TY - JOUR
T1 - Disentangling the biological pathways involved in early features of Alzheimer's disease in the Rotterdam Study
AU - Ahmad, Shahzad
AU - Bannister, Christian
AU - van der Lee, Sven J.
AU - Vojinovic, Dina
AU - Adams, Hieab H.H.
AU - Ramirez, Alfredo
AU - Escott-Price, Valentina
AU - Sims, Rebecca
AU - Baker, Emily
AU - Williams, Julie
AU - Holmans, Peter
AU - Vernooij, Meike W.
AU - Ikram, M. Arfan
AU - Amin, Najaf
AU - van Duijn, Cornelia M.
N1 - Funding Information:
This study was funded by the Netherlands Organisation for Health Research and Development (ZonMW) as part of the Joint Programming for Neurological Disease (JPND) as part of the PERADES Program (Defining Genetic, Polygenic, and Environmental Risk for Alzheimer's disease, using multiple powerful cohorts, focused Epigenetics and Stem cell metabolomics), Project number 733051021. This work was funded also by the European Union Innovative Medicine Initiative (IMI) programme under grant agreement No. 115975 as part of the Alzheimer's Disease Apolipoprotein Pathology for Treatment Elucidation and Development (ADAPTED, https://www.imi-adapted.eu ); and the European Union's Horizon 2020 research and innovation programme as part of the Common mechanisms and pathways in Stroke and Alzheimer's disease CoSTREAM project ( www.costream.eu , grant agreement No. 667375); European Union's Horizon 2020 research and innovation programme Marie Skłodowska-Curie Research and Innovation Staff Exchange (RISE) under the grant agreement No. 645740 as part of the Personalized pREvention of Chronic DIseases (PRECeDI) project. This study was also supported by MRC Dementias Platform UK (DPUK) and the UK Dementia Research Institute (UK DRI). The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS-I, RS-II, RS-III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS data sets are supported by the Netherlands Organization of Scientific Research NWO Investments (Project number 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), and the Netherlands Genomics Initiative (NGI)/Netherlands Organization for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project number 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, MSc, for the creation and analysis of imputed data. I would like to thanks Alzheimer Nederland for providing me travel grant to present my research at AAIC2017.
Publisher Copyright:
© 2018 The Authors
PY - 2018/7
Y1 - 2018/7
N2 - Introduction: Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways. Methods: We constructed weighted Genetic risk scores, first based on 20 genome-wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume. Results: The risk score capturing endocytosis pathway was significantly associated with mild cognitive impairment (P = 1.44 × 10 −4 ). Immune response (P =.016) and clathrin/AP2 adaptor complex pathway (P = 3.55 × 10 −3 ) excluding apolipoprotein E also showed modest association with white matter lesions but did not sustain Bonferroni correction (P = 9.09 × 10 −4 ). Discussion: Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE).
AB - Introduction: Exploring the role of Alzheimer's disease (AD) implicated pathways in the predementia phase may provide new insight for preventive and clinical trials targeting disease specific pathways. Methods: We constructed weighted Genetic risk scores, first based on 20 genome-wide significant AD risk variants and second clustering these variants within pathways. Risk scores were investigated for their association with AD, mild cognitive impairment, and brain magnetic resonance imaging phenotypes including white matter lesions, hippocampal volume, and brain volume. Results: The risk score capturing endocytosis pathway was significantly associated with mild cognitive impairment (P = 1.44 × 10 −4 ). Immune response (P =.016) and clathrin/AP2 adaptor complex pathway (P = 3.55 × 10 −3 ) excluding apolipoprotein E also showed modest association with white matter lesions but did not sustain Bonferroni correction (P = 9.09 × 10 −4 ). Discussion: Our study suggests that the clinical spectrum of early AD pathology is explained by different biological pathways, in particular, the endocytosis, clathrin/AP2 adaptor complex, and immune response pathways, that are independent of apolipoprotein E (APOE).
KW - Alzheimer's disease
KW - Endocytosis
KW - Genetic risk score
KW - Immune response
KW - Mild cognitive impairment
KW - White matter lesions
UR - http://www.scopus.com/inward/record.url?scp=85044253651&partnerID=8YFLogxK
U2 - 10.1016/j.jalz.2018.01.005
DO - 10.1016/j.jalz.2018.01.005
M3 - Article
C2 - 29494809
AN - SCOPUS:85044253651
SN - 1552-5260
VL - 14
SP - 848
EP - 857
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 7
ER -
