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

Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) often coexist in older adults and contribute to cognitive impairment. The Apolipoprotein E (APOE) ε4 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 ε4, plasma NfL, and their association with the comorbidity of AD and CSVD remains unclear. To investigate the longitudinal relationship among APOE ε4, elevated plasma NfL, brain atrophy, and cognitive decline in individuals with comorbid AD and CSVD. We included 570 non-demented participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) study, categorizing them into four groups based on amyloid-β positivity and CSVD burden. Linear mixed-effects models examined the association among APOE ε4, 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 ε4, brain atrophy, and cognitive decline. APOE ε4 carriers showed elevated plasma NfL levels, brain atrophy, and cognitive decline. Plasma NfL mediated the effects of APOE ε4 on brain atrophy and cognitive decline in participants with comorbid AD and CSVD. Our findings suggest that neuroaxonal injury as a potential mechanism in the effects of APOE ε4 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.