The proteomic and metabolomic signature of inherited chromosomally integrated HHV‐6 and its role in all‐cause dementia and mortality risk: The UK Biobank study
Abstract OBJECTIVE To examine associations of inherited chromosomally integrated human herpesvirus 6 (iciHHV‐6) with incident dementia and mortality, characterize proteomic and metabolomic correlates of carrier status, and evaluate whether these biomarkers relate to dementia and mortality risk. METHODS We analyzed UK Biobank participants ≥50 years of age with plasma metabolomics (N = 138,676) and proteomics (N ≤ 15,416) data and ≈15 years of follow‐up. Cox proportional hazards models adjusted for key confounding factors evaluated associations of iciHHV‐6 with dementia and mortality. Multivariable linear models assessed iciHHV‐6 associations with metabolomic and proteomic profiles. Mediation and interaction were evaluated using structural equation models and Cox models with biomarker interactions. Least absolute shrinkage and selection operator regression identified independent proteomic and metabolomic predictors using imputed biomarker data. RESULTS iciHHV‐6 was associated with higher dementia risk (hazard ratio [HR] = 1.32), particularly among women (HR = 1.66) and individuals with elevated Alzheimer's disease polygenic risk (HR = 1.49). Branched‐chain amino acids (leucine and isoleucine) were elevated among carriers without mediating dementia risk. Proteomic analyses identified 126 nominally associated iciHHV‐6–related proteins, many of which (Neurofilament Light Chain (NEFL), Glial Fibrillary Acidic Protein (GFAP), Yes‐Associated Protein 1 (YAP1), Sialic Acid‐binding Immunoglobulin‐like Lectin 5 (SIGLEC5), Interleukin 19 (IL19), A Disintegrin And Metalloproteinase with Thrombospondin Motifs 16 (ADAMTS16), Sphingomyelin Phosphodiesterase 1 (SMPD1)) were also associated with dementia and/or mortality. Exploratory pathway analyses suggested enrichment of proteins related to immune regulation and post‐translational modification. Predictive models identified NEFL, GFAP, Vascular Endothelial Growth Factor A (VEGF), Brevican (BCAN), remnant cholesterol, and polyunsaturated fatty acids as dementia predictors (area under the curve [AUC] = 0.83), whereas NEFL, Growth Differentiation Factor 15 (GDF15) Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), Ectodysplasin A2 Receptor (EDA2R) and Advanced Glycosylation End‐product Specific Receptor (AGER) predicted mortality (AUC = 0.70). DISCUSSION iciHHV‐6 was associated with increased dementia risk, particularly among women and genetically susceptible individuals, with neuroimmune and metabolic biomarker profiles potentially relevant to brain aging and mortality risk.