@article{2566cf2d53db43708d297922721a6ebb,
title = "Association of TLR4 with Alzheimer's disease risk and presymptomatic biomarkers of inflammation",
abstract = "Introduction: A coding variant in the TLR4 receptor (rs4986790), previously associated with longevity and Alzheimer's disease (AD) risk reduction, was examined in a population isolate (Qu{\'e}bec Founder Population [QFP]) and in presymptomatic individuals with a parental history of AD (Pre-Symptomatic Evaluation of Novel or Experimental Treatment for Alzheimer's Disease [PREVENT-AD]). Methods: Genotyping was performed using the Illumina HumanHap 550k (QFP) and the Illumina Omni2.5 beadchips (PREVENT-AD). Cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Whole-brain cortical thickness data were analyzed using CIVET 1.12. Cerebrospinal fluid concentrations of cytokines were obtained by using Milliplex. Results: The minor allele of the rs4986790 polymorphism (G) is associated with a reduced risk of developing AD in the QFP, as well as higher visuospatial and constructional abilities, higher cortical thickness in visual-related regions, and stable cerebrospinal fluid IL-1β levels in the PREVENT-AD cohort. Discussion: The rs4986790 G coding variant in the TLR4 gene appears to reduce AD risk through the modulation of IL-1β synthesis and secretion in the presymptomatic phase of the disease.",
keywords = "Alzheimer's disease, Cortical thickness, Frontal cortex, Fusiform gyrus, Genetics, IL-1β, Inflammation, Occipital cortex, TLR4, Visuospatial and constructional abilities",
author = "{PREVENT-AD Research Group} and Justin Miron and Cynthia Picard and Lafaille-Magnan, {Marie {\'E}lyse} and M{\'e}lissa Savard and Anne Labont{\'e} and John Breitner and Pedro Rosa-Neto and Daniel Auld and Judes Poirier",
note = "Funding Information: This study was supported by the Canadian Institutes of Health Research (MOP- 119321 ), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-03790), the J.-Louis L{\'e}vesque Foundation , the Lemaire Family Foundation , the McGill University and Genome Qu{\'e}bec Innovation Centre , and the ICAO Charity Drive . Justin Miron and Cynthia Picard were supported by the Centre for Studies in the Prevention of Alzheimer's disease. Justin Miron was also supported by the Djavad Mowafaghian Studentship. These funding sources had no involvement in the study design. The authors wish to thank Mrs Danielle C{\'e}cyre and Jos{\'e}e Prud'homme from the Douglas Bell Canada Brain Bank in Montr{\'e}al for the generous donation of the brain tissue samples from the QFP cohort. Funding Information: PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University , the Fonds de Recherche du Qu{\'e}bec–Sant{\'e} (FRQS), an unrestricted research grant from Pfizer Canada , the J-Louis L{\'e}vesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada , and the Canada Fund for Innovation . Private sector contributions were facilitated by the Development Office of the McGill University Faculty of Medicine and by the Douglas Hospital Research Centre Foundation ( http://www.fondationdouglas.qc.ca/ ). Funding Information: This study was supported by the Canadian Institutes of Health Research (MOP-119321), the Natural Sciences and Engineering Research Council of Canada (RGPIN-2015-03790), the J.-Louis L?vesque Foundation, the Lemaire Family Foundation, the McGill University and Genome Qu?bec Innovation Centre, and the ICAO Charity Drive. Justin Miron and Cynthia Picard were supported by the Centre for Studies in the Prevention of Alzheimer's disease. Justin Miron was also supported by the Djavad Mowafaghian Studentship. These funding sources had no involvement in the study design. The authors wish to thank Mrs Danielle C?cyre and Jos?e Prud'homme from the Douglas Bell Canada Brain Bank in Montr?al for the generous donation of the brain tissue samples from the QFP cohort. Data used in the preparation of this article were obtained from the PREVENT-AD program (https://douglas.research.mcgill.ca/stop-ad-centre), data release 5.0 (November 30, 2017). A complete listing of PREVENT-AD Research Group can be found in the PREVENT-AD database: https://preventad.loris.ca/acknowledgements/acknowledgements.php?date=[YYYY-MM-DD]. The investigators of the PREVENT-AD program contributed to the design and implementation of PREVENT-AD and/or provided data but did not participate in analysis or writing of this report. PREVENT-AD was launched in 2011 as a $13.5 million, 7-year public-private partnership using funds provided by McGill University, the Fonds de Recherche du Qu?bec?Sant? (FRQS), an unrestricted research grant from Pfizer Canada, the J-Louis L?vesque Foundation, the Douglas Hospital Research Centre and Foundation, the Government of Canada, and the Canada Fund for Innovation. Private sector contributions were facilitated by the Development Office of the McGill University Faculty of Medicine and by the Douglas Hospital Research Centre Foundation (http://www.fondationdouglas.qc.ca/). The primary goal of PREVENT-AD is to test whether serial determination of multimodal biomarkers of Alzheimer's disease may be measured and used in presymptomatic persons at high risk of subsequent AD dementia to trace the progression of the disease process and to measure effects of any potentially preventive treatment interventions. This work is intended to provide preliminary data regarding the probable efficacy and safety of potential new treatments for prevention of AD dementia. The founders of the program were John C. S. Breitner (MD, MPH), Judes Poirier (PhD), Pierre Etienne (MD), the Douglas Hospital Research Center, and the Faculty of Medicine of McGill University (Montr?al, QC, Canada). The current Program Director is Judes Poirier (PhD), the Co-Director is Sylvia Villeneuve (PhD), and the Study Coordinator is Jennifer Tremblay-Mercier (MSc). PREVENT-AD is the result of efforts of many other co-investigators from a range of academic institutions and private corporations, as well as extraordinarily dedicated and talented clinical and technical assistant staff, students, and postdoctoral fellows. Subjects being recruited from the greater Montr?al area and more distant locations in Qu?bec, the authors would like to take the opportunity to thank the PREVENT-AD volunteers for their extraordinary commitment to this work. For up-to-date information, see https://douglas.research.mcgill.ca/stop-ad-centre. Publisher Copyright: {\textcopyright} 2019 the Alzheimer's Association",
year = "2019",
month = jul,
doi = "10.1016/j.jalz.2019.03.012",
language = "English (US)",
volume = "15",
pages = "951--960",
journal = "Alzheimer's and Dementia",
issn = "1552-5260",
publisher = "Elsevier Inc.",
number = "7",
}