mtDNA

This repository contains R and shell scripts that were used to generate the results, figures, and tables presented in the manuscript “Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer’s disease brain” published in Molecular Neurodegeneration. The data itself is not stored in this repository but can be accessed via the AD Knowledge portal. Please visit the manuscript’s landing page for more details about the datasets.

Analysis, figures, and tables

The R scripts in the main folder were used to generate results, figures and tables shown in the manuscript.

• Figure 1: The mtDNAcn is reduced in cortical brain regions in AD. (fig1_mtDNAcnRaw.R)
• Figure 2: Changes of the mtDNAcn are primarily associated with tau in the DLPFC and TDP-43 in the PCC. (fig2_mtDNAcnAndPathologies.R)
• Figure 3: The mtDNAcn is associated with cognitive functioning independent of brain pathologies. (fig3_cognitionMultivariable.R)
• Figure 4: Frequency of mtDNA heteroplasmic mutations in cortical regions increases with age. (fig4_heteroplasmy.R, fig4B_circusPlot.R)
• Figure 5: Correlates of mitochondrial health demonstrate complex relationship with AD-related traits in the DLPFC. (fig5_mtContent.R)
• Table 1: Characteristics of the ROSMAP cohort. (table1_cohorts.R)
• Table 2: Effect of ApoE e4 genotype on mtDNAcn. (table2_apoe4.R)
• Supplementary Figure 1: Log-transformed mtDNAcn values are approximately normally distributed. (fig1_mtDNAcnRaw.R)
• Supplementary Figure 2: Changes of the mtDNAcn are primarily associated with tau in the DLPFC. (fig2_mtDNAcnAndPathologies.R)
• Supplementary Figure 3: Significant fraction of the ApoE ε4 effect on mtDNAcn is mediated via AD pathologies. (table2_apoe4.R)
• Supplementary Figure 4: Number of mtDNA heteroplasmic mutations in cortical regions is associated with age adjusted for sex, pathologic diagnosis, and mtDNAcn. (fig4_heteroplasmy.R)
• Supplementary Figure 5: Mitochondrial content score and its relation to mtDNAcn, mtDNA heteroplasmy burden and AD-related phenotypes. (fig5_mtContent.R)
• Supplementary Table 1: Characteristics of the Mayo cohort. (table1_cohorts.R)
• Supplementary Table 2: Characteristics of the MSBB cohort. (table1_cohorts.R)
• Supplementary Table 3: Detailed results from the univariate regression analyses shown in Fig. 2A. (fig2_mtDNAcnAndPathologies.R)
• Supplementary Table 4: Association between cell type proportions and mtDNAcn in the DLPFC. (fig2_mtDNAcnAndPathologies.R)
• Supplementary Table 5: Association between number of mtDNA heteroplasmies and age adjusted for pathologic diagnosis. ( fig4_heteroplasmy.R)
• Supplementary Excel File 2: Genetic associations with mtDNAcn (table2_apoe4.R)

mtDNAcn estimation

The mtDNAcn was calculated using the R script located in the mtDNAcn folder.

mtDNA variant calling

mtDNA homoplasmic and heteroplasmic variants were detected using the scripts in the subfolder mtVariantsPipeline. The pipeline replicates the GATK mitochondria pipeline. See the info file in the folder for more information how to invoke the scripts.