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Cited by 59Oral microbiology and periodontitis researchAlzheimer's disease research and treatmentsBacterial Infections and Vaccines

Porphyromonas gingivalis Outer Membrane Vesicles as the Major Driver of and Explanation for Neuropathogenesis, the Cholinergic Hypothesis, Iron Dyshomeostasis, and Salivary Lactoferrin in Alzheimer’s Disease

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Nara, Peter L., Sindelar, Daniel, Penn, Marc S., Potempa, Jan, Griffin, W. Sue T.·2021·Journal of Alzheimer's Disease
DOI 10.3233/jad-210448PMC PMC8461682
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Abstract

Porphyromonas gingivalis (Pg) is a primary oral pathogen in the widespread biofilm-induced “chronic” multi-systems inflammatory disease(s) including Alzheimer’s disease (AD). It is possibly the only second identified unique example of a biological extremophile in the human body. Having a better understanding of the key microbiological and genetic mechanisms of its pathogenesis and disease induction are central to its future diagnosis, treatment, and possible prevention. The published literature around the role of Pg in AD highlights the bacteria’s direct role within the brain to cause disease. The available evidence, although somewhat adopted, does not fully support this as the major process. There are alternative pathogenic/virulence features associated with Pg that have been overlooked and may better explain the pathogenic processes found in the “infection hypothesis” of AD. A better explanation is offered here for the discrepancy in the relatively low amounts of “Pg bacteria” residing in the brain compared to the rather florid amounts and broad distribution of one or more of its major bacterial protein toxins. Related to this, the “Gingipains Hypothesis”, AD-related iron dyshomeostasis, and the early reduced salivary lactoferrin, along with the resurrection of the Cholinergic Hypothesis may now be integrated into one working model. The current paper suggests the highly evolved and developed Type IX secretory cargo system of Pg producing outer membrane vesicles may better explain the observed diseases. Thus it is hoped this paper can provide a unifying model for the sporadic form of AD and guide the direction of research, treatment, and possible prevention.

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  • There is a strong epidemiologic association between periodontitis and Alzheimer's disease and related dementia.

    “There is a strong epidemiologic association between periodontitis (PD) and ADRD [5,6,7,8,9,10,11,12,13] but how these two diseases intersect and whether it is at the level of causation is unclear.”

    From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [7]

    In “The Primary Oral-Systemic Pathogen” (page unavailable), the paper says periodontal disease has been implicated in Alzheimer’s disease and dementia. That supports a reported relationship, but the passages do not establish that the epidemiologic association is strong. The paper also says direct evidence for the proposed mechanism is less convincing than often portrayed. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Nara, P. L., Sindelar, D., Penn, M. S., Potempa, J., & Griffin, W. S. T.
Affiliations
  • Keystone Bio Inc., St. Louis, MO, USA
  • Summa Health System (US)
  • University of Louisville (US)
  • University of Arkansas for Medical Sciences (US)
Corresponding author
Nara, Peter L.
ORCID
Venue
Journal of Alzheimer's Disease
Publisher
SAGE Publications
Published
2021-08-17
Volume
82
Issue
4
Pages
1417-1450
ISSN
  • 1387-2877 (ISSN-L)
  • 1875-8908
DOI
10.3233/jad-210448
PMC
PMC8461682
OpenAlex
W3185060246
Cited by
59
References
5
Citations by year
2026: 6 · 2025: 14 · 2024: 14 · 2023: 9 · 2022: 15 · 2021: 1
FWCI
10.10
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Alzheimer s Disease (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
Funders
  • University of Pennsylvania
  • EU Joint Programme – Neurodegenerative Disease Research
  • National Institutes of Health (AG012411)
  • National Institute on Aging (P01AG012411)
Topics
  • Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
Porphyromonas gingivalis, outer membrane vesicles
MeSH terms
Extremophiles, Alzheimer Disease, Anti-Infective Agents, Bacterial Outer Membrane Proteins, Brain, Humans, Iron, Lactoferrin, Saliva, Bacteroidaceae Infections, Porphyromonas gingivalis, Cholinergic Agents

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