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1. Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia

Author

Jansen, Willemijn J, Ossenkoppele, Rik, Tijms, Betty M, Fagan, Anne M, Hansson, Oskar, Klunk, William E, van der Flier, Wiesje M, Villemagne, Victor L, Frisoni, Giovanni B, Fleisher, Adam S, Lleó, Alberto, Mintun, Mark A, Wallin, Anders, Engelborghs, Sebastiaan, Na, Duk L, Chételat, Gäel, Molinuevo, José Luis, Landau, Susan M, Mattsson, Niklas, Kornhuber, Johannes, Sabri, Osama, Rowe, Christopher C, Parnetti, Lucilla, Popp, Julius, Fladby, Tormod, Jagust, William J, Aalten, Pauline, Lee, Dong Young, Vandenberghe, Rik, de Oliveira, Catarina Resende, Kapaki, Elisabeth, Froelich, Lutz, Ivanoiu, Adrian, Gabryelewicz, Tomasz, Verbeek, Marcel M, Sanchez-Juan, Páscual, Hildebrandt, Helmut, Camus, Vincent, Zboch, Marzena, Brooks, David J, Drzezga, Alexander, Rinne, Juha O, Newberg, Andrew, de Mendonça, Alexandre, Sarazin, Marie, Rabinovici, Gil D, Madsen, Karine, Kramberger, Milica G, Nordberg, Agneta, Mok, Vincent, Mroczko, Barbara, Wolk, David A, Meyer, Philipp T, Tsolaki, Magda, Scheltens, Philip, Verhey, Frans RJ, Visser, Pieter Jelle, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart NM, Blennow, Kaj, van Buchem, Mark A, Cavedo, Enrica, Chen, Kewei, Chipi, Elena, Cohen, Ann D, Förster, Stefan, Fortea, Juan, Frederiksen, Kristian S, Freund-Levi, Yvonne, Gkatzima, Olymbia, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Johannsen, Peter, Klimkowicz-Mrowiec, Aleksandra, Köhler, Sebastian, Koglin, Norman, van Laere, Koen, de Leon, Mony, Lisetti, Viviana, Maier, Wolfgang, Marcusson, Jan, Meulenbroek, Olga, Møllergård, Hanne M, Morris, John C, Nordlund, Arto, Novak, Gerald P, Paraskevas, George P, Perera, Gayan, Peters, Oliver, and Ramakers, Inez HGB

Subjects
Health Services and Systems, Health Sciences, Acquired Cognitive Impairment, Alzheimer's Disease Related Dementias (ADRD), Neurosciences, Aging, Dementia, Brain Disorders, Behavioral and Social Science, Neurodegenerative, Alzheimer's Disease, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Clinical Research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Mental health, Aged, Alzheimer Disease, Amyloid beta-Peptides, Brain, Cognition Disorders, Cognitive Dysfunction, Cross-Sectional Studies, Female, Humans, Male, Memory, Episodic, Mental Status and Dementia Tests, Middle Aged, Positron-Emission Tomography, Reference Values, Amyloid Biomarker Study Group, Other Medical and Health Sciences, Psychology, Cognitive Sciences, Clinical sciences, Clinical and health psychology
Abstract

ImportanceCerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.ObjectiveTo investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.Design, setting, and participantsThis cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Main outcomes and measuresGlobal cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.ResultsAmong 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P

Published
2018

2. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia: A Meta-analysis

Author

Jansen, Willemijn J, Ossenkoppele, Rik, Knol, Dirk L, Tijms, Betty M, Scheltens, Philip, Verhey, Frans RJ, Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart NM, Bibeau, Kristen, Blennow, Kaj, Brooks, David J, van Buchem, Mark A, Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D, Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M, Fladby, Tormod, Fleisher, Adam S, van der Flier, Wiesje M, Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S, Freund-Levi, Yvonne, Frisoni, Giovanni B, Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Hildebrandt, Helmut, Ishihara, Lianna, Ivanoiu, Adrian, Jagust, William J, Johannsen, Peter, Kandimalla, Ramesh, Kapaki, Elisabeth, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E, Köhler, Sebastian, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G, Van Laere, Koen, Landau, Susan M, Lee, Dong Young, de Leon, Mony, Lisetti, Viviana, Lleó, Alberto, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Mattsson, Niklas, de Mendonça, Alexandre, Meulenbroek, Olga, Meyer, Philipp T, Mintun, Mark A, Mok, Vincent, Molinuevo, José Luis, Møllergård, Hanne M, Morris, John C, Mroczko, Barbara, Van der Mussele, Stefan, Na, Duk L, Newberg, Andrew, Nordberg, Agneta, Nordlund, Arto, Novak, Gerald P, Paraskevas, George P, Parnetti, Lucilla, Perera, Gayan, Peters, Oliver, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D, Ramakers, Inez HGB, Rami, Lorena, de Oliveira, Catarina Resende, Rinne, Juha O, Rodrigue, Karen M, and Rodríguez-Rodríguez, Eloy

Subjects
Health Services and Systems, Health Sciences, Clinical Research, Alzheimer's Disease, Vascular Cognitive Impairment/Dementia, Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease Related Dementias (ADRD), Brain Disorders, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Cerebrovascular, Neurodegenerative, Prevention, Dementia, Aging, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Aetiology, 2.1 Biological and endogenous factors, Neurological, Adult, Age Factors, Aged, Aged, 80 and over, Amyloid beta-Peptides, Apolipoprotein E4, Biomarkers, Brain, Cerebrospinal Fluid, Cognitive Dysfunction, Female, Genotype, Humans, Male, Middle Aged, Positron-Emission Tomography, Prevalence, Risk Factors, Amyloid Biomarker Study Group, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract

ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Published
2015

3. Prevalence of the apolipoprotein E ε4 allele in amyloid β positive subjects across the spectrum of Alzheimer's disease

Author

Mattsson, Niklas, Groot, Colin, Jansen, Willemijn J., Landau, Susan M., Villemagne, Victor L., Engelborghs, Sebastiaan, Mintun, Mark M., Lleo, Alberto, Molinuevo, José Luis, Jagust, William J., Frisoni, Giovanni B., Ivanoiu, Adrian, Chételat, Gaël, Resende de Oliveira, Catarina, Rodrigue, Karen M., Kornhuber, Johannes, Wallin, Anders, Klimkowicz-Mrowiec, Aleksandra, Kandimalla, Ramesh, Popp, Julius, Aalten, Pauline P., Aarsland, Dag, Alcolea, Daniel, Almdahl, Ina S., Baldeiras, Inês, van Buchem, Mark A., Cavedo, Enrica, Chen, Kewei, Cohen, Ann D., Förster, Stefan, Fortea, Juan, Frederiksen, Kristian S., Freund-Levi, Yvonne, Gill, Kiran Dip, Gkatzima, Olymbia, Grimmer, Timo, Hampel, Harald, Herukka, Sanna-Kaisa, Johannsen, Peter, van Laere, Koen, de Leon, Mony J., Maier, Wolfgang, Marcusson, Jan, Meulenbroek, Olga, Møllergård, Hanne M., Morris, John C., Mroczko, Barbara, Nordlund, Arto, Prabhakar, Sudesh, Peters, Oliver, Rami, Lorena, Rodríguez-Rodríguez, Eloy, Roe, Catherine M., Rüther, Eckart, Santana, Isabel, Schröder, Johannes, Seo, Sang W., Soininen, Hilkka, Spiru, Luiza, Stomrud, Erik, Struyfs, Hanne, Teunissen, Charlotte E., Verhey, Frans R.J., Vos, Stephanie J.B., van Waalwijk van Doorn, Linda J.C., Waldemar, Gunhild, Wallin, Åsa K., Wiltfang, Jens, Vandenberghe, Rik, Brooks, David J., Fladby, Tormod, Rowe, Christopher C., Drzezga, Alexander, Verbeek, Marcel M., Sarazin, Marie, Wolk, David A., Fleisher, Adam S., Klunk, William E., Na, Duk L., Sánchez-Juan, Pascual, Lee, Dong Young, Nordberg, Agneta, Tsolaki, Magda, Camus, Vincent, Rinne, Juha O., Fagan, Anne M., Zetterberg, Henrik, Blennow, Kaj, Rabinovici, Gil D., Hansson, Oskar, van Berckel, Bart N.M., van der Flier, Wiesje M., Scheltens, Philip, Visser, Pieter Jelle, and Ossenkoppele, Rik

Published
2018
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4. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Author

Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle

Published
2019
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5. Medial Temporal Lobe Atrophy in Predementia Alzheimer’s Disease: A Longitudinal Multi-Site Study Comparing Staging and A/T/N in a Clinical Research Cohort1

Author

Jarholm, Jonas Alexander, primary, Bjørnerud, Atle, additional, Dalaker, Turi Olene, additional, Akhavi, Mehdi Sadat, additional, Kirsebom, Bjørn Eivind, additional, Pålhaugen, Lene, additional, Nordengen, Kaja, additional, Grøntvedt, Gøril Rolfseng, additional, Nakling, Arne, additional, Kalheim, Lisa F., additional, Almdahl, Ina S., additional, Tecelão, Sandra, additional, Fladby, Tormod, additional, and Selnes, Per, additional

Published
2023
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7. GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Author

Rongve, Arvid, Witoelar, Aree, Ruiz, Agustín, Athanasiu, Lavinia, Abdelnour, Carla, Clarimon, Jordi, Heilmann-Heimbach, Stefanie, Hernández, Isabel, Moreno-Grau, Sonia, de Rojas, Itziar, Morenas-Rodríguez, Estrella, Fladby, Tormod, Sando, Sigrid B., Bråthen, Geir, Blanc, Frédéric, Bousiges, Olivier, Lemstra, Afina W., van Steenoven, Inger, Londos, Elisabet, Almdahl, Ina S., Pålhaugen, Lene, Eriksen, Jon A., Djurovic, Srdjan, Stordal, Eystein, Saltvedt, Ingvild, Ulstein, Ingun D., Bettella, Francesco, Desikan, Rahul S., Idland, Ane-Victoria, Toft, Mathias, Pihlstrøm, Lasse, Snaedal, Jon, Tárraga, Lluís, Boada, Mercè, Lleó, Alberto, Stefánsson, Hreinn, Stefánsson, Kári, Ramírez, Alfredo, Aarsland, Dag, and Andreassen, Ole A.

Published
2019
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8. Meta-analysis of Alzheimer’s disease on 9,751 samples from Norway and IGAP study identifies four risk loci

Author

Witoelar, Aree, Rongve, Arvid, Almdahl, Ina S., Ulstein, Ingun D., Engvig, Andreas, White, Linda R., Selbæk, Geir, Stordal, Eystein, Andersen, Fred, Brækhus, Anne, Saltvedt, Ingvild, Engedal, Knut, Hughes, Timothy, Bergh, Sverre, Bråthen, Geir, Bogdanovic, Nenad, Bettella, Francesco, Wang, Yunpeng, Athanasiu, Lavinia, Bahrami, Shahram, Le Hellard, Stephanie, Giddaluru, Sudheer, Dale, Anders M., Sando, Sigrid B., Steinberg, Stacy, Stefansson, Hreinn, Snaedal, Jon, Desikan, Rahul S., Stefansson, Kari, Aarsland, Dag, Djurovic, Srdjan, Fladby, Tormod, and Andreassen, Ole A.

Published
2018
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9. Author Correction: Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Author

Jansen, Iris E., Savage, Jeanne E., Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M., Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K., Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S., Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S., Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J., Jonsson, Palmi V., Kiddle, Steven J., Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B., Selbæk, Geir, Shoai, Maryam, Skene, Nathan G., Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D., Wang, Yunpeng, White, Linda R., Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F., van der Flier, Wiesje M., Dobson, Richard, Davis, Lea K., Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L., Ripke, Stephan, Andreassen, Ole A., and Posthuma, Danielle

Published
2020
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12. sj-pdf-1-jcb-10.1177_0271678X20957604 - Supplemental material for Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns

Author

Pålhaugen, Lene, Sudre, Carole H, Tecelao, Sandra, Nakling, Arne, Almdahl, Ina S, Kalheim, Lisa F, M Jorge Cardoso, Johnsen, Stein H, Rongve, Arvid, Aarsland, Dag, Bjørnerud, Atle, Selnes, Per, and Fladby, Tormod

Subjects
110320 Radiology and Organ Imaging, FOS: Clinical medicine, FOS: Biological sciences, Medicine, Cell Biology, 110305 Emergency Medicine, 110306 Endocrinology, Biochemistry, 69999 Biological Sciences not elsewhere classified, 110904 Neurology and Neuromuscular Diseases, Neuroscience
Abstract

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X20957604 for Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns by Lene Pålhaugen, Carole H Sudre, Sandra Tecelao, Arne Nakling, Ina S Almdahl, Lisa F Kalheim, M Jorge Cardoso, Stein H Johnsen, Arvid Rongve, Dag Aarsland, Atle Bjørnerud, Per Selnes and Tormod Fladby in Journal of Cerebral Blood Flow & Metabolism

Published
2020
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13. Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study (Scientific Reports, (2019), 9, 1, (7013), 10.1038/s41598-019-43458-2)

Author

Rongve, Arvid, Witoelar, Aree, Ruiz, Agustín, Athanasiu, Lavinia, Abdelnour, Carla, Clarimon, Jordi, Heilmann-Heimbach, Stefanie, Hernández, Isabel, Moreno-Grau, Sonia, de Rojas, Itziar, Morenas-Rodríguez, Estrella, Fladby, Tormod, Sando, Sigrid B., Bråthen, Geir, Blanc, Frédéric, Bousiges, Olivier, Lemstra, Afina W., van Steenoven, Inger, Londos, Elisabet, Almdahl, Ina S., Pålhaugen, Lene, Eriksen, Jon A., Djurovic, Srdjan, Stordal, Eystein, Saltvedt, Ingvild, Ulstein, Ingun D., Bettella, Francesco, Desikan, Rahul S., Idland, Ane-Victoria, Toft, Mathias, Pihlstrøm, Lasse, Snaedal, Jon, Tárraga, Lluís, Boada, Mercè, Lleó, Alberto, Stefánsson, Hreinn, Stefánsson, K. ri, Ramírez, Alfredo, Aarsland, Dag, and Andreassen, Ole A.

Abstract

“The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results.” should read: “The authors would like to thank the Norwegian Dementia Genetics Network (DemGene), the European DLB Consortium (E-DLB), Dementia Genetics Spanish Consortium (DEGESCO) and Genomic Research at Fundació ACE (GR@ACE) Consortium. Fundació ACE would like to thank patients and controls who participated in this project. We are indebted to private donors for their support of Fundació ACE research programs. Fundació ACE collaborates with the Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, Spain) and is one of the participating centers of the Dementia Genetics Spanish Consortium (DEGESCO). The study was founded by the Research Council of Norway, Norwegian Regional Health Authorities and Norwegian Health Association and 237250/EU/JPND (APGeM). The Cohort 2 results were generated with the assistance of financial support of grants PI13/02434 and PI16/01861. Acción Estratégica en Salud, integrated in the Spanish National R + D + I Plan and financed by ISCIII (Instituto de Salud Carlos III)-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional (FEDER- “Una manera de Hacer Europa”). GR@ACE project has been funded by Fundación bancaria “La Caixa”, Grifols SA, Fundació ACE. The funding sources did not in any way affect the results or presentation of the results. This paper represents independent research partly funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care”.

Published
2019

15. Brain pathology and cognitive scores prior to onset of late-life depression.

Author

Almdahl, Ina S., Agartz, Ingrid, Hugdahl, Kenneth, Korsnes, Maria S., and Alzheimer’s Disease Neuroimaging Initiative

Subjects
*BRAIN diseases, *MENTAL depression, *OLDER people, *WHITE matter (Nerve tissue), *ALZHEIMER'S disease, *PROTEINS, *RESEARCH, *HIPPOCAMPUS (Brain), *RESEARCH methodology, *COGNITION, *MAGNETIC resonance imaging, *EVALUATION research, *COMPARATIVE studies, *RESEARCH funding, *PEPTIDES, BRAIN metabolism
Abstract

Objectives: Understanding the biological changes that occur prior to onset of late-life depression (LLD) is key to its prevention. To investigate potential predictors of LLD, we assessed cognitive scores and neurodegenerative and vascular biomarkers in healthy older adults who later developed depression.Methods: Longitudinal data from the Alzheimer's Disease Neuroimaging Initiative of 241 cognitively unimpaired and non-depressed older adults aged 56-90 at baseline with at least 4 years of follow-up were included. Participants were classified based on whether they developed an incident depression (n = 96) or not (n = 145). Cognitive measures of memory, executive functioning, and language, and biomarkers proposed to be related to LLD: hippocampal volume, white matter hyperintensity volume (WMH), and cortical and cerebrospinal fluid (CSF) amyloid beta levels, were compared between the incident depression and the never-depressed groups at four time points: at baseline, the visit prior to onset, at onset, and after the onset of depression.Results: In the incident depression group, there was a mild decline in cognitive scores from baseline to the visit before depression onset compared with the never-depressed group. The cognitive differences between the groups became more marked after depression onset. Baseline cortical amyloid burden, CSF amyloid beta levels, and WMH were significant predictors of incident depression. Compared to the non-depressed group, hippocampal volume was not reduced before onset, but was reduced following depression.Conclusions: Amyloid pathology and WMH can predict future development of LLD in cognitively unimpaired individuals and may be involved in precipitating vulnerability for depression in older adults. [ABSTRACT FROM AUTHOR]

Published
2022
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16. Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns

Author

Pålhaugen, Lene, primary, Sudre, Carole H, additional, Tecelao, Sandra, additional, Nakling, Arne, additional, Almdahl, Ina S, additional, Kalheim, Lisa F, additional, Cardoso, M Jorge, additional, Johnsen, Stein H, additional, Rongve, Arvid, additional, Aarsland, Dag, additional, Bjørnerud, Atle, additional, Selnes, Per, additional, and Fladby, Tormod, additional

Published
2020
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17. GBA and APOE epsilon 4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Author

Rongve, Arvid, Witoelar, Aree, Ruiz, Agustin, Athanasiu, Lavinia, Abdelnour, Carla, Clarimon, Jordi, Heilmann-Heimbach, Stefanie, Hernandez, Isabel, Moreno-Grau, Sonia, de Rojas, Itziar, Morenas-Rodriguez, Estrella, Fladby, Tormod, Sando, Sigrid B., Brathen, Geir, Blanc, Frederic, Bousiges, Olivier, Lemstra, Afina W., van Steenoven, Inger, Londos, Elisabet, Almdahl, Ina S., Palhaugen, Lene, Eriksen, Jon A., Djurovic, Srdjan, Stordal, Eystein, Saltvedt, Ingvild, Ulstein, Ingun D., Bettella, Francesco, Desikan, Rahul S., Idland, Ane-Victoria, Toft, Mathias, Pihlstrom, Lasse, Snaedal, Jon, Tarraga, Lluis, Boada, Merce, Lleo, Alberto, Stefansson, Hreinn, Stefansson, Kari, Ramirez, Alfredo, Aarsland, Dag, Andreassen, Ole A., Rongve, Arvid, Witoelar, Aree, Ruiz, Agustin, Athanasiu, Lavinia, Abdelnour, Carla, Clarimon, Jordi, Heilmann-Heimbach, Stefanie, Hernandez, Isabel, Moreno-Grau, Sonia, de Rojas, Itziar, Morenas-Rodriguez, Estrella, Fladby, Tormod, Sando, Sigrid B., Brathen, Geir, Blanc, Frederic, Bousiges, Olivier, Lemstra, Afina W., van Steenoven, Inger, Londos, Elisabet, Almdahl, Ina S., Palhaugen, Lene, Eriksen, Jon A., Djurovic, Srdjan, Stordal, Eystein, Saltvedt, Ingvild, Ulstein, Ingun D., Bettella, Francesco, Desikan, Rahul S., Idland, Ane-Victoria, Toft, Mathias, Pihlstrom, Lasse, Snaedal, Jon, Tarraga, Lluis, Boada, Merce, Lleo, Alberto, Stefansson, Hreinn, Stefansson, Kari, Ramirez, Alfredo, Aarsland, Dag, and Andreassen, Ole A.

Abstract

Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder with poor prognosis and mainly unknown pathophysiology. Heritability estimates exceed 30% but few genetic risk variants have been identified. Here we investigated common genetic variants associated with DLB in a large European multisite sample. We performed a genome wide association study in Norwegian and European cohorts of 720 DLB cases and 6490 controls and included 19 top-associated single-nucleotide polymorphisms in an additional cohort of 108 DLB cases and 75545 controls from Iceland. Overall the study included 828 DLB cases and 82035 controls. Variants in the ASH1L/GBA (Chr1q22) and APOE epsilon 4 (Chr19) loci were associated with DLB surpassing the genome-wide significance threshold (p < 5 x 10(-8)). One additional genetic locus previously linked to psychosis in Alzheimer's disease, ZFPM1 (Chr16q24.2), showed suggestive association with DLB at p-value < 1 x 10(-6). We report two susceptibility loci for DLB at genome-wide significance, providing insight into etiological factors. These findings highlight the complex relationship between the genetic architecture of DLB and other neurodegenerative disorders.

Published
2019

18. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk

Author

Jansen, Iris E, Savage, Jeanne E, Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M, Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K, Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S, Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S, Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J, Jonsson, Palmi V, Kiddle, Steven J, Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B, Selbæk, Geir, Shoai, Maryam, Skene, Nathan G, Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D, Wang, Yunpeng, White, Linda R, Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F, van der Flier, Wiesje M, Dobson, Richard, Davis, Lea K, Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L, Ripke, Stephan, Andreassen, Ole A, Posthuma, Danielle, Jansen, Iris E, Savage, Jeanne E, Watanabe, Kyoko, Bryois, Julien, Williams, Dylan M, Steinberg, Stacy, Sealock, Julia, Karlsson, Ida K, Hägg, Sara, Athanasiu, Lavinia, Voyle, Nicola, Proitsi, Petroula, Witoelar, Aree, Stringer, Sven, Aarsland, Dag, Almdahl, Ina S, Andersen, Fred, Bergh, Sverre, Bettella, Francesco, Bjornsson, Sigurbjorn, Brækhus, Anne, Bråthen, Geir, de Leeuw, Christiaan, Desikan, Rahul S, Djurovic, Srdjan, Dumitrescu, Logan, Fladby, Tormod, Hohman, Timothy J, Jonsson, Palmi V, Kiddle, Steven J, Rongve, Arvid, Saltvedt, Ingvild, Sando, Sigrid B, Selbæk, Geir, Shoai, Maryam, Skene, Nathan G, Snaedal, Jon, Stordal, Eystein, Ulstein, Ingun D, Wang, Yunpeng, White, Linda R, Hardy, John, Hjerling-Leffler, Jens, Sullivan, Patrick F, van der Flier, Wiesje M, Dobson, Richard, Davis, Lea K, Stefansson, Hreinn, Stefansson, Kari, Pedersen, Nancy L, Ripke, Stephan, Andreassen, Ole A, and Posthuma, Danielle

Abstract

Alzheimer's disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD.

Published
2019
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19. Author Correction: GBA and APOE ε4 associate with sporadic dementia with Lewy bodies in European genome wide association study

Author

Rongve, Arvid, primary, Witoelar, Aree, additional, Ruiz, Agustín, additional, Athanasiu, Lavinia, additional, Abdelnour, Carla, additional, Clarimon, Jordi, additional, Heilmann-Heimbach, Stefanie, additional, Hernández, Isabel, additional, Moreno-Grau, Sonia, additional, de Rojas, Itziar, additional, Morenas-Rodríguez, Estrella, additional, Fladby, Tormod, additional, Sando, Sigrid B., additional, Bråthen, Geir, additional, Blanc, Frédéric, additional, Bousiges, Olivier, additional, Lemstra, Afina W., additional, van Steenoven, Inger, additional, Londos, Elisabet, additional, Almdahl, Ina S., additional, Pålhaugen, Lene, additional, Eriksen, Jon A., additional, Djurovic, Srdjan, additional, Stordal, Eystein, additional, Saltvedt, Ingvild, additional, Ulstein, Ingun D., additional, Bettella, Francesco, additional, Desikan, Rahul S., additional, Idland, Ane-Victoria, additional, Toft, Mathias, additional, Pihlstrøm, Lasse, additional, Snaedal, Jon, additional, Tárraga, Lluís, additional, Boada, Mercè, additional, Lleó, Alberto, additional, Stefánsson, Hreinn, additional, Stefánsson, Kári, additional, Ramírez, Alfredo, additional, Aarsland, Dag, additional, and Andreassen, Ole A., additional

Published
2019
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20. Brain amyloid and vascular risk are related to distinct white matter hyperintensity patterns.

Author

Pålhaugen, Lene, Sudre, Carole H, Tecelao, Sandra, Nakling, Arne, Almdahl, Ina S, Kalheim, Lisa F, Cardoso, M Jorge, Johnsen, Stein H, Rongve, Arvid, Aarsland, Dag, Bjørnerud, Atle, Selnes, Per, and Fladby, Tormod

Abstract

White matter hyperintensities (WMHs) are associated with vascular risk and Alzheimer's disease. In this study, we examined relations between WMH load and distribution, amyloid pathology and vascular risk in 339 controls and cases with either subjective (SCD) or mild cognitive impairment (MCI). Regional deep (DWMH) and periventricular (PWMH) WMH loads were determined using an automated algorithm. We stratified on Aβ1-42 pathology (Aβ+/−) and analyzed group differences, as well as associations with Framingham Risk Score for cardiovascular disease (FRS-CVD) and age. Occipital PWMH (p = 0.001) and occipital DWMH (p = 0.003) loads were increased in SCD-Aβ+ compared with Aβ− controls. In MCI-Aβ+ compared with Aβ− controls, there were differences in global WMH (p = 0.003), as well as occipital DWMH (p = 0.001) and temporal DWMH (p = 0.002) loads. FRS-CVD was associated with frontal PWMHs (p = 0.003) and frontal DWMHs (p = 0.005), after adjusting for age. There were associations between global and all regional WMH loads and age. In summary, posterior WMH loads were increased in SCD-Aβ+ and MCI-Aβ+ cases, whereas frontal WMHs were associated with vascular risk. The differences in WMH topography support the use of regional WMH load as an early-stage marker of etiology. [ABSTRACT FROM AUTHOR]

Published
2021
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21. Prevalence of the apolipoprotein E epsilon 4 allele in amyloid beta positive subjects across the spectrum of Alzheimer's disease

Author

Mattsson, Niklas, Mattsson, Niklas, Groot, Colin, Jansen, Willemijn J., Landau, Susan M., Villemagne, Victor L., Engelborghs, Sebastiaan, Mintun, Mark M., Lleo, Alberto, Molinuevo, Jose Luis, Jagust, William J., Frisoni, Giovanni B., Ivanoiu, Adrian, Chetelat, Gael, Oliveira, Catarina Resende, Rodrigue, Karen M., Kornhuber, Johannes, Wallin, Anders, Klimkowicz-Mrowiec, Aleksandra, Kandimalla, Ramesh, Popp, Julius, Aalten, Pauline P., Aarsland, Dag, Alcolea, Daniel, Almdahl, Ina S., Baldeiras, Ines, Buchem, Mark A., Cavedo, Enrica, Chen, Kewei, Cohen, Ann D., Foerster, Stefan, Fortea, Juan, Frederiksen, Kristian S., Freund-Levi, Yvonne, Gill, Kiran Dip, Gkatzima, Olymbia, Grimmer, Timo, Hampel, Harald, Herukka, Sanna-Kaisa, Johannsen, Peter, Laere, Koen, Leon, Mony J., Maier, Wolfgang, Marcusson, Jan, Meulenbroek, Olga, Mollergard, Hanne M., Morris, John C., Mroczko, Barbara, Nordlund, Arto, Prabhakar, Sudesh, Peters, Oliver, Rami, Lorena, Rodriguez-Rodriguez, Eloy, Roe, Catherine M., Ruther, Eckart, Santana, Isabel, Schroder, Johannes, Seo, Sang W., Soininen, Hilkka, Spiru, Luiza, Stomrud, Erik, Struyfs, Hanne, Teunissen, Charlotte E., Verhey, Frans R. J., Vos, Stephanie J. B., Doorn, Linda J. C. van Waalwijk, Waldemar, Gunhild, Wallin, Asa K., Wiltfang, Jens, Vandenberghe, Rik, Brooks, David J., Fladby, Tormod, Rowe, Christopher C., Drzezga, Alexander, Verbeek, Marcel M., Sarazin, Marie, Wolk, David A., Fleisher, Adam S., Klunk, William E., Na, Duk L., Sanchez-Juan, Pascual, Lee, Dong Young, Nordberg, Agneta, Tsolaki, Magda, Camus, Vincent, Rinne, Juha O., Fagan, Anne M., Zetterberg, Henrik, Blennow, Kaj, Rabinovici, Gil D., Hansson, Oskar, Berckel, Bart N. M., Flier, Wiesje M., Scheltens, Philip, Visser, Pieter Jelle, Ossenkoppele, Rik, Mattsson, Niklas, Mattsson, Niklas, Groot, Colin, Jansen, Willemijn J., Landau, Susan M., Villemagne, Victor L., Engelborghs, Sebastiaan, Mintun, Mark M., Lleo, Alberto, Molinuevo, Jose Luis, Jagust, William J., Frisoni, Giovanni B., Ivanoiu, Adrian, Chetelat, Gael, Oliveira, Catarina Resende, Rodrigue, Karen M., Kornhuber, Johannes, Wallin, Anders, Klimkowicz-Mrowiec, Aleksandra, Kandimalla, Ramesh, Popp, Julius, Aalten, Pauline P., Aarsland, Dag, Alcolea, Daniel, Almdahl, Ina S., Baldeiras, Ines, Buchem, Mark A., Cavedo, Enrica, Chen, Kewei, Cohen, Ann D., Foerster, Stefan, Fortea, Juan, Frederiksen, Kristian S., Freund-Levi, Yvonne, Gill, Kiran Dip, Gkatzima, Olymbia, Grimmer, Timo, Hampel, Harald, Herukka, Sanna-Kaisa, Johannsen, Peter, Laere, Koen, Leon, Mony J., Maier, Wolfgang, Marcusson, Jan, Meulenbroek, Olga, Mollergard, Hanne M., Morris, John C., Mroczko, Barbara, Nordlund, Arto, Prabhakar, Sudesh, Peters, Oliver, Rami, Lorena, Rodriguez-Rodriguez, Eloy, Roe, Catherine M., Ruther, Eckart, Santana, Isabel, Schroder, Johannes, Seo, Sang W., Soininen, Hilkka, Spiru, Luiza, Stomrud, Erik, Struyfs, Hanne, Teunissen, Charlotte E., Verhey, Frans R. J., Vos, Stephanie J. B., Doorn, Linda J. C. van Waalwijk, Waldemar, Gunhild, Wallin, Asa K., Wiltfang, Jens, Vandenberghe, Rik, Brooks, David J., Fladby, Tormod, Rowe, Christopher C., Drzezga, Alexander, Verbeek, Marcel M., Sarazin, Marie, Wolk, David A., Fleisher, Adam S., Klunk, William E., Na, Duk L., Sanchez-Juan, Pascual, Lee, Dong Young, Nordberg, Agneta, Tsolaki, Magda, Camus, Vincent, Rinne, Juha O., Fagan, Anne M., Zetterberg, Henrik, Blennow, Kaj, Rabinovici, Gil D., Hansson, Oskar, Berckel, Bart N. M., Flier, Wiesje M., Scheltens, Philip, Visser, Pieter Jelle, and Ossenkoppele, Rik

Abstract

Introduction: Apolipoprotein E (APOE) epsilon 4 is the major genetic risk factor for Alzheimer's disease (AD), but its prevalence is unclear because earlier studies did not require biomarker evidence of amyloid beta(A beta) pathology. Methods: We included 3451 A beta+ subjects (853 AD-type dementia, 1810 mild cognitive impairment, and 788 cognitively normal). Generalized estimating equation models were used to assess APOE epsilon 4 prevalence in relation to age, sex, education, and geographical location. Results: The APOE epsilon 4 prevalence was 66% in AD-type dementia, 64% in mild cognitive impairment, and 51% in cognitively normal, and it decreased with advancing age in A beta+ cognitively normal and A beta+ mild cognitive impairment (P <.05) but not in A beta+ AD dementia (P =.66). The prevalence was highest in Northern Europe but did not vary by sex or education. Discussion: The APOE E4 prevalence in AD was higher than that in previous studies, which did not require presence of A beta pathology. Furthermore, our results highlight disease heterogeneity related to age and geographical location. (C) 2018 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Published
2018

22. Genetic meta-analysis identifies 9 novel loci and functional pathways for Alzheimer’s disease risk

Author

Jansen, Iris E, primary, Savage, Jeanne E, additional, Watanabe, Kyoko, additional, Bryois, Julien, additional, Williams, Dylan M, additional, Steinberg, Stacy, additional, Sealock, Julia, additional, Karlsson, Ida K, additional, Hägg, Sara, additional, Athanasiu, Lavinia, additional, Voyle, Nicola, additional, Proitsi, Petroula, additional, Witoelar, Aree, additional, Stringer, Sven, additional, Aarsland, Dag, additional, Almdahl, Ina S, additional, Andersen, Fred, additional, Bergh, Sverre, additional, Bettella, Francesco, additional, Bjornsson, Sigurbjorn, additional, Brækhus, Anne, additional, Bråthen, Geir, additional, de Leeuw, Christiaan, additional, Desikan, Rahul S, additional, Djurovic, Srdjan, additional, Dumitrescu, Logan, additional, Fladby, Tormod, additional, Homan, Timothy, additional, Jonsson, Palmi V, additional, Kiddle, Steven J, additional, Rongve, K Arvid, additional, Saltvedt, Ingvild, additional, Sando, Sigrid B., additional, Selbæk, Geir, additional, Skenne, Nathan, additional, Snaedal, Jon, additional, Stordal, Eystein, additional, Ulstein, Ingun D., additional, Wang, Yunpeng, additional, White, Linda R, additional, Hjerling-Leffler, Jens, additional, Sullivan, Patrick F, additional, van der Flier, Wiesje M, additional, Dobson, Richard, additional, Davis, Lea K., additional, Stefansson, Hreinn, additional, Stefansson, Kari, additional, Pedersen, Nancy L, additional, Ripke, Stephan, additional, Andreassen, Ole A, additional, and Posthuma, Danielle, additional

Published
2018
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23. Erratum: Corrigendum: Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Author

Styrkarsdottir, Unnur, primary, Helgason, Hannes, additional, Sigurdsson, Asgeir, additional, Norddahl, Gudmundur L, additional, Agustsdottir, Arna B, additional, Reynard, Louise N, additional, Villalvilla, Amanda, additional, Halldorsson, Gisli H, additional, Jonasdottir, Aslaug, additional, Magnusdottir, Audur, additional, Oddson, Asmundur, additional, Sulem, Gerald, additional, Zink, Florian, additional, Sveinbjornsson, Gardar, additional, Helgason, Agnar, additional, Johannsdottir, Hrefna S, additional, Helgadottir, Anna, additional, Stefansson, Hreinn, additional, Gretarsdottir, Solveig, additional, Rafnar, Thorunn, additional, Almdahl, Ina S, additional, Brækhus, Anne, additional, Fladby, Tormod, additional, Selbæk, Geir, additional, Hosseinpanah, Farhad, additional, Azizi, Fereidoun, additional, Koh, Jung Min, additional, Tang, Nelson L S, additional, Danesphour, Maryams, additional, Mayordomo, Jose I, additional, Welt, Corrine, additional, Braund, Peter S, additional, Samani, Nilesh J, additional, Kiemeney, Lambertus A, additional, Lohmander, L Stefan, additional, Christiansen, Claus, additional, Andreassen, Ole A, additional, consortium, arcOGEN, additional, Magnusson, Olafur, additional, Masson, Gisli, additional, Kong, Augustine, additional, Jonsdottir, Ingileif, additional, Gudbjartsson, Daniel, additional, Sulem, Patrick, additional, Jonsson, Helgi, additional, Loughlin, John, additional, Ingvarsson, Thorvaldur, additional, Thorsteinsdottir, Unnur, additional, and Stefansson, Kari, additional

Published
2017
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24. Cerebrospinal Fluid Levels of Amyloid Beta 1-43 Mirror 1-42 in Relation to Imaging Biomarkers of Alzheimer’s Disease

Author

Almdahl, Ina S., primary, Lauridsen, Camilla, additional, Selnes, Per, additional, Kalheim, Lisa F., additional, Coello, Christopher, additional, Gajdzik, Beata, additional, Møller, Ina, additional, Wettergreen, Marianne, additional, Grambaite, Ramune, additional, Bjørnerud, Atle, additional, Bråthen, Geir, additional, Sando, Sigrid B., additional, White, Linda R., additional, and Fladby, Tormod, additional

Published
2017
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25. Prevalence of cerebral amyloid pathology in persons without dementia

Author

Jansen, Willemijn J., Ossenkoppele, Rik, Knol, Dirk L., Tijms, Betty M., Scheltens, Philip, Verhey, Frans R. J., Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Roe, Catherine M., Rot, Uros, Rowe, Christopher C., Rüther, Eckart, Sabri, Osama, Sanchez-Juan, Páscual, Santana, Isabel, Sarazin, Marie, Schröder, Johannes, Schütte, Christin, Almdahl, Ina S., Seo, Sang W., Soetewey, Femke, Soininen, Hilkka, Spiru, Luiza, Struyfs, Hanne, Teunissen, Charlotte E., Tsolaki, Magda, Vandenberghe, Rik, Verbeek, Marcel M., Villemagne, Victor L., Arnold, Steven E., Vos, Stephanie J. B., van Waalwijk van Doorn, Linda J. C., Waldemar, Gunhild, Wallin, Anders, Wallin, Åsa K., Wiltfang, Jens, Wolk, David A., Zboch, Marzena, Zetterberg, Henrik, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart N. M., Bibeau, Kristen, Blennow, Kaj, Brooks, David J., van Buchem, Mark A., Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D., Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M., Fladby, Tormod, Fleisher, Adam S., van der Flier, Wiesje M., Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S., Freund-Levi, Yvonne, Frisoni, Giovanni B., Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Hildebrandt, Helmut, Ishihara, Lianna, Ivanoiu, Adrian, Jagust, William J., Johannsen, Peter, Kandimalla, Ramesh, Kapaki, Elisabeth, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E., Köhler, Sebastian, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G., Van Laere, Koen, Landau, Susan M., Lee, Dong Young, de Leon, Mony, Lisetti, Viviana, Lleó, Alberto, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Mattsson, Niklas, De Mendonça, Alexandre, Meulenbroek, Olga, Meyer, Philipp T., Mintun, Mark A., Mok, Vincent, Molinuevo, José Luis, Møllergård, Hanne M., Morris, John C., Mroczko, Barbara, Van der Mussele, Stefan, Na, Duk L., Newberg, Andrew, Nordberg, Agneta, Nordlund, Arto, Novak, Gerald P., Paraskevas, George P., Parnetti, Lucilla, Perera, Gayan, Peters, Oliver, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D., Ramakers, Inez H. G. B., Rami, Lorena, Resende de Oliveira, Catarina, Rinne, Juha O., Rodrigue, Karen M., Rodríguez-Rodríguez, Eloy, and Repositório da Universidade de Lisboa

Abstract

Copyright © 2015 American Medical Association. All rights reserved., Importance: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. Objective: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). Data sources: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. Study selection: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. Data extraction and synthesis: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. Main outcomes and measures: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. Results: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. Conclusions and relevance: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia., The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under EMIF grant agreement No. 115372, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution. BIOMARKAPD is an EU Joint Programme–Neurodegenerative Disease Research (JPND) project. The project is supported through national funding organizations under the aegis of JPND (http://www.jpnd.eu). In the Netherlands, this is ZonMw. The DESCRIPA study was funded by the European Commission within the 5th framework program (QLRT-2001-2455). The EDAR study was funded by the European Commission as part of the 6th framework programme (contract No. 37670). This research was performed within the framework of the Center for Translational Molecular Medicine (CTTM) (http://www.ctmm.nl), project LeARN (grant 02N-101). The AIBL study was funded in part by the study partners (Australian Commonwealth Scientific Industrial and Research Organization [CSIRO], Edith Cowan University [ECU], Mental Health Research Institute [MHRI], Alzheimer’s Australia [AA], National Ageing Research Institute [NARI], Austin Health, CogState, Hollywood Private Hospital, Sir Charles Gardner Hospital). The study also received support from the National Health and Medical Research Council (NHMRC) and the Dementia Collaborative Research Centres program (DCRC2), as well as ongoing funding from the Science and Industry Endowment Fund (SIEF). Data collection and sharing for this project was funded by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health grant U01 AG024904) and the US Department of Defense ADNI (W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging and the National Institute of Biomedical Imaging and Bioengineering and through generous contributions from the following: Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; BioClinica; Biogen Idec; Bristol-Myers Squibb Company; Eisai; Elan Pharmaceuticals; Eli Lilly; F. Hoffmann-La Roche and its affiliated company Genentech; GE Healthcare; Innogenetics; IXICO; Janssen Alzheimer Immunotherapy Research & Development; Johnson & Johnson Pharmaceutical Research & Development; Medpace; Merck; Meso Scale Diagnostics; NeuroRx Research; Novartis Pharmaceuticals; Pfizer; Piramal Imaging; Servier; Synarc; and Takeda Pharmaceutical. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (http://www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer’s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. The Dementia Competence Network (DCN) has been supported by a grant from the German Federal Ministry of Education and Research (BMBF): Kompetenznetz Demenzen (01GI0420). Additional funding related to the randomized clinical trials came from Janssen-Cilag and Merz Pharmaceuticals. The latter funds were exclusively used for personnel, pharmaceuticals, blistering and shipment of medication, and monitoring and as capitation fees for recruiting centers. Funding source for the Chandigarh study is the Indian Council of Medical Research (ICMR), India. Funding for the St Louis contribution was provided by the National Institute on Aging (P50 AG005681, P01 AG003991, and P01 AG026276); Fred Simmons and Olga Mohan, and the Charles and Joanne Knight Alzheimer’s Research Initiative of the Washington University Knight Alzheimer’s Disease Research Center. The Tours study received financial support of the French Ministry of Health grant PHRC-N 2008 1004 and the EC-FP6-project DiMI, LSHB-CT-2005-512146. The Caen study was funded by Agence Nationale de la Recherche, Programme Hospitalier de Recherche Clinique, Région Basse Normandie, and Institut National de la Santé et de la Recherche Médicale (Inserm). The research leading to the Munich contribution to the Mattsson multicenter study has received funding from the program “Investissements d’avenir” (ANR-10-IAIHU-06). The study from Pittsburgh was supported by National Institutes of Health grants (P50 AG005133, R37 AG025516, P01 AG025204). The New York contributions to the Mattsson multicenter study were in part supported by P30 AG008051, R01 AG13616, R01 AG022374, and R01 AG12101. Data from Brescia in this article were collected by Translational Outpatient Memory Clinic (TOMC) working group at IRCCS Fatebenefratelli in Brescia, Italy. Contributors to the TOMC are G. Amicucci, S. Archetti, L. Benussi, G. Binetti, L. Bocchio-Chiavetto, C. Bonvicini, E. Canu, F. Caobelli, E. Cavedo, E. Chittò, M. Cotelli, M. Gennarelli, S. Galluzzi, C. Geroldi, R. Ghidoni, R. Giubbini, U. P. Guerra, G. Kuffenschin, G. Lussignoli, D. Moretti, B. Paghera, M. Parapini, C. Porteri, M. Romano, S. Rosini, I. Villa, R. Zanardini, and O. Zanetti. The JPND Project is supported in Italy by the Italian Ministry of Health. The assembling of the TU Munich data set was supported in part by the German research foundation (Deutsche Forschungsgemeinschaft) (HE 4560/1-2, DR 445/3-1 and DR 445/4-1 to A.D.), and by a KKF grant for clinical research of the Technische Universität München (to A.D. and T.G.). The Florbetaben phase 2 study from which data were derived for this multicenter evaluation was sponsored by Bayer Healthcare/Piramal Imaging (Berlin, Germany). This work was supported by the University of Antwerp Research Fund; the Alzheimer Research Foundation (SAO-FRA); the Research Foundation Flanders (FWO); the Agency for Innovation by Science and Technology (IWT); the Belgian Science Policy Office Interuniversity Attraction Poles (IAP) program; and the Flemish Government–initiated Methusalem excellence grant.

Published
2015

27. Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Author

Styrkarsdottir, Unnur, Helgason, Hannes, Sigurdsson, Asgeir, Norddahl, Gudmundur L, Agustsdottir, Arna B, Reynard, Louise N, Villalvilla, Amanda, Halldorsson, Gisli H, Jonasdottir, Aslaug, Magnusdottir, Audur, Oddson, Asmundur, Sulem, Gerald, Zink, Florian, Sveinbjornsson, Gardar, Helgason, Agnar, Johannsdottir, Hrefna S, Helgadottir, Anna, Stefansson, Hreinn, Gretarsdottir, Solveig, Rafnar, Thorunn, Almdahl, Ina S, Brækhus, Anne, Fladby, Tormod, Selbæk, Geir, Hosseinpanah, Farhad, Azizi, Fereidoun, Koh, Jung Min, Tang, Nelson L S, Daneshpour, Maryam S, Mayordomo, Jose I, Welt, Corrine, Braund, Peter S, Samani, Nilesh J, Kiemeney, Lambertus A, Lohmander, L Stefan, Christiansen, Claus, Andreassen, Ole A, Magnusson, Olafur, Masson, Gisli, Kong, Augustine, Jonsdottir, Ingileif, Gudbjartsson, Daniel, Sulem, Patrick, Jonsson, Helgi, Loughlin, John, Ingvarsson, Thorvaldur, Thorsteinsdottir, Unnur, and Stefansson, Kari

Abstract

We performed a genome-wide association study of total hip replacements, based on variants identified through whole-genome sequencing, which included 4,657 Icelandic patients and 207,514 population controls. We discovered two rare signals that strongly associate with osteoarthritis total hip replacement: a missense variant, c.1141G>C (p.Asp369His), in the COMP gene (allelic frequency = 0.026%, P = 4.0 × 10−12, odds ratio (OR) = 16.7) and a frameshift mutation, rs532464664 (p.Val330Glyfs*106), in the CHADL gene that associates through a recessive mode of inheritance (homozygote frequency = 0.15%, P = 4.5 × 10−18, OR = 7.71). On average, c.1141G>C heterozygotes and individuals homozygous for rs532464664 had their hip replacement operation 13.5 years and 4.9 years earlier than others (P = 0.0020 and P = 0.0026), respectively. We show that the full-length CHADL transcript is expressed in cartilage. Furthermore, the premature stop codon introduced by the CHADL frameshift mutation results in nonsense-mediated decay of the mutant transcripts.

Published
2017
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28. Corrigendum: Whole-genome sequencing identifies rare genotypes in COMP and CHADL associated with high risk of hip osteoarthritis

Author

Styrkarsdottir, Unnur, Helgason, Hannes, Sigurdsson, Asgeir, Norddahl, Gudmundur L, Agustsdottir, Arna B, Reynard, Louise N, Villalvilla, Amanda, Halldorsson, Gisli H, Jonasdottir, Aslaug, Magnusdottir, Audur, Oddson, Asmundur, Sulem, Gerald, Zink, Florian, Sveinbjornsson, Gardar, Helgason, Agnar, Johannsdottir, Hrefna S, Helgadottir, Anna, Stefansson, Hreinn, Gretarsdottir, Solveig, Rafnar, Thorunn, Almdahl, Ina S, Brækhus, Anne, Fladby, Tormod, Selbæk, Geir, Hosseinpanah, Farhad, Azizi, Fereidoun, Koh, Jung Min, Tang, Nelson L S, Danesphour, Maryams, Mayordomo, Jose I, Welt, Corrine, Braund, Peter S, Samani, Nilesh J, Kiemeney, Lambertus A, Lohmander, L Stefan, Christiansen, Claus, Andreassen, Ole A, consortium, arcOGEN, Magnusson, Olafur, Masson, Gisli, Kong, Augustine, Jonsdottir, Ingileif, Gudbjartsson, Daniel, Sulem, Patrick, Jonsson, Helgi, Loughlin, John, Ingvarsson, Thorvaldur, Thorsteinsdottir, Unnur, and Stefansson, Kari

Published
2017
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29. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer’s disease risk

Author

Julia Sealock, Linda R. White, John Hardy, Geir Bråthen, Danielle Posthuma, Christiaan de Leeuw, Ingvild Saltvedt, Julien Bryois, Lea K. Davis, Timothy J. Hohman, Logan Dumitrescu, Nancy L. Pedersen, Petroula Proitsi, Francesco Bettella, Eystein Stordal, Dylan M. Williams, Sigrid Botne Sando, Sven Stringer, Stacy Steinberg, Jon Snaedal, Steven J. Kiddle, Jens Hjerling-Leffler, Fred Andersen, Ida K. Karlsson, Yunpeng Wang, Palmi V. Jonsson, Nicola Voyle, Jeanne E. Savage, Ingun Ulstein, Stephan Ripke, Richard Dobson, Anne Brækhus, Arvid Rongve, Sverre Bergh, Hreinn Stefansson, Dag Aarsland, Kyoko Watanabe, Patrick F. Sullivan, Maryam Shoai, Geir Selbæk, Sigurbjorn Bjornsson, Rahul S. Desikan, Srdjan Djurovic, Ina S. Almdahl, Sara Hägg, Kari Stefansson, Lavinia Athanasiu, Nathan G. Skene, Aree Witoelar, Iris E. Jansen, Ole A. Andreassen, Wiesje M. van der Flier, Tormod Fladby, Neurology, Amsterdam Neuroscience - Neurodegeneration, APH - Personalized Medicine, APH - Methodology, Epidemiology and Data Science, Human genetics, Amsterdam Reproduction & Development (AR&D), Complex Trait Genetics, Theoretical Computer Science, Functional Genomics, Jansen, Iris E [0000-0003-1901-8131], Savage, Jeanne E [0000-0002-2034-8341], Steinberg, Stacy [0000-0001-7726-5152], Hägg, Sara [0000-0002-2452-1500], Proitsi, Petroula [0000-0002-2553-6974], Stringer, Sven [0000-0003-3115-8532], Almdahl, Ina S [0000-0001-6070-4921], Bråthen, Geir [0000-0003-3224-7983], de Leeuw, Christiaan [0000-0003-1076-9828], Djurovic, Srdjan [0000-0002-8140-8061], Hohman, Timothy J [0000-0002-3377-7014], Kiddle, Steven J [0000-0003-4350-7437], Skene, Nathan G [0000-0002-6807-3180], Stordal, Eystein [0000-0002-2443-7923], Hjerling-Leffler, Jens [0000-0002-4539-1776], Dobson, Richard [0000-0003-4224-9245], Davis, Lea K [0000-0001-5143-2282], Stefansson, Kari [0000-0003-1676-864X], Andreassen, Ole A [0000-0002-4461-3568], Posthuma, Danielle [0000-0001-7582-2365], and Apollo - University of Cambridge Repository

Subjects
MISSENSE MUTATIONS, Male, Genome-wide association study, Disease, VARIANTS, ANNOTATION, 0302 clinical medicine, RARE, Polymorphism (computer science), POLYGENIC RISK, 11 Medical and Health Sciences, GENE-EXPRESSION, Genetics, Genetics & Heredity, 0303 health sciences, DEMENTIA, VDP::Medical disciplines: 700::Clinical medical disciplines: 750::Geriatrics: 778, COGNITIVE RESERVE, ASSOCIATION, Middle Aged, Female, Alzheimer's disease, Life Sciences & Biomedicine, Adult, Risk, VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk genetikk: 714, Quantitative Trait Loci, Biology, Quantitative trait locus, VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical genetics: 714, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, SDG 3 - Good Health and Well-being, Alzheimer Disease, Genetic variation, Mendelian randomization, medicine, Humans, Genetic Predisposition to Disease, 030304 developmental biology, Science & Technology, Case-control study, 06 Biological Sciences, medicine.disease, DISCOVERY, Case-Control Studies, VDP::Medisinske Fag: 700::Klinisk medisinske fag: 750::Geriatri: 778, 030217 neurology & neurosurgery, Genome-Wide Association Study, Developmental Biology
Abstract

Alzheimer’s disease (AD) is highly heritable and recent studies have identified over 20 disease-associated genomic loci. Yet these only explain a small proportion of the genetic variance, indicating that undiscovered loci remain. Here, we performed a large genome-wide association study of clinically diagnosed AD and AD-by-proxy (71,880 cases, 383,378 controls). AD-by-proxy, based on parental diagnoses, showed strong genetic correlation with AD (rg = 0.81). Meta-analysis identified 29 risk loci, implicating 215 potential causative genes. Associated genes are strongly expressed in immune-related tissues and cell types (spleen, liver, and microglia). Gene-set analyses indicate biological mechanisms involved in lipid-related processes and degradation of amyloid precursor proteins. We show strong genetic correlations with multiple health-related outcomes, and Mendelian randomization results suggest a protective effect of cognitive ability on AD risk. These results are a step forward in identifying the genetic factors that contribute to AD risk and add novel insights into the neurobiology of AD. © 2019. This is the authors' accepted and refereed manuscript to the chapter. The final authenticated version is available online at: http://dx.doi.org/10.1038/s41588-018-0311-9

Published
2019

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