook, Julia; Pankratz, V Shane; Carrasquillo, Minerva M; Rowley, Christopher N; Nair, Asha A; Middha, Sumit; Maharjan, Sooraj; Nguyen, Thuy; Ma, Li; Malphrus, Kimberly G; Palusak, Ryan; Lincoln, Sarah; Bisceglio, Gina; Georgescu, Constantin; Kouri, Naomi; Kolbert, Christopher P; Jen, Jin; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A; Schellenberg, Gerard D; Petersen, Ronald C; Graff-Radford, Neill R; Dickson, Dennis W; Younkin, Steven G; Ertekin-Taner, Nilufer; Ferris, Steven; REISBERG, BARRY; Martiniuk, Frank
PLoS genetics 2012 ;8(6):e1002707-e1002707 e1002707
MEDL:22685416  #627182  Click here for full text  10.1371/journal.pgen.1002707

GRANTS:AG003949/AG/NIA NIH HHS/United States;AG010491/AG/NIA NIH HHS/United States;AG017216/AG/NIA NIH HHS/United States;AG019757/AG/NIA NIH HHS/United States;AG021547/AG/NIA NIH HHS/United States;AG025688/AG/NIA NIH HHS/United States;AG025711/AG/NIA NIH HHS/United States;AG027944/AG/NIA NIH HHS/United States;AG030653/AG/NIA NIH HHS/United States;AG17586/AG/NIA NIH HHS/United States;K01 AG030514/AG/NIA NIH HHS/United States;K23 AG034550/AG/NIA NIH HHS/United States;K24 AG027841/AG/NIA NIH HHS/United States;KL2 RR024151/RR/NCRR NIH HHS/United States;MO1RR00096/RR/NCRR NIH HHS/United States;P01 AG002219/AG/NIA NIH HHS/United States;P01 AG019724/AG/NIA NIH HHS/United States;P01 AG03991/AG/NIA NIH HHS/United States;P30 AG008017/AG/NIA NIH HHS/United States;P30 AG010124/AG/NIA NIH HHS/United States;P30 AG010129/AG/NIA NIH HHS/United States;P30 AG010161/AG/NIA NIH HHS/United States;P30 AG012300/AG/NIA NIH HHS/United States;P30 AG013846/AG/NIA NIH HHS/United States;P30 AG013854/AG/NIA NIH HHS/United States;P30 AG019610/AG/NIA NIH HHS/United States;P30 AG028377/AG/NIA NIH HHS/United States;P30 AG028383/AG/NIA NIH HHS/United States;P30 AG08051/AG/NIA NIH HHS/United States;P30 AG10133/AG/NIA NIH HHS/United States;P30 AG1961/AG/NIA NIH HHS/United States;P50 AG005131/AG/NIA NIH HHS/United States;P50 AG005133/AG/NIA NIH HHS/United States;P50 AG005134/AG/NIA NIH HHS/United States;P50 AG005136/AG/NIA NIH HHS/United States;P50 AG005138/AG/NIA NIH HHS/United States;P50 AG005142/AG/NIA NIH HHS/United States;P50 AG005146/AG/NIA NIH HHS/United States;P50 AG005681/AG/NIA NIH HHS/United States;P50 AG008671/AG/NIA NIH HHS/United States;P50 AG008702/AG/NIA NIH HHS/United States;P50 AG016570/AG/NIA NIH HHS/United States;P50 AG016573/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG016574/AG/NIA NIH HHS/United States;P50 AG016575/AG/NIA NIH HHS/United States;P50 AG016576/AG/NIA NIH HHS/United States;P50 AG016577/AG/NIA NIH HHS/United States;P50 AG016582/AG/NIA NIH HHS/United States;P50 AG023501/AG/NIA NIH HHS/United States;R01 032990/PHS HHS/United States;R01 AG009029/AG/NIA NIH HHS/United States;R01 AG015819/AG/NIA NIH HHS/United States;R01 AG017173/AG/NIA NIH HHS/United States;R01 AG018023/AG/NIA NIH HHS/United States;R01 AG019085/AG/NIA NIH HHS/United States;R01 AG020688/AG/NIA NIH HHS/United States;R01 AG025259/AG/NIA NIH HHS/United States;R01 AG026916/AG/NIA NIH HHS/United States;R01 AG027944/AG/NIA NIH HHS/United States;R01 AG031581/AG/NIA NIH HHS/United States;R01 AG032990/AG/NIA NIH HHS/United States;R01 AG15819/AG/NIA NIH HHS/United States;R01 AG17917/AG/NIA NIH HHS/United States;R01 AG30146/AG/NIA NIH HHS/United States;R01 CA129769/CA/NCI NIH HHS/United States;R01 HG02213/HG/NHGRI NIH HHS/United States;R01 MH080295/MH/NIMH NIH HHS/United States;R01 NS059873/NS/NINDS NIH HHS/United States;R37 AG015473/AG/NIA NIH HHS/United States;RC2 AG036528/AG/NIA NIH HHS/United States;RC2 AG036535/AG/NIA NIH HHS/United States;U01 AG006576/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG016976/AG/NIA NIH HHS/United States;U01 AG024904/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG032984/AG/NIA NIH HHS/United States;U01 AG10483/AG/NIA NIH HHS/United States;U24 AG021886/AG/NIA NIH HHS/United States;U24 AG026390/AG/NIA NIH HHS/United States;U24 AG026395/AG/NIA NIH HHS/United States;U24 NS072026/NS/NINDS NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;UL1 RR029893/RR/NCRR NIH HHS/United States;UL1RR02777/RR/NCRR NIH HHS/United States;UO1 AG06781/AG/NIA NIH HHS/United States;UO1 HG004610/HG/NHGRI NIH HHS/United States;Canadian Institutes of Health Research/Canada;Howard Hughes Medical Institute/United States;Wellcome Trust/United Kingdom

Genetic variants that modify brain gene expression may also influence risk for human diseases. We measured expression levels of 24,526 transcripts in brain samples from the cerebellum and temporal cortex of autopsied subjects with Alzheimer's disease (AD, cerebellar n=197, temporal cortex n=202) and with other brain pathologies (non-AD, cerebellar n=177, temporal cortex n=197). We conducted an expression genome-wide association study (eGWAS) using 213,528 cisSNPs within +/- 100 kb of the tested transcripts. We identified 2,980 cerebellar cisSNP/transcript level associations (2,596 unique cisSNPs) significant in both ADs and non-ADs (q<0.05, p=7.70 x 10(-5)-1.67 x 10(-82)). Of these, 2,089 were also significant in the temporal cortex (p=1.85 x 10(-5)-1.70 x 10(-141)). The top cerebellar cisSNPs had 2.4-fold enrichment for human disease-associated variants (p<10(-6)). We identified novel cisSNP/transcript associations for human disease-associated variants, including progressive supranuclear palsy SLCO1A2/rs11568563, Parkinson's disease (PD) MMRN1/rs6532197, Paget's disease OPTN/rs1561570; and we confirmed others, including PD MAPT/rs242557, systemic lupus erythematosus and ulcerative colitis IRF5/rs4728142, and type 1 diabetes mellitus RPS26/rs1701704. In our eGWAS, there was 2.9-3.3 fold enrichment (p<10(-6)) of significant cisSNPs with suggestive AD-risk association (p<10(-3)) in the Alzheimer's Disease Genetics Consortium GWAS. These results demonstrate the significant contributions of genetic factors to human brain gene expression, which are reliably detected across different brain regions and pathologies. The significant enrichment of brain cisSNPs among disease-associated variants advocates gene expression changes as a mechanism for many central nervous system (CNS) and non-CNS diseases. Combined assessment of expression and disease GWAS may provide complementary information in discovery of human disease variants with functional implications. Our findings have implications for the design and interpretation of eGWAS in general and the use of brain expression quantitative trait loci in the study of human disease genetics..


18.

"THE CONCEPT OF RETROGENESIS IN ALZHEIMER'S DISEASE: ETHICAL AND FORENSIC IMPLICATIONS"

Borza, Liana Rada; REISBERG, BARRY; Chiosa, Anca; Astarastoae, Vasile
Revista romana de bioetica = Romanian journal of bioethics 2011 JUL-SEP ;9(3):63-72
ISI:000296480200002  #141093  Click here for full text  

The concept of retrogenesis has been documented by several studies as the process by which degenerative mechanisms in Alzheimer's disease (AD) reverse the order of acquisition in normal human development. The objective of the present study is to offer expert opinion on the possible ethical and forensic implications of retro genesis. In this regard, we constructed a six-item instrument called 'Questionnaire regarding possible ethical and forensic implications of retrogenesis', which we applied to three professional groups that are directly involved in clinical and forensic evaluation of AD persons, namely, psychiatrists, psychologists and forensic pathologists. The majority of experts questioned in this survey considered it ethical to start from the concept of retrogenesis when approaching AD. Moreover, most of the study participants agreed that it would be ethical to use psychometric tests and programs of cognitive stimulation for the child in the patient with AD. It can also be noted that more than half of the professionals involved in our study considered it ethical to apply child abuse evaluation tests to the AD patients. Furthermore, 61.2% of the opinion survey respondents agreed that it would be necessary to use the concept of retrogenesis for assessing mental capacity in these patients. In addition, most professionals surveyed herein pointed out that it would be necessary to enact legislative proposals on the protection of the patient with AD which would be adapted from the model of the current child protection legislation. This study appears to represent the first expert opinion survey that concerns the ethical and forensic implications of the concept of retrogenesis in AD.


19.

"A RETROGENIC MODEL FOR DETECTING ABUSE OF INSTITUTIONALIZED PEOPLE WITH ALZHEIMER'S DISEASE"

Borza, Liana Rada; REISBERG, BARRY; Macarie, George Florian; Astarastoae, Vasile
Revista romana de bioetica = Romanian journal of bioethics 2011 JAN-MAR ;9(1):65-75
ISI:000290178500002  #133323  Click here for full text  

Several studies draw attention to the fact that elder abuse is a complex and multi-dimensional social problem. It has been noticed that institutionalization and disturbing behaviors that result from dementia represent risk factors for mistreatment. In this regard, we have tested if an adapted version of Child Abuse and Trauma Scale can efficiently assess different types of abuse on people with Alzheimer's disease (AD) living in institutional settings. Our choice of an instrument that would ordinarily be used to measure abuse in childhood and adolescence is based on the concept of retrogenesis. This term refers to the process of AD degenerative reversal recapitulation of human ontogenic acquisition patterns. In the present study, we have found that the chosen scale is a reliable screening tool for different forms of abuse in institutionalized AD subjects, providing both a useful, ethically and humanely relevant assessment instrument, and additional evidence for the retrogenesis process. With respect to the frequency of occurrence, neglect and emotional abuse were the most common forms of abuse reported by the study participants, followed by punishment and physical abuse, while sexual abuse was the least reported. Women questioned in this study were found to be more predisposed than men to sexual abuse, while the men were found to be more predisposed to physical abuse. Moreover, the subjects with mild AD reported lower levels of punishment, neglect and emotional abuse when compared to the other AD institutional residents included in this study. In conclusion, our findings will hopefully contribute to the more widespread identification of abuse in persons with dementia, as well as to the development of prevention and intervention strategies.


20.

"Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease"

Naj, Adam C; Jun, Gyungah; Beecham, Gary W; Wang, Li-San; Vardarajan, Badri Narayan; Buros, Jacqueline; Gallins, Paul J; Buxbaum, Joseph D; Jarvik, Gail P; Crane, Paul K; Larson, Eric B; Bird, Thomas D; Boeve, Bradley F; Graff-Radford, Neill R; De Jager, Philip L; Evans, Denis; Schneider, Julie A; Carrasquillo, Minerva M; Ertekin-Taner, Nilufer; Younkin, Steven G; Cruchaga, Carlos; Kauwe, John S K; Nowotny, Petra; Kramer, Patricia; Hardy, John; Huentelman, Matthew J; Myers, Amanda J; Barmada, Michael M; Demirci, F Yesim; Baldwin, Clinton T; Green, Robert C; Rogaeva, Ekaterina; George-Hyslop, Peter St; Arnold, Steven E; Barber, Robert; Beach, Thomas; Bigio, Eileen H; Bowen, James D; Boxer, Adam; Burke, James R; Cairns, Nigel J; Carlson, Chris S; Carney, Regina M; Carroll, Steven L; Chui, Helena C; Clark, David G; Corneveaux, Jason; Cotman, Carl W; Cummings, Jeffrey L; Decarli, Charles; Dekosky, Steven T; Diaz-Arrastia, Ramon; Dick, Malcolm; Dickson, Dennis W; Ellis, William G; Faber, Kelley M; Fallon, Kenneth B; Farlow, Martin R; Ferris, Steven; Frosch, Matthew P; Galasko, Douglas R; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Gilman, Sid; Giordani, Bruno; Glass, Jonathan D; Growdon, John H; Hamilton, Ronald L; Harrell, Lindy E; Head, Elizabeth; Honig, Lawrence S; Hulette, Christine M; Hyman, Bradley T; Jicha, Gregory A; Jin, Lee-Way; Johnson, Nancy; Karlawish, Jason; Karydas, Anna; Kaye, Jeffrey A; Kim, Ronald; Koo, Edward H; Kowall, Neil W; Lah, James J; Levey, Allan I; Lieberman, Andrew P; Lopez, Oscar L; Mack, Wendy J; Marson, Daniel C; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Parisi, Joseph E; Perl, Daniel P; Peskind, Elaine; Petersen, Ronald C; Poon, Wayne W; Quinn, Joseph F; Rajbhandary, Ruchita A; Raskind, Murray; REISBERG, BARRY; Ringman, John M; Roberson, Erik D; Rosenberg, Roger N; Sano, Mary; Schneider, Lon S; Seeley, William; Shelanski, Michael L; Slifer, Michael A; Smith, Charles D; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Tanzi, Rudolph E; Trojanowski, John Q; Troncoso, Juan C; Van Deerlin, Vivianna M; Vinters, Harry V; Vonsattel, Jean Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Williamson, Jennifer; Woltjer, Randall L; Cantwell, Laura B; Dombroski, Beth A; Beekly, Duane; Lunetta, Kathryn L; Martin, Eden R; Kamboh, M Ilyas; Saykin, Andrew J; Reiman, Eric M; Bennett, David A; Morris, John C; Montine, Thomas J; Goate, Alison M; Blacker, Deborah; Tsuang, Debby W; Hakonarson, Hakon; Kukull, Walter A; Foroud, Tatiana M; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A; Schellenberg, Gerard D
Nature genetics 2011 May;43(5):436-441
MEDL:21460841  #134258  Click here for full text  10.1038/ng.801

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The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 x 10(-9), joint analysis P (P(J)) = 1.7 x 10(-9); stages 1, 2 and 3, P(M) = 8.2 x 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 x 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 x 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 x 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 x 10(-10), P(J) = 5.2 x 10(-11)), CLU (rs1532278; P(M) = 8.3 x 10(-8), P(J) = 1.9 x 10(-8)), BIN1 (rs7561528; P(M) = 4.0 x 10(-14), P(J) = 5.2 x 10(-14)) and PICALM (rs561655; P(M) = 7.0 x 10(-11), P(J) = 1.0 x 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.