Salivary lactoferrin levels in Down Syndrome: a case-control study

Abstract

Individuals with Down Syndrome (DS) have a high age-dependent risk of developing Alzheimer's disease (AD). In addition to genetic causes, this high risk involves dysregulated immune-inflammatory system. Low lactoferrin levels, one of the main antimicrobial proteins present in saliva, has been associated with AD. Here, we evaluated whether salivary lactoferrin levels change across the life span of individuals with DS. The study included 152 participants, 72 subjects with DS and 80 euploid individuals, and were divided into those under and over 45 years of age, accordingly with the age-dependent risk of AD. Median of salivary lactoferrin were higher among DS individual, in parallel to salivary total protein, but there were no differences in the ratio of lactoferrin to total protein in saliva between groups. Only DS individuals had higher median salivary lactoferrin levels in the age group under 45 years. Meanwhile non-significant differences were detected for the ratio salivary lactoferrin levels to total salivary protein between groups under 45 years, those levels were lower in DS subjects over 45 years old compared with the age-matched control group. Furthermore, the ratio of salivary lactoferrin levels to total protein in DS was associated with cognitive decline being lower in demented groups compared with mild and moderate cognitive impairment groups. In summary, this study indicates that salivary lactoferrin was dysregulated in DS, with significant lower ratio of salivary lactoferrin levels to total salivary proteins in individuals with DS over 45 years old, a population with a gradually increasing risk of AD.

Keywords: Alzheimer's disease; Biomarkers; Cognition; Down Syndrome; Infections; Lactoferrin; Saliva.

Fig. 1

Concentrations of lactoferrin and total protein in the saliva of Down Syndrome (DS) individuals compared with control subjects. Comparison of salivary lactoferrin (A), and total protein (B) concentrations, and salivary lactoferrin levels in total salivary proteins (D) between the DS and normal groups. (C) Correlation between salivary lactoferrin and total salivary proteins in DS and control groups. (n = 72 DS, 80 control). ∗∗p < 0.01, ∗∗∗p < 0.001.

Fig. 2

Changes with age in salivary concentration levels by study groups. Scatter plots represent the median concentrations of salivary lactoferrin (A), total salivary protein (C), and the ratio of salivary lactoferrin levels in total salivary proteins (E) in DS and control groups subdivided according to age (under and over 45 years of age). Longitudinal changes with age in salivary lactoferrin (B), total salivary protein (D), and the ratio of salivary lactoferrin levels in total salivary proteins (F) using regression curves of the linear (left panels) and LOESS (right panels) models for each group and 95 % CI, representing the evolution of age-related changes. LTF: lactoferrin. (n = 72 DS, 80 control). ∗p < 0.05, ∗∗∗p < 0.001.

Fig. 3

Association of salivary concentrations with cognitive decline in DS subjects. (A) Scatter plots of the median age in the DS group by cognitive decline. (B–D) Scatter plots of the median concentrations of salivary lactoferrin (B), total protein (C), and lactoferrin in total protein (D) in the DS groups according with their cognitive decline score. (E) Longitudinal changes in the ratio of salivary lactoferrin in total protein according to cognitive decline in DS subjects. Colored lines and bands denote the lineal regression and its 95 % CI. (n = 72 DS [32 with mild cognitive impairment, 24 with moderate, 10 with severe, 6 with dementia). ∗p < 0.05, ∗∗∗p < 0.001.

Fig. 4

Diagram on the role of the iron dyshomeostasis. Upper panel: The availability of free iron (Fe³⁺) favors the growth of pathogens and increases their virulence. It also affects immune system cells, which release more pro-inflammatory cytokines, triggering an inflammatory process. Lower panel: Each molecule of lactoferrin is capable of capturing two Fe³⁺, this decreases its availability to pathogenic microorganisms, limiting their growth, adhesion, invasion, and colonization. It also reduces the inflammatory process.