{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:52:05Z","timestamp":1790117525215,"version":"4.0.1"},"reference-count":49,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008460","name":"National Center for Complementary and Integrative Health","doi-asserted-by":"publisher","award":["3P50AT008661-05S1"],"award-info":[{"award-number":["3P50AT008661-05S1"]}],"id":[{"id":"10.13039\/100008460","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Early diagnosis of Alzheimer\u2019s disease (AD) and the identification of significant risk factors are necessary to better understand disease progression, and to develop intervention-based therapies prior to significant neurodegeneration. There is thus a critical need to establish biomarkers which can predict the risk of developing AD before the onset of cognitive decline. A number of studies have indicated that exposure to various microbial pathogens can accelerate AD pathology. Additionally, several studies have indicated that amyloid-\u03b2 possess antimicrobial properties and may act in response to infection as a part of the innate immune system. These findings have led some to speculate that certain types of infections may play a significant role in AD pathogenesis. In this review, we will provide an overview of studies which suggest pathogen involvement in AD. Additionally, we will discuss a number of pathogen-associated biomarkers which may be effective in establishing AD risk. Infections that increase the risk of AD represent a modifiable risk factor which can be treated with therapeutic intervention. Pathogen-based biomarkers may thus be a valuable tool for evaluating and decreasing AD risk across the population.<\/jats:p>","DOI":"10.3390\/jpm10030074","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T07:31:45Z","timestamp":1596007905000},"page":"74","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["The Viral Hypothesis in Alzheimer\u2019s Disease: Novel Insights and Pathogen-Based Biomarkers"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3807-9167","authenticated-orcid":false,"given":"Sean X","family":"Naughton","sequence":"first","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-9932","authenticated-orcid":false,"given":"Urdhva","family":"Raval","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1524-5196","authenticated-orcid":false,"given":"Giulio M.","family":"Pasinetti","sequence":"additional","affiliation":[{"name":"Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"},{"name":"James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nguyen, T.T., Ta, Q.T.H., Nguyen, T.K.O., Nguyen, T.T.D., and Vo, V.G. (2020). Role of Body-Fluid Biomarkers in Alzheimer\u2019s Disease Diagnosis. Diagnostics, 10.","DOI":"10.3390\/diagnostics10050326"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1016\/S0140-6736(14)61347-7","article-title":"The burden of disease in older people and implications for health policy and practice","volume":"385","author":"Prince","year":"2015","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1002\/msj.20157","article-title":"Neuropathology of Alzheimer\u2019s Disease","volume":"77","author":"Perl","year":"2010","journal-title":"Mt. Sinai J. Med. J. Transl. Pers. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1007\/s13273-018-0015-3","article-title":"Clinical genetic strategies for early onset neurodegenerative diseases","volume":"14","author":"Giau","year":"2018","journal-title":"Mol. Cell. Toxicol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zetterberg, H., and Bendlin, B.B. (2020). Biomarkers for Alzheimer\u2019s disease-preparing for a new era of disease-modifying therapies. Mol. Psychiatry.","DOI":"10.1038\/s41380-020-0721-9"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: Structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/S0014-5793(00)02076-7","article-title":"Regulation of APP cleavage by \u03b1-, \u03b2- and \u03b3-secretases","volume":"483","author":"Nunan","year":"2000","journal-title":"FEBS Lett."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1002\/ana.22516","article-title":"Cerebral amyloid angiopathy in the elderly","volume":"70","author":"Viswanathan","year":"2011","journal-title":"Ann. Neurol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1038\/nature02621","article-title":"Pathways towards and away from Alzheimer\u2019s disease","volume":"430","author":"Mattson","year":"2004","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/ni.3102","article-title":"Innate immunity in Alzheimer\u2019s disease","volume":"16","author":"Heneka","year":"2015","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Soscia, S.J., Kirby, J.E., Washicosky, K.J., Tucker, S.M., Ingelsson, M., Hyman, B., Burton, M.A., Goldstein, L.E., Duong, S., and Tanzi, R.E. (2010). The Alzheimer\u2019s Disease-Associated Amyloid \u03b2-Protein Is an Antimicrobial Peptide. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009505"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.3233\/JAD-171133","article-title":"Alzheimer\u2019s Amyloid-\u03b2 is an Antimicrobial Peptide: A Review of the Evidence","volume":"62","author":"Gosztyla","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"859","DOI":"10.3233\/JAD-160517","article-title":"Anti-Viral Properties of Amyloid-\u03b2 Peptides","volume":"54","author":"Bourgade","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"922","DOI":"10.1097\/WNR.0b013e32833da51a","article-title":"Acyclovir or A\u03b242 peptides attenuate HSV-1-induced miRNA-146a levels in human primary brain cells","volume":"21","author":"Lukiw","year":"2010","journal-title":"NeuroReport"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1038\/s41582-020-0323-9","article-title":"Do infections have a role in the pathogenesis of Alzheimer disease?","volume":"16","author":"Itzhaki","year":"2020","journal-title":"Nat. Rev. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.neuron.2018.06.030","article-title":"Alzheimer\u2019s Disease-Associated \u03b2-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection","volume":"99","author":"Eimer","year":"2018","journal-title":"Neuron"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.neuron.2018.05.023","article-title":"Multiscale Analysis of Independent Alzheimer\u2019s Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus","volume":"99","author":"Readhead","year":"2018","journal-title":"Neuron"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaay8828","DOI":"10.1126\/sciadv.aay8828","article-title":"A 3D human brain\u2013like tissue model of herpes-induced Alzheimer\u2019s disease","volume":"6","author":"Cairns","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1097\/WAD.0000000000000133","article-title":"Temporal Cognitive Decline Associated With Exposure to Infectious Agents in a Population-based, Aging Cohort","volume":"30","author":"Nimgaonkar","year":"2016","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3233\/ADR-200174","article-title":"Picornavirus Identified in Alzheimer\u2019s Disease Brains: A Pathogenic Path?","volume":"4","author":"Niklasson","year":"2020","journal-title":"J. Alzheimers Dis. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Canet, G., Dias, C., Gabelle, A., Simonin, Y., Gosselet, F., Marchi, N., Makinson, A., Tuaillon, E., Van de Perre, P., and Givalois, L. (2018). HIV Neuroinfection and Alzheimer\u2019s Disease: Similarities and Potential Links?. Front. Cell. Neurosci., 12.","DOI":"10.3389\/fncel.2018.00307"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1982","DOI":"10.1212\/WNL.0b013e3181c5b445","article-title":"CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease","volume":"73","author":"Clifford","year":"2009","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"14063","DOI":"10.1073\/pnas.0900096106","article-title":"Highly pathogenic H5N1 influenza virus can enter the central nervous system and induce neuroinflammation and neurodegeneration","volume":"106","author":"Jang","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","first-page":"1","article-title":"Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: Experimental evidence for the multi-hit hypothesis","volume":"3","author":"Sadasivan","year":"2017","journal-title":"NPJ Park. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"Kinney","year":"2018","journal-title":"Alzheimers Dement. Transl. Res. Clin. Interv."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"241","DOI":"10.4103\/1947-2714.159325","article-title":"Association between periodontitis and Alzheimer\u2019s disease","volume":"7","author":"Abbayya","year":"2015","journal-title":"North Am. J. Med. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaau3333","DOI":"10.1126\/sciadv.aau3333","article-title":"Porphyromonas gingivalis in Alzheimer\u2019s disease brains: Evidence for disease causation and treatment with small-molecule inhibitors","volume":"5","author":"Dominy","year":"2019","journal-title":"Sci. Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature25158","article-title":"Microglia-derived ASC specks cross-seed amyloid-\u03b2 in Alzheimer\u2019s disease","volume":"552","author":"Venegas","year":"2017","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/S0046-8177(87)80252-6","article-title":"Concurrent neocortical borreliosis and Alzheimer\u2019s disease","volume":"18","author":"MacDonald","year":"1987","journal-title":"Hum. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.mehy.2006.08.043","article-title":"Alzheimer\u2019s neuroborreliosis with trans-synaptic spread of infection and neurofibrillary tangles derived from intraneuronal spirochetes","volume":"68","author":"MacDonald","year":"2007","journal-title":"Med. Hypotheses"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Hammond, C.J., Hallock, L.R., Howanski, R.J., Appelt, D.M., Little, C.S., and Balin, B.J. (2010). Immunohistological detection of Chlamydia pneumoniae in the Alzheimer\u2019s disease brain. BMC Neurosci., 11.","DOI":"10.1186\/1471-2202-11-121"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1009-e11","DOI":"10.1016\/j.neurobiolaging.2011.10.021","article-title":"Impact of chronic Helicobacter pylori infection on Alzheimer\u2019s disease: Preliminary results","volume":"33","author":"Quadrio","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Raval, U., Harary, J., Zeng, E., and Pasinetti, G.M. (2020). The dichotomous role of the gut microbiome in exacerbating and ameliorating neurodegenerative disorders. Expert Rev. Neurother.","DOI":"10.1080\/14737175.2020.1775585"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"559","DOI":"10.3233\/JAD-191328","article-title":"Investigation of Potential Brain Microbiome in Alzheimer\u2019s Disease: Implications of Study Bias","volume":"75","author":"Westfall","year":"2020","journal-title":"J. Alzheimers Dis. JAD"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"301","DOI":"10.3233\/JAD-132681","article-title":"Fungal Infection in Patients with Alzheimer\u2019s Disease","volume":"41","author":"Alonso","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1177\/1533317513517049","article-title":"Possible Link Between Toxoplasma Gondii and the Anosmia Associated With Neurodegenerative Diseases","volume":"29","author":"Prandota","year":"2014","journal-title":"Am. J. Alzheimers Dis. Dementiasr"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Zhao, X., Wu, H., Lu, H., Li, G., and Huang, Q. (2013). LAMP: A Database Linking Antimicrobial Peptides. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0066557"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.3233\/JAD-142286","article-title":"Peripheral \u03b1-Defensins 1 and 2 are Elevated in Alzheimer\u2019s Disease","volume":"44","author":"Watt","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.dadm.2017.04.002","article-title":"Early diagnosis of mild cognitive impairment and Alzheimer\u2019s disease based on salivary lactoferrin","volume":"8","author":"Carro","year":"2017","journal-title":"Alzheimers Dement. Amst. Neth."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Kall\u00f3, G., Emri, M., Varga, Z., Ujhelyi, B., T\u0151zs\u00e9r, J., Csutak, A., and Cs\u0151sz, \u00c9. (2016). Changes in the Chemical Barrier Composition of Tears in Alzheimer\u2019s Disease Reveal Potential Tear Diagnostic Biomarkers. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158000"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3233\/JAD-160563","article-title":"Elevated Epstein-Barr Virus Antibody Level is Associated with Cognitive Decline in the Korean Elderly","volume":"55","author":"Shim","year":"2017","journal-title":"J. Alzheimers Dis."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1111\/j.1532-5415.2005.53204.x","article-title":"High Prevalence of Chlamydia Pneumoniae Antibodies and Increased High-Sensitive C-Reactive Protein in Patients with Vascular Dementia","volume":"53","author":"Yamamoto","year":"2005","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jalz.2014.07.157","article-title":"Herpes simplex infection and the risk of Alzheimer\u2019s disease: A nested case-control study","volume":"11","author":"Gilthorpe","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1016\/j.jalz.2014.04.522","article-title":"Reactivated herpes simplex infection increases the risk of Alzheimer\u2019s disease","volume":"11","author":"Gilthorpe","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"873","DOI":"10.3233\/JAD-150382","article-title":"Cerebrospinal Fluid from Alzheimer\u2019s Disease Patients Contains Fungal Proteins and DNA","volume":"47","author":"Alonso","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1016\/j.jneuroim.2019.01.004","article-title":"Gut microbiota in neurodegenerative disorders","volume":"328","author":"Banerjee","year":"2019","journal-title":"J. Neuroimmunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s13311-018-0611-x","article-title":"Anti-herpetic Medications and Reduced Risk of Dementia in Patients with Herpes Simplex Virus Infections\u2014A Nationwide, Population-Based Cohort Study in Taiwan","volume":"15","author":"Tzeng","year":"2018","journal-title":"Neurotherapeutics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e032112","DOI":"10.1136\/bmjopen-2019-032112","article-title":"Antiviral therapy: Valacyclovir Treatment of Alzheimer\u2019s Disease (VALAD) Trial: Protocol for a randomised, double-blind, placebo-controlled, treatment trial","volume":"10","author":"Devanand","year":"2020","journal-title":"BMJ Open"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1172\/JCI133737","article-title":"Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease","volume":"130","author":"Roy","year":"2020","journal-title":"J. Clin. Investig."}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/10\/3\/74\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:52:30Z","timestamp":1760176350000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/10\/3\/74"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,29]]},"references-count":49,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["jpm10030074"],"URL":"https:\/\/doi.org\/10.3390\/jpm10030074","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,29]]}}}