Circulating biomarkers of immunity and inflammation, risk of Alzheimer’s disease, and hippocampal volume: a Mendelian randomization study

Lana Fani, Marios K. Georgakis, M. Arfan Ikram, M. Kamran Ikram, Rainer Malik, Martin Dichgans*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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The aim of this study was to explore the association between genetically predicted circulating levels of immunity and inflammation, and the risk of Alzheimer’s disease (AD) and hippocampal volume, by conducting a two-sample Mendelian Randomization Study. We identified 12 markers of immune cells and derived ratios (platelet count, eosinophil count, neutrophil count, basophil count, monocyte count, lymphocyte count, platelet-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, CD4 count, CD8 count, CD4-to-CD8 ratio, and CD56) and 5 signaling molecules (IL-6, fibrinogen, CRP, and Lp-PLA2 activity and mass) as primary exposures of interest. Other genetically available immune biomarkers with a weaker a priori link to AD were considered secondary exposures. Associations with AD were evaluated in The International Genomics of Alzheimer’s Project (IGAP) GWAS dataset (21,982 cases; 41,944 controls of European ancestry). For hippocampal volume, we extracted data from a GWAS meta-analysis on 33,536 participants of European ancestry. None of the primary or secondary exposures showed statistically significant associations with AD or with hippocampal volume following P-value correction for multiple comparisons using false discovery rate < 5% (Q-value < 0.05). CD4 count showed the strongest suggestive association with AD (odds ratio 1.32, P < 0.01, Q > 0.05). There was evidence for heterogeneity in the MR inverse variance-weighted meta-analyses as measured by Cochran Q, and weighted median and weighted mode for multiple exposures. Further cluster analyses did not reveal clusters of variants that could influence the risk factor in distinct ways. This study suggests that genetically predicted circulating biomarkers of immunity and inflammation are not associated with AD risk or hippocampal volume. Future studies should assess competing risk, explore in more depth the role of adaptive immunity in AD, in particular T cells and the CD4 subtype, and confirm these findings in other ethnicities.

Original languageEnglish
Article number291
JournalTranslational Psychiatry
Issue number1
Early online date17 May 2021
Publication statusPublished - Jun 2021

Bibliographical note

Funding Information:
This work was supported by the European Union’s Horizon 2020 research and innovation program (grant numbers 667375 [“CoSTREAM”] and 666881 [“SVDs@target”]) and Alzheimer Nederland. The funding source had no role in study design, collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.

Publisher Copyright:
© 2021, The Author(s).


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