Associations of plasma biomarkers with longitudinal co-pathologies in Alzheimer's disease and cerebral small vessel disease comorbidity.

BACKGROUND: Plasma glial fibrillary acidic protein (GFAP), neurofilament light (NfL), phosphorylated tau217 (p-tau217), and the β-amyloid (Aβ) 42/40 ratio are emerging indicators of neuroinflammation, neurodegeneration, and AD-specific pathology, while their specific roles within Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) comorbidity are not fully understood.

METHODS: Participants with normal cognition or mild cognitive impairment were drawn from the Alzheimer's Disease Neuroimaging Initiative database. Multivariable linear regression and linear mixed-effects models were employed to examine associations of baseline plasma biomarkers with neuropathological features and cognition. Furthermore, Cox proportional hazards models assessed the associations of plasma biomarkers with the risk of comorbid AD and CSVD.

RESULTS: In total populations, elevated GFAP and p-tau217 were significantly associated with greater white matter hyperintensity (WMH) burden, hippocampal atrophy, cerebral Aβ burden, and cognitive decline at baseline and with progression over time (|β| = 0.007 to 1.670, p = 0.047 to <0.0001). Within disease-specific subgroups, GFAP, p-tau217, and Aβ42/40 ratio demonstrated associations with hippocampal atrophy or WMH progression in CSVD (|β| = 0.011 to 0.220, p = 0.046 to 0.010), whereas GFAP, NfL, p-tau217, and Aβ42/40 ratio were linked to hippocampal atrophy and/or WMH progression in typical AD (|β| = 0.013 to 0.191, p = 0.044 to 0.0002). For Cox proportional hazards models, p-tau217 demonstrated greater precision in predicting progression to the CSVD phenotype within the AD subgroup (Hazard ratios = 1.267 to 3.811, p = 0.046 to 0.034).

CONCLUSION: These findings underscore the potential role of plasma biomarkers in elucidating the synergistic mechanisms underlying AD and CSVD comorbidity.