The aim of this study was to investigate whether some biomarkers could predict cognitive impairment after stroke. One hundred fifty-two first-ever stroke patients were recruited within 6-72 h after the onset of symptoms. Blood was drawn within 1 h after admission for determining biomarkers. Cognitive function was assayed 2 weeks after stroke. The patients were divided into four groups: stroke, vascular cognitive impairment with no dementia (VCIND), vascular dementia (VaD), and mixed dementia (MD). Forty healthy subjects were used as controls. The results indicated that lower soluble receptor levels for advanced glycation end products (sRAGE) and higher β-secretase enzyme (BACE1) and neprilysin (NEP) levels were found in the VCIND, VaD, and MD groups. In addition, the percentages of ε3/ε4 genotypes and ε4 alleles in the VCIND, VaD, and MD groups were higher than in the stroke group. Correlation analysis determined that sRAGE, BACE1, and NEP were significantly related to the results of neuropsychological assessments. Logistic regression analysis, however, suggested that only sRAGE and BACE1 changed ahead of cognitive impairment after stroke. In conclusion, only BACE1 and sRAGE, not NEP or APOE genotypes, may be biomarkers diagnosing post-stroke cognitive impairment.