Lactoferrin levels in Cerebrospinal fluid exhibits isoform-specific associations with Alzheimer's disease

Background: Pathological changes in Alzheimer's disease (AD) begin years before the onset of clinical symptoms. Developing cost-effective and minimally invasive biomarkers for preclinical diagnosis remains a critical goal in the field. Lactoferrin, an iron-binding glycoprotein, has emerged as a promising candidate due to its multifunctional roles reported in previous studies. However, whether lactoferrin levels in biofluids are associated with established AD biomarkers, and whether it can serve as a reliable diagnostic indicator, remains controversial. Methods: We analyzed SOMAscan proteomic data from 1,367 paired plasma and cerebrospinal fluid (CSF) samples from the ACE Alzheimer's Center Barcelona cohort to evaluate lactoferrin levels. Associations between two lactoferrin-targeting SOMAmers and classical AD biomarkers, including total tau (t-tau), phosphorylated tau (p-tau), and amyloid-beta (Aβ)42, were assessed. The prognostic value of lactoferrin in predicting dementia progression was further evaluated using survival analysis. Findings: Among the two lactoferrin-targeting SOMAmers, one showed a weak and exclusive association with CSF Aβ42 and syndromic status, while the other was weakly associated with CSF p-tau and t-tau AD biomarker levels, and also exhibited a stratification pattern by LTF signal strength. Furthermore, lactoferrin levels were not significantly associated with the progression from mild cognitive impairment (MCI) to dementia. Interpretation: Isoform-specific lactoferrin expression changes in cerebrospinal fluid (CSF), but not plasma, appears to have biological relevance and diagnostic biomarker potential for AD.