Synergistic effects of CSF Aβ42 and p‐Tau on functional resting‐state connectivity in cognitively unimpaired individuals

Abstract

AbstractBackgroundCerebral beta‐amyloid (Aβ) deposition disrupts functional resting‐state connectivity in cognitively unimpaired (CU) individuals. However, only a few studies have investigated these associations using Aβ cerebrospinal fluid (CSF) markers. Moreover, the reorganization of functional brain networks across the progressive stages of preclinical Alzheimer’s disease (AD) remains poorly understood. Here, we aim to identify functional connectivity (FC) differences in middle‐aged CU individuals, grouped as a function of both CSF Aβ (A) and pathological tau (T).MethodWe analyzed CSF and resting‐state functional magnetic resonance imaging (fMRI) data from 349 CU participants of the ALFA study (mean age=60.21 years). CSF Aβ42 and Aβ40 were assessed with the exploratory Roche NeuroToolKit robust prototype immunoassays, while p‐Tau181 was measured with the Elecsys® Phospho‐Tau (181P) CSF immunoassay (Roche Diagnostics International Ltd). Participants were grouped into three categories according to their biomarker status, resulting in three groups: A‐T‐, A+T‐, and A+T+. fMRI volumes were parceled into 218 regions, and correlations in the filtered fMRI signal among parcels were computed. We first assessed the impact of continuous CSFAβ42/40 concentration in the entire sample and subsequently assessed AT biomarker group differences in FC. A threshold of uncorrected p<0.005 using non‐parametric pair‐wise clustering was implemented.ResultA higher cerebral Aβ deposition, reflected by lower CSFAβ42/40, was associated with reduced FC within the default mode network (DMN), but increased FC between the visual network and the DMN, as well as the salience networks. Compared with A‐T‐, A+T‐ showed decreased within‐DMN connectivity (Fig. 1). Finally, compared with A+T‐, A+T+ individuals showed reduced FC within the temporo‐hippocampal (THN) and the executive control networks (ECN) (Fig. 2).ConclusionThis is the first study assessing FC in CU individuals adopting a staging of preclinical AD relying on multiple CSF biomarker classification. We report that CSFAβ42/40 disrupts the DMN but the co‐occurrence of Aβ and tau yields reduced connectivity in the THN and ECN, suggesting that Aβ and tau may interact in promoting a network reconfiguration extending beyond the DMN. Future studies shall clarify whether these differences reflect a correlate of pathology or rather a compensatory strategy to support cognitive performance in the face of AD pathology.