Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function

Panagiota Pagoni; Roxanna S Korologou-Linden; Laura D Howe; George Davey Smith; Yoav Ben-Shlomo; Evie Stergiakouli; Emma L Anderson

doi:10.1016/j.bbi.2022.05.006

Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function

Panagiota Pagoni
, Roxanna S Korologou-Linden
, Laura D Howe
, George Davey Smith
, Yoav Ben-Shlomo
, Evie Stergiakouli
, Emma L Anderson

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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178 Downloads (Pure)

Abstract

BACKGROUND: There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer's disease. Establishing causality is challenging due to bias from reverse causation and residual confounding.

METHODS: We used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer's disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N=8,293), Alzheimer's disease (71,880 cases / 383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051).

RESULTS: Evidence suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR=1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer's disease. There was weak evidence of a causal effect of MIP-1b (CCL4) (OR=1.04 95% CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95% CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95% CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95% CI: 0.97 to 1.41, p=0.10), IL-8 (Wald ratio: OR=1.21 95% CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95% CI: 0.94 to 1.56, p=0.14) on Alzheimer's disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR=1.05 95% CI: 0.98 to 1.13, p=0.14), IL-8 (OR=1.21 95% CI: 1.07 to 1.37, p=0.003) and MCP1 (OR=1.07 95% CI: 1.03 to 1.13, p=0.003) were associated with lower fluid intelligence, and IL-4 (OR=0.86 95%CI: 0.79 to 0.98, p=0.02) with higher.

CONCLUSIONS: Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer's disease and fluid intelligence.

Original language	English
Pages (from-to)	54-64
Number of pages	11
Journal	Brain, Behavior, and Immunity
Volume	104
Early online date	14 May 2022
DOIs	https://doi.org/10.1016/j.bbi.2022.05.006
Publication status	E-pub ahead of print - 14 May 2022

Bibliographical note

Funding Information:
This work was supported by a grant from the BRACE Alzheimer’s Disease charity (BR16/028). PP, ELA, and ES work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6). RKL was supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). ELA is funded by an MRC Skills Development Award from the UK Medical Research Council (MR/P014437/1). LDH is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). This publication is the work of the authors, and ELA, will serve as a guarantor for the contents of this paper.

Publisher Copyright:
© 2022 The Authors

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@article{8214f86e16b24c59935314c79163ca04,

title = "Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function",

abstract = "BACKGROUND: There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer's disease. Establishing causality is challenging due to bias from reverse causation and residual confounding.METHODS: We used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer's disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N=8,293), Alzheimer's disease (71,880 cases / 383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051).RESULTS: Evidence suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR=1.09 95\%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer's disease. There was weak evidence of a causal effect of MIP-1b (CCL4) (OR=1.04 95\% CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95\% CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95\% CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95\% CI: 0.97 to 1.41, p=0.10), IL-8 (Wald ratio: OR=1.21 95\% CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95\% CI: 0.94 to 1.56, p=0.14) on Alzheimer's disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR=1.05 95\% CI: 0.98 to 1.13, p=0.14), IL-8 (OR=1.21 95\% CI: 1.07 to 1.37, p=0.003) and MCP1 (OR=1.07 95\% CI: 1.03 to 1.13, p=0.003) were associated with lower fluid intelligence, and IL-4 (OR=0.86 95\%CI: 0.79 to 0.98, p=0.02) with higher.CONCLUSIONS: Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer's disease and fluid intelligence.",

author = "Panagiota Pagoni and Korologou-Linden, \{Roxanna S\} and Howe, \{Laura D\} and \{Davey Smith\}, George and Yoav Ben-Shlomo and Evie Stergiakouli and Anderson, \{Emma L\}",

note = "Funding Information: This work was supported by a grant from the BRACE Alzheimer{\textquoteright}s Disease charity (BR16/028). PP, ELA, and ES work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC\_UU\_00011/1, MC\_UU\_00011/3, MC\_UU\_00011/6). RKL was supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). ELA is funded by an MRC Skills Development Award from the UK Medical Research Council (MR/P014437/1). LDH is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). This publication is the work of the authors, and ELA, will serve as a guarantor for the contents of this paper. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = may,

day = "14",

doi = "10.1016/j.bbi.2022.05.006",

language = "English",

volume = "104",

pages = "54--64",

journal = "Brain, Behavior, and Immunity",

issn = "0889-1591",

publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function

AU - Pagoni, Panagiota

AU - Korologou-Linden, Roxanna S

AU - Howe, Laura D

AU - Davey Smith, George

AU - Ben-Shlomo, Yoav

AU - Stergiakouli, Evie

AU - Anderson, Emma L

N1 - Funding Information: This work was supported by a grant from the BRACE Alzheimer’s Disease charity (BR16/028). PP, ELA, and ES work in a unit that receives funding from the University of Bristol and the UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6). RKL was supported by a Wellcome Trust PhD studentship (Grant ref: 215193/Z18/Z). ELA is funded by an MRC Skills Development Award from the UK Medical Research Council (MR/P014437/1). LDH is funded by a Career Development Award from the UK Medical Research Council (MR/M020894/1). This publication is the work of the authors, and ELA, will serve as a guarantor for the contents of this paper. Publisher Copyright: © 2022 The Authors

PY - 2022/5/14

Y1 - 2022/5/14

N2 - BACKGROUND: There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer's disease. Establishing causality is challenging due to bias from reverse causation and residual confounding.METHODS: We used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer's disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N=8,293), Alzheimer's disease (71,880 cases / 383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051).RESULTS: Evidence suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR=1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer's disease. There was weak evidence of a causal effect of MIP-1b (CCL4) (OR=1.04 95% CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95% CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95% CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95% CI: 0.97 to 1.41, p=0.10), IL-8 (Wald ratio: OR=1.21 95% CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95% CI: 0.94 to 1.56, p=0.14) on Alzheimer's disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR=1.05 95% CI: 0.98 to 1.13, p=0.14), IL-8 (OR=1.21 95% CI: 1.07 to 1.37, p=0.003) and MCP1 (OR=1.07 95% CI: 1.03 to 1.13, p=0.003) were associated with lower fluid intelligence, and IL-4 (OR=0.86 95%CI: 0.79 to 0.98, p=0.02) with higher.CONCLUSIONS: Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer's disease and fluid intelligence.

AB - BACKGROUND: There is considerable evidence suggesting a role of neuroinflammation in the pathogenesis of Alzheimer's disease. Establishing causality is challenging due to bias from reverse causation and residual confounding.METHODS: We used two-sample MR to explore causal effects of circulating cytokine concentrations on Alzheimer's disease risk and cognitive function. We employed genetic variants from the largest publicly available genome-wide association studies (GWASs) of cytokine concentrations (N=8,293), Alzheimer's disease (71,880 cases / 383,378 controls), prospective memory (N = 152,605 to 462,302), reaction time (N = 454,157 to 459,523) and fluid intelligence (N = 149,051).RESULTS: Evidence suggest that 1 standard deviation (SD) increase in levels of CTACK (CCL27) (OR=1.09 95%CI: 1.01 to 1.19, p=0.03) increased risk of Alzheimer's disease. There was weak evidence of a causal effect of MIP-1b (CCL4) (OR=1.04 95% CI: 0.99 to 1.09, p=0.08), Eotaxin (OR=1.08 95% CI: 0.99 to 1.17, p =0.10), GROa (CXCL1) (OR=1.04 95% CI: 0.99 to 1.10, p=0.15), MIG (CXCL9) (OR=1.17 95% CI: 0.97 to 1.41, p=0.10), IL-8 (Wald ratio: OR=1.21 95% CI: 0.97 to 1.51, p=0.09) and IL-2 (Wald Ratio: OR=1.21 95% CI: 0.94 to 1.56, p=0.14) on Alzheimer's disease risk. A 1 SD increase in concentration of Eotaxin (IVW: OR=1.05 95% CI: 0.98 to 1.13, p=0.14), IL-8 (OR=1.21 95% CI: 1.07 to 1.37, p=0.003) and MCP1 (OR=1.07 95% CI: 1.03 to 1.13, p=0.003) were associated with lower fluid intelligence, and IL-4 (OR=0.86 95%CI: 0.79 to 0.98, p=0.02) with higher.CONCLUSIONS: Our findings suggest a causal role of cytokines in the pathogenesis of Alzheimer's disease and fluid intelligence.

U2 - 10.1016/j.bbi.2022.05.006

DO - 10.1016/j.bbi.2022.05.006

M3 - Article (Academic Journal)

C2 - 35580794

SN - 0889-1591

VL - 104

SP - 54

EP - 64

JO - Brain, Behavior, and Immunity

JF - Brain, Behavior, and Immunity

ER -

Causal effects of circulating cytokine concentrations on risk of Alzheimer's disease and cognitive function

Abstract

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