Exploratory study on the synergistic use of plasma neurofilament light chain, phosphorylated Tau181, and retinal examination for assessing the risk of Alzheimer's disease and mild cognitive impairment

Background Biomarker detection is crucial for diagnosing Alzheimer's disease (AD). A highly promising approach combines non-invasive fundus imaging of the retinal nerve fiber layer (RNFL) with plasma biomarkers. Combining RNFL with plasma neurofilament light chain (pNFL) and phosphorylated Tau181 (P-tau181) may play a significant role in the diagnosis and monitoring of mild cognitive impairment (MCI) and AD. Objective This study aimed to evaluate the utility of combining RNFL thickness with plasma pNFL and P-tau181 levels for assessing the risk of clinically diagnosed AD. Methods A total of 143 patients with AD and MCI underwent clinical and cognitive assessments as well as biomarker evaluations (plasma pNFL, P-tau181, RNFL), and receiver operating characteristic (ROC) analysis was finally employed to assess their diagnostic efficacy for clinically diagnosed AD. Results Significant inverse correlations were found between Mini-Mental State Examination scores and pNFL (R 2 = 0.344, p < 0.001) and P-tau181 (R 2 =0.424, p < 0.001). Temporal RNFL thickness was significantly lower in the MCI group versus healthy control (HCs), while the AD group showed intermediate thickness not significantly different from HCs. For AD diagnosis, pNFL achieved the highest area under the curve (AUC=0.748). Combining pNFL with P-tau181 improved the AUC to 0.784, and models further incorporating Apolipoprotein E ( APOE ) ε4 or RNFL thickness similarly showed high accuracy (AUCs=0.785/0.782). Conclusions Elevated levels of pNFL and P-tau181 are independent risk factors for cognitive decline. Combination with fundus examination confers significant diagnostic utility for clinically diagnosed AD.