Abstract
Cognitive frailty (CF), the co-occurrence of physical frailty and mild cognitive impairment (MCI) without dementia, is an at-risk state for adverse health outcomes. While frailty and MCI are individually linked to cardiovascular dysfunction, mechanisms underlying their co-occurrence remain unclear. To investigate whether CF is associated with circulating biomarkers of cardiac dysfunction, and to examine if these biomarkers modify the associations between CF and future cognitive decline. 303 Singaporean memory clinic patients were followed up annually for five years. Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), growth differentiation factor-15 (GDF-15), and high-sensitivity cardiac troponin T (hs-cTnT) were quantified using immunoassays. Cognitive status was defined using the Clinical Dementia Rating (CDR; 0 = cognitively unimpaired, 0.5 = MCI). Physical frailty was assessed with the 30-item Frailty Index (FI ≥ 0.18 = frail). CF was defined as the presence of both CDR 0.5 and FI ≥ 0.18. Among 303 participants (mean age = 71.7 ± 7.7 years; 52.2% female), 35 (11.6%) met criteria for CF. CF individuals had higher NT-proBNP, GDF-15, and hs-cTnT levels (all p < 0.001) compared to non-CF counterparts. Frailty scores significantly interacted with CDR 0.5 (MCI) for NT-proBNP levels (β = 0.48; 95%CI = 0.14 to 0.83; p = 0.006). CF predicted for greater 5-year cognitive decline (β = -0.15; 95%CI = -0.27 to -0.03; p = 0.013), with steeper decline evident in those with higher NT-proBNP (β = -0.12; 95%CI = -0.23 to -0.01; p = 0.038). CF is associated with elevated cardiac dysfunction biomarkers and accelerated cognitive decline. High NT-proBNP exacerbates this decline, highlighting cardiovascular pathways as potential intervention targets for CF.