Plasma p-tau231 and NfL differently associate with functional connectivity patterns in cognitively unimpaired individuals

Amid the rising relevance of early and non-invasive markers for neurodegenerative diseases, such as Alzheimer's disease, this study addresses the relationship between two promising candidates: electrophysiology and plasma markers. Specifically, functional connectivity, which underlies cognitive function, with p-tau231 (i.e., a marker of incipient Aβ pathology) and neurofilament light chain (NfL, i.e., a neurodegeneration marker) were considered. Seventy-five cognitively unimpaired individuals underwent a blood extraction and two magnetoencephalography recordings, approximately 3 years apart. First, correlation analyses were conducted to examine the association between the pathology markers' concentration and FC. Subsequently, longitudinal FC changes were assessed, and their relationship with the markers' concentration was evaluated. Default mode network regions, including the middle temporal gyrus, precuneus, hippocampus, and inferior parietal lobe, presented a positive association between their alpha FC and p-tau231 positively. In contrast, NfL levels were negatively associated with theta FC in frontotemporal regions. Moreover, these areas exhibit a longitudinal theta FC decrease. Importantly, the theta FC reduction was more pronounced as NfL concentrations increased. The described alpha FC alterations do not follow a maturation trajectory and are age-independent. Thus, the alpha FC increase associated with p-tau231 levels could constitute an early electrophysiological biomarker of Aβ pathology. In contrast, the longitudinal theta FC decrease, enhanced by NfL, could constitute an early sign of neurodegeneration.