Background <p>While blood biomarkers for AD have proven useful in identifying AD pathology from other neurodegenerative conditions, their prognostic value in real-world clinical settings, such as memory clinics, remains unexplored. We aimed to examine the prognostic value of AD plasma biomarkers and their short-term changes within 4 months, for predicting clinical and neuroradiological progression over two years.</p> Method <p>We performed a prospective observational longitudinal cohort study of patients with early stages of AD and followed them for up to 2 years. Plasma was analysed for neurofilament light (NfL), brain-derived tau (BD-tau), phosphorylated tau 217 (p-tau217), and glial fibrillary acidic protein (GFAP) on single molecule array. The outcomes were annual changes in clinical dementia rating scale, sum of boxes (CDR-SB) and changes in [¹⁸F]-fluorodeoxyglucose positron emission tomography ([¹⁸F]FDG-PET) and magnetic resonance imaging (MRI) brain scans. We performed linear regression models with baseline and short-term plasma biomarker changes as predictors, adjusted for age, sex, and creatinine.</p> Results <p>In total, 94 patients with MCI or dementia due to AD had baseline and one-year follow-up, with 85 patients completing two-year follow-up. We found that baseline plasma NfL was significantly associated with an increase in CDR-SB at one- and two-year follow-up. Neither plasma BD-tau, p-tau217 or GFAP were associated with future clinical progression. Short-term changes of plasma NfL were associated with reduced glucose metabolism in the hippocampus and temporal cortex on [¹⁸F]FDG-PET. Short-term changes in plasma p-tau217 were significantly associated with reduced hippocampal glucose metabolism, and further, short-term changes in the p-tau217/BD-tau ratio were significantly associated with reduced metabolism in hippocampal and isthmus cingulate cortex on [¹⁸F]FDG-PET. We found no association between plasma biomarkers and MRI volumetric changes after multiple testing correction.</p> Conclusion <p>Our findings indicate that plasma NfL can serve as a predictor for subsequent clinical progression in early AD. Short-term changes in AD-related plasma biomarkers may reflect underlying disease processes, however, several limitations affect their interpretability. Therefore, short-term changes should be evaluated carefully and always in the context of baseline levels and clinical characteristics.</p> Trial registration <p>Clinicaltrials.gov (NCT05175664), date of registration 2021–12-01.</p>