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Background: We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. Objective: To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. Methods: From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Results: Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (–0.14±0.04) and memory (–0.31±0.09) and with steeper decline in global cognition (–0.07±0.02), memory (–0.09±0.04), attention (–0.05±0.02), and language (–0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (–0.22±0.05), memory (–0.43±0.10), attention (–0.14±0.06), language (–0.15±0.05), and executive functioning (–0.15±0.05) and steeper decline in global cognition (–0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (–0.16±0.04), memory (–0.28±0.09), attention (–0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Conclusions: Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases. [ABSTRACT FROM AUTHOR]