Multidimensional social isolation and cognitive decline in older adults: Dominant mediation by depression and domain-specific pathways

Background Social isolation is a key modifiable risk factor for cognitive decline, yet its mediating mechanisms are not fully understood. Objective This study examines depression and systemic inflammation (neutrophil-to-lymphocyte ratio, NLR) as mediators between social isolation and domain-specific cognitive impairments. Methods Using cross-sectional data from 1272 adults aged ≥60 (NHANES 2011–2014), we constructed a social isolation index (0–4) incorporating marital status, living arrangements, functional limitations, and social participation barriers. Cognition was assessed via Alzheimer's Disease Word Learning Test (CERAD-WL) (verbal memory), Animal Fluency (executive function), Digit Symbol Substitution Test (processing speed), and composite Z-scores. Mediation analyses with PHQ-9 depression scores and NLR controlled for sociodemographic, lifestyle, and clinical factors. Results Severe social isolation (score = 3) showed dose-response associations with cognitive impairment, particularly in processing speed (DSST β = −11.66, p < 0.01) and global cognition (Z-score β = −0.59, p < 0.01). Depression accounted for about 14.5–20.3% of the association with executive function and processing speed, and NLR explained 25.4% of verbal memory problems. Significant direct effects persisted post-mediation (e.g., CERAD-WL β = −0.519; DSST β = −2.374, p < 0.001), suggesting unmeasured pathways. Conclusions Social isolation was associated with cognition through tripartite mechanisms: depression-linked processing speed/executive dysfunction, inflammation-mediated verbal memory decline, and direct neurobiological effects. Integrated interventions targeting social connectivity and depression are clinically prioritized over anti-inflammatory strategies. Findings emphasize domain-specific vulnerabilities requiring precision approaches for isolated older adults.