Journal
ALZHEIMERS & DEMENTIA
Volume 11, Issue 6, Pages 658-671Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2014.05.1757
Keywords
Alzheimer's disease; Dementia; Neurodegeneration; Immune response; Endocytosis; Cholesterol metabolism; Ubiquitination; Pathway analysis; ALIGATOR; Weighted gene co-expression network analysis
Categories
Funding
- Wellcome Trust
- Medical Research Council
- Alzheimer's Research UK
- Welsh Assembly Government
- National Institutes of Health, National Institute on Aging (NIH-NIA)
- Erasmus Medical Center
- Erasmus University
- French National Foundation on Alzheimer's Disease and Related Disorders
- Centre National de Genotypage
- Institut Pasteur de Lille
- Inserm
- FRC (Fondation pour la Recherche sur le Cerveau)
- Rotary
- LABEX (Laboratory of Excellence Program Investment for the Future) DISTALZ grant (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer's disease)
- Alzheimer's Association
- MRC [G0902227, MR/L023784/2, MR/L023784/1, MR/K013041/1, MC_U123160651, MC_U123192748, MC_G1000734] Funding Source: UKRI
- Alzheimers Research UK [ART-BIG2009-1, ARUK-PG2014-1, ARUK-PG2014-2, ARUK-NCG2014A-1] Funding Source: researchfish
- Alzheimer's Society [167, 164] Funding Source: researchfish
- Medical Research Council [MR/K013041/1, MC_U123160651, MC_U123192748, MR/L023784/2, MR/L501517/1, MR/L010305/1, G0902227, MR/L023784/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0611-10084] Funding Source: researchfish
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Background: Late-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. Methods: The ALIGATOR and GSEA algorithms were used in the IGAP data to identify associated functional pathways and correlated gene expression networks in human brain. Results: ALIGATOR identified an excess of curated biological pathways showing enrichment of association. Enriched areas of biology included the immune response (P = 3.27 X 10(-12) after multiple testing correction for pathways), regulation of endocytosis (P = 1.31 X 10(-11)), cholesterol transport (P = 2.96 X 10(-9)), and proteasome-ubiquitin activity (P = 1.34 X 10(-6)). Correlated gene expression analysis identified four significant network modules, all related to the immune response (corrected P = .002-.05). Conclusions: The immime response, regulation of endocytosis, cholesterol transport, and protein ubiquitination represent prime targets for AD therapeutics. (C) 2015 Published by Elsevier Inc. on behalf of The Alzheimer's Association.
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