Objectives: Peripheral neuropathy (PN) of the lower extremities is highly prevalent among older adults, even in the absence of diabetes, and has been linked to substantial morbidity and mortality. However, the biologic pathways underlying PN remain poorly understood. We examined the proteomic profiles of community-dwelling adults aged 70–95 years to identify proteins and pathways associated with PN. Methods: We conducted a prospective cohort analysis within the Atherosclerosis Risk in Communities (ARIC) Study among participants who underwent a monofilament insensitivity test for PN between 2016 and 2017 (ARIC Visit 6). PN was defined as loss of sensation at one or more foot sites. Blood samples collected at Visit 5 (2011-2013) were assayed using the SomaScan 5k proteomics platform. Logistic regression models were used to assess associations between 4,955 proteins and PN adjusting for demographic and clinical covariates. Statistical significance thresholds were set at P < 0.05 (nominal) and P < 0.05/4,955 (Bonferroni correction). Proteins meeting Bonferroni-corrected significance were carried forward for pathway analysis. Over-representation analysis (ORA) was then performed by mapping significant proteins to the Gene Ontology database to identify biological pathways associated with PN. Results: Among 2,514 participants (median age 74.0 years; 43% male; 16% Black adults; 31% with diabetes), 39% had PN based on monofilament testing. After adjustment for demographic and clinical covariates, PN was associated with 301 proteins at the nominal threshold, of which 11 (including Carbonic anhydrase 3, Seizure 6-like protein, Myomesin-2, Alpha-actinin-2, Myosin light chain 6B, and Myosin-binding protein C) remained significant after Bonferroni correction ( Figure ). ORA of the Bonferroni-significant proteins revealed enrichment in biologic processes related to muscle cell development, differentiation, and assembly of structural units (sarcomeres and myofibrils) ( Figure ). Conclusions: Older adults with PN, as detected by monofilament testing, show altered protein expression in pathways related to muscle development and organization. These pathways may explain previous observations in aging population linking PN to reduced functional decline and an increased risk of falls and related morbidities.
Wu et al. (2026) studied this question.