Blood-Based Biomarkers Track Progression Risk in Subjective Cognitive Decline

Longitudinal changes in blood-based biomarkers of Alzheimer disease (AD) were associated with cognitive decline and progression to mild cognitive impairment (MCI) or dementia among individuals with subjective cognitive decline (SCD), according to results of a prospective cohort study published in JAMA Network Open. Plasma phosphorylated tau 217 (p-tau217), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) showed both baseline and longitudinal associations with clinical progression, which according to the study authors, suggests the potential utility of these biomarkers for early intervention and disease monitoring.

The study included 298 individuals with SCD evaluated at a memory clinic in the Netherlands between 2005 and 2023. Participants underwent annual cognitive assessments and biennial blood sampling for plasma amyloid-beta 42/40 (Aβ 42/40), p-tau217, GFAP, and NfL, with baseline amyloid status determined by PET or cerebrospinal fluid (CSF) biomarkers. Biomarkers were measured using Simoa technology (Quanterix, Billerica, MA), including the Simoa Neurology 4-plex E kit (Quanterix, Billerica, MA) and the Simoa p-tau217 kit (Janssen Pharmaceuticals, Beerse, Belgium). Cox proportional hazards models were used to examine associations between biomarker levels, biomarker trajectories, and risk of progression to MCI or dementia.

Key findings included:

• Lower baseline plasma Aβ 42/40 levels were associated with a higher risk of clinical progression (hazard ratio [HR], 4.09; 95% CI, 2.15 to 7.78), improving prognostic accuracy from a concordance index (C-index) of 0.69 to 0.77 (77% prognostic accuracy for disease progression).
• Higher baseline p-tau217 levels were associated with a higher risk of clinical progression (HR, 2.92; 95% CI, 2.07 to 4.11), with prognostic accuracy improving to a C-index of 0.86 from 0.69.
• Longitudinal increases in p-tau217 levels were strongly associated with progression from SCD to MCI or dementia (HR, 3.61 per 0.05-SD annual increase; 95% CI, 1.76 to 7.39).
• Baseline GFAP levels were associated with a higher risk of clinical progression (HR, 1.77; 95% CI, 1.38 to 2.29), and GFAP slope was also predictive (HR, 1.51; 95% CI, 1.02 to 2.23).
• Baseline NfL levels (HR, 1.93; 95% CI, 1.37 to 2.73) and NfL slope (HR, 2.56; 95% CI, 1.27 to 5.18) were associated with a higher risk of clinical progression, though slope measures did not further improve model discrimination.

Source: Trieu C, van Harten AC, van Leeuwenstijn MSSA, et al. Longitudinal Blood-Based Biomarkers and Clinical Progression in Subjective Cognitive Decline. JAMA Netw Open. 2025;8(12):e2545862. doi:10.1001/jamanetworkopen.2025.45862