Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease

Introduction: Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline. Methods: We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation. Results: We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD. Discussion: We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD.