Fig. 6: Pathway analysis and summary of evidence.
a, A canonical pathway plot showing the top six biological pathways enriched for candidate proteins. Values in the nodes correspond to −log(Benjamini-Hochberg corrected) P values derived from Fisher’s exact tests. Values in between nodes correspond to frequencies of overlapping candidate proteins across respective biological pathways, with color coding used to improve interpretability. The results are derived from ingenuity pathway analysis (IPA). b, A radial plot showing resiquimod, an antiviral medication and the top upstream regulator of candidate proteins, as well as its predicted effects on specific candidate proteins. Shapes correspond to protein type (cytokine, enzyme, transmembrane, kinase). Results were derived from Fisher’s exact tests in IPA. c, An upset plot summarizing evidence for candidate proteins, including empirical results obtained from the current analyses, as well as protein–protein interaction networks (STRING; predicted protein conformations are depicted in each circular node), cell-specific expression patterns (Human Protein Atlas), expression levels (RNA, protein) in postmortem AD brain tissue (AMP-AD), nominated therapeutic targets (AMP-AD), and targets of known medications (Open Targets). d, Proposed model by which infections may contribute to increased risk for neurodegeneration. A history of specific infections is linked to increased levels of proteins that exert deleterious effects on brain volumes over time (pathogenic) and decreased levels of proteins associated with stable brain volumes (protective), which are indicated in corresponding circles for each infection type. Protective proteins may exert their effects through alterations to amyloidogenic pathways, as indicated by changes in plasma Aβ42/40 ratio and pTau-181, whereas pathogenic proteins may exert their effects through other mechanisms that require further elucidation. Modulation of the plasma immune proteome among individuals with a prior infection and subsequent changes in rates of brain atrophy over time may ultimately increase risk for cognitive decline and dementia. The exact P values are presented in the source data files of Supplementary Tables 32–39. Diff., differential; RAR, retinoic acid receptor. Panel d was created with BioRender.
