GWAS of longitudinal amyloid accumulation on18F-florbetapir PET in Alzheimer’s disease implicates microglial activation geneIL1RAP | Zendy

Vijay K. Ramanan | Zendy; Shan L. Risacher | Zendy; Kwangsik Nho | Zendy; Sungeun Kim | Zendy; Li Shen | Zendy; Brenna C. McDonald | Zendy; Karmen K. Yoder | Zendy; Gary D. Hutchins | Zendy; John D. West | Zendy; Eileen F. Tallman | Zendy; Sujuan Gao | Zendy; Tatiana Foroud | Zendy; Martin R. Farlow | Zendy; Philip L. De Jager | Zendy; David A. Bennett | Zendy; Paul Aisen | Zendy; Ronald C. Petersen | Zendy; Clifford R. Jack | Zendy; Arthur W. Toga | Zendy; Robert C. Green | Zendy; William J. Jagust | Zendy; Michael W. Weiner | Zendy; Andrew J. Saykin | Zendy

Open Access

GWAS of longitudinal amyloid accumulation on¹⁸F-florbetapir PET in Alzheimer’s disease implicates microglial activation geneIL1RAP

Author(s) -

Vijay K. Ramanan,

Shan L. Risacher,

Kwangsik Nho,

Sungeun Kim,

Li Shen,

Brenna C. McDonald,

Karmen K. Yoder,

Gary D. Hutchins,

John D. West,

Eileen F. Tallman,

Sujuan Gao,

Tatiana Foroud,

Martin R. Farlow,

Philip L. De Jager,

David A. Bennett,

Paul Aisen,

Ronald C. Petersen,

Clifford R. Jack,

Arthur W. Toga,

Robert C. Green,

William J. Jagust,

Michael W. Weiner,

Andrew J. Saykin

Publication year - 2015

Publication title -

brain

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.142

H-Index - 336

eISSN - 1460-2156

pISSN - 0006-8950

DOI - 10.1093/brain/awv231

Subject(s) - disease , genome wide association study , microglia , neuroscience , alzheimer's disease , medicine , gerontology , psychology , biology , gene , genetics , inflammation , genotype , single nucleotide polymorphism

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.

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