GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP.
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.
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.
Vijay K
VK
Ramanan
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.
Shannon L
SL
Risacher
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.
Kwangsik
K
Nho
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.
Sungeun
S
Kim
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.
Li
L
Shen
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.
Brenna C
BC
McDonald
1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Karmen K
KK
Yoder
1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Gary D
GD
Hutchins
1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
John D
JD
West
1 Centre for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Eileen F
EF
Tallman
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.
Sujuan
S
Gao
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.
Tatiana M
TM
Foroud
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.
Martin R
MR
Farlow
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.
Philip L
PL
De Jager
11 Rush Alzheimer's Disease Centre, Rush University Medical Centre, Chicago, IL 60612, USA.
David A
DA
Bennett
12 University of Southern California Alzheimer's Therapeutic Research Institute, San Diego, CA 92121, USA.
Paul S
PS
Aisen
13 Department of Neurology, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
Ronald C
RC
Petersen
14 Department of Radiology, Mayo Clinic Minnesota, Rochester, MN 55905, USA.
Clifford R
CR
Jack
15 Laboratory of NeuroImaging, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Arthur W
AW
Toga
16 Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Robert C
RC
Green
17 Department of Neurology, University of California, Berkeley, CA 94720, USA.
William J
WJ
Jagust
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.
Michael W
MW
Weiner
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.
Andrew J
AJ
Saykin
D000081:Acetamides / Q000493:pharmacokinetics; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D000682:Amyloid / Q000378:metabolism*; D000814:Aniline Compounds / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000473:pathology*; D005026:Ethylene Glycols / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D053577:Interleukin-1 Receptor Accessory Protein / Q000235:genetics*; D008137:Longitudinal Studies; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000493:pharmacokinetics
D000081:Acetamides; D000682:Amyloid; D000814:Aniline Compounds; D053327:Apolipoprotein E4; D005026:Ethylene Glycols; C507765:IL1RAP protein, human; D053577:Interleukin-1 Receptor Accessory Protein; C526798:N-(2-methoxybenzyl)-N-(4-phenoxypyridin-3-yl)acetamide; D011725:Pyridines; C545186:florbetapir
Alzheimer’s disease; amyloid; genetics; interleukin-1; microglia