Central autonomic network dysfunction and plasma Alzheimer's disease biomarkers in older adults

Abstract

Background: Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer's disease (AD) and dementia, but no studies to date have investigated whether plasma AD biomarkers are associated with CAN functional connectivity changes in at risk older adults.

Methods: Independently living older adults (N = 122) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain fMRI and a CAN network derived from a voxel-based meta-analysis was applied for overall, sympathetic, and parasympathetic CAN connectivity using the CONN Functional Toolbox. Sensorimotor network connectivity was studied as a negative control. Plasma levels of amyloid (Aβ₄₂, Aβ₄₀), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were assessed using digital immunoassay. The relationship between plasma AD biomarkers and within-network functional connectivity was studied using multiple linear regression adjusted for demographic covariates and Apolipoprotein E (APOE) genotype. Interactive effects with APOE4 carrier status were also assessed.

Results: All autonomic networks were positively associated with Aβ_42/40 ratio and remained so after adjustment for age, sex, and APOE4 carrier status. Overall and parasympathetic networks were negatively associated with GFAP. The relationship between the parasympathetic CAN and GFAP was moderated by APOE4 carrier status, wherein APOE4 carriers with low parasympathetic CAN connectivity displayed the highest plasma GFAP concentrations (B = 910.00, P = .004). Sensorimotor connectivity was not associated with any plasma AD biomarkers, as expected.

Conclusion: The present study findings suggest that CAN function is associated with plasma AD biomarker levels. Specifically, lower CAN functional connectivity is associated with decreased plasma Aβ_42/40, indicative of cerebral amyloidosis, and increased plasma GFAP in APOE4 carriers at risk for AD. These findings could suggest higher order autonomic and parasympathetic dysfunction in very early-stage AD, which may have clinical implications.

Keywords: Alzheimer’s Disease; Aβ42/40; Central autonomic network; Glial fibrillary acidic protein; Neurofilament light chain.

Fig. 1

Hierarchical linear regression parameters quantifying the additional effect beyond demographic and APOE4 carrier status of resting state within-network functional connectivity on plasma Aβ_42/40 for the (A): Central Autonomic Network (CAN), (B): Parasympathetic CAN, (C): Sympathetic CAN, and (D): Sensorimotor network. (B): unstandardized regression coefficient, SE: standard error, β = standardized regression coefficient, FC: functional connectivity, N = 122

Fig. 2

Hierarchical linear regression parameters quantifying the additional effect beyond demographic and APOE4 carrier status of resting state within-network functional connectivity on fibrillary acidic protein (GFAP) in picograms per milliliter (pg/ml) for the (A): Central Autonomic Network (CAN), (B): Parasympathetic CAN, (C): Sympathetic CAN, and (D): Sensorimotor network. (B): unstandardized regression coefficient, SE: standard error, β = standardized regression coefficient, FC: functional connectivity, N = 94

Fig. 3

(A): The effect of parasympathetic central autonomic network (CAN) functional connectivity (FC) on glial fibrillary acidic protein in picograms per milliliter (GFAP pg/ml) conditional upon APOE4 status is compared in 40 APOE4 carriers and 54 non-carriers. (B): Scatterplot showing the relationship between resting state parasympathetic CAN FC and GFAP pg/ml in 40 APOE4 carriers is shown and within group p-values are provided with and without demographic covariate adjustment

Fig. 4

Hierarchical linear regression parameters quantifying the additional effect beyond demographic and APOE4 carrier status of resting state within-network functional connectivity on plasma neurofilament light chain (NfL) in picograms/millimeter (pg/ml) for the (A): Central Autonomic Network (CAN), (B): Parasympathetic CAN, (C): Sympathetic CAN, and (D): Sensorimotor network. (B): unstandardized regression coefficient, SE: standard error, β = standardized regression coefficient, FC: functional connectivity, N = 94