Systemic inflammation, gut microbiome composition, and cognitive performance among older Ugandans with Alzheimer's disease and related dementias: A cross-sectional study

Systemic inflammation is implicated in neurodegeneration; however, evidence linking circulating inflammatory biomarkers to cognitive decline remains inconsistent, particularly in low- and middle-income countries. High-sensitivity C-reactive protein (hs-CRP) is a standard systemic inflammatory marker; however, its relationship with cognitive performance and gut microbiome composition in sub-Saharan Africa remains underexplored. We investigated the association between hs-CRP and cognitive performance across older Ugandans diagnosed with Alzheimer disease (AD), mild cognitive impairment (MCI), and cognitively intact controls and examined whether gut microbial composition modified this relationship. We conducted a cross-sectional study of community-dwelling older adults in Wakiso District, Uganda. Cognitive performance was assessed using the Education-Adjusted Montreal Cognitive Assessment (MoCA). Systemic inflammation was quantified using plasma hs-CRP, and gut microbial profiles were generated via full-length 16S rRNA gene sequencing. Multivariable linear regression models were used to evaluate the associations between log-transformed hs-CRP concentrations and MoCA scores, adjusting for age, sex, and body mass index. Linear regression assumptions were formally tested. Exploratory analyses examined taxon-level differential abundance across diagnostic categories, hs-CRP-microbiome correlations, and hs-CRP × taxon interaction terms on MoCA scores, with multiple-testing adjustment using the false discovery rate. The analytic cohort comprised 85 participants (mean age 77.5 ± 9.2 years; 67 AD, 10 MCI, and 8 controls). Median hs-CRP was higher in AD (1.96 [0.25-3.75] mg/L) than in MCI (0.25 [0.25-2.73] mg/L) and controls (0.25 [0.25-0.84] mg/L). Higher hs-CRP showed a modest inverse trend with MoCA scores that was not statistically significant after adjustment for age, sex, and body mass index (standardized , ). Advancing age was independently associated with poorer cognitive performance (standardized , ). Several microbial genera exhibited nominal differences across diagnostic groups and hs-CRP levels; however, no individual taxon-level associations or hs-CRP × microbiome interaction terms survived false discovery rate correction (). Circulating hs-CRP was not independently associated with global cognitive performance in this cohort of older Ugandans. Genus-level microbiome analyses yielded exploratory, hypothesis-generating patterns that warrant validation in larger longitudinal cohorts investigating gut-brain axis interactions in African populations.