Midlife ICAM-1 levels may predict cardiovascular disease and cognitive decline in latelife: Insights from the HeartSCORE study

Introduction: Systemic inflammation is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD) and has also been implicated in the progression of neuroinflammation. However, the relationship between inflammation and the combined risk of ASCVD and cognitive decline-particularly during the critical transition from midlife to late life-remains poorly understood. Identifying a shared inflammatory marker that signals vulnerability to both conditions may be an important tool for early intervention. In this study, we examined how baseline inflammatory markers, as well as their changes over one year, relate to long-term risk of ASCVD and cognitive outcomes. Methods: We analyzed baseline and one-year change (1y-Δ) in an inflammatory biomarker panel high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), intracellular Adhesion Molecule 1 (ICAM-1) and CD40 ligand (CD40L_) in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Using logistic and linear Cox regression models, the association of inflammatory markers and 1y-Δ, cognitive assessment by MoCA score, coronary artery calcium (CAC), carotid intima-media thickness (CIMT), and major adverse cardiovascular events (MACE) events were assessed longitudinally. All data were adjusted for the pooled cohort equation (PCE) risk factors and area under the receiver operating characteristic curve (AUC) were calculated for incremental risk prediction. Results: Among 673 participants (mean age 59 ± 6. 8 years; 63. 9 % female; 31. 6 % Black) were followed for 12 years. While both hs-CRP and IL-6 were associated with MACE events at 12 years, only ICAM-1 was linked with long-term MACE (HR 2. 34 1. 02-5. 37, p < 0. 05) as well as lower MoCA scores (β: 0. 47 95 % CI: 0. 93 to -0. 02, p < 0. 05). Compared to the PCE model, inflammatory biomarkers improved risk prediction indices for MACE (0. 812, ΔAUC +0. 056, p = 0. 02) and MoCA (0. 664, ΔAUC +0. 04, p = 0. 048). One-year biomarker changes were not significant for endpoint association. Conclusions: In a community cohort of adults, midlife levels of three inflammatory markers (hs-CRP, IL-6, and ICAM-1) were predictive of late life ASCVD; however, only ICAM-1 was identified as a dual marker for ASCVD and cognitive impairment. The role of ICAM-1 as a prognostic marker for adverse cardiovascular and cognitive health should be explored in future studies.