<h3>Objective:</h3> To explore plasma phosphorylated tau (p-tau) 181 levels in Subjective Cognitive Decline and to investigate its role as a potential biomarker for Alzheimer’s Disease (AD) in Subjective Cognitive Decline (SCD). <h3>Background:</h3> One of the greatest challenges in AD is the discovery of new non-invasive, sensitive and specific biomarkers, which might be useful in the early stages such as SCD. Plasma p-tau181 is becoming increasingly notable in prodromal stages of AD, as a valuable marker for tauopathy, one of the core features of AD. <h3>Design/Methods:</h3> We included 27 SCD patients, who underwent clinical evaluation, neuropsychological assessment, Apolipoprotein E (APOE) genotyping, plasma p-tau181 analysis with SiMoA assay and cerebrospinal fluid (CSF) biomarkers analysis (Aβ1–42, Aβ1–42/1–40, p-tau, t-tau).Patients were rated according to A/T(N) system and classified as carrier of AD pathology (AP+) when A+ was associated with either T+ or N+, or non-carriers (AP−) when they were classified as A− (regardless of T and N classification), or A+/T−/N−. <h3>Results:</h3> Plasma p-tau181 levels were correlated with CSF p-tau (ϱ=0.819, <i>p</i><0.001) and also with age (ϱ=0.605, <i>p</i>=0.001), CSF Aβ1–42 (ϱ= −0.461, <i>p</i>=0.012), CSF Aβ1–42/1–40 (ϱ= −0.770, <i>p</i><0.001) and CSF t-tau (ϱ=0.535, <i>p</i>=0.009). A multivariate linear regression analysis showed that plasma p-tau181 were significantly associated only with CSF p-tau levels (<i>p</i>=0.027). When comparing AP+ and AP− subgroups, we found that plasma p-tau181 levels were significantly higher in the former group (2.85±0.53 vs 1.75±.66, <i>p</i><0.001). A ROC curve analysis demonstrated that plasma p-tau181 was highly accurate for discriminating between AP+ and AP− SCD patients (AUC = 0.908). <h3>Conclusions:</h3> Plasma p-tau181 levels strongly correlated with CSF p-tau. Plasma p-tau showed a high accuracy in differentiating SCD patients who were carriers from SCD patients who were non-carriers of AD pathology. Our preliminary results suggest that plasma p-tau181 might be a promising noninvasive biomarker of AD pathology which might be useful in preclinical stage of AD. <b>Disclosure:</b> Ms. Giacomucci has nothing to disclose. Mr. Mazzeo has nothing to disclose. Dr. Bagnoli has nothing to disclose. Dr. Ingannato has nothing to disclose. Sonia Padiglioni has nothing to disclose. Sandro Sorbi has nothing to disclose. Valentina Bessi has nothing to disclose. Benedetta Nacmias has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier.