Association of Plasma Biomarkers of Alzheimer Disease and Neurodegeneration With Longitudinal Intra-Network Functional Brain Connectivity

Abstract

Background and objectives: Alzheimer disease (AD) is defined by cortical β-amyloid (Aβ), tau, and neurodegeneration, which contribute to cognitive decline, in part, by altering large-scale functional brain networks. While cortical Aβ and tau have been associated with changes in functional brain connectivity, it is unknown whether plasma biomarkers relate to such changes. In a healthy community sample of cognitively unimpaired adults free from major CNS disease from the Baltimore Longitudinal Study of Aging, we examined whether plasma biomarkers of AD pathology (Aβ_42/40, phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal changes in functional connectivity and whether changes in functional connectivity were related to longitudinal cognition.

Methods: Plasma biomarkers were measured using the Quanterix SIMOA assays. Intranetwork connectivity (3T resting-state fMRI) from 7 functional networks was derived using a predefined cortical parcellation mask for each participant visit. Cognitive performance was assessed concurrently with fMRI scan. Covariate-adjusted linear mixed-effect models were used to determine (1) whether plasma biomarkers were associated with longitudinal changes in connectivity, (2) whether the magnitude of the biomarker-connectivity relationships differed by amyloid status, and (3) whether changes in connectivity co-occurred with longitudinal changes in cognition.

Results: Our primary findings (n = 486; age = 65.5 ± 16.2 years; 54% female; mean follow-up time = 4.3 ± 1.7 years) showed that higher baseline GFAP was associated with faster declines in somatomotor (β = -0.04, p = 0.01, 95% CI -0.06 to -0.01), limbic (β = -0.03, p = 0.02, 95% CI -0.06 to -0.005), and frontoparietal (β = -0.04, p = 0.02, 95% CI -0.07 to -0.01) network connectivity. Amyloid status moderated several biomarker-connectivity associations. For instance, higher baseline NfL was related to faster declines in visual and limbic network connectivity, but only among amyloid-positive participants. Among 421 participants with ≥2 fMRI visits (age = 71.7 ± 11.4 years; 55% female; follow-up time = 3.9 ± 1.6 years), longitudinal changes in connectivity were associated with concurrent declines in cognition; however, these results did not survive multiple comparison correction.

Discussion: Among cognitively unimpaired participants, plasma biomarkers of amyloidosis, astrogliosis, and neuronal injury are associated with declines in network connectivity, particularly among amyloid-positive participants. Major limitations include the lack of inclusion of the sensitive pTau-217 and pTau-231 isoforms and comparative PET biomarkers.