Cerebrospinal fluid homocysteine, but not plasma homocysteine, is associated with markers of tau pathology and neurodegeneration

Background Growing evidence links cardiovascular health to Alzheimer's disease (AD). While elevated plasma homocysteine (Hcy) is associated with cognitive decline, the relationship between cerebrospinal fluid (CSF) Hcy and the core pathological biomarkers of AD remains unclear. Objective This study aimed to investigate the associations of CSF Hcy and plasma Hcy with CSF amyloid-β (Aβ 42 ), phosphorylated tau (p-tau), and total tau (t-tau). Methods A total of 294 non-demented participants (110 cognitively normal, 184 with mild cognitive impairment) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were analyzed. Multivariate linear regression was used to analyze the relationships between CSF and plasma Hcy levels and CSF Aβ 42 , phosphorylated tau (p-tau), and total tau (t-tau). Logistic regression analyses assessed the association between Hcy levels and Aβ 42 positivity, tau positivity, and neurodegeneration positivity. Results CSF Hcy levels showed significant positive associations with CSF p-tau and t-tau, as well as tau and neurodegeneration positivity. In contrast, no significant association was found between CSF Hcy and Aβ 42 pathology. Notably, plasma Hcy was not associated with any AD-related biomarkers. Conclusions CSF Hcy, rather than plasma Hcy, was associated with markers of tau pathology and neurodegeneration in non-demented older adults. These findings suggest that CSF Hcy may be more closely associated with tau-related pathological processes during the pre-dementia stages of AD. Further research is needed to explore the mechanisms underlying these associations.