Subjective cognitive decline is proposed as an indicator of transitional disease stage 2 in the Alzheimer's disease continuum. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD support the notion of stage 2 as a distinct stage between stages 1 and 3 of Alzheimer's disease and to identify those at high risk for clinical progression. In a prospective multicenter study involving 457 participants across the Alzheimer's disease continuum, the authors analyzed plasma phospho-tau 181 and neurofilament light chain and assessed their association with longitudinal cognition, hippocampal atrophy, and Alzheimer's disease clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired individuals. In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia Alzheimer's disease stage distinct from A + CU and helps identify individuals at risk for cognitive decline early in the Alzheimer's disease continuum.
