The pertussis hypothesis: Bordetella pertussis colonization in the pathogenesis of Alzheimer's disease.
While a number of endogenous risk factors including age and genetics are established for Alzheimer's disease (AD), identification of acquired, potentially preventable or treatable causes, remains limited. In this paper, we review three epidemiologic case studies and present extensive biologic, immunologic and anatomic evidence to support a novel hypothesis that Bordetella pertussis (BP), the bacterium better known to cause whooping cough, is an important potential cause of AD. Cross-cultural documentation of nasopharyngeal subclinical BP colonization reflecting BP-specific mucosal immunodeficiency, proximate anatomy of intranasal mucosal surfaces to central nervous system (CNS) olfactory pathways, and mechanisms by which BP and BP toxin account for all hallmark pathology of AD are reviewed, substantiating biologic plausibility. Notably, respiratory BP infection and BP toxin secreted from subclinical BP colonization can account for the initiation and accumulation of amyloid β plaques and tau tangles. Additional mechanisms consistent with the immunobiologic effects of subclinical BP colonization include microglial activation and inflammation, atrophy and neurodegeneration, excitotoxicity, distinctive anatomic distribution and sequential spread of disease, impaired glucose utilization, and other characteristic CNS pathology of AD. We conclude by assessing the evidence for causation against the Bradford Hill criteria, and advocate for further investigation into the potential role of BP in the etiology of AD.
ILiAD Biotechnologies, 230 East 15th Street, Suite 1-A, New York, NY 10003, United States. Electronic address: keith@iliadbio.com.
Keith
K
Rubin
ILiAD Biotechnologies, 230 East 15th Street, Suite 1-A, New York, NY 10003, United States. Electronic address: glazer@iliadbio.com.
Steven
S
Glazer
D000544:Alzheimer Disease / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D015415:Biomarkers; D001886:Bordetella pertussis / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D015994:Incidence; D009305:Nasopharynx / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D009474:Neurons / Q000378:metabolism; D018384:Oxidative Stress; D037342:Pertussis Toxin / Q000276:immunology / Q000378:metabolism; D010567:Pertussis Vaccine / Q000276:immunology; D014917:Whooping Cough / Q000150:complications* / Q000175:diagnosis / Q000382:microbiology* / Q000517:prevention & control; D060449:Wnt Signaling Pathway
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010567:Pertussis Vaccine; D018698:Glutamic Acid; D037342:Pertussis Toxin
Alzheimer’s disease; Asymptomatic infections; Bordetella pertussis; Etiology; Pertussis toxin