{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T18:37:12Z","timestamp":1788719832172,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T00:00:00Z","timestamp":1592265600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Alzheimer's &amp;amp; Dementia"],"published-print":{"date-parts":[[2020,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>We aim to explain why salivary lactoferrin (Lf) levels are reduced in patients suffering mild cognitive impairment (MCI) and sporadic Alzheimer's disease (sAD).<jats:sup>1<\/jats:sup> We also will discuss if such Lf decrease could be due to a downregulation of the sAD associated systemic immunity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Background<\/jats:title><jats:p>Several non\u2010neurological 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\u2010related 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>New\/updated hypothesis<\/jats:title><jats:p>Lf has important anti\u2010infectious 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Major challenges for the hypothesis<\/jats:title><jats:p>The major challenge of the Lf as early sAD biomarker would be its validation in other clinical and population\u2010based 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linkage to other major theories<\/jats:title><jats:p>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).<\/jats:p><\/jats:sec>","DOI":"10.1002\/alz.12107","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T08:53:21Z","timestamp":1592297601000},"page":"1196-1204","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":52,"title":["Salivary lactoferrin as biomarker for Alzheimer's disease: Brain\u2010immunity interactions"],"prefix":"10.1002","volume":"16","author":[{"given":"F\u00e9lix","family":"Bermejo\u2010Pareja","sequence":"first","affiliation":[{"name":"Department of Medicine Complutense University  Madrid Spain"},{"name":"Neurodegenerative Disorders Group Instituto de Investigaci\u00f3n Hospital 12 de Octubre (imas12)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodoro","family":"del Ser","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Investigation Research Unit CIEN Foundation Carlos III Institute of Health Queen Sofia Foundation Alzheimer Research Centre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meritxell","family":"Valent\u00ed","sequence":"additional","affiliation":[{"name":"Alzheimer's Disease Investigation Research Unit CIEN Foundation Carlos III Institute of Health Queen Sofia Foundation Alzheimer Research Centre  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"de la Fuente","sequence":"additional","affiliation":[{"name":"Department of Genetics Physiology and Microbiology (Unit of Animal Physiology) Faculty of Biology Complutense University of Madrid  Madrid Spain"},{"name":"Aging Neuroimmunology and Nutrition Group Instituto de Investigaci\u00f3n Hospital 12 de Octubre (imas12)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Bartolome","sequence":"additional","affiliation":[{"name":"Neurodegenerative Disorders Group Instituto de Investigaci\u00f3n Hospital 12 de Octubre (imas12)  Madrid Spain"},{"name":"Networking Biomedical Research Center on Neurodegenerative Diseases (CIBERNED)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Carro","sequence":"additional","affiliation":[{"name":"Neurodegenerative Disorders Group Instituto de Investigaci\u00f3n Hospital 12 de Octubre (imas12)  Madrid Spain"},{"name":"Networking Biomedical Research Center on Neurodegenerative Diseases (CIBERNED)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,6,16]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dadm.2017.04.002"},{"key":"e_1_2_8_3_1","volume-title":"Alzheimer: Prevention from Childhood","author":"Bermejo\u2010Pareja F","year":"2018"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.b.32499"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2014.04.012"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10999"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trci.2017.08.009"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2014.05.006"},{"key":"e_1_2_8_9_1","first-page":"1299","article-title":"Meta\u2010analysis of modifiable risk factors for Alzheimer's disease","volume":"86","author":"Xu W","year":"2015","journal-title":"J Neurol Neurosurg Psychiatry"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504327"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2013.11.003"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2018.06.3040"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-12679-1_1"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12289"},{"key":"e_1_2_8_15_1","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-319-34057-9","volume-title":"Alzheimer's Turning Point. 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