Citations 18
Associations of lifestyle factors with amyloid pathology in persons without dementia
Oomens, Julie Elisabeth , Vos, Stephanie J. B. , Maserejian, Nancy N., Didic, Mira , Engelborghs, Sebastiaan , Fladby, Tormod, Fröhlich, Lutz, Gill, Kiran Dip, Grimmer, Timo, Itoh, Yoshiaki , Landau, Susan, Lleó, Alberto, Meyer, Philipp T. , Pardini, Matteo , Rami, Lorena , Reiman, Eric M. , Rinne, Juha O. , Sánchez‐Juan, Pascual, Scarmeas, Nikolaos , Villeneuve, Sylvia , Waldemar, Gunhild , Alcolea, Daniel, Altomare, Daniele , Baldeiras, Inês , Blennow, Kaj , Cerman, Jiří , Chipi, Elena , Day, Gregory S. , Förster, Stefan , Frings, Lars , Guedj, Éric , Habeck, Christian , Hausner, Lucrezia , Jiménez‐Bonilla, J., Juaristi, Arantxa, Kern, Silke , Kirsebom, Bjørn‐Eivind , Legdeur, Nienke , Xiong, Chengjie , Maier, W., Marquié, Marta, Minatani, Shinobu, Prabhakar, Sudesh, Ramakers, Inez H.G.B. , Rodríguez‐Rodríguez, Eloy , Ruiz, Agustín, Rüther, E., Sakhardande, Jayant, Selnes, Per, Spiru, Luiza , Vermunt, Lisa , Wallin, Åsa K., Zettergren, Anna , (ADNI), for the Alzheimer's Disease Neuroimaging Initiative, group, A4 Study, (DIAN), Dominantly Inherited Alzheimer Network, (KBASE), Japan Alzheimer's Disease Neuroimaging Initiative (J-ADNI), Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, Ossenkoppele, Rik, Verhey, Frans RJ, Visser, Pieter Jelle, Jansen, Willemijn J, Marquié, Marta , Selnes, Per , Day, Gregory S , Xiong, Chengjie , Oomens, Julie E , Boada, Merçé , Fladby, Tormod , Flier, Wiesje M. van der , Frisoni, Giovanni B. , Fröhlich, Lutz, Grimmer, Timo , Hort, Jakub , Iwatsubo, Takeshi , Klimkowicz‐Mrowiec, Aleksandra , Lee, Dong Young , Lleó, Alberto , Martínez‐Lage, Pablo , Mendonça, Alexandre de , Parchi, Piero , Parnetti, Lucilla , Popp, Julius , Rodrigue, Karen M. , Santana, Isabel , Scheltens, Philip , Skoog, Ingmar , Sperling, Reisa Anne , Stern, Yaakov , Wiltfang, Jens , Zetterberg, Henrik , Alcolea, Daniel , Allegri, Ricardo , Bateman, Randall J. , Baiardi, Simone , Braber, Anouk den , Buchem, Mark A. van , Byun, Min Soo , Chen, Kewei , Drzezga, Alexander E. , Ekblad, Laura L. , Fortea, Juan , Freund‐Levi, Yvonne , Handels, Ron , Hellwig, Sabine , Kandimalla, Ramesh , Kornhuber, Johannes , Morbelli, Silvia , Mroczko, Barbara , Ntanasi, Eva , Oliveira, Catarina Resende , Orellana, Adelina , Peters, Oliver , Ruiz, Agustı́n , Silva, Dina , Soininen, Hilkka S. , Takeda, Akitoshi , Teunissen, Charlotte E. , Tijms, Betty M. , Wiels, Wietse A. , Yannakoulia, Mary , Yi, Dahyun , (ADNI), for the Alzheimer's Disease Neuroimaging Initiative, group, A4 Study, (DIAN), Dominantly Inherited Alzheimer Network, (KBASE), Japan Alzheimer's Disease Neuroimaging Initiative (J-ADNI), Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease, Ossenkoppele, Rik, Verhey, Frans R.J. , Visser, Pieter Jelle , Jansen, Willemijn J.
Journal of Alzheimer’s Disease | November 14, 2025 | Volume: 108 | Issue: 3 | Pages: 1043-1059
Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.
Depressive Symptoms and Amyloid Pathology
Oomens, Julie Elisabeth , Engelborghs, Sebastiaan , Arnim, Christine A. F. Von , Boada, Merçé , Didic, Mira , Dubois, Bruno, Fröhlich, Lutz, Gill, Kiran Dip, Grimmer, Timo, Hildebrandt, Helmut , Itoh, Yoshiaki , Lee, Dong Young , Lleó, Alberto, Meyer, Philipp T. , Kapaki, Elisabeth, Pardini, Matteo , Popp, Julius , Rami, Lorena , Reiman, Eric M. , Rinne, Juha O. , Sánchez‐Juan, Pascual, Sarazin, Marie , Scarmeas, Nikolaos , Villeneuve, Sylvia , Wallin, Anders, Vos, Stephanie J. B. , Jansen, Willemijn J. , group, Amyloid Biomarker Study, Altomare, Daniele , Baldeiras, Inês , Blennow, Kaj, Braber, Anouk den , Cerman, Jiří , Chipi, Elena , Eckerström, Marie , Ekblad, Laura L. , Förster, Stefan , Guedj, Éric , Hausner, Lucrezia , Huey, Edward D. , Jiménez‐Bonilla, J., Johnson, Keith A. , Juaristi, Arantxa, Kern, Silke , Kirsebom, Bjørn‐Eivind , Landau, Susan , Legdeur, Nienke , Guerra, Jorge J. Llibre, Maserejian, Nancy N., Marquié, Marta , Minatani, Shinobu, Olivieri, Pauline , Perrin, Richard J., Peters, Oliver , Prabhakar, Sudesh, Ramakers, Inez H., Rodríguez‐Rodríguez, Eloy , Ruiz, Agustín, Rüther, E., Selnes, Per , Spiru, Luiza , Takeda, Akitoshi , Teichmann, Marc , Thompson, Loisa I., Vogelgsangs, Jonathan, Wallin, Åsa K., Zettergren, Anna , Frisoni, Giovanni B. , Boada, Merce , Oomens, Julie E , Bottlaender, Michel , Wiels, Wietse A. , Baeken, Chris , Dubois, Bruno , Fladby, Tormod , Flier, Wiesje M. van der , Frisoni, Giovanni B. , Fröhlich, Lutz, Grimmer, Timo , Hort, Jakub , Iwatsubo, Takeshi , Klimkowicz‐Mrowiec, Aleksandra , Lleó, Alberto , Martínez‐Lage, Pablo , Mendonça, Alexandre de , Parchi, Piero , Parnetti, Lucilla , Rodrigue, Karen M. , Santana, Isabel , Skoog, Ingmar , Snyder, Peter J. , Sperling, Reisa Anne , Wiltfang, Jens , Zetterberg, Henrik , Ossenkoppele, Rik , Verhey, Frans R.J. , Visser, Pieter Jelle , Alcolea, Daniel , Baiardi, Simone , Bateman, Randall J. , Blennow, Kaj , Buchem, Mark A. van , Byun, Min Soo , Chen, Kewei , Day, Gregory S. , Drzezga, Alexander E. , Epelbaum, Stéphane , Fortea, Juan , Freund‐Levi, Yvonne , Frings, Lars , Hellwig, Sabine , Kandimalla, Ramesh , Paraskevas, George P. , Kornhuber, Johannes , Lagarde, Julien , Morbelli, Silvia , Mroczko, Barbara , Ntanasi, Eva , Oliveira, Catarina Resende , Olivieri, Pauline , Orellana, Adelina , Ruiz, Agustı́n , Silva, Dina , Soininen, Hilkka S. , Tijms, Betty M. , Teunissen, Charlotte E. , Vöglein, Jonathan , Waldemar, Gunhild , Yannakoulia, Mary , Yi, Dahyun
JAMA Psychiatry | January 22, 2025 | Volume: 82 | Issue: 3 | Pages: 296
10.1001/jamapsychiatry.2024.4305
Importance Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. Objective To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. Design, Setting, and Participants Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. Main Outcomes and Measures Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. Results In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. Conclusions and Relevance Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.
Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes
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Corma‐Gómez, Anaïs , Custodero, Carlo , Dalmasso, Carolina , Dardiotis, Efthimios , Deyn, Peter Paul De , Ser, Teodoro del , Denning, Nicola , Diehl‐Schmid, Janine , Díez-Fairén, Mónica , Rossi, Paolo Dionigi , Djurovic, Srdjan , Duron, Emmanuelle , Escott-Price, Valentina, Espinosa, Ana , Ferri, Evelyn , Fischer, Peter A. , Fladby, Tormod , Fortea, Juan , Fostinelli, Silvia , Fox, Nick C. , Frank, Ana , Froelich, Lutz , García-González, Pablo, Ghidoni, Roberta , Giegling, Ina, Grimmer, Timo , Guetta‐Baranes, Tamar , Haapasalo, Annakaisa , Hadjigeorgiou, Georgios M. , Hampel, Harald , Hardy, John, Heneka, Michael T. , Hernández, Isabel, Herrmann, Martin J. , Hoffmann, Per, Holmes, Clive , Kivipelto, Miia , Kornhuber, Johannes , Kosmidis, Mary H. , Laukka, Erika J. , Lauria, Alessandra , Lehtisalo, Jenni , Lleó, Alberto , Munain, Adolfo Lopez de, Macías, Juan, MacLeod, Catherine Anne , Mangialasche, Francesca , Marquié, Marta , Marshall, Iain James , Mead, Simon , Medina, Miguel , Meggy, Alun, Menéndez‐González, Manuel , Moebus, Susanne, Mol, Merel O. , Montrreal, Laura , Morgan, Kevin , Ngandu, Tiia , Olaso, Robert , Orellana, Adelina , Ortega, Gemma , Padovani, Alessandro , Pérez‐Cordón, Alba , Pineda, Juan Antonio , Piñol-Ripoll, Gerard, Pisanu, Claudia , Posthuma, Daniëlle , Priller, Josef , Quintela, Inés , Reinders, Marcel J. T. , Roberto, Natalia , Rongve, Arvid, Rosende‐Roca, Maitée , Rubino, Elisa , Rujescu, Dan, Sáez, María Eugenia , Saltvedt, Ingvild Tina , Sanabria, Ángela , Sánchez-García, Florentino , Scarpini, Elio , Scherbaum, Norbert, Scherer, Martin, Schmid, Matthias C. , Schott, Jonathan M., Selbæk, Geir , Shadrin, Alexey A, Soininen, Hilkka S. , Solfrizzi, Vincenzo, Solomon, Alina , Sorbi, Sandro , Sotolongo‐Grau, Óscar , Tárraga, Lluís , Tesi, Niccoló , Thalamuthu, Anbupalam , Uitterlinden, André G. , Valero, Sergi , Lugt, Aad van der , Rooij, Jeroen van , Vandenberghe, Rik , Vidal, Jean‐Sébastien , Vogelgsang, Jonathan S. , Wagner, Michael , Wallon, David , Weinhold, Leonie , Yannakoulia, Mary , Serpente, María , Assogna, Francesca , Piras, Fabrizio , Piras, Federica, Ferrarese, Carlo , Sala, Gessica , Zoia, C , Benussi, Alberto , Takalo, Mari , Laatikainen, Tiina K. , Tuomi, Tiinamaija , Strandberg, Timo E. , Lindström, Jaana , Peltonen, Markku , Abraham, Richard, Al-Chalabi, Ammar, Bass, Nicholas , Brayne, Carol, Gerrish, Amy, Gill, Michael , Harold, Denise , Lawlor, Brian, Livingston, Gill , Lovestone, Simon , Lupton, Michelle K. , Mann, David , McGuinness, Bernadette , McQuillin, Andrew, O‘Donovan, Michael , Powell, John , Proitsi, Petra, Rossor, Martin, Shaw, Christopher E. , Smith, A. David , Todd, Stephen, Macías‐García, Daniel , Carrillo, F, Vargas, Liliana , Marín, M, Alonso, María Dolores, Gómez-Garre, P, Cañabate, Pilar , Escuela, R, Vigo-Ortega, R, Jesús, Silvia , Vacca, Alessandro , Roveta, Fausto , Boecker, Henning , Perneczky, Robert , Anastasiou, Costas Anastasios , Malik, Rainer , Parveen, Kayenat, Mihova, Kalina Yonkova , Weber, Heike , Kochen, Silvia , Saenz, Aldo, Kohler, Matias, Novack, Gisela Vanina , Tagliavini, Fabrizio , Nielsen, Sune Fallgaard, Fenoglio, Chiara , Biessels, Geert Jan , Love, Seth , Broeckhoven, Christine Van , Rubinsztein, David Chaim , Teipel, Stefan Johannes , Deramecourt, Vincent , Martínez-Larrad, María Teresa, Ghanbari, Mohsen , Mather, Karen A. , Ikram, M. Arfan , Rossi, Giacomina, Andreassen, Ole A., Duijn, Cornelia M. van , Alarcon, E, Buendia, M, Cano, Amanda C. , Anchuelo, Arturo Corbatón , Macı́as, Juan , Maroñas, Olalla , Martín, E, Martínez, MT, Marquié, M, Moreno, M. , Núñez‐Llaves, Raúl , Olivé, C, Puerta, R, Serrano‐Ríos, Manuel , Valero, S, Bernal, M, Carrillo, F, Pancorbo, Marian M. de , Escuela, R, Gómez-Garre, P, Munaín, Adolfo López de , Manzanares, Salvadora , Marín, M, Marquié, M, Martínez, B, Martínez, C, Martínez, V, Álvarez, A Martínez-Lage, Iriarte, M Mendioroz, Tur, J. Pérez, Periñán, María Teresa , Rodrigo, S, Valero, S, Vigo-Ortega, R, Vivancos, L. , Shadrin, Alexey A, Bahrami, Shahram , Rongve, Arvid, Athanasiu, Lavinia, Selnes, Per , Bergh, Sverre , Aarsland, Dag, Andreassen, Ole A., Tzourio, Christophe , Brice, Alexis , Ritchie, Karen , Sims, Rebecca, Gerrish, Amy, Williams, Amy, Meggy, Alun, Nash, William, Castillo-Morales, Atahualpa , Hoffmann, Per, Turton, James , Lord, Jenny , Vardy, Emma , Fisher, Elizabeth , Warren, Jason D. , Schott, Jonathan M., Rossor, Martin, Guerreiro, Rita , Al-Chalabi, Ammar, Bass, Nick, Abraham, Richard, Heun, Reinhard , Todd, Stephen, Proitsi, Petra, Hodges, Angela , Becker, Tim , Lawlor, Brian, McQuillin, Andrew, Hardy, John, Brayne, Carol, Deloukas, Panagiotis, Ben‐Shlomo, Yoav , Hooper, Nigel M. , Pickering‐Brown, Stuart , Warner, Nick, Bayer, Anthony, Singleton, Andrew , Rujescu, Dan, Giegling, Ina, Heuser, Isabella , Drichel, Dmitriy , Nöthen, Markus M. , Riemenschneider, Matthias, Gu, Wei , Scherer, Martin, Moebus, Susanne, Morris, John C. , Owen, Michael J. , Escott-Price, Valentina, Chew, Elaine Guo Yan , Chung, Sun Ju , Chao, Yinxia , Ahmad‐Annuar, Azlina , Chen, Yongping , Jiang, Lulu , Lim, Jia Lun , Liu, Chun‐Feng , Mao, Chengjie , Mok, Vincent , Pei, Zhong , Shang, Huifang , Tan, Ai Huey , Xu, Renshi , Zhang, Bao Rong, Koh, Woon‐Puay , Lim, Shen‐Yang , Khor, Chiea Chuen , Liu, Jianjun
Proceedings of the National Academy of Sciences | August 29, 2023 | Volume: 120 | Issue: 36 | Pages: No page available
Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.
Survey of Protocols for the Manual Segmentation of the Hippocampus: Preparatory Steps Towards a Joint EADC-ADNI Harmonized Protocol
Boccardi, Marina , Ganzola, Rossana , Bocchetta, Martina , Pievani, Michela , Redolfi, Alberto , Bartzokis, George, Camicioli, Richard , Csernansky, John G., Leon, Mony J. de , deToledo‐Morrell, Leyla, Lehéricy, Stéphane , Pantel, Johannes, Pruessner, Jens C. , Watson, Craig, Duchesne, Simon , Jack, Clifford R. , Frisoni, Giovanni B. , Boccardi, Marina , Frisoni, Giovanni B. , Jack, Clifford R , Killiany, Ronald , Soininen, Hilkka S. , Bocchetta, Martina
Journal of Alzheimer's Disease | May 16, 2018 | Volume: 26 | Issue: s3 | Pages: 61-75
Relationship between hippocampal atrophy and neuropathology markers: A 7T MRI validation study of the EADC‐ADNI Harmonized Hippocampal Segmentation Protocol
Apostolova, Liana G. , Zarow, Chris, Biado, Kristina, Hurtz, Sona, Boccardi, Marina , Honarpisheh, Hedieh, Blanken, Anna E., Brook, Jenny , Tung, Spencer, Kraft, Emily, Lo, D.C.W. , Ng, Denise , Alger, Jeffry R. , Vinters, Harry V. , Bocchetta, Martina , Duvernoy, Henri M., Jack, Clifford R. , Frisoni, Giovanni B. , Segmentation, EADC‐ADNI Working Group on the Harmonized Protocol for Manual Hippocampal, Bartzokis, George, Csernansky, John G., deToledo‐Morrell, Leyla, Lehéricy, Stéphane , Malykhin, Nikolai , Pantel, Johannes, Pruessner, Jens C. , Watson, Craig, Boccardi, Marina , Frisoni, Giovanni B. , Somme, Johanne Hatteland , Segmentation, EADC‐ADNI Working Group on the Harmonized Protocol for Manual Hippocampal, Leon, Mony J. de , Killiany, Ronald , Soininen, Hilkka S. , Jack, Clifford R , Bocchetta, Martina
Alzheimer's & Dementia | January 22, 2015 | Volume: 11 | Issue: 2 | Pages: 139-150
AbstractObjectiveThe pathologic validation of European Alzheimer's Disease Consortium Alzheimer’s Disease Neuroimaging Initiative Center Harmonized Hippocampal Segmentation Protocol (HarP).MethodsTemporal lobes of nine Alzheimer's disease (AD) and seven cognitively normal subjects were scanned post‐mortem at 7 Tesla. Hippocampal volumes were obtained with HarP. Six‐micrometer‐thick hippocampal slices were stained for amyloid beta (Aβ), tau, and cresyl violet. Hippocampal subfields were manually traced. Neuronal counts, Aβ, and tau burden for each hippocampal subfield were obtained.ResultsWe found significant correlations between hippocampal volume and Braak and Braak staging (ρ = −0.75, P = .001), tau (ρ = −0.53, P = .034), Aβ burden (ρ = −0.61, P = .012), and neuronal count (ρ = 0.77, P < .001). Exploratory subfield‐wise significant associations were found for Aβ in Cornu Ammonis (CA)1 (ρ = −0.58, P = .019) and subiculum (ρ = −0.75, P = .001), tau in CA2 (ρ = −0.59, P = .016), and CA3 (ρ = −0.5, P = .047), and neuronal count in CA1 (ρ = 0.55, P = .028), CA3 (ρ = 0.65, P = .006), and CA4 (ρ = 0.76, P = .001).ConclusionsThe observed associations provide pathological confirmation of hippocampal morphometry as a valid biomarker for AD and pathologic validation of HarP.
Protective variant for hippocampal atrophy identified by whole exome sequencing
Kim, Sungeun , Risacher, Shannon L. , Shen, Li , Corneveaux, Jason J., Swaminathan, Shanker , Lin, Hai , Inlow, Mark , Siniard, Ashley L., Reiman, Rebecca, Aisen, Paul, Petersen, Ronald , Jack, Clifford R. , Weiner, Michael W. , Baldwin, Clinton T., Lunetta, Kathryn L. , Farrer, Lindsay A. , Furney, Simon J. , Lovestone, Simon , Simmons, Andrew , Mecocci, Patrizia , Vellas, Bruno , Tsolaki, Magda , Kłoszewska, Iwona, McDonald, Brenna C. , Farlow, Martin R. , Study, for the Indiana Memory and Aging, Huentelman, Matthew J. , Saykin, Andrew J. , Initiative, for the Alzheimer's Disease Neuroimaging, Nho, Kwangsik T. , Ramanan, Vijay K. , Liu, Yunlong , Foroud, Tatiana , Green, Robert C. , Soininen, Hilkka S. , Ghetti, Bernardino , Study, for the Indiana Memory and Aging, Initiative, for the Alzheimer's Disease Neuroimaging, Jack, Clifford R , Saykin, Andrew J , Shen, Li , Tsolaki, Magda , Mecocci, Patrizia
Annals of Neurology | January 5, 2015 | Volume: 77 | Issue: 3 | Pages: 547-552
We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552
Convergent genetic and expression data implicate immunity in Alzheimer's disease
Jones, Lesley , Lambert, Jean‐Charles , Choi, Seung‐Hoan, Harold, Denise , Vedernikov, Alexey , Escott‐Price, Valentina , Stone, Timothy, Richards, Alexander , Bellenguez, Céline , Sims, Rebecca , DeStefano, Anita L. , Bis, Joshua C. , Beecham, Gary W. , Grenier‐Boley, Benjamin , Russo, Giancarlo , Thornton‐Wells, Tricia A., Jones, Nicola, Smith, Albert V. , Thomas, Charlene , Zélénika, Diana, Kamatani, Yoichiro, Lin, Chiao‐Feng , Schmidt, Helena , Kunkle, Brian W. , Dunstan, Melanie , Ruiz, Agustı́n , Bihoreau, Marie‐Thérèse, Reitz, Christiane, Hollingworth, Paul, Hanon, Olivier , Fitzpatrick, Annette L., Buxbaum, Joseph D. , Campion, Dominique , Crane, Paul K. , Guðnason, Vilmundur , Cruchaga, Carlos , Craig, David W. , Amin, Najaf , Jager, Philip L. De , Deramecourt, Vincent , Johnston, Janet, Evans, Denis A., Lovestone, Simon , Letteneur, Luc, Kornhuber, Johanes, Tárraga, Lluís , Eiriksdottir, Gudny, Goate, Alison , Fiévet, Nathalie, Huentelman, Matthew J. , Gill, Michael , Emilsson, Valur , Brown, Kristelle, Kamboh, M. Ilyas , Keller, Lina, Barberger‐Gateau, Pascale, McGuinness, Bernadette , Larson, Eric B., Dufouil, Carole , Todd, Stephen , Wallon, David , Kehoe, Patrick G. , George‐Hyslop, Peter St , Lleὀ, Alberti, Bayer, Anthony, Tsuang, Debby W. , Yu, Lei, Tsolaki, Magda , Bossù, Paola , Spalletta, Gianfranco , Proitsi, Petra, Collinge, John, Sorbi, Sandro , Hardy, John , Naranjo, María Cándida Déniz, Razquín, Cristina , Bosco, Paola , Clarke, Robert , Brayne, Carol , Galimberti, Daniela , CFAS, MRC, Moebus, Susanne , Mecocci, Patrizia , Zompo, Maria Del, Maier, Wolfgang, Hampel, Harald , Pilotto, Alberto, Bullido, María J. , Panza, Francesco , Caffarra, Paolo , Nacmias, Benedetta , Gilbert, John R., Mayhaus, Manuel, Jessen, Frank , Dichgans, Martin , Lannfelt, Lars , Håkonarson, Håkon , Pichler, Sabrina, Carrasquillo, Minerva M., Beekly, Duane, Alavarez, Victoria, Zou, Fanggeng, Younkin, Steven G., Hamilton‐Nelson, Kara L., Mateo, Ignacio, Faber, Kelley M., Jónsson, Pálmi V. , Combarros, Onofre, O‘Donovan, Michael , Cantwell, Laura B., Blacker, Deborah , Mead, Simon , Harris, Tamara B., Fratiglioni, Laura , Bruijn, Renée F.A.G. de, Passmore, Peter , Montine, Thomas J. , Bettens, Karolien, Rotter, Jerome I. , Brice, Alexis , Morgan, Kevin , Foroud, Tatiana, Kukull, Walter A. , Hannequin, Didier , Powell, John , Nalls, Michael A., Ritchie, Karen , Lunetta, Kathryn L. , Kauwe, John S.K., Boerwinkle, Eric , Riemenschneider, Matthias, Boada, Merçé , Hiltunen, Mikko , Martin, Eden R. , Pástor, Pau , Schmidt, Reinhold, Dartigues, Jean‐François, Mayeux, Richard , Tzourio, Christophe , Hofman, Albert , Nöthen, Markus M. , Graff, Caroline , Haines, Jonathan L. , Lathrop, Mark, Pericak‐Vance, Margaret A. , Launer, Lenore J. , Farrer, Lindsay A. , Duijn, Cornelia M. van , Broeckhoven, Christine Van , Ramı́rez, Alfredo , Schellenberg, Gerard D., Seshadri, Sudha , Amouyel, Philippe , Williams, Julie , Holmans, Peter , Bennett, David A. , Proitsi, Petroula , Ballantyne, Christie M. , Denning, Nicola , Wang, Weixin , Ibrahim‐Verbaas, Carla A. , Naj, Adam Christian , Gerrish, Amy , Jun, Gyungah , Chouraki, Vincent Antoine , Ikram, M. Arfan , Vardarajan, Badri Narayan , Kamatani, Yoichiro, Pasquier, Florence , Becker, Tim , Cruchaga, Carlos , Berr, Claudine , López, Oscar L. , Rubinsztein, David Chaim , Sleegers, Kristel , Myers, Amanda , Love, Seth , Rogaeva, Ekaterina A. , Gallacher, John , Clarimón, Jordi , Bayer, Anthony, Proitsi, Petra, Sánchez-García, Florentino , Fox, Nick C. , Mancuso, Michelangelo , CFAS, MRC, Carrasquillo, Minerva M. , Ingelsson, Martin , Valladares, Otto , Coto, Eliécer , Hamilton‐Nelson, Kara L. , Owen, Michael J. , Soininen, Hilkka S. , Mosley, Thomas H. , Bennett, David , Holmes, Clive , Riemenschneider, Matthias, Rujescu, Dan , Psaty, Bruce M. , Bennett, David A. , Dichgans, Martin , Ramirez, Alfredo , Hakonarson, Hakon , Nöthen, Markus M , Seshadri, Sudha , Hardy, John , Amouyel, Philippe , Tzourio, Christophe , van Duijn, Cornelia M , Smith, Albert V , Ballantyne, Christie M , Rotter, Jerome I , Moebus, Susanne , Ruiz, Agustín , Pastor, Pau , Boada, Merce , Tsolaki, Magda , Brice, Alexis , Goate, Alison M , Galimberti, Daniela , Escott-Price, Valentina , Mecocci, Patrizia , Nacmias, Benedetta , Graff, Caroline , Riemenschneider, Markus J.
Alzheimer's & Dementia | December 20, 2014 | Volume: 11 | Issue: 6 | Pages: 658-671
AbstractBackgroundLate‐onset Alzheimer's disease (AD) is heritable with 20 genes showing genome‐wide association in the International Genomics of Alzheimer's Project (IGAP). To identify the biology underlying the disease, we extended these genetic data in a pathway analysis.MethodsThe ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain.ResultsALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 × 10−12 after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 × 10−11), cholesterol transport (P = 2.96 × 10−9), and proteasome‐ubiquitin activity (P = 1.34 × 10−6). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002–.05).ConclusionsThe immune response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics.
The EADC‐ADNI Harmonized Protocol for manual hippocampal segmentation on magnetic resonance: Evidence of validity
Frisoni, Giovanni B. , Jack, Clifford R. , Bocchetta, Martina , Frederiksen, Kristian Steen , Liu, Yawu , Preboske, Gregory M., Swihart, Tim, Blair, Melanie , Cavedo, Enrica , Grothe, Michel J. , Lanfredi, Mariangela , Martinez, Oliver, Nishikawa, Masami, Portegies, Marileen, Stoub, Travis , Ward, Chadwich, Apostolova, Liana G. , Ganzola, Rossana , Barkhof, Frederik , Bartzokis, George, DeCarli, Charles , Csernansky, John G., deToledo‐Morrell, Leyla, Geerlings, Mirjam I. , Lehéricy, Stéphane , O’Brien, John T. , Silbert, Lisa C. , Scheltens, Philip , Waldemar, Gunhild, Fellgiebel, Andreas , Barnes, Josephine , Gerritsen, Lotte , Henneman, Wouter J.P., Malykhin, Nikolai , Pruessner, Jens C. , Watson, Craig, Leon, Mony J. de , Pantel, Johannes, Ferrari, Clarissa , Bosco, Paolo , Pasqualetti, Patrizio , Duchesne, Simon , Duvernoy, Henri M., Boccardi, Marina , Initiative, EADC‐ADNI Working Group on The Harmonized Protocol for Manual Hippocampal Volumetry and for the Alzheimer's Disease Neuroimaging, Albert, Marilyn S. , Bennet, David, Camicioli, Richard , Collins, D. Louis , Dubois, Bruno , Hampel, Harald , denHeijer, Tom, Hock, Christofer, Jagust, William J. , Launer, Leonore J., Maller, Jerome J. , Mueller, S. G., Sachdev, Perminder S. , Simmons, Andy, Visser, Peter‐Jelle, Wahlund, Lars‐Olof , Weiner, Michael W. , Winblad, Bengt , Boccardi, Marina , Frisoni, Giovanni B. , DeCarli, Charles , Preboske, Gregory, Bauer, Corinna M. , Wolf, Dominik Georg Friedrich , Kaye, Jeffrey , Killiany, Ronald , Matsuda, Hiroshi , O'Brien, John Tiernan , Soininen, Hilkka S. , Teipel, Stefan Johannes , Waldemar, Gunhild , Firbank, Michael John , Wang, Lei , Wolf, Henrike , Initiative, EADC‐ADNI Working Group on The Harmonized Protocol for Manual Hippocampal Volumetry and for the Alzheimer's Disease Neuroimaging, Thompson, Paul M. , Jack, Clifford R , Sachdev, Perminder S , Barkhof, Frederik , Scheltens, Philip , Wahlund, Lars-Olof , Grothe, Michel J , Bocchetta, Martina , Stoub, Travis
Alzheimer's & Dementia | September 27, 2014 | Volume: 11 | Issue: 2 | Pages: 111-125
Abstract Background An international Delphi panel has defined a harmonized protocol (HarP) for the manual segmentation of the hippocampus on MR. The aim of this study is to study the concurrent validity of the HarP toward local protocols, and its major sources of variance. Methods Fourteen tracers segmented 10 Alzheimer's Disease Neuroimaging Initiative (ADNI) cases scanned at 1.5 T and 3T following local protocols, qualified for segmentation based on the HarP through a standard web‐platform and resegmented following the HarP. The five most accurate tracers followed the HarP to segment 15 ADNI cases acquired at three time points on both 1.5 T and 3T. Results The agreement among tracers was relatively low with the local protocols (absolute left/right ICC 0.44/0.43) and much higher with the HarP (absolute left/right ICC 0.88/0.89). On the larger set of 15 cases, the HarP agreement within (left/right ICC range: 0.94/0.95 to 0.99/0.99) and among tracers (left/right ICC range: 0.89/0.90) was very high. The volume variance due to different tracers was 0.9% of the total, comparing favorably to variance due to scanner manufacturer (1.2), atrophy rates (3.5), hemispheric asymmetry (3.7), field strength (4.4), and significantly smaller than the variance due to atrophy (33.5%, P < .001), and physiological variability (49.2%, P < .001). Conclusions The HarP has high measurement stability compared with local segmentation protocols, and good reproducibility within and among human tracers. Hippocampi segmented with the HarP can be used as a reference for the qualification of human tracers and automated segmentation algorithms.
Harmonized benchmark labels of the hippocampus on magnetic resonance: The EADC‐ADNI project
Bocchetta, Martina , Boccardi, Marina , Ganzola, Rossana , Apostolova, Liana G. , Preboske, Gregory M., Ferrari, Clarissa , Pasqualetti, Patrizio , Robitaille, Nicolas , Duchesne, Simon , Jack, Clifford R. , Frisoni, Giovanni B. , Initiative, EADC‐ADNI Working Group on The Harmonized Protocol for Manual Hippocampal Segmentation and for the Alzheimer's Disease Neuroimaging, Bartzokis, George, deToledo‐Morrell, Leyla, Fellgiebel, Andreas , Gerritsen, Lotte , Henneman, Wouter J.P., Malykhin, Nikolai , Pruessner, Jens C. , Watson, Craig, Boccardi, Marina , Frisoni, Giovanni B. , Preboske, Gregory, Wolf, Dominik Georg Friedrich , Initiative, EADC‐ADNI Working Group on The Harmonized Protocol for Manual Hippocampal Segmentation and for the Alzheimer's Disease Neuroimaging, DeCarli, Charles , Firbank, Michael John , Killiany, Ronald , Soininen, Hilkka S. , Wang, Lei , Wolf, Henrike , Jack, Clifford R , Bocchetta, Martina
Alzheimer's & Dementia | September 13, 2014 | Volume: 11 | Issue: 2 | Pages: 151
AbstractBackgroundA globally harmonized protocol (HarP) for manual hippocampal segmentation based on magnetic resonance has been recently developed by a task force from European Alzheimer's Disease Consortium (EADC) and Alzheimer's Disease Neuroimaging Initiative (ADNI). Our aim was to produce benchmark labels based on the HarP for manual segmentation.MethodsFive experts of manual hippocampal segmentation underwent specific training on the HarP and segmented 40 right and left hippocampi from 10 ADNI subjects on both 1.5 T and 3 T scans. An independent expert visually checked segmentations for compliance with the HarP. Descriptive measures of agreement between tracers were intraclass correlation coefficients (ICCs) of crude volumes and similarity coefficients of three‐dimensional volumes.ResultsTwo hundred labels have been provided for the 20 magnetic resonance images. Intra‐ and interrater ICCs were >0.94, and mean similarity coefficients were 1.5 T, 0.73 (95% confidence interval [CI], 0.71–0.75); 3 T, 0.75 (95% CI, 0.74–0.76).ConclusionCertified benchmark labels have been produced based on the HarP to be used for tracers' training and qualification.
Delphi definition of the EADC‐ADNI Harmonized Protocol for hippocampal segmentation on magnetic resonance
Boccardi, Marina , Bocchetta, Martina , Apostolova, Liana G. , Barnes, Josephine , Bartzokis, George, Corbetta, Gabriele , DeCarli, Charles , deToledo‐Morrell, Leyla, Ganzola, Rossana , Gerritsen, Lotte , Henneman, Wouter J.P., Malykhin, Nikolai , Pasqualetti, Patrizio , Pruessner, Jens C. , Redolfi, Alberto , Robitaille, Nicolas , Tolomeo, Daniele , Watson, Craig, Duvernoy, Henri M., Duchesne, Simon , Jack, Clifford R. , Frisoni, Giovanni B. , Segmentation, EADC‐ADNI Working Group on the Harmonized Protocol for Manual Hippocampal, Boccardi, Marina , Frisoni, Giovanni B. , DeCarli, Charles , Firbank, Michael John , Killiany, Ronald , Soininen, Hilkka S. , Wang, Lei , Wolf, Henrike , Segmentation, EADC‐ADNI Working Group on the Harmonized Protocol for Manual Hippocampal, Jack, Clifford R , Bocchetta, Martina
Alzheimer's & Dementia | August 15, 2014 | Volume: 11 | Issue: 2 | Pages: 126-138
Abstract Background This study aimed to have international experts converge on a harmonized definition of whole hippocampus boundaries and segmentation procedures, to define standard operating procedures for magnetic resonance (MR)‐based manual hippocampal segmentation. Methods The panel received a questionnaire regarding whole hippocampus boundaries and segmentation procedures. Quantitative information was supplied to allow evidence‐based answers. A recursive and anonymous Delphi procedure was used to achieve convergence. Significance of agreement among panelists was assessed by exact probability on Fisher's and binomial tests. Results Agreement was significant on the inclusion of alveus/fimbria ( P = .021), whole hippocampal tail ( P = .013), medial border of the body according to visible morphology ( P = .0006), and on this combined set of features ( P = .001). This definition captures 100% of hippocampal tissue, 100% of Alzheimer’s disease‐related atrophy, and demonstrated good reliability on preliminary intrarater (0.98) and inter‐rater (0.94) estimates. Discussion Consensus was achieved among international experts with respect to hippocampal segmentation using MR resulting in a harmonized segmentation protocol.