BMC Med. 2026 Feb 11. doi: 10.1186/s12916-026-04623-3. Online ahead of print.
ABSTRACT
BACKGROUND: We tested whether inflammation indexed by soluble tumor necrosis factor receptor-1 (sTNFR1) is related to cognitive decline. We examined serum sTNFR1 with cognition in the Health and Retirement Study (HRS) and cerebrospinal fluid (CSF) sTNFR1 with tau pathology and magnetic resonance imaging (MRI)-based atrophy in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Finally, we used Mendelian randomization (MR) to assess associations between genetically proxied sTNFR1 and regional brain volumes.
METHODS: Data were from HRS (2016-2020; N = 6028) and ADNI (N = 287). In HRS, serum sTNFR1 was log-transformed (quartiles); in ADNI, CSF sTNFR1 was analyzed. Global cognition included word recall, serial 7 s, and counting backwards. In ADNI, cognition was measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB); CSF total tau/phosphorylated tau and longitudinal MRI regional volumes were analyzed. Associations were estimated with linear and linear mixed-effects models adjusted for demographic, clinical, and genetic covariates including apolipoprotein E ε4 (APOE ε4). Incident mild cognitive impairment (MCI)/dementia was modeled with cause-specific Cox and Fine-Gray models. Incremental prediction used optimism-corrected change in area under the curve (AUC; ΔAUC), net reclassification improvement (NRI)/integrated discrimination improvement (IDI), calibration, and decision curve analysis. MR used genome-wide association study (GWAS) statistics to test effects of genetically proxied sTNFR1 on MRI-derived regional volumes.
RESULTS: In HRS (follow-up 4 years), higher serum sTNFR1 was associated with lower baseline cognition and faster decline in global cognition (β = – 0.16/year). Higher sTNFR1 predicted MCI/dementia (Cox HR ≈ 1.17; Fine-Gray sHR ≈ 1.14); among cognitively normal individuals, risk was elevated (OR = 1.30; 95% CI, 1.03-1.63). Adding sTNFR1 to 2- and 4-year prediction models conferred small discrimination gains after internal validation (ΔAUC ≤ 0.003) and minimal or inconsistent net clinical benefit. In ADNI, higher CSF sTNFR1 was associated with greater CSF total tau and phosphorylated tau, and predicted accelerated caudate atrophy. Exploratory MR suggested a nominal association with reduced right inferior temporal volume, limited by instruments.
CONCLUSIONS: sTNFR1 is associated with cognitive decline and tau-related selective neurodegeneration, but provides limited incremental predictive value beyond established risk factors; external validation and replication are warranted.
PMID:41673623 | DOI:10.1186/s12916-026-04623-3