DNA methylation signature of cognitive reserve moderates CSF tau pathology in prodromal Alzheimer’s disease

David Lukacsovich, Juan I. Young, Lissette Gomez, Brian W. Kunkle, Zhixin Mao, Wei Zhang, X. Steven Chen, Deirdre M. O’Shea, Tatjana Rundek, Eden R. Martin, Lily Wang

Description

This GitHub repository includes scripts used for the analyses in the above manuscript and the resulting summary statistics.

Cognitive reserve (CR) refers to differences in the adaptability of cognitive processes that modify the impact of Alzheimer’s disease (AD) pathology on cognitive performance. Currently there are no established blood-based biomarkers of CR in prodromal AD. In this study, we operationalize CR as memory reserve, defined as moderation (attenuation) of the CSF pTau181-memory association. DNA methylation (DNAm) integrates genetic and environmental influences and may capture biological processes that mitigate the impact of AD pathology on memory. We aimed to identify blood DNAm loci that moderate the association between cerebrospinal fluid (CSF) phosphorylated tau (pTau181) and memory in mild cognitive impairment (MCI). We also sought to determine if a DNAm-based signature of memory reserve predicts future memory decline.

0. Prepare amyloid positive samples

File	Link
code/markdown/00_get_target_samples	Link to the script

1. Pre-processing DNA methylation data

File	Link
code/markdown/01a_get_data.Rmd	Link to the script
code/markdown/01b_filter_probes.Rmd	Link to the script
code/markdown/01c_impute_autosomal.Rmd	Link to the script
code/markdown/01d_normalize_autosomal.Rmd	Link to the script
code/markdown/01e_pca_autosomal.Rmd	Link to the script
code/markdown/01f_batch_autosomal.Rmd	Link to the script
code/markdown/01g_batch_kw_plots.Rmd	Link to the script
code/markdown/01h_compile_characteristics.Rmd	Link to the script

2. Identify memory reserve-related CpGs and DMRs

File	Link
code/markdown/02a_mem_correlation.Rmd	Link to the script
code/markdown/02b_bacon_correct.Rmd	Link to the script
code/markdown/02c_get_signif_table.Rmd	Link to the script
code/markdown/02d_prepare_combp.Rmd	Link to the script
code/markdown/02e_summarise_combp.Rmd	Link to the script
code/markdown/02f_sig_betavals.Rmd	Link to the script
code/markdown/02g_get_miami_ad_statistics.Rmd	Link to the script
summary

3. Summary Statistics for CR-associated DNAm

linke to the file

4. Integrative analyses (pathway analysis, eQTm, brain-blood DNAm correlations)

File	Link
code/markdown/03a_pathway_analysis.Rmd	Link to the script
code/markdown/03b_eQTM_association.Rmd	Link to the script
code/markdown/03c_brain_blood_correlation.Rmd	Link to the script

5. Figures

File	Link
code/markdown/04a_miami_plot.Rmd	Link to the script
No association between DNAm vs. pTau or memory (DMRs)	Link to the script
No association between DNAm vs. pTau or memory (CpGs)	Link to the script

6. Sensitivity analysis that additionally adjusts smoking status

File	Link
code/markdown/05a_mem_correlation.Rmd	Link to the script
code/markdown/05b_bacon_correct.Rmd	Link to the script
code/markdown/05c_prepare_combp.Rmd	Link to the script
code/markdown/05d_summarize_combp.Rmd	Link to the script
code/markdown/05e_get_smoking_summaries.Rmd	Link to the script

7. Methylation-based Reserve Scores

File	Link
compute MRS	Link to the script
MRS predicts future visits	Link to the script