Abstract Protein aggregate species play a pivotal role in the pathology of various degenerative diseases. Their dynamic changes are closely correlated with disease progression, making them promising candidates as diagnostic biomarkers. Given the prevalence of degenerative diseases, growing attention is drawn to develop pragmatic and accessible protein aggregate species detection technology. However, the performance of current detection methods is far from satisfying the requirements of extensive clinical use. In this review, we focus on the design strategies, merits, and potential shortcomings of each class of detection methods. The review is organized into three major parts: native protein sensing, seed amplification, and intricate program, which embody three different but interconnected methodologies. To the best of our knowledge, no systematic review has encompassed the entire workflow, from the molecular level to the apparatus organization. This review emphasizes the feasibility of the methods instead of theoretical detection limitations. We conclude that high selectivity does play a pivotal role, while signal compilation, multilateral profiling, and other patient‐oriented strategies (i.e. less invasiveness and assay speed) are also important.
