Combined use of plasma p-tau217, NfL, and GFAP predicts domain-specific cognitive decline in cognitively unimpaired and MCI individuals.

INTRODUCTION: Accurate identification of individuals at risk for cognitive decline is critical for treatment planning and trial enrichment strategies. We evaluated the combined utility of plasma phosphorylated tau at threonine 217 (p-tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in predicting domain-specific cognitive decline. METHODS: Participants (n = 523; 40.9% cognitively unimpaired [CU]; 59.1% mild cognitive impairment [MCI]) were from the Massachusetts Alzheimer's Disease Research Center. Cognition was assessed using the National Alzheimer's Coordinating Center Uniform Data Set. Participants were classified as high(+)/low(-) for each biomarker using Gaussian mixture models. RESULTS: Among all participants, high p-tau217 alone [p-tau217(+)NfL(-)GFAP(-)] was associated with a steeper decline in episodic/semantic memory and processing speed compared to the all-low group (p ≤ 0.02). With the addition of high GFAP [p-tau217(+)NfL(-)GFAP(+)], steeper decline extended to most cognitive domains, including global cognition and executive function, compared to the all-low group. In CU, faster decline in global cognition and executive function was seen when all biomarkers were elevated ([p-tau217(+)NfL(+)GFAP(+)]; p ≤ 0.04). DISCUSSION: Combined plasma biomarkers predict decline in cognitive domains vulnerable to early disease. HIGHLIGHTS: High phosphorylated tau at threonine 217 (p-tau217) alone was associated with declines in semantic/episodic memory, whereas its combination with elevated glial fibrillary acidic protein (GFAP) predicted declines in a wider range of cognitive domains. Elevated neurofilament light chain (NfL) amplifies the cognitive decline already driven by p-tau217 and GFAP. In cognitively unimpaired individuals, subtle domain-specific cognitive declines can be detected when both core and non-core Alzheimer's disease biomarkers are used. Our finding highlights the importance of focusing on vulnerable cognitive domains during early disease where global cognition may appear stable but specific impairments can be masked within composite scores.