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Genome biology. 2025:26(1).DOI: 10.1186/s13059-025-03564-z

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease

Rajabli, Farid; Benchek, Penelope; Tosto, Giuseppe; Kushch, Nicholas; Sha, Jin; Bazemore, Katrina; Zhu, Congcong; Lee, Wan-Ping; Haut, Jacob; Hamilton-Nelson, Kara L; Wheeler, Nicholas R; Zhao, Yi; Farrell, John J; Grunin, Michelle A; Leung, Yuk Yee; Kuksa, Pavel P; Li, Donghe; da Fonseca, Eder Lucio; Mez, Jesse B; Palmer, Ellen L; Pillai, Jagan; Sherva, Richard M; Song, Yeunjoo E; Zhang, Xiaoling; Ikeuchi, Takeshi; Iqbal, Taha; Pathak, Omkar; Valladares, Otto; Reyes-Dumeyer, Dolly; Kuzma, Amanda B; Abner, Erin; Adams, Larry D; Adams, Perrie M; Aguirre, Alyssa; Albert, Marilyn S; Albin, Roger L; Allen, Mariet; Alvarez, Lisa; Apostolova, Liana G; Arnold, Steven E; Asthana, Sanjay; Atwood, Craig S; Auerbach, Sanford; Ayres, Gayle; Baldwin, Clinton T; Barber, Robert C; Barnes, Lisa L; Barral, Sandra; Beach, Thomas G; Becker, James T; Beecham, Gary W; Beekly, Duane; Benitez, Bruno A; Bennett, David; Bertelson, John; Bird, Thomas D; Blacker, Deborah; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Brewer, James; Burke, James R; Burns, Jeffrey M; Buxbaum, Joseph D; Cairns, Nigel J; Cantwell, Laura B; Cao, Chuanhai; Carlson, Christopher S; Carlsson, Cynthia M; Carney, Regina M; Carrasquillo, Minerva M; Chasse, Scott; Chesselet, Marie-Francoise; Chin, Nathaniel A; Chui, Helena C; Chung, Jaeyoon; Craft, Suzanne; Crane, Paul K; Cribbs, David H; Crocco, Elizabeth A; Cruchaga, Carlos; Cuccaro, Michael L; Cullum, Munro; Darby, Eveleen; Davis, Barbara; De Jager, Philip L; DeCarli, Charles; DeToledo, John; Dick, Malcolm; Dickson, Dennis W; Dombroski, Beth A; Doody, Rachelle S; Duara, Ranjan; Ertekin-Taner, NIlüfer; Evans, Denis A; Faber, Kelley M; Fairchild, Thomas J; Fallon, Kenneth B; Fardo, David W; Farlow, Martin R; Fernandez-Hernandez, Victoria; Ferris, Steven; Friedland, Robert P; Foroud, Tatiana M; Frosch, Matthew P; Fulton-Howard, Brian; Galasko, Douglas R; Gamboa, Adriana; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Go, Rodney C P; Goate, Alison M; Grabowski, Thomas J; Graff-Radford, Neill R; Green, Robert C; Growdon, John H; Hakonarson, Hakon; Hall, James; Hamilton, Ronald L; Harari, Oscar; Hardy, John; Harrell, Lindy E; Head, Elizabeth; Henderson, Victor W; Hernandez, Michelle; Hohman, Timothy; Honig, Lawrence S; Huebinger, Ryan M; Huentelman, Matthew J; Hulette, Christine M; Hyman, Bradley T; Hynan, Linda S; Ibanez, Laura; Jarvik, Gail P; Jayadev, Suman; Jin, Lee-Way; Johnson, Kim; Johnson, Leigh; Kamboh, M Ilyas; Karydas, Anna M; Katz, Mindy J; Kauwe, John S; Kaye, Jeffrey A; Keene, C Dirk; Khaleeq, Aisha; Kikuchi, Masataka; Kim, Ronald; Knebl, Janice; Kowall, Neil W; Kramer, Joel H; Kukull, Walter A; LaFerla, Frank M; Lah, James J; Larson, Eric B; Lerner, Alan; Leverenz, James B; Levey, Allan I; Lieberman, Andrew P; Lipton, Richard B; Logue, Mark; Lopez, Oscar L; Lunetta, Kathryn L; Lyketsos, Constantine G; Mains, Douglas; Margaret, Flanagan E; Marson, Daniel C; Martin, Eden Rr; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; Massman, Paul; Masurkar, Arjun; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McDonough, Stefan; McKee, Ann C; Mesulam, Marsel; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Montine, Thomas J; Monuki, Edwin S; Morris, John C; Mukherjee, Shubhabrata; Myers, Amanda J; Nguyen, Trung; Obisesan, Thomas; O'Bryant, Sid; Olichney, John M; Ory, Marcia; Palmer, Raymond; Parisi, Joseph E; Paulson, Henry L; Pavlik, Valory; Paydarfar, David; Perez, Victoria; Peskind, Elaine; Petersen, Ronald C; Petrovitch, Helen; Pierce, Aimee; Polk, Marsha; Poon, Wayne W; Potter, Huntington; Qu, Liming; Quiceno, Mary; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reiman, Eric M; Reisberg, Barry; Reisch, Joan S; Ringman, John M; Roberson, Erik D; Rodriguear, Monica; Rogaeva, Ekaterina; Rosen, Howard J; Rosenberg, Roger N; Royall, Donald R; Sabbagh, Marwan; Sadovnick, A Dessa; Sager, Mark A; Sano, Mary; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Slifer, Susan H; Small, Scott; Smith, Amanda G; Smith, Janet P; Sonnen, Joshua A; Spina, Salvatore; George-Hyslop, Peter St; Starks, Takiyah D; Stern, Robert A; Stevens, Alan B; Strittmatter, Stephen M; Sultzer, David; Swerdlow, Russell H; Tanzi, Rudolph E; Tilson, Jeffrey L; Trojanowski, John Q; Troncoso, Juan C; Tsolaki, Magda; Tsuang, Debby W; Van Deerlin, Vivianna M; van Eldik, Linda J; Vance, Jeffery M; Vardarajan, Badri N; Vassar, Robert; Vinters, Harry V; Vonsattel, Jean-Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Whitehead, Patrice L; Wijsman, Ellen M; Wilhelmsen, Kirk C; Williams, Benjamin; Williamson, Jennifer; Wilms, Henrik; Wingo, Thomas S; Wisniewski, Thomas; Woltjer, Randall L; Woon, Martin; Wright, Clinton B; Wu, Chuang-Kuo; Younkin, Steven G; Yu, Chang-En; Yu, Lei; Zhu, Xiongwei; Kunkle, Brian W; Bush, William S; Miyashita, Akinori; Byrd, Goldie S; Wang, Li-San; Farrer, Lindsay A; Haines, Jonathan L; Mayeux, Richard; Pericak-Vance, Margaret A; Schellenberg, Gerard D; Jun, Gyungah R; Reitz, Christiane; Naj, Adam C; ,
BACKGROUND:Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS:We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS:Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.
PMCID:12273372
PMID: 40676597
ISSN: 1474-760x
CID: 5897492
Neuropsychology. 2023:37(4):463-499.DOI: 10.1037/neu0000888

Linking self-perceived cognitive functioning questionnaires using item response theory: The subjective cognitive decline initiative

Rabin, Laura A; Sikkes, Sietske A M; Tommet, Douglas; Jones, Richard N; Crane, Paul K; Elbulok-Charcape, Milushka M; Dubbelman, Mark A; Koscik, Rebecca; Amariglio, Rebecca E; Buckley, Rachel F; Boada, Mercè; Chételat, Gaël; Dubois, Bruno; Ellis, Kathryn A; Gifford, Katherine A; Jefferson, Angela L; Jessen, Frank; Johnson, Sterling; Katz, Mindy J; Lipton, Richard B; Luck, Tobias; Margioti, Eleni; Maruff, Paul; Molinuevo, Jose Luis; Perrotin, Audrey; Petersen, Ronald C; Rami, Lorena; Reisberg, Barry; Rentz, Dorene M; Riedel-Heller, Steffi G; Risacher, Shannon L; Rodriguez-Gomez, Octavio; Sachdev, Perminder S; Saykin, Andrew J; Scarmeas, Nikolaos; Smart, Colette; Snitz, Beth E; Sperling, Reisa A; Taler, Vanessa; van der Flier, Wiesje M; van Harten, Argonde C; Wagner, Michael; Wolfsgruber, Steffen
OBJECTIVE:Self-perceived cognitive functioning, considered highly relevant in the context of aging and dementia, is assessed in numerous ways-hindering the comparison of findings across studies and settings. Therefore, the present study aimed to link item-level self-report questionnaire data from international aging studies. METHOD/METHODS:We harmonized secondary data from 24 studies and 40 different questionnaires with item response theory (IRT) techniques using a graded response model with a Bayesian estimator. We compared item information curves to identify items with high measurement precision at different levels of the self-perceived cognitive functioning latent trait. Data from 53,030 neuropsychologically intact older adults were included, from 13 English language and 11 non-English (or mixed) language studies. RESULTS:We successfully linked all questionnaires and demonstrated that a single-factor structure was reasonable for the latent trait. Items that made the greatest contribution to measurement precision (i.e., "top items") assessed general and specific memory problems and aspects of executive functioning, attention, language, calculation, and visuospatial skills. These top items originated from distinct questionnaires and varied in format, range, time frames, response options, and whether they captured ability and/or change. CONCLUSIONS:This was the first study to calibrate self-perceived cognitive functioning data of geographically diverse older adults. The resulting item scores are on the same metric, facilitating joint or pooled analyses across international studies. Results may lead to the development of new self-perceived cognitive functioning questionnaires guided by psychometric properties, content, and other important features of items in our item bank. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
PMID: 37276136
ISSN: 1931-1559
CID: 5541632
Alzheimer's & dementia. 2022:18(S8).DOI: 10.1002/alz.068107

Functional Outcomes of a Comprehensive, Individualized, Person-Centered Management Program in Advanced Alzheimer"™s Disease(AD): Results from a 52-Week Randomized Controlled Trial

Kenowsky, Sunnie; Shao, Yongzhao; Zhang, Qiao; Dafflisio, Gianna; Vedvyas, Alok; Vedvyas, Gaurav; Golomb, James B.; Torossian, Carol; Marsh, Karyn; Heller, Sloane; Sadowski, Martin J.; Reisberg, Barry
Background: We conducted a 28-week, single-blind, randomized, controlled trial of the efficacy of Comprehensive, Individualized, Person-Centered Management (CI-PCM) and memantine treatment (Reisberg et al., Dement Geriatr Cogn Disord, 2017) in advanced AD persons. CI-PCM and memantine was approximately 7.5 times more beneficial to AD persons on the Functional Assessment Staging Tool (FAST) (Kenowsky et. al., Alzheimer"™s and Dementia, 2017) than to AD persons who received memantine alone in the memantine FDA approval pivotal trial conducted by Reisberg et. al., (NEJM 2003). We also conducted a 24-week extension study. Herein, we report the difference in functional outcomes between the CI-PCM and Usual Community Care (UCC+FC) groups at 52-weeks on the FAST and the ADCS-ADLSev-Abv. See Figures 1 and 2. Method: After screening, 20 eligible subject-carepartner dyads were randomized equally to the CI-PCM and UCC+FC groups. All 20 dyads completed the 28-week study and entered the 24-week extension study. One subject in the UCC+FC group died during the extension study. The FAST and ADCS-ADLsev-abv were conducted at baseline, and weeks 4, 12, 28, and 52. P values were calculated using the Wilcoxon Mann Whitney test. Result: The mean FAST total score from baseline (6.6±0.1SE) to week 52 (6.5±0.01SE) showed an improvement of functional limitations in the CI-PCM group. The mean FAST total score for the UCC+FC group showed a functional decline from baseline (6.6±0.1SE) to week 52 (6.8±0.1SE), displaying a robustly significant difference between the two groups (p<0.0014). The mean ADCS-ADL-sev-abv total score for the CI-PCM group demonstrated a 20.9% improvement in functioning from baseline (15.3±2.0SE) to week 52 (18.5±2.5SE). The mean ADCS-ADL-sev-abv total score for the UCC+FC group showed a decline of 48.6% from baseline (14.8±2.1SE) to week 52 (7.6±2.3SE), indicating a significant difference between the two groups (p<0.009). Conclusion: The CI-PCM program is the only evidenced-based treatment to date that can significantly improve and reverse functional deterioration in advanced AD persons. The functional success of the CI-PCM program may primarily be attributed to care partners learning to memory coach AD persons to perform daily activities such as bathing, dressing, feeding and toileting themselves, and to become/maintain urinary and fecal continence.
SCOPUS:85144362721
ISSN: 1552-5260
CID: 5393842
Neuroimage. 2022.DOI: 10.1016/j.neuroimage.2022.119743

Cortical Myelin Profile Variations in Healthy Aging Brain: A T1w/T2w Ratio Study

Sui, Yu-Veronica; Masurkar, Arjun V; Rusinek, Henry; Reisberg, Barry; Lazar, Mariana
Demyelination is observed in both healthy aging and age-related neurodegenerative disorders. While the significance of myelin within the cortex is well acknowledged, studies focused on intracortical demyelination and depth-specific structural alterations in normal aging are lacking. Using the recently available Human Connectome Project Aging dataset, we investigated intracortical myelin in a normal aging population using the T1w/T2w ratio. To capture the fine changes across cortical depths, we employed a surface-based approach by constructing cortical profiles traveling perpendicularly through the cortical ribbon and sampling T1w/T2w values. The curvatures of T1w/T2w cortical profiles may be influenced by differences in local myeloarchitecture and other tissue properties, which are known to vary across cortical regions. To quantify the shape of these profiles, we parametrized the level of curvature using a nonlinearity index (NLI) that measures the deviation of the profile from a straight line. We showed that NLI exhibited a steep decline in aging that was independent of local cortical thinning. Further examination of the profiles revealed that lower T1w/T2w near the gray-white matter boundary and superficial cortical depths were major contributors to the apparent NLI variations with age. These findings suggest that demyelination and changes in other T1w/T2w related tissue properties in normal aging may be depth-specific and highlight the potential of NLI as a unique marker of microstructural alterations within the cerebral cortex.
PMID: 36368498
ISSN: 1095-9572
CID: 5357642
Acta neurologica Belgica. 2022:122(4):987-996.DOI: 10.1007/s13760-021-01686-2

Translation and psychometric evaluation of a Persian version of the functional assessment staging scale (I-FAST) in older patients with mild cognitive impairment and Alzheimer's disease in Iran

Noroozian, Maryam; Reisberg, Barry; Farhadi, Akram; Sharifi, Farshad; Sadeghi Zangeneh, Arghavan; Mohammadi, Maryam
The Functional Assessment Staging procedure is a clinical instrument which has been designed for staging Alzheimer's disease (AD) from the stage of no deficits to the pre-clinical stage of subjective deficits, to Mild Cognitive Impairment (MCI), to the stages of AD. This study examined the psychometric properties and the validity of the Persian version of the FAST (I-FAST) in an elderly outpatient population in Iran. We conducted a validation study of the FAST scale at the two referral centers for dementia and cognitive disorders in Tehran, Iran. The participants consisted of subjects with normal cognition, MCI and AD. The scores of the Persian version of the Mini-Mental State Examination (MMSE) and the Persian version of the I-FAST were examined. Demographic variables were also collected. The diagnosis of MCI was made based on Petersen criteria and AD based on the McKhann et al. criteria by a neurologist with expertise in dementia. Data was collected from 219 participants. A total of 54.7% of the sample was female and their mean age was 72.54 ± 8.88 years. The area under the ROC curve was calculated 0.952 and 0.982. The I-FAST had a sensitivity of 92.2% and specificity of 98.0% for the differentiation of normal cognition from MCI. The sensitivity of the I-FAST for discrimination of subjects with AD from MCI was 99.0% and the specificity was 93.7%. The I-FAST showed good psychometric characteristics in the discrimination of MCI from both normal elderly and patients with Alzheimer's. The I-FAST is also a sensitive and accurate instrument for staging persons at risk for MCI and Alzheimer's, relatively free of the confounding effects of education, culture and language in comparison with the MMSE.
PMID: 34152582
ISSN: 2240-2993
CID: 4918162
Nature genetics. 2022:54(4):412-436.DOI: 10.1038/s41588-022-01024-z

New insights into the genetic etiology of Alzheimer's disease and related dementias

Bellenguez, Céline; Küçükali, Fahri; Jansen, Iris E; Kleineidam, Luca; Moreno-Grau, Sonia; Amin, Najaf; Naj, Adam C; Campos-Martin, Rafael; Grenier-Boley, Benjamin; Andrade, Victor; Holmans, Peter A; Boland, Anne; Damotte, Vincent; van der Lee, Sven J; Costa, Marcos R; Kuulasmaa, Teemu; Yang, Qiong; de Rojas, Itziar; Bis, Joshua C; Yaqub, Amber; Prokic, Ivana; Chapuis, Julien; Ahmad, Shahzad; Giedraitis, Vilmantas; Aarsland, Dag; Garcia-Gonzalez, Pablo; Abdelnour, Carla; Alarcón-Martín, Emilio; Alcolea, Daniel; Alegret, Montserrat; Alvarez, Ignacio; Álvarez, Victoria; Armstrong, Nicola J; Tsolaki, Anthoula; Antúnez, Carmen; Appollonio, Ildebrando; Arcaro, Marina; Archetti, Silvana; Pastor, Alfonso Arias; Arosio, Beatrice; Athanasiu, Lavinia; Bailly, Henri; Banaj, Nerisa; Baquero, Miquel; Barral, Sandra; Beiser, Alexa; Pastor, Ana Belén; Below, Jennifer E; Benchek, Penelope; Benussi, Luisa; Berr, Claudine; Besse, Céline; Bessi, Valentina; Binetti, Giuliano; Bizarro, Alessandra; Blesa, Rafael; Boada, Mercè; Boerwinkle, Eric; Borroni, Barbara; Boschi, Silvia; Bossù, Paola; BrÃ¥then, Geir; Bressler, Jan; Bresner, Catherine; Brodaty, Henry; Brookes, Keeley J; Brusco, Luis Ignacio; Buiza-Rueda, Dolores; Bûrger, Katharina; Burholt, Vanessa; Bush, William S; Calero, Miguel; Cantwell, Laura B; Chene, Geneviève; Chung, Jaeyoon; Cuccaro, Michael L; Carracedo, Ángel; Cecchetti, Roberta; Cervera-Carles, Laura; Charbonnier, Camille; Chen, Hung-Hsin; Chillotti, Caterina; Ciccone, Simona; Claassen, Jurgen A H R; Clark, Christopher; Conti, Elisa; Corma-Gómez, Anaïs; Costantini, Emanuele; Custodero, Carlo; Daian, Delphine; Dalmasso, Maria Carolina; Daniele, Antonio; Dardiotis, Efthimios; Dartigues, Jean-François; de Deyn, Peter Paul; de Paiva Lopes, Katia; de Witte, Lot D; Debette, Stéphanie; Deckert, Jürgen; Del Ser, Teodoro; Denning, Nicola; DeStefano, Anita; Dichgans, Martin; Diehl-Schmid, Janine; Diez-Fairen, Mónica; Rossi, Paolo Dionigi; Djurovic, Srdjan; Duron, Emmanuelle; Düzel, Emrah; Dufouil, Carole; Eiriksdottir, Gudny; Engelborghs, Sebastiaan; Escott-Price, Valentina; Espinosa, Ana; Ewers, Michael; Faber, Kelley M; Fabrizio, Tagliavini; Nielsen, Sune Fallgaard; Fardo, David W; Farotti, Lucia; Fenoglio, Chiara; Fernández-Fuertes, Marta; Ferrari, Raffaele; Ferreira, Catarina B; Ferri, Evelyn; Fin, Bertrand; Fischer, Peter; Fladby, Tormod; Fließbach, Klaus; Fongang, Bernard; Fornage, Myriam; Fortea, Juan; Foroud, Tatiana M; Fostinelli, Silvia; Fox, Nick C; Franco-Macías, Emlio; Bullido, María J; Frank-García, Ana; Froelich, Lutz; Fulton-Howard, Brian; Galimberti, Daniela; García-Alberca, Jose Maria; García-González, Pablo; Garcia-Madrona, Sebastian; Garcia-Ribas, Guillermo; Ghidoni, Roberta; Giegling, Ina; Giorgio, Giaccone; Goate, Alison M; Goldhardt, Oliver; Gomez-Fonseca, Duber; González-Pérez, Antonio; Graff, Caroline; Grande, Giulia; Green, Emma; Grimmer, Timo; Grünblatt, Edna; Grunin, Michelle; Gudnason, Vilmundur; Guetta-Baranes, Tamar; Haapasalo, Annakaisa; Hadjigeorgiou, Georgios; Haines, Jonathan L; Hamilton-Nelson, Kara L; Hampel, Harald; Hanon, Olivier; Hardy, John; Hartmann, Annette M; Hausner, Lucrezia; Harwood, Janet; Heilmann-Heimbach, Stefanie; Helisalmi, Seppo; Heneka, Michael T; Hernández, Isabel; Herrmann, Martin J; Hoffmann, Per; Holmes, Clive; Holstege, Henne; Vilas, Raquel Huerto; Hulsman, Marc; Humphrey, Jack; Biessels, Geert Jan; Jian, Xueqiu; Johansson, Charlotte; Jun, Gyungah R; Kastumata, Yuriko; Kauwe, John; Kehoe, Patrick G; Kilander, Lena; StÃ¥hlbom, Anne Kinhult; Kivipelto, Miia; Koivisto, Anne; Kornhuber, Johannes; Kosmidis, Mary H; Kukull, Walter A; Kuksa, Pavel P; Kunkle, Brian W; Kuzma, Amanda B; Lage, Carmen; Laukka, Erika J; Launer, Lenore; Lauria, Alessandra; Lee, Chien-Yueh; Lehtisalo, Jenni; Lerch, Ondrej; Lleó, Alberto; Longstreth, William; Lopez, Oscar; de Munain, Adolfo Lopez; Love, Seth; Löwemark, Malin; Luckcuck, Lauren; Lunetta, Kathryn L; Ma, Yiyi; Macías, Juan; MacLeod, Catherine A; Maier, Wolfgang; Mangialasche, Francesca; Spallazzi, Marco; Marquié, Marta; Marshall, Rachel; Martin, Eden R; Montes, Angel Martín; Rodríguez, Carmen Martínez; Masullo, Carlo; Mayeux, Richard; Mead, Simon; Mecocci, Patrizia; Medina, Miguel; Meggy, Alun; Mehrabian, Shima; Mendoza, Silvia; Menéndez-González, Manuel; Mir, Pablo; Moebus, Susanne; Mol, Merel; Molina-Porcel, Laura; Montrreal, Laura; Morelli, Laura; Moreno, Fermin; Morgan, Kevin; Mosley, Thomas; Nöthen, Markus M; Muchnik, Carolina; Mukherjee, Shubhabrata; Nacmias, Benedetta; Ngandu, Tiia; Nicolas, Gael; Nordestgaard, Børge G; Olaso, Robert; Orellana, Adelina; Orsini, Michela; Ortega, Gemma; Padovani, Alessandro; Paolo, Caffarra; Papenberg, Goran; Parnetti, Lucilla; Pasquier, Florence; Pastor, Pau; Peloso, Gina; Pérez-Cordón, Alba; Pérez-Tur, Jordi; Pericard, Pierre; Peters, Oliver; Pijnenburg, Yolande A L; Pineda, Juan A; Piñol-Ripoll, Gerard; Pisanu, Claudia; Polak, Thomas; Popp, Julius; Posthuma, Danielle; Priller, Josef; Puerta, Raquel; Quenez, Olivier; Quintela, Inés; Thomassen, Jesper Qvist; Rábano, Alberto; Rainero, Innocenzo; Rajabli, Farid; Ramakers, Inez; Real, Luis M; Reinders, Marcel J T; Reitz, Christiane; Reyes-Dumeyer, Dolly; Ridge, Perry; Riedel-Heller, Steffi; Riederer, Peter; Roberto, Natalia; Rodriguez-Rodriguez, Eloy; Rongve, Arvid; Allende, Irene Rosas; Rosende-Roca, Maitée; Royo, Jose Luis; Rubino, Elisa; Rujescu, Dan; Sáez, María Eugenia; Sakka, Paraskevi; Saltvedt, Ingvild; Sanabria, Ángela; Sánchez-Arjona, María Bernal; Sanchez-Garcia, Florentino; Juan, Pascual Sánchez; Sánchez-Valle, Raquel; Sando, Sigrid B; Sarnowski, Chloé; Satizabal, Claudia L; Scamosci, Michela; Scarmeas, Nikolaos; Scarpini, Elio; Scheltens, Philip; Scherbaum, Norbert; Scherer, Martin; Schmid, Matthias; Schneider, Anja; Schott, Jonathan M; Selbæk, Geir; Seripa, Davide; Serrano, Manuel; Sha, Jin; Shadrin, Alexey A; Skrobot, Olivia; Slifer, Susan; Snijders, Gijsje J L; Soininen, Hilkka; Solfrizzi, Vincenzo; Solomon, Alina; Song, Yeunjoo; Sorbi, Sandro; Sotolongo-Grau, Oscar; Spalletta, Gianfranco; Spottke, Annika; Squassina, Alessio; Stordal, Eystein; Tartan, Juan Pablo; Tárraga, Lluís; Tesí, Niccolo; Thalamuthu, Anbupalam; Thomas, Tegos; Tosto, Giuseppe; Traykov, Latchezar; Tremolizzo, Lucio; Tybjærg-Hansen, Anne; Uitterlinden, Andre; Ullgren, Abbe; Ulstein, Ingun; Valero, Sergi; Valladares, Otto; Broeckhoven, Christine Van; Vance, Jeffery; Vardarajan, Badri N; van der Lugt, Aad; Dongen, Jasper Van; van Rooij, Jeroen; van Swieten, John; Vandenberghe, Rik; Verhey, Frans; Vidal, Jean-Sébastien; Vogelgsang, Jonathan; Vyhnalek, Martin; Wagner, Michael; Wallon, David; Wang, Li-San; Wang, Ruiqi; Weinhold, Leonie; Wiltfang, Jens; Windle, Gill; Woods, Bob; Yannakoulia, Mary; Zare, Habil; Zhao, Yi; Zhang, Xiaoling; Zhu, Congcong; Zulaica, Miren; Farrer, Lindsay A; Psaty, Bruce M; Ghanbari, Mohsen; Raj, Towfique; Sachdev, Perminder; Mather, Karen; Jessen, Frank; Ikram, M Arfan; de Mendonça, Alexandre; Hort, Jakub; Tsolaki, Magda; Pericak-Vance, Margaret A; Amouyel, Philippe; Williams, Julie; Frikke-Schmidt, Ruth; Clarimon, Jordi; Deleuze, Jean-François; Rossi, Giacomina; Seshadri, Sudha; Andreassen, Ole A; Ingelsson, Martin; Hiltunen, Mikko; Sleegers, Kristel; Schellenberg, Gerard D; van Duijn, Cornelia M; Sims, Rebecca; van der Flier, Wiesje M; Ruiz, Agustín; Ramirez, Alfredo; Lambert, Jean-Charles; Laczo, Jan; Matoska, Vaclav; Serpente, Maria; Assogna, Francesca; Piras, Fabrizio; Piras, Federica; Ciullo, Valentina; Shofany, Jacob; Ferrarese, Carlo; Andreoni, Simona; Sala, Gessica; Zoia, Chiara Paola; Zompo, Maria Del; Benussi, Alberto; Bastiani, Patrizia; Takalo, Mari; Natunen, Teemu; Laatikainen, Tiina; Tuomilehto, Jaakko; Antikainen, Riitta; Strandberg, Timo; Lindström, Jaana; Peltonen, Markku; Abraham, Richard; Al-Chalabi, Ammar; Bass, Nicholas J; Brayne, Carol; Brown, Kristelle S; Collinge, John; Craig, David; Deloukas, Pangiotis; Fox, Nick; Gerrish, Amy; Gill, Michael; Gwilliam, Rhian; Harold, Denise; Hollingworth, Paul; Johnston, Jarret A; Jones, Lesley; Lawlor, Brian; Livingston, Gill; Lovestone, Simon; Lupton, Michelle; Lynch, Aoibhinn; Mann, David; McGuinness, Bernadette; McQuillin, Andrew; O'Donovan, Michael C; Owen, Michael J; Passmore, Peter; Powell, John F; Proitsi, Petra; Rossor, Martin; Shaw, Christopher E; Smith, A David; Gurling, Hugh; Todd, Stephen; Mummery, Catherine; Ryan, Nathalie; Lacidogna, Giordano; Adarmes-Gómez, Ad; Mauleón, Ana; Pancho, Ana; Gailhajenet, Anna; Lafuente, Asunción; Macias-García, D; Martín, Elvira; Pelejà, Esther; Carrillo, F; Merlín, Isabel Sastre; Garrote-Espina, L; Vargas, Liliana; Carrion-Claro, M; Marín, M; Labrador, Ma; Buendia, Mar; Alonso, María Dolores; Guitart, Marina; Moreno, Mariona; Ibarria, Marta; Periñán, Mt; Aguilera, Nuria; Gómez-Garre, P; Cañabate, Pilar; Escuela, R; Pineda-Sánchez, R; Vigo-Ortega, R; Jesús, S; Preckler, Silvia; Rodrigo-Herrero, Silvia; Diego, Susana; Vacca, Alessandro; Roveta, Fausto; Salvadori, Nicola; Chipi, Elena; Boecker, Henning; Laske, Christoph; Perneczky, Robert; Anastasiou, Costas; Janowitz, Daniel; Malik, Rainer; Anastasiou, Anna; Parveen, Kayenat; Lage, Carmen; López-García, Sara; Antonell, Anna; Mihova, Kalina Yonkova; Belezhanska, Diyana; Weber, Heike; Kochen, Silvia; Solis, Patricia; Medel, Nancy; Lisso, Julieta; Sevillano, Zulma; Politis, Daniel G; Cores, Valeria; Cuesta, Carolina; Ortiz, Cecilia; Bacha, Juan Ignacio; Rios, Mario; Saenz, Aldo; Abalos, Mariana Sanchez; Kohler, Eduardo; Palacio, Dana Lis; Etchepareborda, Ignacio; Kohler, Matias; Novack, Gisela; Prestia, Federico Ariel; Galeano, Pablo; Castaño, Eduardo M; Germani, Sandra; Toso, Carlos Reyes; Rojo, Matias; Ingino, Carlos; Mangone, Carlos; Rubinsztein, David C; Teipel, Stefan; Fievet, Nathalie; Deramerourt, Vincent; Forsell, Charlotte; Thonberg, HÃ¥kan; Bjerke, Maria; Roeck, Ellen De; Martínez-Larrad, María Teresa; Olivar, Natividad; Aguilera, Nuria; Cano, Amanda; Cañabate, Pilar; Macias, Juan; Maroñas, Olalla; Nuñez-Llaves, Raúl; Olivé, Clàudia; Pelejá, Ester; Adarmes-Gómez, Astrid D; Alonso, María Dolores; Amer-Ferrer, Guillermo; Antequera, Martirio; Burguera, Juan Andrés; Carrillo, Fátima; Carrión-Claro, Mario; Casajeros, María José; Martinez de Pancorbo, Marian; Escuela, Rocío; Garrote-Espina, Lorena; Gómez-Garre, Pilar; Hevilla, Saray; Jesús, Silvia; Espinosa, Miguel Angel Labrador; Legaz, Agustina; López-García, Sara; Macias-García, Daniel; Manzanares, Salvadora; Marín, Marta; Marín-Muñoz, Juan; Marín, Tamara; Martínez, Begoña; Martínez, Victoriana; Martínez-Lage Álvarez, Pablo; Iriarte, Maite Mendioroz; Periñán-Tocino, María Teresa; Pineda-Sánchez, Rocío; Real de Asúa, Diego; Rodrigo, Silvia; Sastre, Isabel; Vicente, Maria Pilar; Vigo-Ortega, Rosario; Vivancos, Liliana; Epelbaum, Jacques; Hannequin, Didier; Campion, Dominique; Deramecourt, Vincent; Tzourio, Christophe; Brice, Alexis; Dubois, Bruno; Williams, Amy; Thomas, Charlene; Davies, Chloe; Nash, William; Dowzell, Kimberley; Morales, Atahualpa Castillo; Bernardo-Harrington, Mateus; Turton, James; Lord, Jenny; Brown, Kristelle; Vardy, Emma; Fisher, Elizabeth; Warren, Jason D; Rossor, Martin; Ryan, Natalie S; Guerreiro, Rita; Uphill, James; Bass, Nick; Heun, Reinhard; Kölsch, Heike; Schürmann, Britta; Lacour, André; Herold, Christine; Johnston, Janet A; Passmore, Peter; Powell, John; Patel, Yogen; Hodges, Angela; Becker, Tim; Warden, Donald; Wilcock, Gordon; Clarke, Robert; Deloukas, Panagiotis; Ben-Shlomo, Yoav; Hooper, Nigel M; Pickering-Brown, Stuart; Sussams, Rebecca; Warner, Nick; Bayer, Anthony; Heuser, Isabella; Drichel, Dmitriy; Klopp, Norman; Mayhaus, Manuel; Riemenschneider, Matthias; Pinchler, Sabrina; Feulner, Thomas; Gu, Wei; van den Bussche, Hendrik; Hüll, Michael; Frölich, Lutz; Wichmann, H-Erich; Jöckel, Karl-Heinz; O'Donovan, Michael; Owen, Michael; Bahrami, Shahram; Bosnes, Ingunn; Selnes, Per; Bergh, Sverre; Palotie, Aarno; Daly, Mark; Jacob, Howard; Matakidou, Athena; Runz, Heiko; John, Sally; Plenge, Robert; McCarthy, Mark; Hunkapiller, Julie; Ehm, Meg; Waterworth, Dawn; Fox, Caroline; Malarstig, Anders; Klinger, Kathy; Call, Kathy; Behrens, Tim; Loerch, Patrick; Mäkelä, Tomi; Kaprio, Jaakko; Virolainen, Petri; Pulkki, Kari; Kilpi, Terhi; Perola, Markus; Partanen, Jukka; Pitkäranta, Anne; Kaarteenaho, Riitta; Vainio, Seppo; Turpeinen, Miia; Serpi, Raisa; Laitinen, Tarja; Mäkelä, Johanna; Kosma, Veli-Matti; Kujala, Urho; Tuovila, Outi; Hendolin, Minna; Pakkanen, Raimo; Waring, Jeff; Riley-Gillis, Bridget; Liu, Jimmy; Biswas, Shameek; Diogo, Dorothee; Marshall, Catherine; Hu, Xinli; Gossel, Matthias; Graham, Robert; Cummings, Beryl; Ripatti, Samuli; Schleutker, Johanna; Arvas, Mikko; Carpén, Olli; Hinttala, Reetta; Kettunen, Johannes; Mannermaa, Arto; Laukkanen, Jari; Julkunen, Valtteri; Remes, Anne; Kälviäinen, Reetta; Peltola, Jukka; Tienari, Pentti; Rinne, Juha; Ziemann, Adam; Waring, Jeffrey; Esmaeeli, Sahar; Smaoui, Nizar; Lehtonen, Anne; Eaton, Susan; Lahdenperä, Sanni; van Adelsberg, Janet; Michon, John; Kerchner, Geoff; Bowers, Natalie; Teng, Edmond; Eicher, John; Mehta, Vinay; Gormley, Padhraig; Linden, Kari; Whelan, Christopher; Xu, Fanli; Pulford, David; Färkkilä, Martti; Pikkarainen, Sampsa; Jussila, Airi; Blomster, Timo; Kiviniemi, Mikko; Voutilainen, Markku; Georgantas, Bob; Heap, Graham; Rahimov, Fedik; Usiskin, Keith; Lu, Tim; Oh, Danny; Kalpala, Kirsi; Miller, Melissa; McCarthy, Linda; Eklund, Kari; Palomäki, Antti; Isomäki, Pia; Pirilä, Laura; Kaipiainen-Seppänen, Oili; Huhtakangas, Johanna; Lertratanakul, Apinya; Hochfeld, Marla; Bing, Nan; Gordillo, Jorge Esparza; Mars, Nina; Pelkonen, Margit; Kauppi, Paula; Kankaanranta, Hannu; Harju, Terttu; Close, David; Greenberg, Steven; Chen, Hubert; Betts, Jo; Ghosh, Soumitra; Salomaa, Veikko; Niiranen, Teemu; Juonala, Markus; Metsärinne, Kaj; Kähönen, Mika; Junttila, Juhani; Laakso, Markku; Pihlajamäki, Jussi; Sinisalo, Juha; Taskinen, Marja-Riitta; Tuomi, Tiinamaija; Challis, Ben; Peterson, Andrew; Chu, Audrey; Parkkinen, Jaakko; Muslin, Anthony; Joensuu, Heikki; Meretoja, Tuomo; Aaltonen, Lauri; Mattson, Johanna; Auranen, Annika; Karihtala, Peeter; Kauppila, Saila; Auvinen, Päivi; Elenius, Klaus; Popovic, Relja; Schutzman, Jennifer; Loboda, Andrey; Chhibber, Aparna; Lehtonen, Heli; McDonough, Stefan; Crohns, Marika; Kulkarni, Diptee; Kaarniranta, Kai; Turunen, Joni A; Ollila, Terhi; Seitsonen, Sanna; Uusitalo, Hannu; Aaltonen, Vesa; Uusitalo-Järvinen, Hannele; Luodonpää, Marja; Hautala, Nina; Loomis, Stephanie; Strauss, Erich; Chen, Hao; Podgornaia, Anna; Hoffman, Joshua; Tasanen, Kaisa; Huilaja, Laura; Hannula-Jouppi, Katariina; Salmi, Teea; Peltonen, Sirkku; Koulu, Leena; Harvima, Ilkka; Wu, Ying; Choy, David; Pussinen, Pirkko; Salminen, Aino; Salo, Tuula; Rice, David; Nieminen, Pekka; Palotie, Ulla; Siponen, Maria; Suominen, Liisa; Mäntylä, Päivi; Gursoy, Ulvi; Anttonen, Vuokko; Sipilä, Kirsi; Davis, Justin Wade; Quarless, Danjuma; Petrovski, Slavé; Wigmore, Eleonor; Chen, Chia-Yen; Bronson, Paola; Tsai, Ellen; Huang, Yunfeng; Maranville, Joseph; Shaikho, Elmutaz; Mohammed, Elhaj; Wadhawan, Samir; Kvikstad, Erika; Caliskan, Minal; Chang, Diana; Bhangale, Tushar; Pendergrass, Sarah; Holzinger, Emily; Chen, Xing; Hedman, Ã…sa; King, Karen S; Wang, Clarence; Xu, Ethan; Auge, Franck; Chatelain, Clement; Rajpal, Deepak; Liu, Dongyu; Call, Katherine; Xia, Tai-He; Brauer, Matt; Kurki, Mitja; Karjalainen, Juha; Havulinna, Aki; Jalanko, Anu; Palta, Priit; Della Briotta Parolo, Pietro; Zhou, Wei; Lemmelä, Susanna; Rivas, Manuel; Harju, Jarmo; Lehisto, Arto; Ganna, Andrea; Llorens, Vincent; Laivuori, Hannele; Rüeger, Sina; Niemi, Mari E; Tukiainen, Taru; Reeve, Mary Pat; Heyne, Henrike; Palin, Kimmo; Garcia-Tabuenca, Javier; Siirtola, Harri; Kiiskinen, Tuomo; Lee, Jiwoo; Tsuo, Kristin; Elliott, Amanda; Kristiansson, Kati; Hyvärinen, Kati; Ritari, Jarmo; Koskinen, Miika; Pylkäs, Katri; Kalaoja, Marita; Karjalainen, Minna; Mantere, Tuomo; Kangasniemi, Eeva; Heikkinen, Sami; Laakkonen, Eija; Sipeky, Csilla; Heron, Samuel; Karlsson, Antti; Jambulingam, Dhanaprakash; Rathinakannan, Venkat Subramaniam; Kajanne, Risto; Aavikko, Mervi; Jiménez, Manuel González; Della Briotta Parola, Pietro; Lehistö, Arto; Kanai, Masahiro; Kaunisto, Mari; Kilpeläinen, Elina; Sipilä, Timo P; Brein, Georg; Awaisa, Ghazal; Shcherban, Anastasia; Donner, Kati; Loukola, Anu; Laiho, Päivi; Sistonen, Tuuli; Kaiharju, Essi; Laukkanen, Markku; Järvensivu, Elina; Lähteenmäki, Sini; Männikkö, Lotta; Wong, Regis; Mattsson, Hannele; Hiekkalinna, Tero; Paajanen, Teemu; Pärn, Kalle; Gracia-Tabuenca, Javier; Abner, Erin; Adams, Perrie M; Aguirre, Alyssa; Albert, Marilyn S; Albin, Roger L; Allen, Mariet; Alvarez, Lisa; Apostolova, Liana G; Arnold, Steven E; Asthana, Sanjay; Atwood, Craig S; Ayres, Gayle; Baldwin, Clinton T; Barber, Robert C; Barnes, Lisa L; Barral, Sandra; Beach, Thomas G; Becker, James T; Beecham, Gary W; Beekly, Duane; Below, Jennifer E; Benchek, Penelope; Benitez, Bruno A; Bennett, David; Bertelson, John; Margaret, Flanagan E; Bird, Thomas D; Blacker, Deborah; Boeve, Bradley F; Bowen, James D; Boxer, Adam; Brewer, James; Burke, James R; Burns, Jeffrey M; Bush, Will S; Buxbaum, Joseph D; Cairns, Nigel J; Cao, Chuanhai; Carlson, Christopher S; Carlsson, Cynthia M; Carney, Regina M; Carrasquillo, Minerva M; Chasse, Scott; Chesselet, Marie-Francoise; Chesi, Alessandra; Chin, Nathaniel A; Chui, Helena C; Chung, Jaeyoon; Craft, Suzanne; Crane, Paul K; Cribbs, David H; Crocco, Elizabeth A; Cruchaga, Carlos; Cuccaro, Michael L; Cullum, Munro; Darby, Eveleen; Davis, Barbara; De Jager, Philip L; DeCarli, Charles; DeToledo, John; Dick, Malcolm; Dickson, Dennis W; Dombroski, Beth A; Doody, Rachelle S; Duara, Ranjan; Ertekin-Taner, Nilüfer; Evans, Denis A; Fairchild, Thomas J; Fallon, Kenneth B; Farlow, Martin R; Farrell, John J; Fernandez-Hernandez, Victoria; Ferris, Steven; Frosch, Matthew P; Fulton-Howard, Brian; Galasko, Douglas R; Gamboa, Adriana; Gearing, Marla; Geschwind, Daniel H; Ghetti, Bernardino; Gilbert, John R; Grabowski, Thomas J; Graff-Radford, Neill R; Grant, Struan F A; Green, Robert C; Growdon, John H; Haines, Jonathan L; Hakonarson, Hakon; Hall, James; Hamilton, Ronald L; Harari, Oscar; Harrell, Lindy E; Haut, Jacob; Head, Elizabeth; Henderson, Victor W; Hernandez, Michelle; Hohman, Timothy; Honig, Lawrence S; Huebinger, Ryan M; Huentelman, Matthew J; Hulette, Christine M; Hyman, Bradley T; Hynan, Linda S; Ibanez, Laura; Jarvik, Gail P; Jayadev, Suman; Jin, Lee-Way; Johnson, Kim; Johnson, Leigh; Kamboh, M Ilyas; Karydas, Anna M; Katz, Mindy J; Kaye, Jeffrey A; Keene, C Dirk; Khaleeq, Aisha; Kim, Ronald; Knebl, Janice; Kowall, Neil W; Kramer, Joel H; Kuksa, Pavel P; LaFerla, Frank M; Lah, James J; Larson, Eric B; Lee, Chien-Yueh; Lee, Edward B; Lerner, Alan; Leung, Yuk Yee; Leverenz, James B; Levey, Allan I; Li, Mingyao; Lieberman, Andrew P; Lipton, Richard B; Logue, Mark; Lyketsos, Constantine G; Malamon, John; Mains, Douglas; Marson, Daniel C; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; Massman, Paul; Masurkar, Arjun; McCormick, Wayne C; McCurry, Susan M; McDavid, Andrew N; McDonough, Stefan; McKee, Ann C; Mesulam, Marsel; Mez, Jesse; Miller, Bruce L; Miller, Carol A; Miller, Joshua W; Montine, Thomas J; Monuki, Edwin S; Morris, John C; Myers, Amanda J; Nguyen, Trung; O'Bryant, Sid; Olichney, John M; Ory, Marcia; Palmer, Raymond; Parisi, Joseph E; Paulson, Henry L; Pavlik, Valory; Paydarfar, David; Perez, Victoria; Peskind, Elaine; Petersen, Ronald C; Phillips-Cremins, Jennifer E; Pierce, Aimee; Polk, Marsha; Poon, Wayne W; Potter, Huntington; Qu, Liming; Quiceno, Mary; Quinn, Joseph F; Raj, Ashok; Raskind, Murray; Reiman, Eric M; Reisberg, Barry; Reisch, Joan S; Ringman, John M; Roberson, Erik D; Rodriguear, Monica; Rogaeva, Ekaterina; Rosen, Howard J; Rosenberg, Roger N; Royall, Donald R; Sager, Mark A; Sano, Mary; Saykin, Andrew J; Schneider, Julie A; Schneider, Lon S; Seeley, William W; Slifer, Susan H; Small, Scott; Smith, Amanda G; Smith, Janet P; Song, Yeunjoo E; Sonnen, Joshua A; Spina, Salvatore; George-Hyslop, Peter St; Stern, Robert A; Stevens, Alan B; Strittmatter, Stephen M; Sultzer, David; Swerdlow, Russell H; Tanzi, Rudolph E; Tilson, Jeffrey L; Trojanowski, John Q; Troncoso, Juan C; Tsuang, Debby W; Valladares, Otto; Van Deerlin, Vivianna M; van Eldik, Linda J; Vassar, Robert; Vinters, Harry V; Vonsattel, Jean-Paul; Weintraub, Sandra; Welsh-Bohmer, Kathleen A; Whitehead, Patrice L; Wijsman, Ellen M; Wilhelmsen, Kirk C; Williams, Benjamin; Williamson, Jennifer; Wilms, Henrik; Wingo, Thomas S; Wisniewski, Thomas; Woltjer, Randall L; Woon, Martin; Wright, Clinton B; Wu, Chuang-Kuo; Younkin, Steven G; Yu, Chang-En; Yu, Lei; Zhang, Yuanchao; Zhao, Yi; Zhu, Xiongwei; Adams, Hieab; Akinyemi, Rufus O; Ali, Muhammad; Armstrong, Nicola; Aparicio, Hugo J; Bahadori, Maryam; Becker, James T; Breteler, Monique; Chasman, Daniel; Chauhan, Ganesh; Comic, Hata; Cox, Simon; Cupples, Adrienne L; Davies, Gail; DeCarli, Charles S; Duperron, Marie-Gabrielle; Dupuis, Josée; Evans, Tavia; Fan, Frank; Fitzpatrick, Annette; Fohner, Alison E; Ganguli, Mary; Geerlings, Mirjam; Glatt, Stephen J; Gonzalez, Hector M; Goss, Monica; Grabe, Hans; Habes, Mohamad; Heckbert, Susan R; Hofer, Edith; Hong, Elliot; Hughes, Timothy; Kautz, Tiffany F; Knol, Maria; Kremen, William; Lacaze, Paul; Lahti, Jari; Grand, Quentin Le; Litkowski, Elizabeth; Li, Shuo; Liu, Dan; Liu, Xuan; Loitfelder, Marisa; Manning, Alisa; Maillard, Pauline; Marioni, Riccardo; Mazoyer, Bernard; van Lent, Debora Melo; Mei, Hao; Mishra, Aniket; Nyquist, Paul; O'Connell, Jeffrey; Patel, Yash; Paus, Tomas; Pausova, Zdenka; Raikkonen-Talvitie, Katri; Riaz, Moeen; Rich, Stephen; Rotter, Jerome; Romero, Jose; Roshchupkin, Gena; Saba, Yasaman; Sargurupremraj, Murali; Schmidt, Helena; Schmidt, Reinhold; Shulman, Joshua M; Smith, Jennifer; Sekhar, Hema; Rajula, Reddy; Shin, Jean; Simino, Jeannette; Sliz, Eeva; Teumer, Alexander; Thomas, Alvin; Tin, Adrienne; Tucker-Drob, Elliot; Vojinovic, Dina; Wang, Yanbing; Weinstein, Galit; Williams, Dylan; Wittfeld, Katharina; Yanek, Lisa; Yang, Yunju
Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.
PMCID:9005347
PMID: 35379992
ISSN: 1546-1718
CID: 5213092
International psychogeriatrics. 2022:1-10.DOI: 10.1017/S1041610222000047

Global cognitive trajectory patterns in Alzheimer's disease

Cohen, Carl I; Reisberg, Barry; Yaffee, Robert
OBJECTIVES/OBJECTIVE:The literature on Alzheimer's disease (AD) provides little data about long-term cognitive course trajectories. We identify global cognitive outcome trajectories and associated predictor variables that may inform clinical research and care. DESIGN/METHODS:Data derived from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set were used to examine the cognitive course of persons with possible or probable AD, a Mini-Mental State Examination (MMSE) of ≥10, and complete annual assessments for 5 years. SETTING/METHODS:Thirty-six Alzheimer's Disease Research Centers. PARTICIPANTS/METHODS:Four hundred and fourteen persons. MEASUREMENTS/METHODS:We used a hybrid approach comprising qualitative analysis of MMSE trajectory graphs that were operationalized empirically and binary logistic regression analyses to assess 19 variables' associations with each trajectory. MMSE scores of ±3 points or greater were considered clinically meaningful. RESULTS:Five distinct cognitive trajectories were identified: fast decliners (32.6%), slow decliners (30.7%), zigzag stable (15.9%), stable (15.9%), and improvers (4.8%). The decliner groups had three subtypes: curvilinear, zigzag, and late decline. The fast decliners were associated with female gender, lower baseline MMSE scores, a shorter illness duration, or receiving a cognitive enhancer. An early MMSE decline of ≥3 points predicted a worse outcome. A higher rate of traumatic brain injury, the absence of an ApoE ϵ4 allele, and male gender were the strongest predictors of favorable outcomes. CONCLUSIONS:Our hybrid approach revealed five distinct cognitive trajectories and a variegated pattern within the decliners and stable/improvers that was more consistent with real-world clinical experience than prior statistically modeled studies. Future investigations need to determine the consistency of the distribution of these categories across settings.
PMID: 35331359
ISSN: 1741-203x
CID: 5200632
Journal of neuropathology & experimental neurology. 2021:80(1):21-44.DOI: 10.1093/jnen/nlaa140

Clinicopathological Staging of Dynamics of Neurodegeneration and Neuronal Loss in Alzheimer Disease

Wegiel, Jerzy; Flory, Michael; Kuchna, Izabela; Nowicki, Krzysztof; Ma, Shuang Yong; Wegiel, Jarek; Badmaev, Eulalia; de Leon, Mony; Wisniewski, Thomas; Reisberg, Barry
Clinical and neuropathological staging of Alzheimer's disease (AD) neurodegeneration and neuronal loss dynamics is the baseline for identification of treatment targets and timing. The aim of this study of 14 brain regions in 25 subjects diagnosed with AD and 13 age-matched control subjects was to establish the pattern of neurodegeneration, and the severity and rate of neuronal loss in mild cognitive impairment/mild AD (Functional Assessment Staging [FAST] test 3-4), moderate to moderately severe AD (FAST 5-6), and severe AD (FAST 7). The study revealed (1) the most severe neuronal loss in FAST 3-4; (2) the highest rate of neuronal loss in FAST 5-6, to the "critical" point limiting further increase in neuronal loss; (3) progression of neurofibrillary degeneration, but decline of neuronal loss to a floor level in FAST 7; and (4) structure-specific rate of neuronal loss caused by neurofibrillary degeneration and a large pool of neuronal loss caused by other mechanisms. This study defines a range and speed of progression of AD pathology and functional decline that might potentially be prevented by the arrest of neuronal loss, both related and unrelated to neurofibrillary degeneration, during the 9-year duration of mild cognitive impairment/mild AD.
PMID: 33270870
ISSN: 1554-6578
CID: 4694342
Dementia geriatric & cognitive disorders. 2020:1-6.DOI: 10.1159/000507286

Psychometric Cognitive Decline Precedes the Advent of Subjective Cognitive Decline in the Evolution of Alzheimer's Disease

Reisberg, Barry; Shao, Yongzhao; Moosavi, Mesum; Kenowsky, Sunnie; Vedvyas, Alok; Marsh, Karyn; Bao, Jia; Buj, Maja; Torossian, Carol; Kluger, Alan; Vedvyas, Gaurav; Oo, Thet; Malik, Fawad; Arain, Fauzia; Masurkar, Arjun V; Wisniewski, Thomas
BACKGROUND:We have described the clinical stages of the brain aging and Alzheimer's disease (AD) continuum. In terms of the pre-dementia stages of AD, we introduced the terminology "mild cognitive impairment" (MCI) for the first pre-dementia stage and "subjective cognitive decline" (SCD) for the pre-MCI stage. We now report the characteristics of a pre-SCD condition eventuating in likely AD. OBJECTIVE:The aim of this study was to characterize a pre-SCD condition eventuating in AD. METHOD/METHODS:Sixty healthy persons with "no cognitive decline" (NCD) were recruited and 47 were followed (mean baseline age, 64.1 ± 8.9 years; mean follow-up time, 6.7 ± 3.1 years). Outcome was determined at the final assessment prior to 2002 as "decliner," if SCD or worse, or "nondecliner" if NCD. RESULTS:After controlling for age, gender, years of education, and follow-up time, there was a between-group difference in the decline rate (p < 0.001). Also, after controlling for demographic variables and follow-up time, the combinatorial psychometric score was lower at baseline in the future decliners (p = 0.035). Of the 9 psychometric variables, after controlling for demographic variables and follow-up time, 3 were significantly lower at baseline in future decliners. Since AD is known to be age related and all subjects in this study were otherwise healthy, we also did an analysis without controlling for age. The combinatorial psychometric score was highly significantly better at baseline in the future nondecliners than in the future decliners (p = 0.008). CONCLUSION/CONCLUSIONS:This is ostensibly the first study to link psychometric cognitive decline to the subsequent SCD stage of eventual AD.
PMID: 32388509
ISSN: 1421-9824
CID: 4428002
Nature genetics. 2019:51(9):1423-1424.DOI: 10.1038/s41588-019-0495-7

Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing

Kunkle, Brian W; Grenier-Boley, Benjamin; Sims, Rebecca; Bis, Joshua C; Damotte, Vincent; Naj, Adam C; Boland, Anne; Vronskaya, Maria; van der Lee, Sven J; Amlie-Wolf, Alexandre; Bellenguez, Céline; Frizatti, Aura; Chouraki, Vincent; Martin, Eden R; Sleegers, Kristel; Badarinarayan, Nandini; Jakobsdottir, Johanna; Hamilton-Nelson, Kara L; Moreno-Grau, Sonia; Olaso, Robert; Raybould, Rachel; Chen, Yuning; Kuzma, Amanda B; Hiltunen, Mikko; Morgan, Taniesha; Ahmad, Shahzad; Vardarajan, Badri N; Epelbaum, Jacques; Hoffmann, Per; Boada, Merce; Beecham, Gary W; Garnier, Jean-Guillaume; Harold, Denise; Fitzpatrick, Annette L; Valladares, Otto; Moutet, Marie-Laure; Gerrish, Amy; Smith, Albert V; Qu, Liming; Bacq, Delphine; Denning, Nicola; Jian, Xueqiu; Zhao, Yi; Del Zompo, Maria; Fox, Nick C; Choi, Seung-Hoan; Mateo, Ignacio; Hughes, Joseph T; Adams, Hieab H; Malamon, John; Sanchez-Garcia, Florentino; Patel, Yogen; Brody, Jennifer A; Dombroski, Beth A; Naranjo, Maria Candida Deniz; Daniilidou, Makrina; Eiriksdottir, Gudny; Mukherjee, Shubhabrata; Wallon, David; Uphill, James; Aspelund, Thor; Cantwell, Laura B; Garzia, Fabienne; Galimberti, Daniela; Hofer, Edith; Butkiewicz, Mariusz; Fin, Bertrand; Scarpini, Elio; Sarnowski, Chloe; Bush, Will S; Meslage, Stéphane; Kornhuber, Johannes; White, Charles C; Song, Yuenjoo; Barber, Robert C; Engelborghs, Sebastiaan; Sordon, Sabrina; Voijnovic, Dina; Adams, Perrie M; Vandenberghe, Rik; Mayhaus, Manuel; Cupples, L Adrienne; Albert, Marilyn S; De Deyn, Peter P; Gu, Wei; Himali, Jayanadra J; Beekly, Duane; Squassina, Alessio; Hartmann, Annette M; Orellana, Adelina; Blacker, Deborah; Rodriguez-Rodriguez, Eloy; Lovestone, Simon; Garcia, Melissa E; Doody, Rachelle S; Munoz-Fernadez, Carmen; Sussams, Rebecca; Lin, Honghuang; Fairchild, Thomas J; Benito, Yolanda A; Holmes, Clive; Karamujić-ÄŒomić, Hata; Frosch, Matthew P; Thonberg, Hakan; Maier, Wolfgang; Roshchupkin, Gennady; Ghetti, Bernardino; Giedraitis, Vilmantas; Kawalia, Amit; Li, Shuo; Huebinger, Ryan M; Kilander, Lena; Moebus, Susanne; Hernández, Isabel; Kamboh, M Ilyas; Brundin, RoseMarie; Turton, James; Yang, Qiong; Katz, Mindy J; Concari, Letizia; Lord, Jenny; Beiser, Alexa S; Keene, C Dirk; Helisalmi, Seppo; Kloszewska, Iwona; Kukull, Walter A; Koivisto, Anne Maria; Lynch, Aoibhinn; Tarraga, Lluís; Larson, Eric B; Haapasalo, Annakaisa; Lawlor, Brian; Mosley, Thomas H; Lipton, Richard B; Solfrizzi, Vincenzo; Gill, Michael; Longstreth, W T; Montine, Thomas J; Frisardi, Vincenza; Diez-Fairen, Monica; Rivadeneira, Fernando; Petersen, Ronald C; Deramecourt, Vincent; Alvarez, Ignacio; Salani, Francesca; Ciaramella, Antonio; Boerwinkle, Eric; Reiman, Eric M; Fievet, Nathalie; Rotter, Jerome I; Reisch, Joan S; Hanon, Olivier; Cupidi, Chiara; Uitterlinden, A G Andre; Royall, Donald R; Dufouil, Carole; Maletta, Raffaele Giovanni; de Rojas, Itziar; Sano, Mary; Brice, Alexis; Cecchetti, Roberta; George-Hyslop, Peter St; Ritchie, Karen; Tsolaki, Magda; Tsuang, Debby W; Dubois, Bruno; Craig, David; Wu, Chuang-Kuo; Soininen, Hilkka; Avramidou, Despoina; Albin, Roger L; Fratiglioni, Laura; Germanou, Antonia; Apostolova, Liana G; Keller, Lina; Koutroumani, Maria; Arnold, Steven E; Panza, Francesco; Gkatzima, Olymbia; Asthana, Sanjay; Hannequin, Didier; Whitehead, Patrice; Atwood, Craig S; Caffarra, Paolo; Hampel, Harald; Quintela, Inés; Carracedo, Ángel; Lannfelt, Lars; Rubinsztein, David C; Barnes, Lisa L; Pasquier, Florence; Frölich, Lutz; Barral, Sandra; McGuinness, Bernadette; Beach, Thomas G; Johnston, Janet A; Becker, James T; Passmore, Peter; Bigio, Eileen H; Schott, Jonathan M; Bird, Thomas D; Warren, Jason D; Boeve, Bradley F; Lupton, Michelle K; Bowen, James D; Proitsi, Petra; Boxer, Adam; Powell, John F; Burke, James R; Kauwe, John S K; Burns, Jeffrey M; Mancuso, Michelangelo; Buxbaum, Joseph D; Bonuccelli, Ubaldo; Cairns, Nigel J; McQuillin, Andrew; Cao, Chuanhai; Livingston, Gill; Carlson, Chris S; Bass, Nicholas J; Carlsson, Cynthia M; Hardy, John; Carney, Regina M; Bras, Jose; Carrasquillo, Minerva M; Guerreiro, Rita; Allen, Mariet; Chui, Helena C; Fisher, Elizabeth; Masullo, Carlo; Crocco, Elizabeth A; DeCarli, Charles; Bisceglio, Gina; Dick, Malcolm; Ma, Li; Duara, Ranjan; Graff-Radford, Neill R; Evans, Denis A; Hodges, Angela; Faber, Kelley M; Scherer, Martin; Fallon, Kenneth B; Riemenschneider, Matthias; Fardo, David W; Heun, Reinhard; Farlow, Martin R; Kölsch, Heike; Ferris, Steven; Leber, Markus; Foroud, Tatiana M; Heuser, Isabella; Galasko, Douglas R; Giegling, Ina; Gearing, Marla; Hüll, Michael; Geschwind, Daniel H; Gilbert, John R; Morris, John; Green, Robert C; Mayo, Kevin; Growdon, John H; Feulner, Thomas; Hamilton, Ronald L; Harrell, Lindy E; Drichel, Dmitriy; Honig, Lawrence S; Cushion, Thomas D; Huentelman, Matthew J; Hollingworth, Paul; Hulette, Christine M; Hyman, Bradley T; Marshall, Rachel; Jarvik, Gail P; Meggy, Alun; Abner, Erin; Menzies, Georgina E; Jin, Lee-Way; Leonenko, Ganna; Real, Luis M; Jun, Gyungah R; Baldwin, Clinton T; Grozeva, Detelina; Karydas, Anna; Russo, Giancarlo; Kaye, Jeffrey A; Kim, Ronald; Jessen, Frank; Kowall, Neil W; Vellas, Bruno; Kramer, Joel H; Vardy, Emma; LaFerla, Frank M; Jöckel, Karl-Heinz; Lah, James J; Dichgans, Martin; Leverenz, James B; Mann, David; Levey, Allan I; Pickering-Brown, Stuart; Lieberman, Andrew P; Klopp, Norman; Lunetta, Kathryn L; Wichmann, H-Erich; Lyketsos, Constantine G; Morgan, Kevin; Marson, Daniel C; Brown, Kristelle; Martiniuk, Frank; Medway, Christopher; Mash, Deborah C; Nöthen, Markus M; Masliah, Eliezer; Hooper, Nigel M; McCormick, Wayne C; Daniele, Antonio; McCurry, Susan M; Bayer, Anthony; McDavid, Andrew N; Gallacher, John; McKee, Ann C; van den Bussche, Hendrik; Mesulam, Marsel; Brayne, Carol; Miller, Bruce L; Riedel-Heller, Steffi; Miller, Carol A; Miller, Joshua W; Al-Chalabi, Ammar; Morris, John C; Shaw, Christopher E; Myers, Amanda J; Wiltfang, Jens; O'Bryant, Sid; Olichney, John M; Alvarez, Victoria; Parisi, Joseph E; Singleton, Andrew B; Paulson, Henry L; Collinge, John; Perry, William R; Mead, Simon; Peskind, Elaine; Cribbs, David H; Rossor, Martin; Pierce, Aimee; Ryan, Natalie S; Poon, Wayne W; Nacmias, Benedetta; Potter, Huntington; Sorbi, Sandro; Quinn, Joseph F; Sacchinelli, Eleonora; Raj, Ashok; Spalletta, Gianfranco; Raskind, Murray; Caltagirone, Carlo; Bossù, Paola; Orfei, Maria Donata; Reisberg, Barry; Clarke, Robert; Reitz, Christiane; Smith, A David; Ringman, John M; Warden, Donald; Roberson, Erik D; Wilcock, Gordon; Rogaeva, Ekaterina; Bruni, Amalia Cecilia; Rosen, Howard J; Gallo, Maura; Rosenberg, Roger N; Ben-Shlomo, Yoav; Sager, Mark A; Mecocci, Patrizia; Saykin, Andrew J; Pastor, Pau; Cuccaro, Michael L; Vance, Jeffery M; Schneider, Julie A; Schneider, Lori S; Slifer, Susan; Seeley, William W; Smith, Amanda G; Sonnen, Joshua A; Spina, Salvatore; Stern, Robert A; Swerdlow, Russell H; Tang, Mitchell; 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; Wilhelmsen, Kirk C; Williamson, Jennifer; Wingo, Thomas S; Woltjer, Randall L; Wright, Clinton B; Yu, Chang-En; Yu, Lei; Saba, Yasaman; Pilotto, Alberto; Bullido, Maria J; Peters, Oliver; Crane, Paul K; Bennett, David; Bosco, Paola; Coto, Eliecer; Boccardi, Virginia; De Jager, Phil L; Lleo, Alberto; Warner, Nick; Lopez, Oscar L; Ingelsson, Martin; Deloukas, Panagiotis; Cruchaga, Carlos; Graff, Caroline; Gwilliam, Rhian; Fornage, Myriam; Goate, Alison M; Sanchez-Juan, Pascual; Kehoe, Patrick G; Amin, Najaf; Ertekin-Taner, Nilifur; Berr, Claudine; Debette, Stéphanie; Love, Seth; Launer, Lenore J; Younkin, Steven G; Dartigues, Jean-Francois; Corcoran, Chris; Ikram, M Arfan; Dickson, Dennis W; Nicolas, Gael; Campion, Dominique; Tschanz, JoAnn; Schmidt, Helena; Hakonarson, Hakon; Clarimon, Jordi; Munger, Ron; Schmidt, Reinhold; Farrer, Lindsay A; Van Broeckhoven, Christine; O'Donovan, Michael C; DeStefano, Anita L; Jones, Lesley; Haines, Jonathan L; Deleuze, Jean-Francois; Owen, Michael J; Gudnason, Vilmundur; Mayeux, Richard; Escott-Price, Valentina; Psaty, Bruce M; Ramirez, Alfredo; Wang, Li-San; Ruiz, Agustin; van Duijn, Cornelia M; Holmans, Peter A; Seshadri, Sudha; Williams, Julie; Amouyel, Phillippe; Schellenberg, Gerard D; Lambert, Jean-Charles; Pericak-Vance, Margaret A
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
PMID: 31417202
ISSN: 1546-1718
CID: 4042762