To examine the associations between plasma and cerebrospinal fluid (CSF) biomarkers of neuronal and glial dysfunction, white matter hyperintensities (WMH), and episodic memory and executive function performance among non-demented and demented older adults.

563 older adults ages 55 to 91 years (mean age = 72; SD = 6.9; mean education = 16; SD = 2.6) from the Alzheimer’s Disease (AD) Neuroimaging Initiative completed biomarker collection, brain Magnetic Resonance Imaging (MRI), and neuropsychological testing. Biomarkers of neuronal and glial dysfunction (plasma neurofilament light chain [NfL], CSF growth associated protein 43 [GAP-43], CSF soluble TREM2 [sTREM2]), total WMH volume, and composite episodic memory and executive function scores were examined. Participants were classified into three groups based on the 2018 Amyloid/Tau/Neurodegeneration (AT[N]) system: no AD pathology (A-T-[N-]; n = 176), suspected non-AD pathophysiology (A-T±[N]+ or A-T+[N]±; n = 87), or AD continuum (A+T±[N]±; n = 300). This framework stratified participants based on presence or absence of pathological CSF amyloid-β [A], CSF phosphorylated tau [T], and FDG-PET [N]. Relative importance analyses, which quantifies the contribution of an individual variable to a regression model, explored the relative contribution of demographic, health, biomarker, and WMH variables to episodic memory and executive function performance. Multiple linear regressions examined associations between biomarkers of neuronal and glial dysfunction, WMH, and specific cognitive domains. To examine whether these relationships were dependent on AT(N) group status, separate models tested Biomarker x AT(N) group or WMH x AT(N) group interactions. Analyses were adjusted for demographic (age, sex, years of education), health (APOE-ε4 status, vascular risk factors), and AD biomarker (amyloid-β, p-tau, FDG-PET) variables.

NfL was a relatively important and a significant predictor (β = -0.07, p = 0.04) of episodic memory across older adults and AT(N) status. There was a significant GAP-43 x AT(N) group interaction and a sTREM2 x AT(N) group interaction. There was a negative relationship between GAP-43 and episodic memory for AD continuum (β = -0.25, p < 0.001) compared to the no pathology group. There was also a negative relationship between sTREM2 and episodic memory for suspected non-AD pathophysiology (β = -0.29, p < 0.01) and AD continuum (β = -0.20, p < 0.01) relative to the no pathology group. For executive function, there was a negative relationship between GAP-43 and executive function for AD continuum relative to the no pathology group (β = -0.24, p < 0.01). No interaction effect was observed between WMH or NfL and AT(N) group status on cognition.

These findings implicate plasma NfL as an important non-specific biomarker of neuro-axonal injury associated with episodic memory performance in older adults. In contrast, CSF GAP-43 and sTREM2 were associated with differential episodic memory and executive function performance depending on the presence of AD pathology, suggesting that greater levels of biomarkers reflecting synaptic and glial dysfunction were associated with worse cognitive performance particularly in individuals along the AD continuum. These biomarkers of neuronal and glial dysfunction may serve as important cognitive correlates in the context of AD.