Abstract Background Aging is associated with declining protective immunity and persistent low-grade inflammatory responses, which significantly contribute to Alzheimer’s disease (AD) pathogenesis. Detecting aging-related cerebral vulnerability associated with deterioration of the immune system requires from non-invasive biomarkers able to detect failures in the brain-immunity connection. Reduced levels of salivary lactoferrin (sLF), an iron-binding protein with immunomodulatory activity, have been related to AD diagnosis. However, it remains unknown whether decreased sLF is associated with increased cortical amyloid-beta (Aβ) load and/or with loss of cortical integrity in normal aging. Methods Seventy-four cognitively normal older adults (51 females) participated in the study. We applied multiple linear regression analyses to assess (i) whether sLF is associated with cortical Aβ load measured by 18F-Florbetaben (FBB)-positron emission tomography (PET), (ii) whether sLF-related variations in cortical thickness and cortical glucose metabolism depend on global Aβ burden, and (iii) whether such sLF-related cortical abnormalities moderate the relationship between sLF and cognition. Results sLF was negatively associated with Aβ load in parieto-temporal regions. Moreover, sLF was related to thickening of the middle temporal cortex, increased FDG uptake in the posterior cingulate cortex, and poorer memory. These associations were stronger in individuals showing the highest Aβ burden. Conclusions sLF levels are sensitive to variations in cortical Aβ load, structural and metabolic cortical abnormalities, and subclinical memory impairment in asymptomatic older adults. These findings provide support for the use of sLF as a non-invasive biomarker of cerebral vulnerability in the general aging population.