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Inflammation and Brain Structure in Alzheimer’s Disease and Other Neurodegenerative Disorders: a Mendelian Randomization Study

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Abstract

Previous in vitro and post-mortem studies have reported the role of inflammation in neurodegenerative disorders. However, the association between inflammation and brain structure in vivo and the transcriptome-driven functional basis with relevance to neurodegenerative disorders remains elusive. The aim of the present study is to identify the association among inflammation, brain structure, and neurodegenerative disorders at genetic and transcriptomic levels. Genetic variants associated with inflammatory cytokines were selected from the latest and largest genome-wide association studies of European ancestry. Neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and dementia with Lewy bodies (DLB) and brain structure imaging measures were selected as the outcomes. Two-sample Mendelian randomization analyses were conducted to identify the causal associations. Single-nucleus transcriptome data of the occipitotemporal cortex was further analyzed to identify the differential expressed genes in AD, which were tested for biological processes and protein interaction network. MR analysis indicated that genetically predicted TREM2 and sTREM2 were significantly associated with AD (TREM2: z-score = −9.088, p-value = 1.02 × 10−19; sTREM2: z-score = −7.495, p-value = 6.61 × 10−14). The present study found no evidence to support the causal associations between other inflammatory cytokines and the risks of AD, PD, ALS, or DLB. Genetically predicted TREM2 was significantly associated with the cortical thickness of inferior temporal (z-score = −4.238, p-value = 2.26 × 10−5) and pole temporal (z-score = −4.549, p-value = 5.40 × 10−6). In the occipitotemporal cortex samples, microglia were the main source of TREM2 gene and showed increasing expression of genes associated with inflammation and immunity. The present study has leveraged genetic and transcriptomic data to identify the association among TREM2, temporal lobe, and AD and the underlying cellular and molecular basis, thus providing a new perspective on the role of TREM2 in AD and insights into the complex associations among inflammation, brain structure, and neurodegenerative disorders, particularly AD.

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Data Availability

All data used in the present study were publicly available. The summary-level GWAS datasets of inflammatory cytokines and neurodegenerative disorders were acquired from GWAS Catalog website (https://www.ebi.ac.uk/gwas). The summary-level GWAS datasets of brain structure imaging measures were acquired from Oxford Brain Imaging Genetics Server BIG40 (https://open.win.ox.ac.uk/ukbiobank/big40/).

Abbreviations

AD:

Alzheimer’s disease

ALS:

Amyotrophic lateral sclerosis

CRP:

C-reactive protein

CSF:

Cerebrospinal fluid

CTR:

Control

CX3CL1:

Fractalkine

DEG:

Differentially expressed gene

DLB:

Dementia due to Lewy’s bodies

GO:

Gene Ontology

GSEA:

Gene-set enrichment analysis

GWAS:

Genome-wide association study

IL-1:

Interleukin-1

IL-2:

Interleukin-2

IL-6:

Interleukin-6

IVW:

Inverse-variance weighted

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MR:

Mendelian randomization

MSigDB:

Molecular Signatures Database

PD:

Parkinson’s disease

TREM2:

Triggering receptor expressed on myeloid cell 2

TNFR1:

Tumor necrosis factor receptor 1

TNFR2:

Tumor necrosis factor receptor 2

TNFSF14:

Tumor necrosis factor ligand superfamily member 14

TRAIL:

TNF-related apoptosis-inducing ligand

TRAILR2:

TNF-related apoptosis-inducing ligand receptor 2

TRANCE:

TNF-related activation-induced cytokine

UKB:

UK Biobank

YKL40:

Chitinase-3-like protein 1

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Acknowledgements

The authors gratefully thanked all the studies or consortia mentioned in the present study for providing summary-level GWAS data and expression matrix of single-nucleus transcriptome.

Funding

This work was funded by the Science and Technology Innovation 2030 Major Projects (2022ZD0211600), the National Natural Science Foundation of China (92249305, 82071201, 82071997), the Shanghai Municipal Science and Technology Major Project (2018SHZDZX01), the Research Start-up Fund of Huashan Hospital (2022QD002), the Excellence 2025 Talent Cultivation Program at Fudan University (3030277001), the Shanghai Talent Development Funding for the Project (2019074), the ZHANGJIANG Lab, the Tianqiao and Chrissy Chen Institute, and the State Key Laboratory of Neurobiology and Frontiers Center for Brain Science of Ministry of Education, Fudan University.

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Authors and Affiliations

  1. Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China

    Wei-Shi Liu, Ya-Ru Zhang, Hui-Fu Wang & **-Tai Yu

  2. Department of Neurology, Qingdao Municipal Hospital, Qingdao University, Qingdao, China

    Yi-Jun Ge

  3. Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China

    Wei Cheng

  4. Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Fudan University, Ministry of Education, Shanghai, China

    Wei Cheng

  5. Fudan ISTBI—ZJNU Algorithm Centre for Brain-Inspired Intelligence, Zhejiang Normal University, **hua, China

    Wei Cheng

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Contributions

JTY conceptualized the study and revised the manuscript. WSL, YRZ, WC, and YJG analyzed and interpreted the data. WSL and HFW prepared all the figures and tables. WSL and YRZ drafted and revised the manuscript. All authors contributed to the writing and revisions of the paper and approved the final version.

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Correspondence to **-Tai Yu.

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Informed consent was obtained from all individual participants included in the GWAS study and single-nucleus transcriptomic study used in the present study.

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All data in this study were obtained from the published GWAS studies or single-nucleus transcriptomic study, and the participants had signed informed consent in the published original studies.

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Liu, WS., Zhang, YR., Ge, YJ. et al. Inflammation and Brain Structure in Alzheimer’s Disease and Other Neurodegenerative Disorders: a Mendelian Randomization Study. Mol Neurobiol 61, 1593–1604 (2024). https://doi.org/10.1007/s12035-023-03648-6

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