Plasma neurofilament light mediates the effects of Apolipoprotein E on brain atrophy and cognitive decline in the comorbid Alzheimer's disease and cerebral small vessel disease

Background: Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) often coexist in older adults and contribute to cognitive impairment. The Apolipoprotein E (APOE) E 4 allele and neuroaxonal injury, measured by plasma neurofilament light chain (NfL), are associated with an increased risk for both AD and CSVD. However, the relationship between APOE E 4, plasma NfL, and their association with the comorbidity of AD and CSVD remains unclear. Objective: To investigate the longitudinal relationship among APOE E 4, elevated plasma NfL, brain atrophy, and cognitive decline in individuals with comorbid AD and CSVD. Methods: We included 570 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, categorizing them into four groups based on amyloid-p positivity and CSVD burden. Linear mixed- effects models examined the association among APOE E 4, plasma NfL, brain volume measured by magnetic resonance imaging, and cognition over 2 years. Mediation analyses assessed the role of elevated plasma NfL in the relationship between APOE E 4, brain atrophy, and cognitive decline. Results: APOE E 4 carriers showed elevated plasma NfL levels, brain atrophy, and cognitive decline. Plasma NfL mediated the effects of APOE E 4 on brain atrophy and cognitive decline in participants with comorbid AD and CSVD. Conclusion: Our findings suggest that neuroaxonal injury as a potential mechanism in the effects of APOE E 4 on brain atrophy and cognitive decline, highlighting the clinical utility of plasma NfL as a potential biomarker for disease progression and response to therapeutic intervention in comorbid AD and CSVD.