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; Arthur W. Toga; Robert C. Green; William J. Jagust; Michael W. Weiner; Andrew J. Saykin

doi:10.1093/brain/awv231

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, Arthur W. Toga, Robert C. GreenWilliam J. Jagust, Michael W. Weiner, Andrew J. Saykin

Research output: Contribution to journal › Article › peer-review

76 Scopus citations

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 language	English (US)
Pages (from-to)	3076-3088
Number of pages	13
Journal	Brain
Volume	138
Issue number	10
DOIs	https://doi.org/10.1093/brain/awv231
State	Published - Oct 1 2015

Keywords

Alzheimer's disease
amyloid
genetics
interleukin-1
microglia

ASJC Scopus subject areas

Medicine(all)

Access to Document

10.1093/brain/awv231

Cite this

Ramanan, V. K., Risacher, S. L., Nho, K., Kim, S., Shen, L., McDonald, B. C., Yoder, K. K., Hutchins, G. D., West, J. D., Tallman, E. F., Gao, S., Foroud, T. M., Farlow, M. R., De Jager, P. L., Bennett, D. A., Aisen, P. S., Petersen, R. C., Jack, C. R., Toga, A. W., ... Saykin, A. J. (2015). GWAS of longitudinal amyloid accumulation on ¹⁸F-florbetapir PET in Alzheimer's disease implicates microglial activation gene IL1RAP. Brain, 138(10), 3076-3088. https://doi.org/10.1093/brain/awv231

Ramanan, VK, Risacher, SL, Nho, K, Kim, S, Shen, L, McDonald, BC, Yoder, KK, Hutchins, GD, West, JD, Tallman, EF, Gao, S, Foroud, TM, Farlow, MR, De Jager, PL, Bennett, DA, Aisen, PS, Petersen, RC , Jack, CR, Toga, AW, Green, RC, Jagust, WJ, Weiner, MW & Saykin, AJ 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

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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 - Kim, Sungeun

AU - Shen, Li

AU - McDonald, Brenna C.

AU - Yoder, Karmen K.

AU - Hutchins, Gary D.

AU - West, John D.

AU - Tallman, Eileen F.

AU - Gao, Sujuan

AU - Foroud, Tatiana M.

AU - Farlow, Martin R.

AU - De Jager, Philip L.

AU - Bennett, David A.

AU - Aisen, Paul S.

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 J.

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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.

AB - 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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