Abstract INTRODUCTION Plasma biomarkers offer promise for improving the diagnosis of Alzheimer's disease (AD) and differentiating AD and other neurodegenerative disorders (NDs) like frontotemporal dementia (FTD) from primary psychiatric disorders (PPDs), particularly in younger patients. METHODS In this prospective study, we investigated plasma phosphorylated tau 217 (p‐tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in 341 unselected participants from a neuropsychiatry memory clinic, including AD ( n = 40), behavioral variant FTD (bvFTD) ( n = 15), PPD ( n = 69), other NDs, and controls. RESULTS Plasma p‐tau217 showed strong diagnostic performance for distinguishing AD from bvFTD (96% accuracy) and PPD (93% accuracy). NfL best distinguished all NDs from PPD, while GFAP did not bring additional value. Biomarker profiles using predefined cut‐offs and age‐adjusted z‐scores further clarified group differences. DISCUSSION Plasma p‐tau217 and NfL have strong diagnostic utility in real‐world, diagnostically complex cohorts. These findings support implementation of scalable blood‐based biomarkers to improve early and accurate diagnosis in memory clinical settings. Highlights Plasma p‐tau217 was significantly elevated in AD compared to other disorders. P‐tau217 distinguished AD from bvFTD with high accuracy. P‐tau217 distinguished AD from PPDs with high accuracy. NfL/p‐tau217 ratio and GFAP added limited diagnostic value compared to p‐tau217 and NfL. Findings support blood biomarkers in younger, real‐world clinical cohorts.