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

Vijay K Ramanan; Shannon 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 M Foroud; Martin R Farlow; Philip L De Jager; David A Bennett; Paul S Aisen; Ronald C Petersen; Clifford R Jack Jr; Arthur W Toga; Robert C Green; William J Jagust; Michael W Weiner; Andrew J Saykin; Alzheimer’s Disease Neuroimaging Initiative (ADNI)

doi:10.1093/brain/awv231

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

Brain. 2015 Oct;138(Pt 10):3076-88. doi: 10.1093/brain/awv231. Epub 2015 Aug 11.

Authors

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 Jack Jr¹³, Arthur W Toga¹⁴, Robert C Green¹⁵, William J Jagust¹⁶, Michael W Weiner¹⁷, Andrew J Saykin¹⁸; Alzheimer’s Disease Neuroimaging Initiative (ADNI)

Affiliations

¹ 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
² 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
³ 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA 5 Centre for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁴ 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA 6 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁵ 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁶ 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA 7 Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁷ 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA 5 Centre for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁸ 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA 6 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
⁹ 8 Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA 02115, USA 9 Departments of Neurology and Psychiatry, Harvard Medical School, Boston, MA 02115, USA 10 Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02142, USA.
¹⁰ 11 Rush Alzheimer's Disease Centre, Rush University Medical Centre, Chicago, IL 60612, USA.
¹¹ 12 University of Southern California Alzheimer's Therapeutic Research Institute, San Diego, CA 92121, USA.
¹² 13 Department of Neurology, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
¹³ 14 Department of Radiology, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
¹⁴ 15 Laboratory of NeuroImaging, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
¹⁵ 16 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
¹⁶ 17 Department of Neurology, University of California, Berkeley, CA 94720, USA.
¹⁷ 18 Departments of Radiology, Medicine, and Psychiatry, University of California-San Francisco, San Francisco, CA 94143, USA 19 Department of Veterans Affairs Medical Centre, San Francisco, CA 94121, USA.
¹⁸ 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA 4 Indiana Alzheimer Disease Centre, Indiana University School of Medicine, Indianapolis, IN 46202, USA 5 Centre for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN 46202, USA asaykin@iupui.edu.

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.

Keywords: Alzheimer’s disease; amyloid; genetics; interleukin-1; microglia.

Publication types

Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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
Polymorphism, Single Nucleotide / genetics*
Positron-Emission Tomography
Pyridines / pharmacokinetics

Substances

Acetamides
Amyloid
Aniline Compounds
Apolipoprotein E4
Ethylene Glycols
IL1RAP protein, human
Interleukin-1 Receptor Accessory Protein
N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide
Pyridines
florbetapir

Abstract

Publication types

MeSH terms

Substances

Grants and funding