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

Brain
Authors
Keywords
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.

Year of Publication
2015
Journal
Brain
Volume
138
Issue
Pt 10
Pages
3076-88
Date Published
2015 Oct
ISSN
1460-2156
URL
DOI
10.1093/brain/awv231
PubMed ID
26268530
PubMed Central ID
PMC4671479
Links
Grant list
P41 EB015922 / EB / NIBIB NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
RR020128 / RR / NCRR NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
R00 LM011384 / LM / NLM NIH HHS / United States
P30 AG10133 / AG / NIA NIH HHS / United States
AG17917 / AG / NIA NIH HHS / United States
R01 LM011360 / LM / NLM NIH HHS / United States
P01 AG09466 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
AG34374 / AG / NIA NIH HHS / United States
UL1 TR001108 / TR / NCATS NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
K01 AG030514 / AG / NIA NIH HHS / United States
RR027710-01 / RR / NCRR NIH HHS / United States
R01 AG19771 / AG / NIA NIH HHS / United States
R01 AG034374 / AG / NIA NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
U54 RR025761 / RR / NCRR NIH HHS / United States