The prognosis of PDAC is dismal, 5-yrs OS less than 10%, early diagnosis can improve the prognosis, but early detection depends on CA19-9 lacks sensitivity and specificity. Tumor specific genetic and epigenetic alternations could be detected in peripheral circulation as biomarkers for early diagnosis of PDAC. In our study, we found Plasma cfDNA can provide both genetic and methylation alternations in PDAC patients which showed a different pattern with healthy control; cfDNA-based multi-omics diagnostic model showed promising performance and the sensitivity may be further improved when combined with CA19-9; The mutation status and MPS of cfDNA may extinguish the PDAC patients with different prognosis.