GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP

• Published in: Brain (London, England : 1878) Vol. 138; no. Pt 10; pp. 3076 - 3088
• Main Authors: Ramanan, Vijay K, Risacher, Shannon L, Nho, Kwangsik, Kim, Sungeun, Shen, Li, McDonald, Brenna C, Yoder, Karmen K, Hutchins, Gary D, West, John D, Tallman, Eileen F, Gao, Sujuan, Foroud, Tatiana M, Farlow, Martin R, De Jager, Philip L, Bennett, David A, Aisen, Paul S, Petersen, Ronald C, Jack, Jr, Clifford R, Toga, Arthur W, Green, Robert C, Jagust, William J, Weiner, Michael W, Saykin, Andrew J
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-10-2015
• Subjects: Acetamides - pharmacokinetics; Aged; Aged, 80 and over; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Amyloid - metabolism; Aniline Compounds - metabolism; Apolipoprotein E4 - genetics; Cerebral Cortex - diagnostic imaging; Cerebral Cortex - pathology; Ethylene Glycols - metabolism; Female; Genetic Association Studies; Genotype; Humans; Interleukin-1 Receptor Accessory Protein - genetics; Longitudinal Studies; Male; Original; Polymorphism, Single Nucleotide - genetics; Positron-Emission Tomography; Pyridines - pharmacokinetics; amyloid; genetics; interleukin-1; Alzheimer’s disease; microglia
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awv231

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.