Seed amplification assays (SAAs) are highly sensitive and advanced techniques originally developed for the study and diagnosis of prion diseases. Thanks to their remarkably high sensitivity and specificity, SAAs are now widely employed in both research and clinical settings for prion detection, especially in peripheral tissues of patients with prion disorders. Many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, frontotemporal dementia, and amyotrophic lateral sclerosis, show prion-like mechanisms involving the misfolding and self-propagation of pathological proteins. As a result, SAAs are being adapted and refined for clinical use to improve the diagnosis of these conditions. This includes detecting traces of pathological proteins in cerebrospinal fluid as well as in minimally or noninvasively collected samples, such as blood, urine, skin, and olfactory mucosa. This chapter offers an overview of the role of SAAs in the clinical diagnosis of neurodegenerative diseases.