A comparison of blood and brain‐derived ageing and inflammation‐related DNA methylation signatures and their association with microglial burdens

Stevenson, Anna J.; McCartney, Daniel L.; Gadd, Danni A; Shireby, Gemma; Hillary, Robert F.; King, Declan; Tzioras, Makis; Wrobel, Nicola; McCafferty, Sarah; Murphy, Lee; McColl, Barry W.; Redmond, Paul; Taylor, Adele M.; Harris, Sarah E.; Russ, Tom C.; McIntosh, Andrew M.; Mill, Jonathan; Smith, Colin; Deary, Ian J.; Cox, Simon R.; Marioni, Riccardo E.; Spires‐Jones, Tara L.

doi:10.1111/ejn.15661

Cited by 11 publications

(5 citation statements)

References 55 publications

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“…This increase could also be in response to Aβ burden although higher levels of GFAP burdens seen in hippocampus regions across all cohorts do not mirror Aβ burdens in the same region comparison suggesting other factors were at play. Previous studies investigating DNA methylation signatures in the LBC1936 cohort have indicated CD68 burdens are highest in the hippocampal brain region [36]. Here we again show evidence of this neuroimmune response; however, we also highlight significant cohort variation although burden levels were relatively low and below 0.5% for all regions apart from the hippocampus.…”

Section: Discussionsupporting

confidence: 72%

Synaptic resilience is associated with maintained cognition during ageing

King

Holt

Toombs

et al. 2022

Preprint

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INTRODUCTION It remains unclear why age increases risk of Alzheimer’s disease and why some people experience age-related cognitive decline in the absence of dementia. Here we test the hypothesis that resilience to molecular changes in synapses contribute to healthy cognitive ageing. METHODS We examined post-mortem brain from people in mid-life (n=15), healthy ageing with either maintained cognition (n=8) or lifetime cognitive decline (n=7), and Alzheimer’s disease (n=13). Synapses were examined with high resolution imaging, proteomics, and RNA sequencing. Stem cell-derived neurons were challenged with Alzheimer’s brain homogenate. RESULTS Synaptic pathology increased, and expression of genes involved in synaptic signalling decreased between mid-life, healthy ageing and Alzheimer’s. In contrast, brain tissue and neurons from people with maintained cognition during ageing exhibited decreases in synaptic signalling genes compared to people with cognitive decline. DISCUSSION Efficient synaptic networks without pathological protein accumulation may contribute to maintained cognition during ageing.

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Section: Discussionsupporting

confidence: 72%

Synaptic resilience is associated with maintained cognition during ageing

King

Holt

Toombs

et al. 2022

Preprint

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“…Detailed information about the cohort, brain imaging and post-mortem brain samples can be found in a cohort update and brain protocol papers (14,15). DNAm from whole blood and 5 post-mortem brain tissues has been measured using Illumina Infinium HumanMethylation450 BeadChip array (16). Quality control and processing details are provided in Supplemental Table 2 .…”

Section: Methodsmentioning

confidence: 99%

“…DNAm was measured in 5 brain regions (hippocampus - BA35, dorsolateral prefrontal cortex – BA46, primary visual cortex - BA17, anterior cingulate cortex - BA24, ventral/lateral inferior temporal cortex - BA20/21) from post-mortem brain samples of 14 LBC1936 individuals, with one sample missing from hippocampus. Tissue acquisition and processing details are detailed in Stevenson et al (16). Using blood-DNAm measured at wave 1 and brain-DNAm data, exploratory EWAS analyses were performed (CpG ∼ age + sex + smoking).…”

Section: Methodsmentioning

confidence: 99%

Blood- and brain-based genome-wide association studies of smoking

Chybowska,

Bernabeu,

Yousefi

et al. 2024

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Background: Self-reported smoking is often incorporated into disease prediction tools but suffers from recall bias and does not capture passive exposure. Blood-based DNA methylation (DNAm) is an objective way to assess smoking. However, studies have not fully explored tissue-specificity or epigenome-wide coverage beyond array data. Here, we update the existing biomarkers of smoking and conduct a detailed analysis of the associations between blood DNAm and self-reported smoking.Methods and Findings: A blood-based Bayesian epigenome-wide association study (EWAS) of smoking was carried out in 17,865 Generation Scotland individuals at ~850k CpG sites (Illumina EPIC array). For 24 pairs of smokers and non-smokers a high-resolution approach was implemented (~4 million sites, TWIST methylome panel). A DNAm-derived biomarker of smoking (mCigarette) was tested in the independent Lothian Birth Cohort 1936 (n=882, Illumina 450k array) and in the ALSPAC parents and offspring at four time points (range n=496-1,207). To explore tissue specific signals, EWASs of smoking were run across five brain regions for 14 individuals using DNAm from the EPIC array. Lastly, genome-wide association studies (GWASs) of smoking pack years and an epigenetic score for smoking (GrimAge DNAm pack years) were conducted (n=17,105). The primary EWAS analyses identified two novel genome-wide significant loci, mapping to genes related to addiction and carcinogenesis. Associations with CpG sites which are currently absent from methylation arrays were identified by the high resolution EWAS of smoking (n=48). The mCigarette pack years biomarker showed excellent discrimination across all smoking categories (current, former, never), and outperformed existing predictors in associations with pack years in an external test dataset (Pearson r=0.75). Several CpGs showed near-perfect discrimination of smoking status in both blood and brain, but these loci did not overlap across tissues. The GWAS of DNAm (but not self-reported) pack years identified novel and established smoking-related loci. However, the self-reported phenotype GWAS had a higher genetic correlation with a large meta-analysis GWAS of self-reported pack years. Among the study shortcomings are its potential lack of generalizability to non-Europeans and the absence of serum cotinine data.Conclusion: A multi-tissue, multi-cohort analysis of the relationship between smoking, DNA and DNAm (assessed via arrays and targeted sequencing) has improved our understanding of the biological consequences of smoking.

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“…To investigate the relationship between DNA methylation patterns of ageing and inflammation in the blood and in the brain, Stevenson et al performed a matched analysis of DNA methylation data from blood and specific post-mortem brain regions from 14 individuals aged 70-79 years. This study, although limited by small sample size, identified potential vulnerability of the hippocampus, evidenced by ageing-related DNA methylation signatures (Stevenson et al, 2022). In a comprehensive, systematic review of the association between CSF protein markers of synapse loss and neuronal injury with cognition, Saunders et al come to the conclusion that due to substantial heterogeneity, no formal conclusions can be drawn, but suggest that neurofilament-light may be associated with worse cognition in AD, frontotemporal dementia and typical cognitive ageing, whereas the cerebrospinal fluid level of neurogranin is associated with cognition in those with AD-like biomarker profiles and neuronal pentraxin-2 correlates with cognition across dementia syndromes.…”

Section: Clinical Research and Biomarkersmentioning

confidence: 98%