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

Alzheimers Res Ther. 2024 Jun 8;16(1):124. doi: 10.1186/s13195-024-01486-9.

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 Aβ42/40 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 Aβ42/40, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease* / blood
  • Alzheimer Disease* / diagnostic imaging
  • Alzheimer Disease* / physiopathology
  • Amyloid beta-Peptides* / blood
  • Autonomic Nervous System / physiopathology
  • Autonomic Nervous System Diseases / blood
  • Autonomic Nervous System Diseases / etiology
  • Autonomic Nervous System Diseases / physiopathology
  • Biomarkers* / blood
  • Brain / diagnostic imaging
  • Brain / physiopathology
  • Female
  • Glial Fibrillary Acidic Protein / blood
  • Humans
  • Magnetic Resonance Imaging*
  • Male
  • Neurofilament Proteins / blood
  • Peptide Fragments / blood

Substances

  • Biomarkers
  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Glial Fibrillary Acidic Protein
  • Neurofilament Proteins
  • amyloid beta-protein (1-40)
  • neurofilament protein L