Microbes and Alzheimer’s Disease

Itzhaki, Ruth F.; Lathe, Richard; Balin, Brian J.; Ball, Melvyn J.; Bearer, Elaine L.; Braak, Heiko; Bullido, Maria J.; Carter, Chris; Clerici, Mario; Cosby, S. Louise; Del Tredici, Kelly; Field, Hugh; Fulop, Tamas; Grassi, Claudio; Griffin, W. Sue T.; Haas, Jürgen; Hudson, Alan P.; Kamer, Angela R.; Kell, Douglas B.; Licastro, Federico; Letenneur, Luc; Lövheim, Hugo; Mancuso, Roberta; Miklossy, Judith; Otth, Carola; Palamara, Anna Teresa; Perry, George; Preston, Christopher; Pretorius, Etheresia; Strandberg, Timo; Tabet, Naji; Taylor-Robinson, Simon D.; Whittum-Hudson, Judith A.

doi:10.3233/jad-160152

Cited by 532Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Microbes and Alzheimer’s Disease

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Itzhaki, Ruth F., Lathe, Richard, Balin, Brian J., Ball, Melvyn J., Bearer, Elaine L., Braak, Heiko, Bullido, Maria J., Carter, Chris +25 more·2016·Journal of Alzheimer’s Disease

DOI 10.3233/jad-160152PMC PMC5457904

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Abstract

We are researchers and clinicians working on Alzheimer's disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD. Fungal infection of AD brain has also been described, as well as abnormal microbiota in AD patient blood. The first observations of HSV1 in AD brain were reported almost three decades ago. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

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C. pneumoniae has been linked to late-onset dementia (late-onset Alzheimer's disease).
“C. pneumoniae primarily infects the pulmonary and nasal mucosa, but has in recent years been linked to diseases distinct from the respiratory tract, such as atherosclerosis/coronary disease3, asthma4, inflammatory arthritis5, multiple sclerosis6 and, in particular, late-onset dementia (late-onset Alzheimer’s disease)7,8.”
From Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk (2022) · cites this paper as [8]

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Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123 · cited 1× · see citing works
“AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid- (A ) peptide, a cleavage product of the amyloid- protein precursor (A PP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease [9, 10].”
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Harold, D., Abraham, R., Hollingworth, P., Sims, R., Gerrish, A., Hamshere, M. L., Pahwa, J. S., Moskvina, V., Dowzell, K., Williams, A., et al. (2009) · Nature Genetics · doi:10.1038/ng.440 · Cited by 3,326 · see citing works
Alzheimer’s disease drug-development pipeline: Few candidates, frequent failures
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Apolipoprotein E in Alzheimer’s disease and other neurological disorders
Verghese, P. B., Castellano, J. M., & Holtzman, D. M. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70325-2 · Cited by 857 · cited 1× · see citing works
“(vi) Polymorphisms in the apolipoprotein E gene, APOE, that modulate immune function and susceptibility to infectious disease [24], also govern AD risk (reviewed in [25, 26]).”
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Braak, H., Braak, E., & Bohl, J. (2008) · European Neurology · doi:10.1159/000116984 · Cited by 836 · see citing works
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Apolipoprotein E: structure determines function, from atherosclerosis to Alzheimer's disease to AIDS
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β-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1
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Research works printed but not linked: 65

[1]De Chiara G Marcocci ME Sgarbanti R Civitelli L Ripoli C Piacentini R Garaci E Grassi C Palamara AT 2012 Infectious agents and neurodegeneration Mol Neurobiol 46 614 638 22899188 PMC3496540
[2]Itzhaki RF 2014 Herpes simplex virus type 1 and Alzheimer’s disease: Increasing evidence for a major role of the virus Front Aging Neurosci 6 202 25157230 PMC4128394
[3]Balin BJ Hudson AP 2014 Etiology and pathogenesis of late-onset Alzheimer’s disease Curr Allergy Asthma Rep 14 417 24429902
[4]Miklossy J 2015 Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease Front Aging Neurosci 7 46 25932012 PMC4399390
[5]Alonso R Pisa D Marina AI Morato E Rabano A Carrasco L 2014 Fungal infection in patients with Alzheimer’s disease J Alzheimers Dis 41 301 311 24614898
[6]Pisa D Alonso R Rabano A Rodal I Carrasco L 2015 Different brain regions are infected with fungi in Alzheimer’s disease Sci Rep 5 15015 26468932 PMC4606562
[7]Potgieter M Bester J Kell DB Pretorius E 2015 The dormant blood microbiome in chronic, inflammatory diseases FEMS Microbiol Rev 39 567 591 25940667 PMC4487407
[8]Jamieson GA Maitland NJ Wilcock GK Craske J Itzhaki RF 1991 Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains J Med Virol 33 224 227 1649907
[9]Mirra SS Heyman A McKeel D Sumi SM Crain BJ Brownlee LM Vogel FS Hughes JP van BG Berg L 1991 The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease Neurology 41 479 486 2011243
[11]Jamieson GA Maitland NJ Wilcock GK Craske J Itzhaki RF 1991 Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains J Med Virol 33 224 227 1649907
[12]Miklossy J 1993 Alzheimer’s disease – a spirochetosis? Neuroreport 4 841 848 8369471
[13]Balin BJ Gerard HC Arking EJ Appelt DM Branigan PJ Abrams JT Whittum-Hudson JA Hudson AP 1998 Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain Med Microbiol Immunol 187 23 42 9749980
[14]Saldanha J Sutton RN Gannicliffe A Farragher B Itzhaki RF 1986 Detection of HSV1 DNA by in situ hybridisation in human brain after immunosuppression J Neurol Neurosurg Psychiatry 49 613 619 3016195 PMC1028840
[15]Roos KL 2014 Encephalitis Handb Clin Neurol 121 1377 1381 24365426
[16]Miklossy J Khalili K Gern L Ericson RL Darekar P Bolle L Hurlimann J Paster BJ 2004 Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease J Alzheimers Dis 6 639 649 15665404
[17]Wozniak MA Mee AP Itzhaki RF 2009 Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques J Pathol 217 131 138 18973185
[18]Letenneur L Peres K Fleury H Garrigue I Barberger-Gateau P Helmer C Orgogozo JM Gauthier S Dartigues JF 2008 Seropositivity to herpes simplex virus antibodies and risk of Alzheimer’s disease: A population-based cohort study PLoS One 3 e3637 18982063 PMC2572852
[19]Mancuso R Baglio F Cabinio M Calabrese E Hernis A Nemni R Clerici M 2014 Titers of herpes simplex virus type 1 antibodies positively correlate with grey matter volumes in Alzheimer’s disease J Alzheimers Dis 38 741 745 24072067
[20]Lövheim H Gilthorpe J Johansson A Eriksson S Hallmans G Elgh F 2015 Herpes simplex infection and the risk of Alzheimer’s disease: A nested case-control study Alzheimers Dement 11 587 592 25304990
[21]Lövheim H Gilthorpe J Adolfsson R Nilsson LG Elgh F 2015 Reactivated herpes simplex infection increases the risk of Alzheimer’s disease Alzheimers Dement 11 593 599 25043910
[22]Wyss-Coray T Rogers J 2012 Inflammation in Alzheimer disease – a brief review of the basic science and clinical literature Cold Spring Harb Perspect Med 2 a006346 22315714 PMC3253025
[23]Stefaniak J O’Brien J 2015 Imaging of neuroinflammation in dementia: A review J Neurol Neurosurg Psychiatry 87 21 28 26384512
[28]Porcellini E Carbone I Ianni M Licastro F 2010 Alzheimer’s disease gene signature says: Beware of brain viral infections Immun Ageing 7 16 21156047 PMC3019140
[29]Carter CJ 2010 APP, APOE, complement receptor 1, clusterin and PICALM and their involvement in the herpes simplex life cycle Neurosci Lett 483 96 100 20674675
[30]Lambert JC Zelenika D Hiltunen M Chouraki V Combarros O Bullido MJ Tognoni G Fievet N Boland A Arosio B Coto E Del ZM Mateo I Frank-Garcia A Helisalmi S Porcellini E Pilotto A Forti P Ferri R Delepine M Scarpini E Siciliano G Solfrizzi V Sorbi S Spalletta G Ravaglia G Valdivieso F Alvarez V Bosco P Mancuso M Panza F Nacmias B Bossu P Piccardi P Annoni G Seripa D Galimberti D Licastro F Lathrop M Soininen H Amouyel P 2011 Evidence of the association of BIN1 and PICALM with the AD risk in contrasting European populations Neurobiol Aging 32 756e11 e15 21220176
[31]Licastro F Carbone I Ianni M Porcellini E 2011 Gene signature in Alzheimer’s disease and environmental factors: The virus chronicle J Alzheimers Dis 27 809 817 21891868
[32]Carter CJ 2013 Susceptibility genes are enriched in those of the herpes simplex virus 1/host interactome in psychiatric and neurological disorders Pathog Dis 69 240 261 23913659
[33]Baker HF Ridley RM Duchen LW Crow TJ Bruton CJ 1994 Induction of beta (A4)-amyloid in primates by injection of Alzheimer’s disease brain homogenate. Comparison with transmission of spongiform encephalopathy Mol Neurobiol 8 25 39 8086126
[34]Ridley RM Baker HF Windle CP Cummings RM 2006 Very long term studies of the seeding of beta-amyloidosis in primates J Neural Transm 113 1243 1251 16362635
[35]Kane MD Lipinski WJ Callahan MJ Bian F Durham RA Schwarz RD Roher AE Walker LC 2000 Evidence for seeding of beta-amyloid by intracerebral infusion of Alzheimer brain extracts in beta-amyloid precursor protein-transgenic mice J Neurosci 20 3606 3611 10804202 PMC6772682
[37]Stanley LC Mrak RE Woody RC Perrot LJ Zhang S Marshak DR Nelson SJ Griffin WS 1994 Glial cytokines as neuropathogenic factors in HIV infection: Pathogenic similarities to Alzheimer’s disease J Neuropathol Exp Neurol 53 231 238 8176406
[38]Esiri MM Biddolph SC Morris CS 1998 Prevalence of Alzheimer plaques in AIDS J Neurol Neurosurg Psychiatry 65 29 33 9667557 PMC2170157
[41]Smith DB Simmonds P Bell JE 2014 Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users J Neurovirol 20 28 38 24420447
[42]McQuaid S Allen IV McMahon J Kirk J 1994 Association of measles virus with neurofibrillary tangles in subacute sclerosing panencephalitis: A combined in situ hybridization and immunocytochemical investigation Neuropathol Appl Neurobiol 20 103 110 8072641
[43]Wozniak MA Itzhaki RF Shipley SJ Dobson CB 2007 Herpes simplex virus infection causes cellular beta-amyloid accumulation and secretase upregulation Neurosci Lett 429 95 100 17980964
[44]Wozniak MA Frost AL Itzhaki RF 2009 Alzheimer’s disease-specific tau phosphorylation is induced by herpes simplex virus type 1 J Alzheimers Dis 16 341 350 19221424
[45]Zambrano A Solis L Salvadores N Cortes M Lerchundi R Otth C 2008 Neuronal cytoskeletal dynamic modification and neurodegeneration induced by infection with herpes simplex virus type 1 J Alzheimers Dis 14 259 269 18599953
[46]De Chiara G Marcocci ME Civitelli L Argnani R Piacentini R Ripoli C Manservigi R Grassi C Garaci E Palamara AT 2010 APP processing induced by herpes simplex virus type 1 (HSV-1) yields several APP fragments in human and rat neuronal cells PLoS One 5 e13989 21085580 PMC2981559
[47]Lerchundi R Neira R Valdivia S Vio K Concha MI Zambrano A Otth C 2011 Tau cleavage at D421 by caspase-3 is induced in neurons and astrocytes infected with herpes simplex virus type 1 J Alzheimers Dis 23 513 520 21098975
[48]Ill-Raga G Palomer E Wozniak MA Ramos-Fernandez E Bosch-Morato M Tajes M Guix FX Galan JJ Clarimon J Antunez C Real LM Boada M Itzhaki RF Fandos C Munoz FJ 2011 Activation of PKR causes amyloid beta-peptide accumulation via de-repression of BACE1 expression PLoS One 6 e21456 21738672 PMC3125189
[49]Santana S Recuero M Bullido MJ Valdivieso F Aldudo J 2012 Herpes simplex virus type I induces the accumulation of intracellular beta-amyloid in autophagic compartments and the inhibition of the non-amyloidogenic pathway in human neuroblastoma cells Neurobiol Aging 33 430 433 21272962
[50]Martin C Aguila B Araya P Vio K Valdivia S Zambrano A Concha MI Otth C 2014 Inflammatory and neurodegeneration markers during asymptomatic HSV-1 reactivation J Alzheimers Dis 39 849 859 24296813
[51]Civitelli L Marcocci ME Celestino I Piacentini R Garaci E Grassi C De Chiara G Palamara AT 2015 Herpes simplex virus type 1 infection in neurons leads to production and nuclear localization of APP intracellular domain (AICD): Implications for Alzheimer’s disease pathogenesis J Neurovirol 21 480 490 25925093
[52]Piacentini R Li Puma DD Ripoli C Marcocci ME De Chiara G Garaci E Palamara AT Grassi C 2015 Herpes simplex virus type-1 infection induces synaptic dysfunction in cultured cortical neurons via GSK-3 activation and intraneuronal amyloid-beta protein accumulation Sci Rep 5 15444 26487282 PMC4614347
[53]Little CS Hammond CJ MacIntyre A Balin BJ Appelt DM 2004 Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice Neurobiol Aging 25 419 429 15013562
[54]Miklossy J Kis A Radenovic A Miller L Forro L Martins R Reiss K Darbinian N Darekar P Mihaly L Khalili K 2006 Beta-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes Neurobiol Aging 27 228 236 15894409
[55]Boelen E Stassen FR van der Ven AJ Lemmens MA Steinbusch HP Bruggeman CA Schmitz C Steinbusch HW 2007 Detection of amyloid beta aggregates in the brain of BALB/c mice after Chlamydia pneumoniae infection Acta Neuropathol 114 255 261 17581756 PMC2039821
[56]Cheng SB Ferland P Webster P Bearer EL 2011 Herpes simplex virus dances with amyloid precursor protein while exiting the cell PLoS One 6 e17966 21483850 PMC3069030
[57]Wozniak MA Frost AL Preston CM Itzhaki RF 2011 Antivirals reduce the formation of key Alzheimer’s disease molecules in cell cultures acutely infected with herpes simplex virus type 1 PLoS One 6 e25152 22003387 PMC3189195
[58]Velayudhan L Gasper A Pritchard M Baillon S Messer C Proitsi P 2015 Pattern of smell identification impairment in Alzheimer’s disease J Alzheimers Dis 46 381 387 25757648
[60]Ball MJ Lukiw WJ Kammerman EM Hill JM 2013 Intracerebral propagation of Alzheimer’s disease: Strengthening evidence of a herpes simplex virus etiology Alzheimers Dement 9 169 175 23159044 PMC3578985
[61]Mori I Nishiyama Y Yokochi T Kimura Y 2005 Olfactory transmission of neurotropic viruses J Neurovirol 11 129 137 16036791
[62]Gillet L Frederico B Stevenson PG 2015 Host entry by gamma-herpesviruses – lessons from animal viruses? Curr Opin Virol 15 34 40 26246389
[63]Little CS Bowe A Lin R Litsky J Fogel RM Balin BJ Fresa-Dillon KL 2005 Age alterations in extent and severity of experimental intranasal infection with Chlamydophila pneumoniae in BALB/c mice Infect Immun 73 1723 1734 15731073 PMC1064908
[64]Braak H Del Tredici K 2015 The preclinical phase of the pathological process underlying sporadic Alzheimer’s disease Brain 138 2814 2833 26283673
[65]Blanc M Hsieh WY Robertson KA Kropp KA Forster T Shui G Lacaze P Watterson S Griffiths SJ Spann NJ Meljon A Talbot S Krishnan K Covey DF Wenk MR Craigon M Ruzsics Z Haas J Angulo A Griffiths WJ Glass CK Wang Y Ghazal P 2013 The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response Immunity 38 106 118 23273843 PMC3556782
[66]Liu SY Aliyari R Chikere K Li G Marsden MD Smith JK Pernet O Guo H Nusbaum R Zack JA Freiberg AN Su L Lee B Cheng G 2013 Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol Immunity 38 92 105 23273844 PMC3698975
[67]Papassotiropoulos A Lambert JC Wavrant-De Vrieze F Wollmer MA von der KH Streffer JR Maddalena A Huynh KD Wolleb S Lutjohann D Schneider B Thal DR Grimaldi LM Tsolaki M Kapaki E Ravid R Konietzko U Hegi T Pasch T Jung H Braak H Amouyel P Rogaev EI Hardy J Hock C Nitsch RM 2005 Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer’s disease Neurodegener Dis 2 233 241 16909003
[68]Lathe R Sapronova S Kotelevtsev Y 2014 Atherosclerosis and Alzheimer – diseases with a common cause? Inflammation, oxysterols, vasculature BMC Geriatrics 14 36 24656052 PMC3994432
[69]Soscia SJ Kirby JE Washicosky KJ Tucker SM Ingelsson M Hyman B Burton MA Goldstein LE Duong S Tanzi RE Moir RD 2010 The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide PLoS One 5 e9505 20209079 PMC2831066
[73]Williams WM Torres S Siedlak SL Castellani RJ Perry G Smith MA Zhu X 2013 Antimicrobial peptide beta-defensin-1 expression is upregulated in Alzheimer’s brain J Neuroinflammation 10 127 24139179 PMC3817866
[74]Itzhaki RF Lin WR Shang D Wilcock GK Faragher B Jamieson GA 1997 Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease Lancet 349 241 244 9014911
[76]Marques AR Straus SE Fahle G Weir S Csako G Fischer SH 2001 Lack of association between HSV-1 DNA in the brain, Alzheimer’s disease and apolipoprotein E4 J Neurovirol 7 82 83 11519487
[77]Hemling N Roytta M Rinne J Pollanen P Broberg E Tapio V Vahlberg T Hukkanen V 2003 Herpesviruses in brains in Alzheimer’s and Parkinson’s diseases Ann Neurol 54 267 271 12891684
[78]Beffert U Bertrand P Champagne D Gauthier S Poirier J 1998 HSV-1 in brain and risk of Alzheimer’s disease Lancet 351 1330 1331 9643802

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Background
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Chidambaram, S. B., Essa, M. M., Rathipriya, A. G., Bishir, M., Ray, B., Mahalakshmi, A. M., Tousif, A. H., Sakharkar, M. K., Kashyap, R. S., Friedland, R. P., et al. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.107988 · Cited by 204 · see citing works
Hospital-treated infectious diseases and the risk of dementia: a large, multicohort, observational study with a replication cohort
Sipilä, P. N., Heikkilä, N., Lindbohm, J. V., Hakulinen, C., Vahtera, J., Elovainio, M., Suominen, S., Väänänen, A., Koskinen, A., Nyberg, S. T., et al. (2021) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(21)00144-4 · Cited by 197 · see citing works
Self-citation
Heterogeneity in Alzheimer’s Disease Diagnosis and Progression Rates: Implications for Therapeutic Trials
Duara, R., & Barker, W. (2022) · Neurotherapeutics · doi:10.1007/s13311-022-01185-z · Cited by 187 · see citing works
The Possibility of an Infectious Etiology of Alzheimer Disease
Ashraf, G. M., Tarasov, V. V., Makhmutovа, A., Chubarev, V. N., Avila-Rodriguez, M., Bachurin, S. O., & Aliev, G. (2019) · Molecular Neurobiology · doi:10.1007/s12035-018-1388-y · Cited by 175 · see citing works
Time to test antibacterial therapy in Alzheimer’s disease
Panza, F., Lozupone, M., Solfrizzi, V., Watling, M., & Imbimbo, B. P. (2019) · Brain · doi:10.1093/brain/awz244 · Cited by 161 · see citing works
Relevance of gutmicrobiota in cognition, behaviour and Alzheimer’s disease
de J.R. De-Paula, V., Forlenza, A. S., & Forlenza, O. V. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.07.007 · Cited by 145 · see citing works
Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity
Spitzer, P., Condic, M., Herrmann, M., Oberstein, T. J., Scharin-Mehlmann, M., Gilbert, D. F., Friedrich, O., Grömer, T., Kornhuber, J., Lang, R., et al. (2016) · Scientific Reports · doi:10.1038/srep32228 · Cited by 128 · see citing works
Infectious agents and Alzheimer's disease
Piekut, T., Hurła, M., Banaszek, N., Szejn, P., Dorszewska, J., Kozubski, W., & Prendecki, M. (2022) · Journal of Integrative Neuroscience · doi:10.31083/j.jin2102073 · Cited by 123 · see citing works
Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease –conformist, nonconformist, and realistic prospects for AD pathogenesis
Li, H., Liu, C.-C., Zheng, H., & Huang, T. Y. (2018) · Translational Neurodegeneration · doi:10.1186/s40035-018-0139-3 · Cited by 103 · see citing works
Analysis the Link between Periodontal Diseases and Alzheimer’s Disease: A Systematic Review
Borsa, L., Dubois, M., Sacco, G., & Lupi, L. (2021) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph18179312 · Cited by 109 · see citing works
Interaction between Cytomegalovirus and Herpes Simplex Virus Type 1 Associated with the Risk of Alzheimer’s Disease Development
Lövheim, H., Olsson, J., Weidung, B., Johansson, A., Eriksson, S., Hallmans, G., & Elgh, F. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-161305 · Cited by 103 · see citing works
Self-citation
Infectious origin of Alzheimer’s disease: Amyloid beta as a component of brain antimicrobial immunity
Vojtechova, I., Machacek, T., Kristofikova, Z., Stuchlik, A., & Petrasek, T. (2022) · PLOS Pathogens · doi:10.1371/journal.ppat.1010929 · Cited by 92 · see citing works
Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics?
Hoeijmakers, L., Heinen, Y., van Dam, A.-M., Lucassen, P. J., & Korosi, A. (2016) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2016.00398 · Cited by 85 · see citing works
Hyperactivation of monocytes and macrophages in MCI patients contributes to the progression of Alzheimer's disease
Munawara, U., Catanzaro, M., Xu, W., Tan, C., Hirokawa, K., Bosco, N., Dumoulin, D., Khalil, A., Larbi, A., Lévesque, S., et al. (2021) · Immunity & Ageing · doi:10.1186/s12979-021-00236-x · Cited by 74 · see citing works
Self-citation
The viral hypothesis: how herpesviruses may contribute to Alzheimer’s disease
Wainberg, M., Luquez, T., Koelle, D. M., Readhead, B., Johnston, C., Darvas, M., & Funk, C. C. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01138-6 · Cited by 74 · see citing works
Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk
Chacko, A., Delbaz, A., Walkden, H., Basu, S., Armitage, C. W., Eindorf, T., Trim, L. K., Miller, E., West, N. P., St John, J. A., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-06749-9 · Cited by 65 · see citing works
The microbiota protects from viral-induced neurologic damage through microglia-intrinsic TLR signaling
Brown, D. G., Soto, R., Yandamuri, S., Stone, C., Dickey, L., Gomes-Neto, J. C., Pastuzyn, E. D., Bell, R., Petersen, C., Buhrke, K., et al. (2019) · eLife · doi:10.7554/elife.47117 · Cited by 60 · see citing works
Alzheimer disease and the periodontal patient: New insights, connections, and therapies
Ryder, M. I., & Xenoudi, P. (2021) · Periodontology 2000 · doi:10.1111/prd.12389 · Cited by 55 · see citing works
Perspectives for New and More Efficient Multifunctional Ligands for Alzheimer′s Disease Therapy
Zagórska, A., & Jaromin, A. (2020) · Molecules · doi:10.3390/molecules25153337 · Cited by 51 · see citing works
Testing the amyloid cascade hypothesis: Prevention trials in autosomal dominant Alzheimer disease
Levin, J., Vöglein, J., Quiroz, Y. T., Bateman, R. J., Ghisays, V., Lopera, F., McDade, E., Reiman, E., Tariot, P. N., & Morris, J. C. (2022) · Alzheimer's & Dementia · doi:10.1002/alz.12624 · Cited by 40 · see citing works
Herpes viruses and Alzheimer's disease: new evidence in the debate
Balin, B. J., & Hudson, A. P. (2018) · The Lancet Neurology · doi:10.1016/s1474-4422(18)30316-8 · Cited by 38 · see citing works
Self-citation
Alzheimer’s Disease (AD) Therapeutics—2: Beyond Amyloid—Re-Defining AD and Its Causality to Discover Effective Therapeutics
Mullane, K., & Williams, M. (2018) · Biochemical Pharmacology · doi:10.1016/j.bcp.2018.09.027 · Cited by 32 · see citing works
Host response: a trigger for neurodegeneration?
Stilling, R. M., & Cryan, J. F. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.129 · Cited by 18 · see citing works
Potential Role for Herpesviruses in Alzheimer’s Disease
Duggan, M. R., Torkzaban, B., Ahooyi, T. M., & Khalili, K. (2020) · Journal of Alzheimer's Disease · doi:10.3233/jad-200814 · Cited by 13 · see citing works
Most prominent challenges in translational neuroscience and strategic solutions to bridge the gaps: Perspectives from an editorial board interrogation
Hermann, D. M., Bacigaluppi, M., Bassetti, C. L., Bassotti, G., Boltze, J., Chan, A., Dalkara, T., Denes, A., Diez-Tejedor, E., Dodel, R., et al. (2025) · Exploration of Neuroscience · doi:10.37349/en.2025.1006106 · Cited by 13 · see citing works
Common bacterial infections and risk of incident cognitive decline or dementia: a systematic review protocol
Muzambi, R., Bhaskaran, K., Brayne, C., Smeeth, L., & Warren-Gash, C. (2019) · BMJ Open · doi:10.1136/bmjopen-2019-030874 · Cited by 11 · see citing works

Authors: Itzhaki, R. F., Lathe, R., Balin, B. J., Ball, M. J., Bearer, E. L., Braak, H., Bullido, M. J., Carter, C., Clerici, M., Cosby, S. L., Del Tredici, K., Field, H., Fulop, T., Grassi, C., Griffin, W. S. T., Haas, J., Hudson, A. P., Kamer, A. R., Kell, D. B., Licastro, F., Letenneur, L., Lövheim, H., Mancuso, R., Miklossy, J., Otth, C., Palamara, A. T., Perry, G., Preston, C., Pretorius, E., Strandberg, T., Tabet, N., Taylor-Robinson, S. D., & Whittum-Hudson, J. A.
Affiliations: University of Manchester (GB)
University of Edinburgh (GB)
Philadelphia College of Osteopathic Medicine (US)
Oregon Health & Science University (US)
University of New Mexico Health Sciences Center (US)
Universität Ulm (DE)
Consejo Superior de Investigaciones Científicas (ES)
Polygenic Pathways, Hastings, East Sussex, UK
University of Milan (IT)
Queen's University Belfast (GB)
Clinical Neuroanatomy Section, Department of Neurology, Center for Biomedical Research, University of Ulm, Ulm, Germany
University of Cambridge (GB)
Department of Medicine, Division of Geriatrics, Université de Sherbrooke, Sherbrooke, PQ, Canada
Institute of Human Physiology, Medical School, Universitá Cattolica, Rome; San Raffaele Pisana Scientific Institute for Research, Hospitalization, and Health Care, Rome, Italy
University of Arkansas for Medical Sciences (US)
Wayne State University (US)
New York University (US)
University of Bologna (IT)
Université de Bordeaux (FR)
Umeå University (SE)
Don Carlo Gnocchi Foundation (IT)
Prevention Alzheimer International Foundation, International Alzheimer Research Center, Martigny-Croix, Switzerland
Institute of Clinical Microbiology, Faculty of Medicine, Austral University of Chile, Valdivia, Chile
Istituto Pasteur (IT)
The University of Texas at San Antonio (US)
Institute of Virology, Glasgow, UK
University of Pretoria (ZA)
University of Helsinki (FI)
Brighton and Sussex Medical School (GB)
St Mary's Hospital (GB)
Departments of Immunology and Microbiology, Internal Medicine (Rheumatology), and Ophthalmology, Wayne State University School of Medicine, Detroit, MI, USA
Corresponding author: Lathe, Richard
ORCID: Itzhaki, Ruth F.
Lathe, Richard
Balin, Brian J.
Bearer, Elaine L.
Braak, Heiko
Bullido, Maria J.
Clerici, Mario
Cosby, S. Louise
Grassi, Claudio
Griffin, W. Sue T.
Haas, Jürgen
Kamer, Angela R.
Kell, Douglas B.
Letenneur, Luc
Lövheim, Hugo
Mancuso, Roberta
Palamara, Anna Teresa
Perry, George
Preston, Christopher
Pretorius, Etheresia
Strandberg, Timo
Tabet, Naji
Taylor-Robinson, Simon D.
Venue: Journal of Alzheimer’s Disease
Publisher: SAGE Publications
Published: 2016-03-08
Volume: 51
Issue: 4
Pages: 979-984
ISSN: 1387-2877 (ISSN-L)
1875-8908
DOI: 10.3233/jad-160152
PMC: PMC5457904
OpenAlex: W2294532941
Cited by: 532
References: 12
Citations by year: 2026: 36 · 2025: 30 · 2024: 56 · 2023: 36 · 2022: 43 · 2021: 73 · 2020: 69 · 2019: 51 · 2018: 63 · 2017: 43 · 2016: 32
FWCI: 7.14
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: journals.sagepub.com/page/policies/text-and-data-mining-license (tdm)
Locations: Journal of Alzheimer s Disease (publishedVersion)
PubMed (publishedVersion)
Research Explorer (The University of Manchester) (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Digital Commons - PCOM (Philadelphia College of Osteopathic Medicine) (submittedVersion)
Figshare (submittedVersion, cc-by)
IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
Spiral (Imperial College London) (submittedVersion)
Sussex Research Online (University of Sussex) (submittedVersion)
Funders: National Institutes of Health (5r01ns046810-04)
National Institute of Mental Health (R01MH096093)
National Institute of Neurological Disorders and Stroke (R01-NS046810, R01NS062184)
National Institute on Minority Health and Health Disparities (G12MD007591)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords: Alzheimer's disease, microbial etiology
MeSH terms: Alzheimer Disease, Animals, Brain, Communicable Diseases, Humans, Amyloid beta-Peptides, Microbiota

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