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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ad_mci]

ABSTRACT: Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ad_mci]

PROVIDER: PRJNA591098 | ENA |

REPOSITORIES: ENA

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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ad_mci]

Project description:The role of peripheral inflammation in dementia is an important but complex topic. We present here the largest cohort of peripheral blood gene expression data ever assembled from patients with dementia and matching controls. Importantly, this cohort includes individuals from a diverse set of dementia disorders, including Alzheimer’s Disease (AD), mild cognitive impairment (MCI), and multiple disorders within the frontotemporal dementia (FTD) spectrum. We found strong transcriptional evidence of an innate immune inflammatory response, mediated by monocytes and neutrophils, in AD, MCI, and two FTD subtypes, PSP and nfvPPA. This transcriptional inflammatory response is enriched for genetic risk for AD, in part because it is also enriched for microglial genes, which have previously been implicated in AD risk. Finally, we show that this transcriptional response is strongly enriched for binding of the transcription factors PU.1 and RELA, which have previously been linked to AD risk and progression.

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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders [ftd]

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Systems-level analysis of peripheral blood gene expression in dementia patients reveals an innate immune response shared across multiple disorders

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Project description:People with neurodegenerative disorders have diverse clinical syndromes, genetic heterogeneity, and distinct brain pathological changes, but studies report overlap between these features. DNA methylation (DNAm) is a widely studied chemical modification to DNA, and increasing evidence suggests that DNAm alterations play an important role in neurodegenerative disorders. In this study we aimed to identify shared blood DNAm differences between 471-1,522 controls and people with Alzheimer’s disease (N = 161), amyotrophic lateral sclerosis (N = 3,032) and Parkinson’s disease (N = 1,132). We used a mixed-linear model method (MOMENT) that has been shown to account for the effect of (un)known confounders, to test for association of each DNAm site with each disorder. A fixed-effects meta-analysis of Alzheimer’s disease, amyotrophic lateral sclerosis, and Parkinson’s disease results identified 12 differentially methylated positions passing a genome-wide significant threshold. Predicted immune cell-type proportions were disrupted across all neurodegenerative disorders, as well as schizophrenia and rheumatoid arthritis. Protein inflammatory markers were correlated with profile sum-scores derived from disease-associated immune cell-type proportions in a healthy ageing cohort. In contrast, they were not correlated with MOMENT DNAm-derived profile sum-scores, calculated using effect sizes of the 12 differentially methylated positions as weights. We have identified shared differentially methylated positions in whole blood between neurodegenerative disorders that point to shared pathogenic mechanisms. These shared differentially methylated positions may reflect causes or consequences of disease, but they are unlikely to reflect cell-type proportion differences.

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