The amyloid cascade hypothesis, focusing on pathological proteins aggregation, has so far failed to uncover the root cause of Alzheimer's disease (AD), or to provide an effective therapy. This traditional paradigm essentially explains a mechanism involved in the development of sporadic AD rather than its cause. The failure of an overwhelming majority of clinical studies (99.6%) demonstrates that a breakthrough in therapy would be difficult if not impossible without understanding the etiology of AD. It becomes more and more apparent that the AD pathology might originate from brain infection. In this review, we discuss a potential role of bacteria, viruses, fungi, and eukaryotic parasites as triggers of AD pathology. We show evidence from the current literature that amyloid beta, traditionally viewed as pathological, actually acts as an antimicrobial peptide, protecting the brain against pathogens. However, in case of a prolonged or excessive activation of a senescent immune system, amyloid beta accumulation and aggregation becomes damaging and supports runaway neurodegenerative processes in AD. This is paralleled by the recent study by Alam and colleagues (2022) who showed that alpha-synuclein, the protein accumulating in synucleinopathies, also plays a critical physiological role in immune reactions and inflammation, showing an unforeseen link between the 2 unrelated classes of neurodegenerative disorders. The multiplication of the amyloid precursor protein gene, recently described by Lee and collegues (2018), and possible reactivation of human endogenous retroviruses by pathogens fits well into the same picture. We discuss these new findings from the viewpoint of the infection hypothesis of AD and offer suggestions for future research.

Department of Parasitology Faculty of Science Charles University Prague Czech Republic

Laboratory of Neurophysiology of Memory Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

National Institute of Mental Health Klecany Czech Republic

Zobrazit více v PubMed

Carreiras M, Mendes E, Perry M, Francisco A, Marco-Contelles J. The multifactorial nature of Alzheimer’s disease for developing potential therapeutics. Curr Top Med Chem. 2013;13:1745–1770. doi: 10.2174/15680266113139990135 PubMed DOI

Itzhaki RF, Lathe R, Balin BJ, Ball MJ, Bearer EL, Braak H, et al. Microbes and Alzheimer’s disease. J Alzheimers Dis. 2016;51:979–984. doi: 10.3233/JAD-160152 PubMed DOI PMC

Banik A, Brown RE, Bamburg J, Lahiri DK, Khurana D, Friedland RP, et al. Translation of pre-clinical studies into successful clinical trials for Alzheimer’s disease: What are the roadblocks and how can they be overcome? J Alzheimers Dis. 2015;47:815–843. doi: 10.3233/JAD-150136 PubMed DOI

Cummings JL, Morstorf T, Zhong K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther. 2014;6:37. doi: 10.1186/alzrt269 PubMed DOI PMC

Geldenhuys WJ, Darvesh AS. Pharmacotherapy of Alzheimer’s disease: current and future trends. Expert Rev Neurother. 2015;15:3–5. doi: 10.1586/14737175.2015.990884 PubMed DOI

Budson AE, Solomon PR. New diagnostic criteria for Alzheimer’s disease and mild cognitive impairment for the practical neurologist. Pract Neurol. 2012;12:88–96. doi: 10.1136/practneurol-2011-000145 PubMed DOI

Murphy C. Olfactory and other sensory impairments in Alzheimer disease. Nat Rev Neurol. 2019;15:11–24. doi: 10.1038/s41582-018-0097-5 PubMed DOI

Alzheimer’s Association. Alzheimer’s disease facts and figures. Alzheimers Dement. 2017;2017(13):325–373.

Hardy J. Amyloid, the presenilins and Alzheimer’s disease. Trends Neurosci. 1997;20:154–159. doi: 10.1016/S0166-2236(96)01030-2 PubMed DOI

Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, et al. Mutation of the β-amyloid precursor protein in familial Alzheimer’s disease increases β-protein production. Nature. 1992;360:672–674. doi: 10.1038/360672a0 PubMed DOI

Haass C. Mutations associated with a locus for familial Alzheimer’s disease result in alternative processing of amyloid β-protein precursor. J Biol Chem. 1994;269:17741–17748. PubMed

Haass C, Lemere CA, Capell A, Citron M, Seubert P, Schenk D, et al. The Swedish mutation causes early-onset Alzheimer’s disease by β-secretase cleavage within the secretory pathway. Nat Med. 1995;1:1291–1296. doi: 10.1038/nm1295-1291 PubMed DOI

Haass C, De Strooper B. The presenilins in Alzheimer’s disease—proteolysis holds the key. Science. 1999;286:916–919. doi: 10.1126/science.286.5441.916 PubMed DOI

Drummond E, Wisniewski T. Alzheimer’s disease: experimental models and reality. Acta Neuropathol (Berl). 2017;133:155–175. doi: 10.1007/s00401-016-1662-x PubMed DOI PMC

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science. 1993;261:921–923. doi: 10.1126/science.8346443 PubMed DOI

Farrer LA. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease: a meta-analysis. J Am Med Assoc. 1997;278:1349–1356. doi: 10.1001/jama.1997.03550160069041 PubMed DOI

Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, Patterson BW, et al. Human apoE isoforms differentially regulate brain amyloid-β peptide clearance. Sci Transl Med. 2011;3:13. doi: 10.1126/scitranslmed.3002156 PubMed DOI PMC

Cerf E, Gustot A, Goormaghtigh E, Ruysschaert J-M, Raussens V. High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer’s disease. FASEB J. 2011;25:1585–1595. doi: 10.1096/fj.10-175976 PubMed DOI

Benilova I, Karran E, De Strooper B. The toxic Aβ oligomer and Alzheimer’s disease: an emperor in need of clothes. Nat Neurosci. 2012;15:349–357. doi: 10.1038/nn.3028 PubMed DOI

Goedert M, Spillantini MG. A century of Alzheimer’s disease. Science. 2006;314:777–781. doi: 10.1126/science.1132814 PubMed DOI

Wirths O, Multhaup G, Bayer TA. A modified β-amyloid hypothesis: intraneuronal accumulation of the β-amyloid peptide–the first step of a fatal cascade. J Neurochem. 2004;91:513–520. doi: 10.1111/j.1471-4159.2004.02737.x PubMed DOI

Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, et al. Amyloid β-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322–325. doi: 10.1038/359322a0 PubMed DOI

Brothers HM, Gosztyla ML, Robinson SR. The physiological roles of amyloid-ß peptide hint at new ways to treat Alzheimer’s disease. Front Aging Neurosci. 2018;10:118. doi: 10.3389/fnagi.2018.00118 PubMed DOI PMC

James OG, Doraiswamy PM, Borges-Neto S. PET imaging of tau pathology in Alzheimer’s disease and tauopathies. Front Neurol. 2015:6. doi: 10.3389/fneur.2015.00038 PubMed DOI PMC

Iqbal K, Alonso Adel C, Chen S, Chohan MO, El-Akkad E, Gong C-X, et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta. 2005;1739:198–210. doi: 10.1016/j.bbadis.2004.09.008 PubMed DOI

Tabaton M, Cammarata S, Mancardi G, Manetto V, Autilio-Gambetti L, Perry G, et al. Ultrastructural localization of beta-amyloid, tau, and ubiquitin epitopes in extracellular neurofibrillary tangles. Proc Natl Acad Sci U S A. 1991;88:2098–2102. doi: 10.1073/pnas.88.6.2098 PubMed DOI PMC

Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–791. doi: 10.1126/science.1074069 PubMed DOI

Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014;82:756–771. doi: 10.1016/j.neuron.2014.05.004 PubMed DOI PMC

Karran E, Mercken M, Strooper BD. The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics. Nat Rev Drug Discov. 2011;10:698–712. doi: 10.1038/nrd3505 PubMed DOI

Selkoe DJ, Hardy J. The amyloid hypothesis of Alzheimer’s disease at 25 years. EMBO Mol Med. 2016;8:595–608. doi: 10.15252/emmm.201606210 PubMed DOI PMC

Lee CYD, Landreth GE. The role of microglia in amyloid clearance from the AD brain. J Neural Transm. 2010;117:949–960. doi: 10.1007/s00702-010-0433-4 PubMed DOI PMC

Wang W-Y, Tan M-S, Yu J-T, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med. 2015a;3:136. doi: 10.3978/j.issn.2305-5839.2015.03.49 PubMed DOI PMC

Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007;53:337–351. doi: 10.1016/j.neuron.2007.01.010 PubMed DOI

Bhaskar K, Konerth M, Kokiko-Cochran ON, Cardona A, Ransohoff RM, Lamb BT. Regulation of tau pathology by the microglial fractalkine receptor. Neuron. 2010;68:19–31. doi: 10.1016/j.neuron.2010.08.023 PubMed DOI PMC

Mosher KI, Wyss-Coray T. Microglial dysfunction in brain aging and Alzheimer’s disease. Biochem Pharmacol. 2014;88:594–604. doi: 10.1016/j.bcp.2014.01.008 PubMed DOI PMC

von Bernhardi R, Eugenín-von Bernhardi L, Eugenín J. Microglial cell dysregulation in brain aging and neurodegeneration. Front Aging Neurosci. 2015;7:124. doi: 10.3389/fnagi.2015.00124 PubMed DOI PMC

Lee JW, Lee YK, Yuk DY, Choi DY, Ban SB, Oh KW, et al. Neuro-inflammation induced by lipopolysaccharide causes cognitive impairment through enhancement of beta-amyloid generation. J Neuroinflammation. 2008;5:37. doi: 10.1186/1742-2094-5-37 PubMed DOI PMC

Hur J-Y, Frost GR, Wu X, Crump C, Pan SJ, Wong E, et al. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease. Nature. 2020;586:735–740. doi: 10.1038/s41586-020-2681-2 PubMed DOI PMC

Yamamoto M, Kiyota T, Horiba M, Buescher JL, Walsh SM, Gendelman HE, et al. Interferon-γ and tumor necrosis factor-α regulate amyloid-β plaque deposition and β-secretase expression in Swedish mutant APP transgenic mice. Am J Pathol. 2007;170:680–692. doi: 10.2353/ajpath.2007.060378 PubMed DOI PMC

Gómez-Isla T, Frosch MP. Lesions without symptoms: Understanding resilience to Alzheimer disease neuropathological changes. Nat Rev Neurol. 2022;18:323–332. doi: 10.1038/s41582-022-00642-9 PubMed DOI PMC

Bellenguez C, Grenier-Boley B, Lambert J-C. Genetics of Alzheimer’s disease: Where we are, and where we are going. Curr Opin Neurobiol. 2020;61:40–48. doi: 10.1016/j.conb.2019.11.024 PubMed DOI

Goedert M. Oskar Fischer and the study of dementia. Brain. 2009;132:1102–1111. doi: 10.1093/brain/awn256 PubMed DOI PMC

Miklossy J. Alzheimer’s disease—a neurospirochetosis. Analysis of the evidence following Koch’s and Hill’s criteria. J Neuroinflammation. 2011;8:90. doi: 10.1186/1742-2094-8-90 PubMed DOI PMC

Miklossy J, Khalili K, Gern L, Ericson RL, Darekar P, Bolle L, et al. PubMed DOI

Livengood JA, Gilmore RD. Invasion of human neuronal and glial cells by an infectious strain of PubMed DOI

MacDonald AB, Miranda JM. Concurrent neocortical borreliosis and Alzheimer’s disease. Hum Pathol. 1987;18:759–761. doi: 10.1016/s0046-8177(87)80252-6 PubMed DOI

Miklossy J. Alzheimer Disease—A Spirochetosis? In: Giacobini E, Becker RE, editors. Alzheimer Disease. Boston, MA: Birkhäuser Boston; 1994. p. 41–45.

Miklossy J, Kis A, Radenovic A, Miller L, Forro L, Martins R, et al. Beta-amyloid deposition and Alzheimer’s type changes induced by PubMed DOI

Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS ONE. 2016;11:e0151081. doi: 10.1371/journal.pone.0151081 PubMed DOI PMC

Kamer AR, Craig RG, Dasanayake AP, Brys M, Glodzik-Sobanska L, de Leon MJ. Inflammation and Alzheimer’s disease: possible role of periodontal diseases. Alzheimers Dement. 2008;4:242–250. doi: 10.1016/j.jalz.2007.08.004 PubMed DOI

Kamer AR, Fortea JO, Videla S, Mayoral A, Janal M, Carmona-Iragui M, et al. Periodontal disease’s contribution to Alzheimer’s disease progression in Down syndrome. Alzheimers Dement Diagn Assess Dis Monit. 2016;2:49–57. doi: 10.1016/j.dadm.2016.01.001 PubMed DOI PMC

Leira Y, Domínguez C, Seoane J, Seoane-Romero J, Pías-Peleteiro JM, Takkouche B, et al. Is periodontal disease associated with Alzheimer’s disease? A systematic review with meta-analysis. Neuroepidemiology. 2017;48:21–31. doi: 10.1159/000458411 PubMed DOI

Riviere GR, Riviere KH, Smith KS. Molecular and immunological evidence of oral PubMed DOI

Gutacker M, Valsangiacomo C, Balmelli T, Bernasconi MV, Bouras C, Piffaretti JC. Arguments against the involvement of PubMed DOI

McLaughlin R, Kin NM, Chen MF, Nair NP, Chan EC. Alzheimer’s disease may not be a spirochetosis. Neuroreport. 1999;10:1489–1491. doi: 10.1097/00001756-199905140-00018 PubMed DOI

Pappolla MA, Omar R, Saran B, Andorn A, Suarez M, Pavia C, et al. Concurrent neuroborreliosis and Alzheimer’s disease: Analysis of the evidence. Hum Pathol. 1989;20:753–757. doi: 10.1016/0046-8177(89)90068-3 PubMed DOI

Dominy SS, Lynch C, Ermini F, Benedyk M, Marczyk A, Konradi A, et al. PubMed DOI PMC

Liu Y, Wu Z, Nakanishi Y, Ni J, Hayashi Y, Takayama F, et al. Infection of microglia with PubMed DOI PMC

GlobalData Healthcare. Despite new biomarker data for AD drug COR388, clinical efficacy remains unproven. In: Clinical Trials Arena [Internet]. 24 Mar 2022 [cited 2022 Sep 21]. https://www.clinicaltrialsarena.com/comment/biomarker-data-cor388-clinical-efficacy/.

Díaz-Zúñiga J, More J, Melgar-Rodríguez S, Jiménez-Unión M, Villalobos-Orchard F, Muñoz-Manríquez C, et al. Alzheimer’s disease-like pathology triggered by PubMed DOI PMC

Balin BJ, Hammond CJ, Little CS, Hingley ST, Al-Atrache Z, Appelt DM, et al. PubMed DOI PMC

Grayston JT. PubMed DOI

Koskiniemi M, Gencay M, Salonen O, Puolakkainen M, Färkkilä M, Saikku P, et al. PubMed DOI

Wimmer M, Sandmann-Strupp R, Saikku P, Haberl RL. Association of chlamydial infection with cerebrovascular disease. Stroke. 1996;27:2207–2210. doi: 10.1161/01.str.27.12.2207 PubMed DOI

Balin BJ, Gérard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, et al. Identification and localization of PubMed DOI

Dreses-Werringloer U, Bhuiyan M, Zhao Y, Gérard HC, Whittum-Hudson JA, Hudson AP. Initial characterization of PubMed DOI PMC

Gérard HC, Wildt KL, Whittum-Hudson JA, Lai Z, Ager J, Hudson AP. The load of PubMed DOI

Gérard HC, Dreses-Werringloer U, Wildt KS, Deka S, Oszust C, Balin BJ, et al. PubMed DOI

Gieffers J, Reusche E, Solbach W, Maass M. Failure to detect PubMed PMC

Ring RH, Lyons JM. Failure to detect PubMed PMC

Taylor GS, Vipond IB, Paul ID, Matthews S, Wilcock GK, Caul EO. Failure to correlate PubMed DOI

Hammond CJ, Hallock LR, Howanski RJ, Appelt DM, Little CS, Balin BJ. Immunohistological detection of PubMed DOI PMC

Balin B. Proof of concept studies of

Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. Infiltration of the brain by pathogens causes Alzheimer’s disease. Neurobiol Aging. 2004;25:619–627. doi: 10.1016/j.neurobiolaging.2003.12.021 PubMed DOI

Little CS, Bowe A, Lin R, Litsky J, Fogel RM, Balin BJ, et al. Age alterations in extent and severity of experimental intranasal infection with PubMed PMC

Little CS, Joyce TA, Hammond CJ, Matta H, Cahn D, Appelt DM, et al. Detection of bacterial antigens and Alzheimer’s disease-like pathology in the central nervous system of BALB/c mice following intranasal infection with a laboratory isolate of PubMed DOI PMC

Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. PubMed DOI

Malaguarnera M, Bella R, Alagona G, Ferri R, Carnemolla A, Pennisi G. PubMed DOI

Roubaud-Baudron C, Krolak-Salmon P, Quadrio I, Mégraud F, Salles N. Impact of chronic PubMed DOI

Wang X-L, Zeng J, Yang Y, Xiong Y, Zhang Z-H, Qiu M, et al. PubMed DOI

Kountouras J, Boziki M, Gavalas E, Zavos C, Deretzi G, Chatzigeorgiou S, et al. Five-year survival after PubMed DOI

Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, et al. 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci. 2017;9:195. doi: 10.3389/fnagi.2017.00195 PubMed DOI PMC

Kornhuber HH. PubMed DOI

Li F, Hearn M, Bennett LE. The role of microbial infection in the pathogenesis of Alzheimer’s disease and the opportunity for protection by anti-microbial peptides. Crit Rev Microbiol. 2021;47:240–253. doi: 10.1080/1040841X.2021.1876630 PubMed DOI

Ball MJ. PubMed DOI

Itzhaki RF, Wozniak MA. PubMed DOI

Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR. Cutting edge: TLR2-mediated proinflammatory cytokine and chemokine production by microglial cells in response to PubMed DOI

Cacquevel M, Lebeurrier N, Cheenne S, Vivien D. Cytokines in neuroinflammation and Alzheimer’s disease. Curr Drug Targets. 2004;5:529–534. doi: 10.2174/1389450043345308 PubMed DOI

De Chiara G, Piacentini R, Fabiani M, Mastrodonato A, Marcocci ME, Limongi D, et al. Recurrent PubMed DOI PMC

Letenneur L, Pérès K, Fleury H, Garrigue I, Barberger-Gateau P, Helmer C, et al. Seropositivity to PubMed DOI PMC

Jamieson GA, Maitland NJ, Wilcock GK, Craske J, Itzhaki RF. Latent PubMed DOI

Wozniak M, Mee A, Itzhaki R. PubMed DOI

Pisa D, Alonso R, Fernández-Fernández AM, Rábano A, Carrasco L. Polymicrobial infections in brain tissue from Alzheimer’s disease patients. Sci Rep. 2017;7:5559. doi: 10.1038/s41598-017-05903-y PubMed DOI PMC

Itzhaki RF, Lin W-R, Shang D, Wilcock GK, Faragher B, Jamieson GA. PubMed DOI

Linard M, Letenneur L, Garrigue I, Doize A, Dartigues J-F, Helmer C. Interaction between APOE4 and PubMed DOI

Burgos JS, Ramirez C, Sastre I, Bullido MJ, Valdivieso F. ApoE4 is more effcient than E3 in brain access by PubMed DOI

Burgos JS, Ramirez C, Sastre I, Valdivieso F. Effect of apolipoprotein E on the cerebral load of latent PubMed DOI PMC

Wozniak MA, Itzhaki RF, Shipley SJ, Dobson CB. PubMed DOI

Ill-Raga G, Palomer E, Wozniak MA, Ramos-Fernández E, Bosch-Morató M, Tajes M, et al. Activation of PKR causes amyloid ß-peptide accumulation via de-repression of BACE1 expression. PLoS ONE. 2011;6:e21456. doi: 10.1371/journal.pone.0021456 PubMed DOI PMC

Wozniak MA, Frost AL, Itzhaki RF. Alzheimer’s disease-specific tau phosphorylation is induced by PubMed DOI

Zambrano Á, Solis L, Salvadores N, Cortés M, Lerchundi R, Otth C. Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with PubMed DOI

Piacentini R, Li Puma DD, Ripoli C, Marcocci ME, De Chiara G, Garaci E, et al. PubMed DOI PMC

Penzes P, Cahill ME, Jones KA, VanLeeuwen J-E, Woolfrey KM. Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci. 2011;14:285–293. doi: 10.1038/nn.2741 PubMed DOI PMC

Cairns DM, Rouleau N, Parker RN, Walsh KG, Gehrke L, Kaplan DL. A 3D human brain–like tissue model of PubMed DOI PMC

Tzeng N-S, Chung C-H, Lin F-H, Chiang C-P, Yeh C-B, Huang S-Y, et al. Anti-herpetic medications and reduced risk of dementia in patients with PubMed DOI PMC

Wozniak MA, Frost AL, Itzhaki RF. The helicase-primase inhibitor BAY 57–1293 reduces the Alzheimer’s disease-related molecules induced by PubMed DOI

Wozniak M, Bell T, Dénes Á, Falshaw R, Itzhaki R. Anti-HSV1 activity of brown algal polysaccharides and possible relevance to the treatment of Alzheimer’s disease. Int J Biol Macromol. 2015;74:530–540. doi: 10.1016/j.ijbiomac.2015.01.003 PubMed DOI

Wozniak MA, Frost AL, Preston CM, Itzhaki RF. Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with PubMed DOI PMC

Wozniak MA, Itzhaki RF. Intravenous immunoglobulin reduces beta amyloid and abnormal tau formation caused by PubMed DOI

Devanand DP. Viral hypothesis and antiviral treatment in Alzheimer’s disease. Curr Neurol Neurosci Rep. 2018;18:55. doi: 10.1007/s11910-018-0863-1 PubMed DOI PMC

Devanand DP, Andrews H, Kreisl WC, Razlighi Q, Gershon A, Stern Y, et al. Antiviral therapy: Valacyclovir treatment of Alzheimer’s disease (VALAD) trial: protocol for a randomised, double-blind, placebo-controlled, treatment trial. BMJ Open. 2020;10:e032112. doi: 10.1136/bmjopen-2019-032112 PubMed DOI PMC

Lindblom N, Lindquist L, Westman J, Åström M, Bullock R, Hendrix S, et al. Potential virus involvement in Alzheimer’s disease: Results from a phase IIa trial evaluating Apovir, an antiviral drug combination. J Alzheimers Dis Rep. 2021;5:413–431. doi: 10.3233/ADR-210301 PubMed DOI PMC

Hemmingsson E-S, Hjelmare E, Weidung B, Olsson J, Josefsson M, Adolfsson R, et al. Antiviral treatment associated with reduced risk of clinical Alzheimer’s disease—A nested case-control study. Alzheimers Dement Transl Res Clin Interv. 2021;7:e12187. doi: 10.1002/trc2.12187 PubMed DOI PMC

Itzhaki RF. Corroboration of a major role for PubMed DOI PMC

Lin W-R, Wozniak MA, Cooper RJ, Wilcock GK, Itzhaki RF. Herpesviruses in brain and Alzheimer’s disease. J Pathol. 2002;197:395–402. doi: 10.1002/path.1127 PubMed DOI

Rizzo R, Bortolotti D, Gentili V, Rotola A, Bolzani S, Caselli E, et al. KIR2DS2/KIR2DL2/HLA-C1 haplotype is associated with Alzheimer’s disease: Implication for the role of herpesvirus infections. J Alzheimers Dis. 2019;67:1379–1389. doi: 10.3233/JAD-180777 PubMed DOI

Carbone I, Lazzarotto T, Ianni M, Porcellini E, Forti P, Masliah E, et al. PubMed DOI

Bae S, Yun S-C, Kim M-C, Yoon W, Lim JS, Lee S-O, et al. Association of herpes zoster with dementia and effect of antiviral therapy on dementia: A population-based cohort study. Eur Arch Psychiatry Clin Neurosci. 2021;271:987–997. doi: 10.1007/s00406-020-01157-4 PubMed DOI

Chen C-H, Wu S-I, Huang K-Y, Yang Y-H, Kuo T-Y, Liang H-Y, et al. Herpes zoster and dementia: A nationwide population-based cohort study. J Clin Psychiatry. 2018;79:8164. doi: 10.4088/JCP.16m11312 PubMed DOI

Lopatko Lindman K, Hemmingsson E, Weidung B, Brännström J, Josefsson M, Olsson J, et al. PubMed DOI PMC

Cairns DM, Itzhaki RF, Kaplan DL. Potential Involvement of PubMed DOI

Lurain NS, Hanson BA, Martinson J, Leurgans SE, Landay AL, Bennett DA, et al. Virological and immunological characteristics of human PubMed DOI PMC

Lövheim H, Olsson J, Weidung B, Johansson A, Eriksson S, Hallmans G, et al. Interaction between PubMed DOI

Caruso C, Buffa S, Candore G, Colonna-Romano G, Dunn-Walters D, Kipling D, et al. Mechanisms of immunosenescence. Immun Ageing. 2009;6:1–4. PubMed PMC

Fulop T, Witkowski JM, Larbi A, Khalil A, Herbein G, Frost EH. Does HIV infection contribute to increased beta-amyloid synthesis and plaque formation leading to neurodegeneration and Alzheimer’s disease? J Neuro-Oncol. 2019;25:634–647. doi: 10.1007/s13365-019-00732-3 PubMed DOI

Corder EH, Robertson K, Lannfelt L, Bogdanovic N, Eggertsen G, Wilkins J, et al. HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy. Nat Med. 1998;4:1182–1184. doi: 10.1038/2677 PubMed DOI

Letendre SL, Ellis RJ, Ances BM, McCutchan JA. Neurologic complications of HIV disease and their treatment. Top HIV Med. 2010;18:45–55. PubMed PMC

Wu Y, Du S, Johnson JL, Tung H-Y, Landers CT, Liu Y, et al. Microglia and amyloid precursor protein coordinate control of transient PubMed DOI PMC

Alonso R, Pisa D, Marina AI, Morato E, Rábano A, Carrasco L. Fungal infection in patients with Alzheimer’s disease. J Alzheimers Dis. 2014;41:301–311. doi: 10.3233/JAD-132681 PubMed DOI

Alonso R, Pisa D, Rábano A, Rodal I, Carrasco L. Cerebrospinal fluid from Alzheimer’s disease patients contains fungal proteins and DNA. J Alzheimers Dis. 2015;47:873–876. doi: 10.3233/JAD-150382 PubMed DOI

Alonso R, Pisa D, Aguado B, Carrasco L. Identification of fungal species in brain tissue from Alzheimer’s disease by next-generation sequencing. J Alzheimers Dis. 2017;58:55–67. doi: 10.3233/JAD-170058 PubMed DOI

Alonso R, Pisa D, Fernández-Fernández AM, Carrasco L. Infection of fungi and bacteria in brain tissue from elderly persons and patients with Alzheimer’s disease. Front Aging Neurosci. 2018;10:159. doi: 10.3389/fnagi.2018.00159 PubMed DOI PMC

Pisa D, Alonso R, Juarranz A, Rábano A, Carrasco L. Direct visualization of fungal infection in brains from patients with Alzheimer’s disease. J Alzheimers Dis. 2015a;43:613–624. doi: 10.3233/JAD-141386 PubMed DOI

Pisa D, Alonso R, Rábano A, Rodal I, Carrasco L. Different brain regions are infected with fungi in Alzheimer’s disease. Sci Rep. 2015b;5:15015. doi: 10.1038/srep15015 PubMed DOI PMC

Bedarf JR, Beraza N, Khazneh H, Özkurt E, Baker D, Borger V, et al. Much ado about nothing? Off-target amplification can lead to false-positive bacterial brain microbiome detection in healthy and Parkinson’s disease individuals. Microbiome. 2021;9:75. doi: 10.1186/s40168-021-01012-1 PubMed DOI PMC

Le Govic Y, Demey B, Cassereau J, Bahn Y-S, Papon N. Pathogens infecting the central nervous system. PLoS Pathog. 2022;18:e1010234. doi: 10.1371/journal.ppat.1010234 PubMed DOI PMC

Janecek E, Wilk E, Schughart K, Geffers R, Strube C. Microarray gene expression analysis reveals major differences between PubMed DOI

Waindok P, Strube C. Neuroinvasion of PubMed DOI PMC

Janecek E, Waindok P, Bankstahl M, Strube C. Abnormal neurobehaviour and impaired memory function as a consequence of PubMed DOI PMC

Chou C-M, Lee Y-L, Liao C-W, Huang Y-C, Fan C-K. Enhanced expressions of neurodegeneration-associated factors, UPS impairment, and excess Aβ accumulation in the hippocampus of mice with persistent cerebral toxocariasis. Parasit Vectors. 2017;10:620. doi: 10.1186/s13071-017-2578-6 PubMed DOI PMC

Liao C-W, Fan C-K, Kao T-C, Ji D-D, Su K-E, Lin Y-H, et al. Brain injury-associated biomarkers of TGF-beta1, S100B, GFAP, NF-L, tTG, AbetaPP, and tau were concomitantly enhanced and the UPS was impaired during acute brain injury caused by PubMed DOI PMC

Heuer L, Beyerbach M, Lühder F, Beineke A, Strube C. Neurotoxocarosis alters myelin protein gene transcription and expression. Parasitol Res. 2015;114:2175–2186. doi: 10.1007/s00436-015-4407-1 PubMed DOI

Springer A, Heuer L, Janecek-Erfurth E, Beineke A, Strube C. Histopathological characterization of PubMed DOI

Dobolyi A, Vincze C, Pál G, Lovas G. The neuroprotective functions of transforming growth factor beta proteins. Int J Mol Sci. 2012;13:8219–8258. doi: 10.3390/ijms13078219 PubMed DOI PMC

Lesné S, Docagne F, Gabriel C, Liot G, Lahiri DK, Buée L, et al. Transforming growth factor-β1 potentiates amyloid-β generation in astrocytes and in transgenic mice. J Biol Chem. 2003;278:18408–18418. doi: 10.1074/jbc.M300819200 PubMed DOI

Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, et al. Amyloidogenic role of cytokine TGF-β1 in transgenic mice and in Alzheimer’s disease. Nature. 1997;389:603–606. doi: 10.1038/39321 PubMed DOI

Fan C-K, Holland CV, Loxton K, Barghouth U. Cerebral toxocariasis: Silent progression to neurodegenerative disorders? Clin Microbiol Rev. 2015;28:663–686. doi: 10.1128/CMR.00106-14 PubMed DOI PMC

Flegr J. How and why PubMed DOI

Flegr J. Influence of latent PubMed DOI

Kusbeci OY, Miman O, Yaman M, Aktepe OC, Yazar S. Could PubMed DOI

Mahami-Oskouei M, Hamidi F, Talebi M, Farhoudi M, Taheraghdam AA, Kazemi T, et al. Toxoplasmosis and Alzheimer: Can PubMed DOI

Perry CE, Gale SD, Erickson L, Wilson E, Nielsen B, Kauwe J, et al. Seroprevalence and serointensity of latent PubMed DOI

Torniainen-Holm M, Suvisaari J, Lindgren M, Härkänen T, Dickerson F, Yolken RH. The lack of association between PubMed DOI

Bayani M, Riahi SM, Bazrafshan N, Gamble HR, Rostami A. PubMed DOI

Tooran NC, Sarvi S, Moosazadeh M, Sharif M, Aghayan SA, Amouei A, et al. Is PubMed DOI

Jung B-K, Pyo K-H, Shin KY, Hwang YS, Lim H, Lee SJ, et al. PubMed DOI PMC

Möhle L, Israel N, Paarmann K, Krohn M, Pietkiewicz S, Müller A, et al. Chronic PubMed DOI PMC

Cabral CM, McGovern KE, MacDonald WR, Franco J, Koshy AA. Dissecting amyloid beta deposition using distinct strains of the neurotropic parasite PubMed DOI PMC

Torres L, Robinson S-A, Kim D-G, Yan A, Cleland TA, Bynoe MS. PubMed DOI PMC

Li Y, Severance EG, Viscidi RP, Yolken RH, Xiao J. Persistent PubMed DOI PMC

Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, et al. Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron. 2018;99:56–63.e3. doi: 10.1016/j.neuron.2018.06.030 PubMed DOI PMC

Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer’s disease. Alzheimers Dement. 2018;14:1602–1614. doi: 10.1016/j.jalz.2018.06.3040 PubMed DOI

Kagan BL, Jang H, Capone R, Teran Arce F, Ramachandran S, Lal R, et al. Antimicrobial properties of amyloid peptides. Mol Pharm. 2012;9:708–717. doi: 10.1021/mp200419b PubMed DOI PMC

Alam MM, Yang D, Li X-Q, Liu J, Back TC, Trivett A, et al. Alpha synuclein, the culprit in Parkinson disease, is required for normal immune function. Cell Rep. 2022;38:110090. doi: 10.1016/j.celrep.2021.110090 PubMed DOI PMC

Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, Hyman B, et al. The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide. PLoS ONE. 2010;5:e9505. doi: 10.1371/journal.pone.0009505 PubMed DOI PMC

Spitzer P, Condic M, Herrmann M, Oberstein TJ, Scharin-Mehlmann M, Gilbert DF, et al. Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci Rep. 2016;6:32228. doi: 10.1038/srep32228 PubMed DOI PMC

Javed I, Zhang Z, Adamcik J, Andrikopoulos N, Li Y, Otzen DE, et al. Accelerated amyloid beta pathogenesis by bacterial amyloid FapC. Adv Sci. 2020;7:2001299. doi: 10.1002/advs.202001299 PubMed DOI PMC

Friedland RP, McMillan JD, Kurlawala Z. What are the molecular mechanisms by which functional bacterial amyloids influence amyloid beta deposition and neuroinflammation in neurodegenerative disorders? Int J Mol Sci. 2020;21:1652. doi: 10.3390/ijms21051652 PubMed DOI PMC

Nizet V. Antimicrobial peptide resistance mechanisms of human bacterial pathogens. Curr Issues Mol Biol. 2006;8:11–26. doi: 10.21775/cimb.008.011 PubMed DOI

Bourgade K, Garneau H, Giroux G, Le Page AY, Bocti C, Dupuis G, et al. β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated PubMed DOI

Lukiw WJ, Cui JG, Yuan LY, Bhattacharjee PS, Corkern M, Clement C, et al. Acyclovir and Aβ42 peptide attenuates HSV-1-induced miRNA-146a levels in human brain cells. Neuroreport. 2010;21:922–927. doi: 10.1097/WNR.0b013e32833da51a PubMed DOI PMC

Bigley TM, Xiong M, Ali M, Chen Y, Wang C, Serrano JR, et al. Murine roseolovirus does not accelerate amyloid-β pathology and human roseoloviruses are not over-represented in Alzheimer disease brains. Mol Neurodegener. 2022;17:10. doi: 10.1186/s13024-021-00514-8 PubMed DOI PMC

Bocharova O, Pandit NP, Molesworth K, Fisher A, Mychko O, Makarava N, et al. Alzheimer’s disease-associated β-amyloid does not protect against PubMed DOI PMC

White MR, Kandel R, Tripathi S, Condon D, Qi L, Taubenberger J, et al. Alzheimer’s associated β-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS ONE. 2014;9:e101364. doi: 10.1371/journal.pone.0101364 PubMed DOI PMC

Di Domizio J, Dorta-Estremera S, Gagea M, Ganguly D, Meller S, Li P, et al. Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity. Proc Natl Acad Sci U S A. 2012;109:14550–14555. doi: 10.1073/pnas.1206923109 PubMed DOI PMC

Roy ER, Wang B, Wan Y, Chiu G, Cole A, Yin Z, et al. Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease. J Clin Invest. 2020;130:1912–1930. doi: 10.1172/JCI133737 PubMed DOI PMC

Sainz B, Halford WP. Alpha/beta interferon and gamma interferon synergize to inhibit the replication of PubMed PMC

Vollstedt S, Arnold S, Schwerdel C, Franchini M, Alber G, Di Santo JP, et al. Interplay between alpha/beta and gamma interferons with B, T, and Natural Killer cells in the defense against PubMed PMC

Kumar DKV, Eimer WA, Tanzi RE, Moir RD. Alzheimer’s disease: the potential therapeutic role of the natural antibiotic amyloid-β peptide. Neurodegener Dis Manag. 2016;6:345–348. doi: 10.2217/nmt-2016-0035 PubMed DOI PMC

Butterfield SM, Lashuel HA. Amyloidogenic protein–membrane interactions: Mechanistic insight from model systems. Angew Chem Int Ed. 2010;49:5628–5654. doi: 10.1002/anie.200906670 PubMed DOI

Choi SH, Kim YH, Hebisch M, Sliwinski C, Lee S, D’Avanzo C, et al. A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature. 2014;515:274–278. doi: 10.1038/nature13800 PubMed DOI PMC

Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain—implications for Alzheimer disease. Nat Rev Neurol. 2015;11:457–470. doi: 10.1038/nrneurol.2015.119 PubMed DOI PMC

Silva I, Silva J, Ferreira R, Trigo D. Glymphatic system, AQP4, and their implications in Alzheimer’s disease. Neurol Res Pract. 2021;3:1–9. doi: 10.1186/s42466-021-00102-7 PubMed DOI PMC

Ishida K, Yamada K, Nishiyama R, Hashimoto T, Nishida I, Abe Y, et al. Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration. J Exp Med. 2022;219:e20211275. doi: 10.1084/jem.20211275 PubMed DOI PMC

Proukakis C. Somatic mutations in neurodegeneration: An update. Neurobiol Dis. 2020;144:105021. doi: 10.1016/j.nbd.2020.105021 PubMed DOI

Miller MB, Reed HC, Walsh CA. Brain somatic mutation in aging and Alzheimer’s disease. Annu Rev Genomics Hum Genet. 2021;22:239–256. doi: 10.1146/annurev-genom-121520-081242 PubMed DOI PMC

Bushman DM, Kaeser GE, Siddoway B, Westra JW, Rivera RR, Rehen SK, et al. Genomic mosaicism with increased PubMed DOI PMC

Lee M-H, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, et al. Somatic PubMed DOI PMC

Kaeser GE, Chun J. Mosaic somatic gene recombination as a potentially unifying hypothesis for Alzheimer’s disease. Front Genet. 2020;11:390. doi: 10.3389/fgene.2020.00390 PubMed DOI PMC

Shanbhag NM, Evans MD, Mao W, Nana AL, Seeley WW, Adame A, et al. Early neuronal accumulation of DNA double strand breaks in Alzheimer’s disease. Acta Neuropathol Commun. 2019;7:77. doi: 10.1186/s40478-019-0723-5 PubMed DOI PMC

Zhu L-S, Wang D-Q, Cui K, Liu D, Zhu L-Q. Emerging perspectives on DNA double-strand breaks in neurodegenerative diseases. Curr Neuropharmacol. 2019;17:1146–1157. doi: 10.2174/1570159X17666190726115623 PubMed DOI PMC

Thadathil N, Delotterie DF, Xiao J, Hori R, McDonald MP, Khan MM. DNA double-strand break accumulation in Alzheimer’s disease: Evidence from experimental models and postmortem human brains. Mol Neurobiol. 2021;58:118–131. doi: 10.1007/s12035-020-02109-8 PubMed DOI

Larek-Rąpała A, Żaba R, Kowalczyk MJ, Szramka-Pawlak B, Schwartz RA.

Römer C. Viruses and endogenous retroviruses as roots for neuroinflammation and neurodegenerative diseases. Front Neurosci. 2021;15:648629. doi: 10.3389/fnins.2021.648629 PubMed DOI PMC

Gorbunova V, Seluanov A, Mita P, McKerrow W, Fenyö D, Boeke JD, et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature. 2021;596:43–53. doi: 10.1038/s41586-021-03542-y PubMed DOI PMC

Ochoa Thomas E, Zuniga G, Sun W, Frost B. Awakening the dark side: retrotransposon activation in neurodegenerative disorders. Curr Opin Neurobiol. 2020;61:65–72. doi: 10.1016/j.conb.2020.01.012 PubMed DOI PMC

Kim J, Zhao B, Huang AY, Miller MB, Lodato MA, Walsh CA, et al. PubMed DOI PMC

Lee M-H, Liu CS, Zhu Y, Kaeser GE, Rivera R, Romanow WJ, et al. Reply to: PubMed DOI PMC

Park JS, Lee J, Jung ES, Kim M-H, Kim IB, Son H, et al. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nat Commun. 2019;10:3090. doi: 10.1038/s41467-019-11000-7 PubMed DOI PMC

Ivashko-Pachima Y, Hadar A, Grigg I, Korenková V, Kapitansky O, Karmon G, et al. Discovery of autism/intellectual disability somatic mutations in Alzheimer’s brains: Mutated ADNP cytoskeletal impairments and repair as a case study. Mol Psychiatry. 2021;26:1619–1633. doi: 10.1038/s41380-019-0563-5 PubMed DOI PMC

Perez-Rodriguez D, Kalyva M, Leija-Salazar M, Lashley T, Tarabichi M, Chelban V, et al. Investigation of somatic CNVs in brains of synucleinopathy cases using targeted SNCA analysis and single cell sequencing. Acta Neuropathol Commun. 2019;7:219. doi: 10.1186/s40478-019-0873-5 PubMed DOI PMC

Loeb MB, Molloy DW, Smieja M, Standish T, Goldsmith CH, Mahony J, et al. A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease. J Am Geriatr Soc. 2004;52:381–387. doi: 10.1111/j.1532-5415.2004.52109.x PubMed DOI

Allen HB. Alzheimer’s disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid-β with regard to potential treatment and prevention. J Alzheimers Dis. 2016;53:1271–1276. doi: 10.3233/JAD-160388 PubMed DOI PMC

Iqbal UH, Zeng E, Pasinetti GM. The use of antimicrobial and antiviral drugs in Alzheimer’s disease. Int J Mol Sci. 2020;21:4920. doi: 10.3390/ijms21144920 PubMed DOI PMC

No evidence of Alzheimer's disease pathology in mice infected with Toxocara canis

A brain microbiome in salmonids at homeostasis