Associations of plasma phosphorylated tau181 and neurofilament light chain with brain amyloid burden and cognition in objectively defined subtle cognitive decline patients

Aims There is increasing evidence that plasma biomarkers are specific biomarkers for Alzheimer's disease (AD) pathology, but their potential utility in Obj-SCD (objectively defined subtle cognitive decline) remains unclear. Methods A total of 234 subjects, including 65 with brain amyloid beta (A beta) negative normal cognition (A beta- NC), 58 with A beta-positive NC (A beta+ NC), 63 with A beta- Obj-SCD, and 48 with A beta+ Obj-SCD were enrolled. Plasma A beta 42, A beta 40, A beta 42/A beta 40 ratio, phosphorylated tau181 (p-tau181), neurofilament light chain (NfL), and total tau (T-tau) were measured using Simoa assays. Logistic and linear regression analyses were used to examine the relationship between plasma biomarkers and brain amyloid, cognition, and imaging measures adjusting for age, sex, education, APOE epsilon 4 status, and vascular risk scores. Receiver operating characteristics were used to evaluate the discriminative validity of biomarkers. Results After adjustment, only plasma p-tau181 and NfL were significantly elevated in A beta+ Obj-SCD participants compared to A beta- NC group. Elevated p-tau181 was associated with brain amyloid accumulation, worse cognitive performance (visual episodic memory, executive function, and visuospatial function), and hippocampal atrophy. These associations mainly occurred in A beta+ individuals. In contrast, higher NfL was correlated with brain amyloid burden and verbal memory decline. These associations predominantly occurred in A beta- individuals. The adjusted diagnostic model combining p-tau181 and NfL levels showed the best performance in identifying A beta+ Obj-SCD from A beta- NC [area under the curve (AUC) = 0.814], which did not differ from the adjusted p-tau181 model (AUC = 0.763). Conclusions Our findings highlight that plasma p-tau181, alone or combined with NfL, contributes to identifying high-risk AD populations.