White matter structure-function coupling alteration is associated with plasma biomarkers and cognition in Alzheimer's disease.

Objectives: There were white matter (WM) microstructural abnormalities in Alzheimer's disease (AD), and it may affect information transmission along WM tracts. We aim to investigate AD-related changes in the structure-function coupling of WM and their associations with AD plasma biomarkers and cognitive performance.

Methods: This retrospective study evaluated participants who provided blood samples, underwent MR brain scans, and completed neuropsychological assessments. Plasma biomarker levels of β-amyloid (Aβ), phosphorylated tau181 (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) were measured using the Single Molecule Array platform. We used a structure-function coupling approach, combining spatial-temporal correlations of functional signals with diffusion tensor orientations in the WM circuit derived from functional and diffusion magnetic resonance imaging (MRI). Association and mediation analyses were conducted to explore the relationships among plasma biomarkers, structure-function coupling, and cognitive performance in AD.

Results: Compared with the cognitively normal (CN) and mild cognitive impairment (MCI) groups, the AD dementia group showed a widespread increase in structure-function coupling within WM regions, including the body and splenium of the corpus callosum. Additionally, structure-function coupling in WM tracts was significantly associated with the levels of p-tau181 and NfL. Moreover, structure-function coupling mediated the relationship between memory and the level of p-tau181 or NfL.

Conclusion: Our findings suggest that there is altered information transmission along WM tracts in patients with AD. The brain structure-function coupling is associated with plasma biomarkers and cognitive scores, suggesting that abnormal signal transfer of neuronal fiber pathways could be a potential mechanism of AD neuropathology.

Key points: Question White matter (WM) microstructural abnormalities may affect information transmission along WM tracts, resulting in cognitive decline in Alzheimer's disease (AD). Findings The AD dementia group showed a widespread increase in structure-function coupling within WM regions, which was associated with plasma biomarkers and cognitive scores. Clinical relevance The brain structure-function coupling is associated with plasma biomarkers and cognitive scores, suggesting that abnormal signal transfer of neuronal fiber pathways could be a potential mechanism of the neuropathology of AD.