Salivary lactoferrin as biomarker for Alzheimer's disease: Brain‐immunity interactions

Abstract

Objective We aim to explain why salivary lactoferrin (Lf) levels are reduced in patients suffering mild cognitive impairment (MCI) and sporadic Alzheimer's disease (sAD).1 We also will discuss if such Lf decrease could be due to a downregulation of the sAD associated systemic immunity. Background Several non‐neurological alterations have been described in sAD, mainly in skin, blood cell, and immunological capacities. We reviewed briefly the main pathophysiological theories of sAD (amyloid cascade, tau, unfolder protein tau, and amyloid deposits) emphasizing the most brain based hypotheses such as the updated tau‐related neuron skeletal hypothesis; we also comment on the systemic theories that emphasize the fetal origin of the complex disorders that include the low inflammatory and immunity theories of sAD. New/updated hypothesis Lf has important anti‐infectious and immunomodulatory roles in health and disease. We present the hypothesis that the reduced levels of saliva Lf could be an effect of immunological disturbances associated to sAD. Under this scenario, two alternative pathways are possible: first, whether sAD could be a systemic disorder (or disorders) related to early immunological and low inflammatory alterations; second, if systemic immunity alterations of sAD manifestations could be downstream of early sAD brain affectations. Major challenges for the hypothesis The major challenge of the Lf as early sAD biomarker would be its validation in other clinical and population‐based studies. It is possible the decreased salivary Lf in early sAD could be related to immunological modulation actions, but other different unknown mechanisms could be the origin of such reduction. Linkage to other major theories This hypothesis is in agreement with two physiopathological explanations of the sAD as a downstream process determined by the early lesions of the hypothalamus and autonomic vegetative system (neurodegeneration), or as a consequence of low neuroinflammation and dysimmunity since the early life aggravated in the elderly (immunosenescence).

Salivary lactoferrin is associated with cortical amyloid-beta load, cortical integrity, and memory in aging

“…In this vein, previous studies have shown an association between periodontal disease and brain Aβ accumulation in normal aging, suggesting that periodontal inflammation/infection may accelerate brain Aβ deposition [ 63 , 64 ]. Our results complement these findings, suggesting that reductions of sLF relate to increased regional Aβ burden, which may reflect early immunological alterations potentially associated with higher risk of developing AD [ 60 ]. Alternatively, a recent study has shown that levels of LF in either saliva or cerebrospinal fluid (CSF) were not able to differentiate between controls, MCI/AD, and non-AD dementias.…”

“…In consonance with previous results obtained in MCI and AD patients [ 29 , 30 ], decreased levels of sLF were related to increased Aβ burden in left parieto-temporal regions of cognitively normal older adults. We have recently hypothesized that reduced sLF observed in prodromal and clinical stages of AD may indicate early immunological disturbances that eventually increase the risk of AD [ 60 ]. Low levels of sLF may assist oral dysbiosis, which, in turn, may produce long-term infections and a pro-inflammatory response that weakens the blood brain barrier, facilitating colonization of brain tissue by periodontal bacteria [ 61 ] and accelerating neuroinflammation that contribute to AD pathology [ 62 ].…”

The fluid biomarkers of Alzheimer’s disease

“…Reduced Lf levels can be used to identify subjects with positive cerebral amyloidosis [99], and this finding is consistent with a previous study [100]. Bermejo-Pareja et al hypothesized that the reduced levels of salivary (Lf) may be related to immunological disturbances in AD, and this observation agrees with the physiopathological explanations of AD [101]. In a pilot study, a targeted and quantitative metabolomics approach is applied, and several panels composed of urinary metabolites are identified to distinguish MCI and AD from cognitively healthy controls with high sensitivity and specificity [102].…”

Decreased salivary lactoferrin levels are specific to Alzheimer's disease

“…This approach opened the way for a paradigm shift in studying a new “infection hypothesis,” or perhaps more broadly, “innate immune system dysregulation hypothesis”. It suggests the role of chronic infections in the development of AD, as well as a potential deregulation of the human innate immune response to these infections, as a plausible route for new investigations of the aetiology and pathophysiology of AD [43] . Although AD is a complex disease and microbial infection may not be the sole cause, this new paradigm may provide novel targets for the prevention and treatment of this devastating disease.…”