Brain. 2026 Jul 18:awag246. doi: 10.1093/brain/awag246. Online ahead of print.
ABSTRACT
Strong evidence supports the role of low-grade systemic inflammation in neurodegeneration, including cognitive decline. Given the literature documenting chronic persistent inflammation in older Black adults, we investigated the association between circulating inflammatory proteins and cognitive decline in this high-risk population. We used data (n = 642) from the Minority Aging Research Study (MARS) and the Rush Clinical Core, including plasma samples to assess circulating inflammatory proteins (Olink® Target-96 Inflammation) and cognition (global cognition and five cognitive domains) assessed annually following proteomics measurement using previously stored blood samples. Linear mixed-effect and latent class mixed models (age at blood draw for proteomics measurement, sex, and education-adjusted), and elastic-net regression were used. Statistical significance was determined using an FDR threshold of 10%. Participants (62.3 to 99.4 years) were mostly women (80.68%) with 15.1 years of education. In multivariable linear mixed-effect models, we found that higher levels of osteoprotegerin (OPG) and chemokine (C-C motif) ligand 23 (CCL23) were cross-sectionally associated with poorer global cognition (beta=-0.205 and beta=-0.148), and higher CCL23 was associated with poorer semantic memory (beta=-0.206). Furthermore, protein × time interaction analyses indicated that higher OPG, Stem cell factor (SCF), and chemokine (C-X-C motif) ligand 9 (CXCL9) levels were associated with faster decline in global cognition (OPG × time term: beta=-0.042), semantic memory (SCF × time term: beta=-0.059, OPG × time term: beta=-0.043), episodic memory (SCF × time term: beta=-0.064; OPG × time term: beta=-0.044), and visuospatial ability (CXCL9×time term: beta=-0.012). In latent class mixed models, several significant protein × time interactions were observed for episodic memory in the subgroup with initial below-average performance and gradual decline. Using elastic net regression, we identified signatures of global cognitive level (26 proteins), but the prediction of cognitive decline was poor. In older Black adults, circulating inflammatory proteins were linked to cognition, reinforcing the role of systemic inflammation as a potential driver of neurodegeneration in this population.
PMID:42470112 | DOI:10.1093/brain/awag246
