Shahzad Ahmad1, Christian Bannister2, Sven J van der Lee1, Dina Vojinovic1, Hieab H H Adams3, Alfredo Ramirez4, Valentina Escott-Price2, Rebecca Sims2, Emily Baker2, Julie Williams2, Peter Holmans2, Meike W Vernooij3, M Arfan Ikram3, Najaf Amin1, Cornelia M van Duijn5. 1. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. 2. MRC Centre for Neuropsychiatric Genetics & Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. 3. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. 4. Department for Neurodegenerative Diseases and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany; Department of Psychiatry and Psychotherapy, University Hospital Cologne, Cologne, Germany; Institute of Human Genetics, University of Bonn, Bonn, Germany. 5. Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands. Electronic address: c.vanduijn@erasmusmc.nl.
Abstract
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).
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).
Authors: Xiaoling Zhang; Congcong Zhu; Gary Beecham; Badri N Vardarajan; Yiyi Ma; Daniel Lancour; John J Farrell; Jaeyoon Chung; Richard Mayeux; Jonathan L Haines; Gerard D Schellenberg; Margaret A Pericak-Vance; Kathryn L Lunetta; Lindsay A Farrer Journal: Alzheimers Dement Date: 2019-01-03 Impact factor: 21.566
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Authors: Niccolò Tesi; Sven J van der Lee; Marc Hulsman; Iris E Jansen; Najada Stringa; Natasja M van Schoor; Philip Scheltens; Wiesje M van der Flier; Martijn Huisman; Marcel J T Reinders; Henne Holstege Journal: Transl Psychiatry Date: 2020-09-29 Impact factor: 6.222