Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer’s disease

Introduction Subjective cognitive decline (SCD) is proposed to indicate transitional stage-2 in the AD continuum, yet longitudinal fluid biomarker data for this stage is scarce. We investigated if blood-based biomarkers in amyloid-positive individuals with SCD (A+SCD) support stage-2 as distinct from AD stages-1 and -3 and identify those at high risk for progression. Methods We analyzed plasma phospho-tau-181 (p181) and neurofilament-light-chain (NfL) in a prospective multicenter study of 460 participants across the AD continuum, assessing their association with cognition, hippocampal atrophy, and clinical progression. Results Baseline plasma p181 was elevated and increased faster in A+SCD compared to amyloid-positive cognitively unimpaired (A+CU) individuals (stage-1). NfL rose across A+CU, A+SCD, and A+MCI (stage-3). In A+SCD, higher p181 predicted cognitive decline and transition to MCI. Discussion Plasma p181 provides biomarker evidence for A+SCD as a distinct pre-dementia AD stage and helps identify individuals at risk for cognitive decline early in the AD continuum. Research in Context Systematic Review Research on subjective cognitive decline (SCD) and its association with Alzheimer’s disease (AD), as well as investigations into stage-2 of the AD continuum, is quickly expanding, but fluid biomarker evidence is scarce. We conducted a comprehensive review across PubMed, recent meeting abstracts, and oral presentations, focusing on cross-sectional and longitudinal case-control studies, cohort studies, and meta-analyses. Interpretation Our plasma phospho-181 tau (p181) findings provide molecular fluid biomarker evidence for A+SCD as a pre-dementia AD stage (stage-2) distinct from A+CU (stage-1). Plasma p181 assessment aids in identifying individuals at risk of future disease progression early in the AD continuum. Future directions The here proposed concept of SCD as an indicator of stage 2 of the Alzheimer’s disease continuum - supported and stratified by easily accessible blood-based biomarkers - warrants further validation in memory clinics. It could facilitate earlier- and thus even higher-effect - treatments in the pre-dementia stages of AD. Highlights A+SCD exhibits a distinct trajectory of plasma p181 compared to A+CU Higher plasma p181 levels in A+SCD predict PACC5 decline and transition to MCI Plasma p181 serves as a biomarker that delineates the A+SCD stage from A+CU Plasma p181 levels stratify SCD patients, facilitating early interventions