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Both plasma biomarkers and brain network topology have shown great potential in the early diagnosis of Alzheimer's disease (AD). However, the specific associations between plasma AD biomarkers, structural network topology, and cognition across the AD continuum have yet to be fully elucidated. This retrospective study evaluated participants from the Sino Longitudinal Study of Cognitive Decline cohort between September 2009 and October 2022 with available blood samples or 3.0‐T MRI brain scans. Plasma biomarker levels were measured using the Single Molecule Array platform, including β‐amyloid (Aβ), phosphorylated tau181 (p‐tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). The topological structure of brain white matter was assessed using network efficiency. Trend analyses were carried out to evaluate the alterations of the plasma markers and network efficiency with AD progression. Correlation and mediation analyses were conducted to further explore the relationships among plasma markers, network efficiency, and cognitive performance across the AD continuum. Among the plasma markers, GFAP emerged as the most sensitive marker (linear trend: t = 11.164, p = 3.59 × 10−24; quadratic trend: t = 7.708, p = 2.25 × 10−13; adjusted R2 = 0.475), followed by NfL (linear trend: t = 6.542, p = 2.9 × 10−10; quadratic trend: t = 3.896, p = 1.22 × 10−4; adjusted R2 = 0.330), p‐tau181 (linear trend: t = 8.452, p = 1.61 × 10−15; quadratic trend: t = 6.316, p = 1.05 × 10−9; adjusted R2 = 0.346) and Aβ42/Aβ40 (linear trend: t = −3.257, p = 1.27 × 10−3; quadratic trend: t = −1.662, p = 9.76 × 10−2; adjusted R2 = 0.101). Local efficiency decreased in brain regions across the frontal and temporal cortex and striatum. The principal component of local efficiency within these regions was correlated with GFAP (Pearson's R = −0.61, p = 6.3 × 10−7), NfL (R = −0.57, p = 6.4 × 10−6), and p‐tau181 (R = −0.48, p = 2.0 × 10−4). Moreover, network efficiency mediated the relationship between general cognition and GFAP (ab = −0.224, 95% confidence interval [CI] = [−0.417 to −0.029], p =.0196 for MMSE; ab = −0.198, 95% CI = [−0.42 to −0.003], p =.0438 for MOCA) or NfL (ab = −0.224, 95% CI = [−0.417 to −0.029], p =.0196 for MMSE; ab = −0.198, 95% CI = [−0.42 to −0.003], p =.0438 for MOCA). Our findings suggest that network efficiency mediates the association between plasma biomarkers, specifically GFAP and NfL, and cognitive performance in the context of AD progression, thus highlighting the potential utility of network‐plasma approaches for early detection, monitoring, and intervention strategies in the management of AD. [ABSTRACT FROM AUTHOR]

The polymorphism of the Apolipoprotein E (APOE) promoter rs405509 can regulate the transcriptional activity of the APOE gene and is related to Alzheimer's disease (AD). However, its effects on cognitive performance and the underlying brain mechanisms remain unknown. Here, we performed a battery of neuropsychological tests in a large sample (837 subjects) of nondemented elderly Chinese people, and explored the related brain mechanisms via the construction of diffusion MRI-based structural connectome and graph analysis from a subset (84 subjects) of the sample. Cognitively, the rs405509 risk allele (TT) carriers showed decreased attention and execution functions compared with noncarriers (GG/GT). Regarding the topological alterations of the brain connectome, the risk allele group exhibited reduced global and local efficiency of white matter structural networks, mainly in the left anterior and posterior cingulate cortices (PCC). Importantly, the efficiency of the left PCC is correlated with the impaired attention function and mediates the impacts of the rs405509 genotype on attention. These results demonstrated that the rs405509 polymorphism affects attention function in nondemented elderly people, possibly by modulating brain structural connectivity of the PCC. This polymorphism may help us to understand the neural mechanisms of cognitive aging and to serve as a potential marker assessing the risk of AD. [ABSTRACT FROM AUTHOR]