Neuronal and Glial Dysfunction, White Matter Hyperintensities, and Cognition in Aging and Alzheimer’s Disease

This cross-sectional study examined associations between multiple fluid biomarkers of neuronal and glial dysfunction (plasma neurofilament light chain, CSF growth-associated protein 43, CSF soluble triggering receptor expressed on myeloid cells 2 [sTREM2]), total white matter hyperintensity volume, and episodic memory and executive function performance in the context of Alzheimer’s disease biomarker status. 563 participants (mean age = 71.9 years, SD = 7.2) from the Alzheimer’s Disease Neuroimaging Initiative were classified by the Amyloid-β/Tau/Neurodegeneration framework into no Alzheimer’s disease pathology (n = 176), suspected non-Alzheimer’s disease pathophysiology (n = 87), or Alzheimer’s disease continuum (n = 300) groups. Participants completed baseline neuropsychological assessment, plasma/CSF biomarker collection, and Magnetic Resonance Imaging. Analyses explored the relative contributions of biomarkers to episodic memory and executive function performance and whether relationships varied by Amyloid-β/Tau/Neurodegeneration group status. Across all participants, neurofilament light chain (β ̂ = -0.14) and growth-associated protein 43 (β ̂ = -0.13) were the strongest biomarkers associated with episodic memory performance, such that greater levels were associated with worse episodic memory. There was a group by growth-associated protein 43 interaction with episodic memory: greater growth-associated protein 43 was associated with lower episodic memory performance in participants classified as Alzheimer’s disease continuum relative to the no Alzheimer’s disease pathology group (β ̂ = -0.26). No robust associations between biomarkers and executive function performance or between sTREM2, white matter hyperintensity volume, and cognition were observed. Biomarkers of neuro-axonal injury and synaptic dysfunction may independently contribute to episodic memory performance across participants with differing Amyloid-β/Tau/Neurodegeneration profiles. Growth-associated protein 43 may predict worse episodic memory performance in participants with greater Alzheimer’s disease pathology. These biomarkers of neuronal dysfunction may serve as domain-specific cognitive correlates in the context of Alzheimer’s disease biomarker status.