| Literature DB >> 26268530 |
Vijay K Ramanan1, Shannon L Risacher2, Kwangsik Nho3, Sungeun Kim3, Li Shen3, Brenna C McDonald4, Karmen K Yoder5, Gary D Hutchins5, John D West5, Eileen F Tallman5, Sujuan Gao6, Tatiana M Foroud7, Martin R Farlow8, Philip L De Jager9, David A Bennett10, Paul S Aisen11, Ronald C Petersen12, Clifford R Jack13, Arthur W Toga14, Robert C Green15, William J Jagust16, Michael W Weiner17, Andrew J Saykin18.
Abstract
Brain amyloid deposition is thought to be a seminal event in Alzheimer's disease. To identify genes influencing Alzheimer's disease pathogenesis, we performed a genome-wide association study of longitudinal change in brain amyloid burden measured by (18)F-florbetapir PET. A novel association with higher rates of amyloid accumulation independent from APOE (apolipoprotein E) ε4 status was identified in IL1RAP (interleukin-1 receptor accessory protein; rs12053868-G; P = 1.38 × 10(-9)) and was validated by deep sequencing. IL1RAP rs12053868-G carriers were more likely to progress from mild cognitive impairment to Alzheimer's disease and exhibited greater longitudinal temporal cortex atrophy on MRI. In independent cohorts rs12053868-G was associated with accelerated cognitive decline and lower cortical (11)C-PBR28 PET signal, a marker of microglial activation. These results suggest a crucial role of activated microglia in limiting amyloid accumulation and nominate the IL-1/IL1RAP pathway as a potential target for modulating this process.Entities:
Keywords: Alzheimer’s disease; amyloid; genetics; interleukin-1; microglia
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Year: 2015 PMID： 26268530 PMCID： PMC4671479 DOI： 10.1093/brain/awv231
Source DB: PubMed Journal: Brain ISSN： 0006-8950 Impact factor: 13.501