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 McDonald, Karmen Yoder, Gary Hutchins, John D. West, Eileen F. Tallman, Sujuan Gao, Tatiana Foroud, Martin Farlow, Philip L. De Jager, David A. Bennett, Paul S. Aisen, Ronald C. Petersen, Clifford R. Jack, Arthur W. Toga, Robert C. GreenWilliam J. Jagust, Michael W. Weiner, Andrew Saykin

Research output: Contribution to journalArticle

50 Citations (Scopus)

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 18F-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 11C-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.

Original languageEnglish (US)
Pages (from-to)3076-3088
Number of pages13
JournalBrain
Volume138
Issue number10
DOIs
StatePublished - Oct 1 2015

Fingerprint

Genome-Wide Association Study
Amyloid
Transcriptional Activation
Alzheimer Disease
Interleukin-1 Receptor Accessory Protein
Apolipoprotein E4
High-Throughput Nucleotide Sequencing
Brain
Microglia
Temporal Lobe
Interleukin-1
Atrophy
florbetapir
Genes
Cognitive Dysfunction

Keywords

  • Alzheimer's disease
  • amyloid
  • genetics
  • interleukin-1
  • microglia

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP. / Ramanan, Vijay K.; Risacher, Shannon L.; Nho, Kwangsik; Kim, Sungeun; Shen, Li; McDonald, Brenna; Yoder, Karmen; Hutchins, Gary; West, John D.; Tallman, Eileen F.; Gao, Sujuan; Foroud, Tatiana; Farlow, Martin; De Jager, Philip L.; Bennett, David A.; Aisen, Paul S.; Petersen, Ronald C.; Jack, Clifford R.; Toga, Arthur W.; Green, Robert C.; Jagust, William J.; Weiner, Michael W.; Saykin, Andrew.

In: Brain, Vol. 138, No. 10, 01.10.2015, p. 3076-3088.

Research output: Contribution to journalArticle

Ramanan, VK, Risacher, SL, Nho, K, Kim, S, Shen, L, McDonald, B, Yoder, K, Hutchins, G, West, JD, Tallman, EF, Gao, S, Foroud, T, Farlow, M, De Jager, PL, Bennett, DA, Aisen, PS, Petersen, RC, Jack, CR, Toga, AW, Green, RC, Jagust, WJ, Weiner, MW & Saykin, A 2015, 'GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP', Brain, vol. 138, no. 10, pp. 3076-3088. https://doi.org/10.1093/brain/awv231
Ramanan, Vijay K. ; Risacher, Shannon L. ; Nho, Kwangsik ; Kim, Sungeun ; Shen, Li ; McDonald, Brenna ; Yoder, Karmen ; Hutchins, Gary ; West, John D. ; Tallman, Eileen F. ; Gao, Sujuan ; Foroud, Tatiana ; Farlow, Martin ; De Jager, Philip L. ; Bennett, David A. ; Aisen, Paul S. ; Petersen, Ronald C. ; Jack, Clifford R. ; Toga, Arthur W. ; Green, Robert C. ; Jagust, William J. ; Weiner, Michael W. ; Saykin, Andrew. / GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP. In: Brain. 2015 ; Vol. 138, No. 10. pp. 3076-3088.
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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 18F-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 11C-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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AU - Ramanan, Vijay K.

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AU - Shen, Li

AU - McDonald, Brenna

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AU - Petersen, Ronald C.

AU - Jack, Clifford R.

AU - Toga, Arthur W.

AU - Green, Robert C.

AU - Jagust, William J.

AU - Weiner, Michael W.

AU - Saykin, Andrew

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N2 - 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 18F-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 11C-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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