CoChat
Sign Up
Cited by 37Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Clinical evidence of human pathogens implicated in Alzheimer’s disease pathology and the therapeutic efficacy of antimicrobials: an overview

Open access
Catumbela, Celso S. G., Giridharan, Vijayasree V., Barichello, Tatiana, Morales, Rodrigo·2023·Translational Neurodegeneration
DOI 10.1186/s40035-023-00369-7PMC PMC10369764
Open this paper in CoChat — free accountOpen PDF

Abstract

A wealth of pre-clinical reports and data derived from human subjects and brain autopsies suggest that microbial infections are relevant to Alzheimer’s disease (AD). This has inspired the hypothesis that microbial infections increase the risk or even trigger the onset of AD. Multiple models have been developed to explain the increase in pathogenic microbes in AD patients. Although this hypothesis is well accepted in the field, it is not yet clear whether microbial neuroinvasion is a cause of AD or a consequence of the pathological changes experienced by the demented brain. Along the same line, the gut microbiome has also been proposed as a modulator of AD. In this review, we focus on human-based evidence demonstrating the elevated abundance of microbes and microbe-derived molecules in AD hosts as well as their interactions with AD hallmarks. Further, the direct-purpose and potential off-target effects underpinning the efficacy of anti-microbial treatments in AD are also addressed.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s40035-023-00369-7

Cites

15 of 15 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Pathogens may act as environmental triggers for Alzheimer's disease through direct cytotoxicity, in which pathogens infect central nervous system cells, leading to neuronal injury, cell death, and release of DAMPs that initiate chronic inflammation.

    “The first posits direct cytotoxicity, in which pathogens infect central nervous system cells, leading to neuronal injury, cell death, and the release of damage-associated molecular patterns (DAMPs) that initiate chronic inflammation [164].”

    From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [164]

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 139

  1. [1]Fulop T Witkowski JM Bourgade K Khalil A Zerif E Larbi A Can an infection hypothesis explain the beta amyloid hypothesis of Alzheimer’s disease? Front Aging Neurosci 2018 10 224 10.3389/fnagi.2018.00224 30087609 PMC6066504 · DOI
  2. [2]Zhu J Ge F Zeng Y Qu Y Chen W Yang H Physical and mental activity, disease susceptibility, and risk of dementia: a prospective cohort study based on UK biobank Neurology 2022 99 E799 813 10.1212/WNL.0000000000200701 35896434 PMC9484730 · DOI
  3. [4]Zazzara MB Vetrano DL Carfì A Liperoti R Damiano C Onder G Comorbidity patterns in institutionalized older adults affected by dementia Alzheimers Dement 2022 14 e12320 PMC9197250 35734097
  4. [5]Lagisetty Y Bourquard T Al-Ramahi I Mangleburg CG Mota S Soleimani S Identification of risk genes for Alzheimer’s disease by gene embedding Cell Genom 2022 2 100162 10.1016/j.xgen.2022.100162 36268052 PMC9581494 · DOI
  5. [6]Go M Kou J Lim JE Yang J Fukuchi KI Microglial response to LPS increases in wild-type mice during aging but diminishes in an Alzheimer’s mouse model: Implication of TLR4 signaling in disease progression Biochem Biophys Res Commun 2016 479 331 337 10.1016/j.bbrc.2016.09.073 27641666 PMC5048480 · DOI
  6. [8]Asby D Boche D Allan S Love S Miners JS Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease Brain 2021 144 1869 1883 10.1093/brain/awab094 33723589 PMC8320299 · DOI
  7. [10]Haditsch U Roth T Rodriguez L Hancock S Cecere T Nguyen M Alzheimer’s disease-like neurodegeneration in Porphyromonas gingivalis infected neurons with persistent expression of active gingipains J Alzheimers Dis 2020 75 1301 1317 10.3233/JAD-200393 32390638 PMC7369049 · DOI
  8. [11]Eimer WA Vijaya Kumar DK Navalpur Shanmugam NK Rodriguez AS Mitchell T Washicosky KJ Alzheimer’s disease-associated β-amyloid is rapidly seeded by Herpesviridae to protect against brain infection Neuron 2018 99 56 63.e3 10.1016/j.neuron.2018.06.030 30001512 PMC6075814 · DOI · Paper page
  9. [12]Kumar DKV Choi HS Washicosky KJ Eimer WA Tucker S Ghofrani J Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease Sci Transl Med 2016 8 340ra72 10.1126/scitranslmed.aaf1059 27225182 PMC5505565 · DOI · Paper page
  10. [13]Wozniak MA Itzhaki RF Shipley SJ Dobson CB Herpes simplex virus infection causes cellular β-amyloid accumulation and secretase upregulation Neurosci Lett 2007 429 95 100 10.1016/j.neulet.2007.09.077 17980964 · DOI
  11. [14]Itzhaki RF Golde TE Heneka MT Readhead B Do infections have a role in the pathogenesis of Alzheimer disease? Nat Rev Neurol 2020 16 193 197 10.1038/s41582-020-0323-9 32152461 · DOI
  12. [15]Sochocka M Zwolińska K Leszek J The infectious etiology of Alzheimer’s disease Curr Neuropharmacol 2017 15 996 10.2174/1570159X15666170313122937 28294067 PMC5652018 · DOI · Paper page
  13. [16]Vigasova D Nemergut M Liskova B Damborsky J Multi-pathogen infections and Alzheimer’s disease Microb Cell Fact 2021 20 1 25 10.1186/s12934-021-01520-7 33509204 PMC7844946 · DOI
  14. [17]Uwishema O Mahmoud A Sun J Correia IFS Bejjani N Alwan M Is Alzheimer’s disease an infectious neurological disease? A review of the literature Brain Behav 2022 12 8 e2728 10.1002/brb3.2728 35879909 PMC9392514 · DOI
  15. [18]Deshpande D Alffenaar JWC Köser CU Dheda K Chapagain ML Simbar N D-Cycloserine pharmacokinetics/pharmacodynamics, susceptibility, and dosing implications in multidrug-resistant Tuberculosis: a Faustian deal Clin Inf Dis 2018 67 S308 S316 10.1093/cid/ciy624 PMC6260153 30496460 · DOI
  16. [20]Schwartz BL Hashtroudi S Herting RL Schwartz P Deutsch SI d-Cycloserine enhances implicit memory in Alzheimer patients Neurology 1996 46 420 424 10.1212/WNL.46.2.420 8614505 · DOI
  17. [21]Tsai GE Falk WE Gunther J Coyle JT Improved cognition in Alzheimer’s disease with short-term D-cycloserine treatment Amer J Psych 1999 156 467 469 10.1176/ajp.156.3.467 10080566 · DOI
  18. [22]Wesnes K Simpson P White L Pinker S The cognitive drug research computerized assessment systems for elderly, AAMI & demented Patients J Psychopharm 1992 6 108 10.1177/026988119200600135 22291263 · DOI
  19. [23]Fakouhi TD Jhee SS Sramek JJ Benes C Schwartz P Hantsburger G Evaluation of cycloserine in the treatment of Alzheimer’s disease J Geriatr Psychiatry Neurol 1995 8 226 230 10.1177/089198879500800405 8561836 · DOI
  20. [24]Yu R Zheng L Cui Y Zhang H Ye H Doxycycline exerted neuroprotective activity by enhancing the activation of neuropeptide GPCR PAC1 Neuropharm 2016 103 1 15 10.1016/j.neuropharm.2015.11.032 26700245 · DOI
  21. [25]Bi W Zhu L Wang C Liang Y Liu J Shi Q Rifampicin inhibits microglial inflammation and improves neuron survival against inflammation Brain Res 2011 1395 12 20 10.1016/j.brainres.2011.04.019 21555117 · DOI
  22. [26]Loeb MB Molloy DW Smieja M Standish T Goldsmith CH Mahony J A randomized, controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease J Am Geriatr Soc 2004 52 381 387 10.1111/j.1532-5415.2004.52109.x 14962152 · DOI
  23. [27]Li XQ Andersson TB Ahlström M Weidolf L Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities Drug Metab Disp 2004 32 821 827 10.1124/dmd.32.8.821 15258107 · DOI
  24. [28]Alder J Mitten M Jarvis K Gupta P Clement J Efficacy of clarithromycin for treatment of experimental Lyme disease in vivo Antimicrob Agents Chemother 1993 37 1329 1333 10.1128/AAC.37.6.1329 8328782 PMC187961 · DOI
  25. [29]Bodey GP Nance J Amoxicillin: in vitro and pharmacological studies Antimicrob Agents Chemother 1972 1 358 362 10.1128/AAC.1.4.358 4598841 PMC444222 · DOI
  26. [30]Melhus Å Effects of amoxicillin on the expression of cytokines during experimental acute otitis media caused by non-typeable Haemophilus influenzae J Antimicrob Chemother 2001 48 397 402 10.1093/jac/48.3.397 11533005 · DOI
  27. [31]Kountouras J Boziki M Gavalas E Zavos C Grigoriadis N Deretzi G Eradication of Helicobacter pylori may be beneficial in the management of Alzheimer’s disease J Neurol 2009 256 758 767 10.1007/s00415-009-5011-z 19240960 · DOI
  28. [33]Wang X Sun G Feng T Zhang J Huang X Wang T Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression Cell Res 2019 29 787 803 10.1038/s41422-019-0216-x 31488882 PMC6796854 · DOI · Paper page
  29. [35]Pedre B Barayeu U Ezeriņa D Dick TP The mechanism of action of N-acetylcysteine (NAC): the emerging role of H2S and sulfane sulfur species Pharmacol Ther 2021 228 107916 10.1016/j.pharmthera.2021.107916 34171332 · DOI
  30. [36]Wyss-Coray T Lin C Yan F Yu GQ Rohde M Mcconlogue L TGF-β1 promotes microglial amyloid-β clearance and reduces plaque burden in transgenic mice Nat Med 2001 7 612 618 10.1038/87945 11329064 · DOI · Paper page
  31. [37]Tichauer JE von Bernhardi R Transforming growth factor-β stimulates β amyloid uptake by microglia through Smad3-dependent mechanisms J Neurosci Res 2012 90 1970 1980 10.1002/jnr.23082 22715062 · DOI
  32. [38]Olofsson AC Hermansson M Elwing H N-acetyl-L-cysteine affects growth, extracellular polysaccharide production, and bacterial biofilm formation on solid surfaces Appl Environ Microbiol 2003 69 4814 4822 10.1128/AEM.69.8.4814-4822.2003 12902275 PMC169071 · DOI
  33. [39]Zhao T Liu Y N-acetylcysteine inhibit biofilms produced by Pseudomonas aeruginosa BMC Microbiol 2010 10 1 8 10.1186/1471-2180-10-140 20462423 PMC2882372 · DOI
  34. [40]Picchi SC Takita MA Coletta-Filho HD Machado MA de Souza AA N-acetylcysteine interferes with the biofilm formation, motility and epiphytic behaviour of Xanthomonas citri subsp. Citri. Plant Pathol 2016 65 561 569 10.1111/ppa.12430 · DOI
  35. [42]Remington R Chan A Paskavitz J Shea TB Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage alzheimer’s disease: a placebo-controlled pilot study Am J Alzheimers Dis Other Demen 2009 24 27 33 10.1177/1533317508325094 19056706 PMC10846219 · DOI
  36. [43]Soscia SJ Kirby JE Washicosky KJ Tucker SM Ingelsson M Hyman B The Alzheimer’s disease-associated amyloid β-protein is an antimicrobial peptide PLoS ONE 2010 5 e9505 10.1371/journal.pone.0009505 20209079 PMC2831066 · DOI · Paper page
  37. [44]Mrak RE Sheng JG Griffin WST Correlation of astrocytic S100β expression with dystrophie neurites in amyloid plaques of Alzheimer’s disease J Neuropathol Exp Neurol 1996 55 273 279 10.1097/00005072-199603000-00002 8786385 PMC3833601 · DOI
  38. [47]Bhat J Kabelitz D Kabelitz D Bhat J An introduction to immunology and epigenetics Epigenetics of the Immune System 2020 Elsevier 1 23
  39. [48]Kwiecinski JM Horswill AR Staphylococcus aureus bloodstream infections: pathogenesis and regulatory mechanisms Curr Opin Microbiol 2020 53 51 60 10.1016/j.mib.2020.02.005 32172183 PMC7244392 · DOI
  40. [51]Latour S Fischer A Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases Immunol Rev 2019 291 1 174 189 10.1111/imr.12791 31402499 · DOI
  41. [52]Spel L Martinon F Detection of viruses by inflammasomes Curr Opin Virol 2021 46 59 64 10.1016/j.coviro.2020.10.001 33176273 PMC7959698 · DOI
  42. [53]James C Harfouche M Welton NJ Turner KME Abu-Raddad LJ Gottlieb SL Herpes simplex virus: global infection prevalence and incidence estimates, 2016 Bull World Health Organ 2020 98 315 329 10.2471/BLT.19.237149 32514197 PMC7265941 · DOI
  43. [54]Croen KD Ostrove JM Dragovic LJ Smialek JE Straus SE Latent herpes simplex virus in human trigeminal ganglia New Engl J Med 1987 317 1427 1432 10.1056/NEJM198712033172302 2825014 · DOI
  44. [55]Ball MJ Nuttall K Warren KG Neuronal and lymphocytic populations in human trigeminal ganglia: implications for ageing and for latent virus Neuropathol Appl Neurobiol 1982 8 177 187 10.1111/j.1365-2990.1982.tb00273.x 7121735 · DOI
  45. [56]Kurki SN Kantonen J Kaivola K Hokkanen L Mäyränpää MI Puttonen H APOE ε4 associates with increased risk of severe COVID-19, cerebral microhaemorrhages and post-COVID mental fatigue: a Finnish biobank, autopsy and clinical study Acta Neuropathol Commun 2021 9 1 13 10.1186/s40478-021-01302-7 34949230 PMC8696243 · DOI
  46. [57]Zhao C Strobino K Moon YP Cheung YK Sacco RL Stern Y APOE ε4 modifies the relationship between infectious burden and poor cognition Neurol Genet 2020 10.1212/NXG.0000000000000462 32754642 PMC7357411 · DOI
  47. [58]Linard M Letenneur L Garrigue I Doize A Dartigues JF Helmer C Interaction between APOE4 and herpes simplex virus type 1 in Alzheimer’s disease Alzheimers Dement 2020 16 200 208 10.1002/alz.12008 31914220 · DOI · Paper page
  48. [59]Jamieson GA Maitland NJ Wilcock GK Craske J Itzhaki RF Latent herpes simplex virus type 1 in normal and Alzheimer’s disease brains J Med Virol 1991 33 224 227 10.1002/jmv.1890330403 1649907 · DOI
  49. [60]Gannicliffe A Sutton PRN Itzhak RF Viruses, brain and immunosuppression Psychol Med 1986 16 2 247 249 10.1017/S0033291700009053 3014587 · DOI
  50. [61]Itzhaki RF Lin WR Shang D Wilcock GK Faragher B Jamieson GA Herpes simplex virus type 1 in brain and risk of Alzheimer’s disease Lancet 1997 349 241 244 10.1016/S0140-6736(96)10149-5 9014911 · DOI
  51. [62]Lin W-R Wozniak MA Cooper RJ Wilcock GK Itzhaki RF Herpesviruses in brain and Alzheimer’s disease J Pathol 2002 197 395 402 10.1002/path.1127 12115887 · DOI
  52. [63]Allnutt MA Johnson K Bennett DA Connor SM Troncoso JC Pletnikova O Human herpesvirus 6 detection in Alzheimer’s disease cases and controls across multiple cohorts Neuron 2020 105 1027 1035.e2 10.1016/j.neuron.2019.12.031 31983538 PMC7182308 · DOI · Paper page
  53. [64]Wozniak M Mee AP Itzhaki RF Herpes simplex virus type 1 DNA is located within Alzheimer’s disease amyloid plaques J Pathol 2009 217 131 138 10.1002/path.2449 18973185 · DOI · Paper page
  54. [65]Warren-Gash C Forbes HJ Williamson E Breuer J Hayward AC Mavrodaris A Human herpesvirus infections and dementia or mild cognitive impairment: a systematic review and meta-analysis Sci Rep 2019 9 1 10 10.1038/s41598-019-41218-w 30894595 PMC6426940 · DOI · Paper page
  55. [66]Rouse BT Sehrawat S Immunity and immunopathology to viruses: what decides the outcome? Nat Rev Immunol 2010 10 7 514 526 10.1038/nri2802 20577268 PMC3899649 · DOI
  56. [67]Deeks SG Overbaugh J Phillips A Buchbinder S HIV infection Nat Rev Dis Primers 2015 1 1 22 10.1038/nrdp.2015.35 27188527 · DOI
  57. [68]Lutgen V Narasipura SD Barbian HJ Richards M Wallace J Razmpour R HIV infects astrocytes in vivo and egresses from the brain to the periphery PLoS Pathog 2020 16 e1008381 10.1371/journal.ppat.1008381 32525948 PMC7289344 · DOI
  58. [69]Donoso M D’Amico D Valdebenito S Hernandez CA Prideaux B Eugenin EA Identification, quantification, and characterization of HIV-1 reservoirs in the human brain Cells 2022 11 2379 10.3390/cells11152379 35954221 PMC9367788 · DOI
  59. [70]Corder EH Robertson K Lannfelt L Bogdanovic N Eggertsen G Wilkins J HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy Nat Med 1998 4 1182 1184 10.1038/2677 9771753 · DOI
  60. [71]Andres MA Feger U Nath A Munsaka S Jiang CS Chang L APOE ε4 allele and CSF APOE on cognition in HIV-infected subjects J Neuroimm Pharmacol 2011 6 389 398 10.1007/s11481-010-9254-3 PMC4899041 21184197 · DOI
  61. [72]Burt TD Agan BK Marconi VC He W Kulkarni H Mold JE Apolipoprotein (apo) E4 enhances HIV-1 cell entry in vitro, and the APOE ε4/ε4 genotype accelerates HIV disease progression Proc Natl Acad Sci U S A 2008 105 8718 8723 10.1073/pnas.0803526105 18562290 PMC2438419 · DOI
  62. [73]Esiri MM Prevalence of Alzheimer plaques in AIDS J Neurol Neurosurg Psychiatry 1998 65 29 33 10.1136/jnnp.65.1.29 9667557 PMC2170157 · DOI
  63. [75]Smith DB Simmonds P Bell JE Brain viral burden, neuroinflammation and neurodegeneration in HAART-treated HIV positive injecting drug users J Neurovirol 2014 20 28 38 10.1007/s13365-013-0225-3 24420447 · DOI
  64. [76]Ide M Harris M Stevens A Sussams R Hopkins V Culliford D Periodontitis and cognitive decline in Alzheimer’s disease PLoS ONE 2016 11 e0151081 10.1371/journal.pone.0151081 26963387 PMC4786266 · DOI · Paper page
  65. [77]Poole S Singhrao SK Kesavalu L Curtis MA Crean SJ Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue J Alzheimers Dis 2013 36 665 677 10.3233/JAD-121918 23666172 · DOI
  66. [78]Raiziss GW Severac M Rapidity with which spirochaeta pallida invades the blood stream Arch Derm Syphilol 1937 35 1101 1109 10.1001/archderm.1937.01470240093008 · DOI
  67. [80]Lithgow KV Tsao E Schovanek E Gomez A Swayne LA Cameron CE Treponema pallidum disrupts VE-cadherin intercellular junctions and traverses endothelial barriers using a cholesterol-dependent mechanism Front Microbiol 2021 12 1790 10.3389/fmicb.2021.691731 PMC8329343 34354688 · DOI
  68. [82]Moter A Hoenig C Choi BK Riep B Göbel UB Molecular epidemiology of oral treponemes associated with periodontal disease J Clin Microbiol 1998 36 1399 1403 10.1128/JCM.36.5.1399-1403.1998 9574713 PMC104836 · DOI
  69. [83]You M Mo S Leung WK Watt RM Comparative analysis of oral treponemes associated with periodontal health and disease BMC Infect Dis 2013 13 1 13 10.1186/1471-2334-13-174 23578286 PMC3637317 · DOI
  70. [84]Riviere G Riviere KH Smith KS Molecular and immunological evidence of oral Treponema in the human brain and their association with Alzheimer’s disease Oral Microbiol Immunol 2002 17 113 118 10.1046/j.0902-0055.2001.00100.x 11929559 · DOI
  71. [85]Miklossy J Alzheimer’s disease: a neurospirochetosis: analysis of the evidence following Koch’s and Hill’s criteria J Neuroinflam 2011 8 90 10.1186/1742-2094-8-90 PMC3171359 21816039 · DOI
  72. [86]Su X Tang Z Lu Z Liu Y He W Jiang J Oral Treponema denticola infection induces Aβ1–40 and Aβ1–42 accumulation in the hippocampus of C57BL/6 Mice J Mol Neurosci 2021 71 1506 1514 10.1007/s12031-021-01827-5 33763842 · DOI
  73. [87]Nemergut M Batkova T Vigasova D Bartos M Hlozankova M Schenkmayerova A Increased occurrence of Treponema spp. and double-species infections in patients with Alzheimer’s disease Sci Tot Env. 2022 844 157114 10.1016/j.scitotenv.2022.157114 35787909 · DOI
  74. [88]Miklossy J Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease Front Aging Neurosci 2015 7 46 10.3389/fnagi.2015.00046 25932012 PMC4399390 · DOI · Paper page
  75. [89]Peng X, Cheng L, You Y, Tang C, Ren B, Li Y, et al. Oral microbiota in human systematic diseases. Int J Oral Sci. 2022. PMC8891310 35236828
  76. [90]Dando SJ Mackay-Sim A Norton R Currie BJ St. John JA Ekberg JAK Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion Clin Microbiol Rev 2014 27 691 726 10.1128/CMR.00118-13 25278572 PMC4187632 · DOI · Paper page
  77. [91]Cain MD Salimi H Diamond MS Klein RS Mechanisms of pathogen invasion into the central nervous system Neuron 2019 103 5 771 783 10.1016/j.neuron.2019.07.015 31487528 · DOI
  78. [92]Porritt RA Crother TR Chlamydia pneumoniae infection and inflammatory diseases For Immunopathol Dis Therap 2016 7 3–4 237 254 30687565 PMC6345537
  79. [93]Balin BJ Hammond CJ Little CS Hingley ST Al-Atrache Z Appelt DM Chlamydia pneumoniae: An etiologic agent for late-onset dementia Front Aging Neurosci 2018 10 302 10.3389/fnagi.2018.00302 30356749 PMC6189393 · DOI · Paper page
  80. [94]Balin BJ Gérard HC Arking EJ Appelt DM Branigan PJ Abrams JT Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain Med Microbiol Immunol 1998 187 23 42 10.1007/s004300050071 9749980 · DOI · Paper page
  81. [95]Gérard HC Dreses-Werringloer U Wildt KS Deka S Oszust C Balin BJ Chlamydophila (Chlamydia) pneumoniae in the Alzheimer’s brain FEMS Immunol Med Microbiol 2006 48 355 366 10.1111/j.1574-695X.2006.00154.x 17052268 · DOI · Paper page
  82. [96]Kountouras J Boziki M Gavalas E Zavos C Deretzi G Grigoriadis N Increased cerebrospinal fluid Helicobacter pylori antibody in Alzheimer’s disease Int J Neurosc 2009 119 765 777 10.1080/00207450902782083 19326283 · DOI
  83. [97]Vargas-Caraveo A Sayd A Maus SR Caso JR Madrigal JLM García-Bueno B Lipopolysaccharide enters the rat brain by a lipoprotein-mediated transport mechanism in physiological conditions Sci Rep 2017 7 1 15 10.1038/s41598-017-13302-6 29030613 PMC5640642 · DOI
  84. [98]Needham BD Carroll SM Giles DK Georgiou G Whiteley M Trent MS Modulating the innate immune response by combinatorial engineering of endotoxin Proc Natl Acad Sci USA 2013 110 1464 1469 10.1073/pnas.1218080110 23297218 PMC3557076 · DOI
  85. [99]Zhao Y Jaber V Lukiw WJ Secretory products of the human GI tract microbiome and their potential impact on Alzheimer’s disease (AD): detection of lipopolysaccharide (LPS) in AD hippocampus Front Cell Infect Microbiol 2017 7 318 10.3389/fcimb.2017.00318 28744452 PMC5504724 · DOI · Paper page
  86. [100]Zhan X Stamova B Jin LW Decarli C Phinney B Sharp FR Gram-negative bacterial molecules associate with Alzheimer disease pathology Neurology 2016 87 2324 2332 10.1212/WNL.0000000000003391 27784770 PMC5135029 · DOI · Paper page
  87. [101]Pisa D Alonso R Rábano A Horst MN Carrasco L Fungal enolase, β-tubulin, and chitin are detected in brain tissue from Alzheimer’s disease patients Front Microbiol 2016 7 1772 10.3389/fmicb.2016.01772 27872620 PMC5097921 · DOI
  88. [102]Pisa D Alonso R Rábano A Rodal I Carrasco L Different brain regions are infected with fungi in Alzheimer’s disease Sci Rep 2015 5 1 10.1038/srep15015 PMC4606562 26468932 · DOI · Paper page
  89. [103]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 10.3389/fnagi.2018.00159 29881346 PMC5976758 · DOI
  90. [104]Liu Y Mittal R Solis NV Prasadarao NV Filler SG Mechanisms of Candida albicans trafficking to the brain PLoS Pathog 2011 7 e1002305 10.1371/journal.ppat.1002305 21998592 PMC3188548 · DOI · Paper page
  91. [105]Pérez-Torrado R Querol A Saccharomyces cerevisiae show low levels of traversal across human endothelial barrier in vitro F100Res 2017 6 944 PMC5605952 28979764
  92. [106]Xu W Wong G Hwang YY Larbi A The untwining of immunosenescence and aging Semin Immunopathol 2020 42 5 559 572 10.1007/s00281-020-00824-x 33165716 PMC7665974 · DOI
  93. [107]Teissier T Boulanger E Cox LS Interconnections between inflammageing and immunosenescence during ageing Cells 2022 11 3 359 10.3390/cells11030359 35159168 PMC8834134 · DOI
  94. [108]Kovaiou RD Herndler-Brandstetter D Grubeck-Loebenstein B Age-related changes in immunity: implications for vaccination in the elderly Expert Rev Mol Med 2007 9 3 1 17 10.1017/S1462399407000221 17266794 · DOI
  95. [109]Hazeldine J Harris P Chapple IL Grant M Greenwood H Livesey A Impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals Aging Cell 2014 13 690 698 10.1111/acel.12222 24779584 PMC4326942 · DOI
  96. [110]Rémond D Shahar DR Gille D Pinto P Kachal J Peyron MA Understanding the gastrointestinal tract of the elderly to develop dietary solutions that prevent malnutrition Oncotarget 2015 6 13858 13898 10.18632/oncotarget.4030 26091351 PMC4546438 · DOI
  97. [111]Meyer KC The role of immunity in susceptibility to respiratory infection in the aging lung Respir Physiol 2001 128 1 23 31 10.1016/S0034-5687(01)00261-4 11535259 PMC7130717 · DOI
  98. [112]Renvoize EB Awad LO Hambling MH A sero-epidemiological study of conventional infectious agents in Alzheimer’s disease Age Ageing 1987 16 311 314 10.1093/ageing/16.5.311 3687571 · DOI · Paper page
  99. [113]Ounanian A Seigneurin JM Guilbert B Avrameas S Renverez JC Antibodies to viral antigens, xenoantigens, and autoantigens in Alzheimer’s disease J Clin Lab Anal 1990 4 367 375 10.1002/jcla.1860040510 2172499 · DOI · Paper page
  100. [114]Letenneur L Pérès K Fleury H Garrigue I Barberger-Gateau P Helmer C Seropositivity to Herpes simplex virus antibodies and risk of Alzheimer’s disease: a population-based cohort study PLoS ONE 2008 3 e3637 10.1371/journal.pone.0003637 18982063 PMC2572852 · DOI · Paper page
  101. [115]Lövheim H Gilthorpe J Adolfsson R Nilsson LG Elgh F Reactivated herpes simplex infection increases the risk of Alzheimer’s disease Alzheimers Dement 2015 11 593 599 10.1016/j.jalz.2014.04.522 25043910 · DOI
  102. [116]Sparks Stein P Steffen MJ Smith C Jicha G Ebersole JL Abner E Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease Alzheimers Dement 2012 8 196 203 10.1016/j.jalz.2011.04.006 22546352 PMC3712346 · DOI
  103. [117]Kamer AR Pirraglia E Tsui W Rusinek H Vallabhajosula S Mosconi L Periodontal disease associates with higher brain amyloid load in normal elderly Neurobiol Aging 2015 36 627 633 10.1016/j.neurobiolaging.2014.10.038 25491073 PMC4399973 · DOI
  104. [118]Alonso R Pisa D Rábano A Carrasco L Alzheimer’s disease and disseminated mycoses Eur J Clin Microb Infec Dis 2014 33 1125 1132 10.1007/s10096-013-2045-z 24452965 · DOI · Paper page
  105. [119]Kline KA Bowdish DM Infection in an aging population Curr Opin Microbiol 2016 29 63 67 10.1016/j.mib.2015.11.003 26673958 · DOI
  106. [120]Paone P Cani PD Mucus barrier, mucins and gut microbiota: the expected slimy partners? Gut 2020 69 12 2232 2243 10.1136/gutjnl-2020-322260 32917747 PMC7677487 · DOI
  107. [121]Magne F Gotteland M Gauthier L Zazueta A Pesoa S Navarrete P The firmicutes/bacteroidetes ratio: a relevant marker of gut dysbiosis in obese patients? Nutrients 2020 12 5 1474 10.3390/nu12051474 32438689 PMC7285218 · DOI · Paper page
  108. [122]Vaiserman A Romanenko M Piven L Moseiko V Lushchak O Kryzhanovska N Differences in the gut Firmicutes to Bacteroidetes ratio across age groups in healthy Ukrainian population BMC Microbiol 2020 20 1 10.1186/s12866-020-01903-7 32698765 PMC7374892 · DOI
  109. [123]Indiani CMDSP Rizzardi KF Castelo PM Ferraz LFC Darrieux M Parisotto TM Childhood obesity and Firmicutes/Bacteroidetes ratio in the gut microbiota: a systematic review Child Obes 2018 14 8 501 509 10.1089/chi.2018.0040 30183336 · DOI
  110. [124]Larsen N Vogensen FK van den Berg FWJ Nielsen DS Andreasen AS Pedersen BK Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults PLoS ONE 2010 5 e9085 10.1371/journal.pone.0009085 20140211 PMC2816710 · DOI · Paper page
  111. [125]Saji N Murotani K Hisada T Tsuduki T Sugimoto T Kimura A The relationship between the gut microbiome and mild cognitive impairment in patients without dementia: a cross-sectional study conducted in Japan Sci Rep 2019 9 1 10 31852995 PMC6920432
  112. [126]Vogt NM Kerby RL Dill-McFarland KA Harding SJ Merluzzi AP Johnson SC Gut microbiome alterations in Alzheimer’s disease Sci Rep 2017 7 13537 10.1038/s41598-017-13601-y 29051531 PMC5648830 · DOI · Paper page
  113. [127]Cattaneo A Cattane N Galluzzi S Provasi S Lopizzo N Festari C Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly Neurobiol Aging 2017 49 60 68 10.1016/j.neurobiolaging.2016.08.019 27776263 · DOI · Paper page
  114. [130]Lanza M Campolo M Casili G Filippone A Paterniti I Cuzzocrea S Sodium butyrate exerts neuroprotective effects in spinal cord injury Mol Neurobiol 2019 56 3937 3947 10.1007/s12035-018-1347-7 30229438 · DOI
  115. [131]Kukkar A Singh N Jaggi AS Attenuation of neuropathic pain by sodium butyrate in an experimental model of chronic constriction injury in rats J Formos Med Assoc 2014 113 921 928 10.1016/j.jfma.2013.05.013 23870713 · DOI
  116. [132]Liu P Wu L Peng G Han Y Tang R Ge J Altered microbiomes distinguish Alzheimer’s disease from amnestic mild cognitive impairment and health in a Chinese cohort Brain Behav Immun 2019 80 633 643 10.1016/j.bbi.2019.05.008 31063846 · DOI · Paper page
  117. [133]Haran JP Bhattarai SK Foley SE Dutta P Ward DV Bucci V Alzheimer’s disease microbiome is associated with dysregulation of the anti-inflammatory P-glycoprotein pathway MBio 2019 10 10 10.1128/mBio.00632-19 PMC6509190 31064831 · DOI · Paper page
  118. [134]Ling Z Zhu M Yan X Cheng Y Shao L Liu X Structural and functional dysbiosis of fecal microbiota in Chinese patients with Alzheimer’s disease Front Cell Dev Biol 2021 8 634069 10.3389/fcell.2020.634069 33614635 PMC7889981 · DOI
  119. [135]Trumble BC Stieglitz J Blackwell AD Allayee H Beheim B Finch CE Apolipoprotein E4 is associated with improved cognitive function in Amazonian forager-horticulturalists with a high parasite burden FASEB J 2017 31 1508 1515 10.1096/fj.201601084R 28031319 PMC5349792 · DOI
  120. [136]Van Exel E Koopman JJE Van Bodegom D Meij JJ De Knijff P Ziem JB Effect of APOE ε4 allele on survival and fertility in an adverse environment PLoS ONE 2017 12 e0179497 10.1371/journal.pone.0179497 28683096 PMC5500260 · DOI
  121. [137]Sadowski LA Upadhyay R Greeley ZW Margulies BJ Current drugs to treat infections with herpes simplex viruses-1 and -2 Viruses 2021 13 1228 10.3390/v13071228 34202050 PMC8310346 · DOI
  122. [138]Bukhbinder AS Ling Y Hasan O Jiang X Kim Y Phelps KN Risk of Alzheimer’s disease following Influenza vaccination: a claims-based cohort study using propensity score matching J Alzheimers Dis 2022 88 1061 1074 10.3233/JAD-220361 35723106 PMC9484126 · DOI
  123. [139]Randolph C Roberts JW Tierney MC Bravi D Mouradian MM Chase TN D-Cycloserine treatment of Alzheimer disease Alzheimer Dis Assoc Disord 1994 8 198 205 10.1097/00002093-199408030-00006 7986489 · DOI
  124. [140]Jones R Laake K Øksengård AR D-cycloserine for Alzheimer’s disease Cochrane Database Syst Rev 2002 2002 2 CD003153 12076471 PMC6718229
  125. [141]Han P Tang Z Yin J Maalouf M Beach TG Reiman EM Pituitary adenylate cyclase-activating polypeptide protects against β-amyloid toxicity Neurobiol Aging 2014 35 2064 2071 10.1016/j.neurobiolaging.2014.03.022 24726470 · DOI
  126. [142]Rat D Schmitt U Tippmann F Dewachter I Theunis C Wieczerzak E Neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) slows down Alzheimer’s disease-like pathology in amyloid precursor protein-transgenic mice FASEB J 2011 25 3208 3218 10.1096/fj.10-180133 21593432 PMC3157688 · DOI
  127. [143]Tesseur I Zou K Esposito L Bard F Berber E van Can J Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology J Clin Invest 2006 116 3060 3069 10.1172/JCI27341 17080199 PMC1626127 · DOI · Paper page
  128. [144]Fink J Steer JH Joyce DA McWilliam AS Stewart GA Pro-inflammatory effects of Burkholderia cepacia on cystic fibrosis respiratory epithelium FEMS Immunol Med Microbiol 2003 38 273 282 10.1016/S0928-8244(03)00169-X 14522463 · DOI
  129. [145]Barocchi MA Ries J Zogaj X Hemsley C Albiger B Kanth A A pneumococcal pilus influences virulence and host inflammatory responses Proc Natl Acad Sci U S A 2006 103 2857 2862 10.1073/pnas.0511017103 16481624 PMC1368962 · DOI
  130. [146]Kim YJ Jeon H Na SH Kwon H Selasi GN Nicholas A Stenotrophomonas maltophilia outer membrane vesicles elicit a potent inflammatory response in vitro and in vivo Pathog Dis 2016 74 104 10.1093/femspd/ftw104 27756813 · DOI
  131. [147]Dong Y Glaser K Schlegel N Claus H Speer CP An underestimated pathogen: Staphylococcus epidermidis induces pro-inflammatory responses in human alveolar epithelial cells Cytokine 2019 123 154761 10.1016/j.cyto.2019.154761 31226437 · DOI
  132. [148]Markazi A Bracci PM McGrath M Gao SJ Pseudomonas aeruginosa stimulates inflammation and enhances kaposi’s sarcoma herpesvirus-induced cell proliferation and cellular transformation through both lipopolysaccharide and flagellin MBio 2020 11 1 16 10.1128/mBio.02843-20 PMC7667028 33173008 · DOI
  133. [149]Bruno F Malvaso A Canterini S Bruni AC Antimicrobial peptides (AMPs) in the pathogenesis of Alzheimer’s disease: implications for diagnosis and treatment Antibiotics 2022 11 6 726 10.3390/antibiotics11060726 35740133 PMC9220182 · DOI
  134. [150]Bermejo-Pareja F del Ser T Valentí M de la Fuente M Bartolome F Carro E Salivary lactoferrin as biomarker for Alzheimer’s disease: brain-immunity interactions Alzheimers Dement 2020 16 1196 1204 10.1002/alz.12107 32543760 PMC7984071 · DOI
  135. [151]Generoso JS Thorsdottir S Collodel A Dominguini D Santo RRE Petronilho F Dysfunctional glymphatic system with disrupted aquaporin 4 expression pattern on astrocytes causes bacterial product accumulation in the CSF during Pneumococcal meningitis MBio 2022 13 e01886 10.1128/mbio.01886-22 36036510 PMC9600563 · DOI
  136. [153]Nunomura A Castellani RJ Zhu X Moreira PI Perry G Smith MA Involvement of oxidative stress in Alzheimer disease J Neuropathol Exp Neurol 2006 65 7 631 641 10.1097/01.jnen.0000228136.58062.bf 16825950 · DOI · Paper page
  137. [154]Giridharan VV Collodel A Generoso JS Scaini G Wassather R Selvaraj S Neuroinflammation trajectories precede cognitive impairment after experimental meningitis-evidence from an in vivo PET study J Neuroinflammation 2020 17 1 20 10.1186/s12974-019-1692-0 31901235 PMC6942362 · DOI
  138. [155]Guthrie B Makubate B Hernandez-Santiago V Dreischulte T The rising tide of polypharmacy and drug-drug interactions: population database analysis 1995–2010 BMC Med 2015 13 1 10.1186/s12916-015-0322-7 25889849 PMC4417329 · DOI
  139. [156]Fahmi A Wong D Walker L Buchan I Pirmohamed M Sharma A Combinations of medicines in patients with polypharmacy aged 65–100 in primary care: large variability in risks of adverse drug related and emergency hospital admissions PLoS ONE 2023 18 e0281466 10.1371/journal.pone.0281466 36753492 PMC9907844 · DOI

Cited by

Sorted by citations

Authors
Catumbela, C. S. G., Giridharan, V. V., Barichello, T., & Morales, R.
Affiliations
  • The University of Texas Health Science Center at Houston (US)
  • Universidade do Extremo Sul Catarinense (BR)
  • Universidad Bernardo O'Higgins (CL)
Corresponding author
Morales, Rodrigo
ORCID
Venue
Translational Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2023-07-26
Volume
12
Issue
1
Pages
37-37
ISSN
2047-9158 (ISSN-L)
DOI
10.1186/s40035-023-00369-7
PMC
PMC10369764
OpenAlex
W4385276901
Cited by
37
References
15
Citations by year
2026: 15 · 2025: 13 · 2024: 8 · 2023: 1
FWCI
1.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Neurodegeneration (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (RF1AG072491)
  • Alzheimer's Association (AARGD-22-972125, AARG-D-NTF-19-61645)
  • Texas Alzheimer's Research and Care Consortium (AGT009122)
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 infection, neuroinflammation, gut microbiota, antimicrobial therapy, off-target effects, neurodegeneration
MeSH terms
Alzheimer Disease, Brain, Humans

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review