Proteomic markers linking anxiety phenotypes to Alzheimers disease risk: a multi-analyte proteomic analysis

Importance: Anxiety phenotypes - rumination, global anxiety, and worry (RAW) - are increasingly associated with Alzheimer's disease and related dementias (ADRD) risk, yet how anxiety phenotypes relate to coordinated, multi-system biology in the at-risk older adults is unknown. Objective: To map associations between anxiety phenotypes and plasma proteomic profile across five ADRD-relevant biological domains in older adults with high anxiety symptoms. Design, Setting, and Participants: Cross-sectional analysis of 110 older adults (aged 53-75 years) without dementia from the observational longitudinal RAW Brain study in Pittsburgh, Pennsylvania. Main Outcome(s) and Measure(s): Plasma was profiled with the NULISAseq CNS panel. Principal component (PC) analysis was conducted with Horn's parallel analyses across five ADRD-relevant biological domains (amyloid/tau pathology, inflammation, neurodegeneration, synuclein/synaptic disorders, and vascular) yielded 14 PCs (37.4-64.9% within-domain variance). Associations with each phenotype were tested by linear regression adjusted for age and sex, with Benjamini-Hochberg false discovery rate correction (p-FDR<0.05). Results: A neurodegeneration component (higher neuronal pentraxins and neurofilament light, with lower neurogranin) was associated with all three phenotypes (rumination, {beta} =0.26; global anxiety, {beta}= 0.39; worry, {beta} =0.36; all p-FDR<0.05). Inflammatory, VEGF receptor-ligand, and phospho-tau versus amyloid-processing components showed phenotype-specific associations, most often with worry severity. Conclusion and Relevance: Distinct anxiety phenotypes map onto dissociable plasma proteomic profiling, converging on a shared neurodegeneration axis reflecting neuronal injury, while diverging across neuroimmune, vascular, and proteostatic domains. These results point toward the biological heterogeneity of anxiety phenotypes as risk factors for ADRD. Further research is needed to clarify these biological pathways and explore targeted prevention strategies.