Associations between Cognitive Frailty and Circulating Cardiovascular Biomarkers in a Memory Clinic Cohort

Background: Cognitive frailty (CF), the co-occurrence of physical frailty and mild cognitive impairment (MCI) without dementia, is an at-risk state for adverse outcomes. While frailty and MCI are individually linked to cardiovascular dysfunction, mechanisms underlying their co-occurrence remain unclear. Purpose: To investigate whether CF is associated with circulating biomarkers of cardiac dysfunction, and to examine if these biomarkers modify associations between CF and future cognitive decline. Methods: 303 Singaporean memory clinic patients were followed up annually for five years. Plasma levels 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 measured by immunoassays. Cognitive status was defined using the Clinical Dementia Rating (CDR; 0 = unimpaired, 0.5 = MCI). Physical frailty was measured with 30-item Frailty Index (FI ≥0.18 = frail). CF was defined as CDR 0.5 and FI ≥0.18. Results: Among 303 participants (mean age, 71.7±7.7years; 52.1% female), 35 (11.6%) had CF. CF participants had higher NT-proBNP, GDF-15, and hs-cTnT levels (all p < 0.001). Frailty significantly interacted with MCI (CDR=0.5) for NT-proBNP (β 2.10; 95% C.I. 0.59-3.61; p=0.006). CF predicted for greater 5-year cognitive decline (β –0.15; 95% C.I. -0.27 to -0.03; p=0.013), with steeper decline evident in those with higher NT-proBNP (β –0.27; 95% C.I. -0.53 to -0.01; p=0.038). Conclusion: 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.