Decreased salivary lactoferrin levels are specific to Alzheimer's disease

Abstract

Background: Evidences of infectious pathogens in Alzheimer's disease (AD) brains may suggest a deteriorated innate immune system in AD pathophysiology. We previously demonstrated reduced salivary lactoferrin (Lf) levels, one of the major antimicrobial proteins, in AD patients.

Methods: To assess the clinical utility of salivary Lf for AD diagnosis, we examine the relationship between salivary Lf and cerebral amyloid-β (Aβ) load using amyloid-Positron-Emission Tomography (PET) neuroimaging, in two different cross-sectional cohorts including patients with different neurodegenerative disorders.

Findings: The diagnostic performance of salivary Lf in the cohort 1 had an area under the curve [AUC] of 0•95 (0•911-0•992) for the differentiation of the prodromal AD/AD group positive for amyloid-PET (PET⁺) versus healthy group, and 0•97 (0•924-1) versus the frontotemporal dementia (FTD) group. In the cohort 2, salivary Lf had also an excellent diagnostic performance in the health control group versus prodromal AD comparison: AUC 0•93 (0•876-0•989). Salivary Lf detected prodromal AD and AD dementia distinguishing them from FTD with over 87% sensitivity and 91% specificity.

Interpretation: Salivary Lf seems to have a very good diagnostic performance to detect AD. Our findings support the possible utility of salivary Lf as a new non-invasive and cost-effective AD biomarker.

Funding: Instituto de Salud Carlos III (FIS15/00780, FIS18/00118), FEDER, Comunidad de Madrid (S2017/BMD-3700; NEUROMETAB-CM), and CIBERNED (PI2016/01) to E.C.; Spanish Ministry of Economy and Competitiveness (SAF2017-85310-R) to J.L.C., and (PSI2017-85311-P) to M.A.; International Centre on ageing CENIE-POCTEP (0348_CIE_6_E) to M.A.; Instituto de Salud Carlos III (PIE16/00021, PI17/01799), to H.B.

Keywords: Alzheimer´s disease; Biomarkers; Frontotemporal dementia; Lactoferrin; Pet imaging; Saliva.

Fig. 1

Salivary Lf levels by clinical diagnosis and amyloid-PET biomarker profile. Box and whisker plots showing salivary Lf levels across diagnostic groups within (a) cohort 1, and (b) cohort 2. Boxes represent the 25th, 50th and 75th data percentiles. Whiskers represent the lowest and highest data. Scatter plots showing salivary Lf levels in (c) all subjects grouped as negative (n = 165) and positive (n = 85) amyloid-PET biomarker profile (excluding the control-PET⁺ subjects), and (d) in patients (excluding healthy asymptomatic controls) grouped as negative (n = 47) and positive (n = 85) amyloid-PET biomarker profile. Differences between groups were assessed using Kruskal-Wallis test or one-way ANOVA followed by Bonferroni and Student's t-test. *p < 0•05; ****p < 0•0001. Lf, lactoferrin; MCI, Mild cognitive impairment; AD, Alzheimer´s disease dementia; FTD, frontotemporal dementia; PET⁺, positive amyloid-PET scan; PET⁻, negative amyloid-PET scan.

Fig. 2

Receiver operating characteristic (ROC) analysis of salivary Lf in cohort 1 and cohort 2. ROC curves and their corresponding areas under the curve (AUCs) to differentiate between (a) MCI/AD-PET⁺ patients and control-PET⁻, (b) MCI/AD-PET⁺ and MCI/FTD-PET⁻ patients, and (c) MCI/AD-PET⁺ and PET^– in cohort 1. ROC curves and their corresponding areas under the curve (AUCs) to differentiate between (d) MCI-PET⁺ patients and control-PET⁻, (e) MCI-PET⁺ and MCI-PET⁻ patients, and (f) MCI-PET⁺ and PET^– in cohort 2. ROC; receiver operating characteristic; MCI, mild cognitive impairment; AD, Alzheimer's disease dementia; FTD, frontotemporal dementia; PET⁺, positive amyloid-PET scan; PET⁻, negative amyloid-PET scan.