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, cerebrospinal fluid (CSF) growth associated protein-43, CSF soluble TREM2), total white matter hyperintensity volume, and episodic memory and executive function performance in the context of Alzheimer’s disease (AD) 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 AD pathology (n =176), suspected non-AD pathophysiology (n = 87), or AD continuum (n = 300) groups. Participants completed baseline neuropsychological assessment, plasma/CSF biomarker collection, and Magnetic Resonance Imaging. Analyses explored the importance 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 = -0.12) 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 AD continuum relative to the no AD pathology group (β = -0.26). No robust associations between biomarkers and executive function performance or between soluble TREM2, 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 AD pathology. These biomarkers of neuronal dysfunction may serve as domain-specific cognitive correlates in the context of AD biomarker status.