Alzheimer’s Disease is the 6th leading cause of death in the U.S. with approximately 5.7 million Americans currently living with this devastating disease. By 2050 the number is projected to rise to 14 million people. The financial burden of Alzheimer’s and Dementia is astounding. It will cost our nation roughly $277 billion in 2018. To date, ineffective therapies targeting Amyloid Beta highlight the need for innovation. At Intracell Research Group we believe that a significant subset of dementia and Alzheimer’s patients are experiencing a “syndrome” being driven by one or more infectious pathogens. Chlamydia pneumoniae, Herpes Viruses, and Spirochetes have all been published in correlation to the onset and progression of Dementia/Alzheimer’s. Amyloid-Beta has been identified as the body’s response to infection. It exhibits antibacterial and antiviral activity. This and several other clues substantiated by the research below are in desperate need of attention. We advocate a randomized, controlled trial to examine the effectiveness of generic antimicrobial agents in early dementia.
Alzheimer’s and Infection
In examining the correlation between intracellular infection and Alzheimer’s, it is important to note that the research below pertains largely to Late-Onset Alzheimer’s Disease (LOAD), not the condition linked to APOE ε4 allele on human chromosome 19 (Familial Alzheimer’s Disease). The etiology of LOAD does not appear to necessarily arise from the expression of that gene. Evidence provided below indicates that there is ample proof to suggest a correlation between Chlamydia pneumoniae (the predominant intracellular pathogen identified) and the onset of Dementia and Alzheimer’s in a significant number of patients. Several clues point to an infection. One is the olfactory pathway which C. pneumoniae uses to enter the CNS. Damage to olfactory bulbs is present early in the disease as elucidated by Dr. Balin, his colleagues, and other researchers. C. pneumoniae genetic material was found in these bulbs in post-autopsy LOAD samples. To quote Dr. Balin “These findings bring into question how specific infection(s), inflammation, and/or damage of the olfactory bulbs could lead to damage in deeper cortical and limbic structures, thereby resulting in symptoms of LOAD”(JAD, 2008)“. The features of Dementia and Alzheimer’s which include olfactory dysfunction and mitochondrial damage/dysfunction also fit with the infection hypothesis and provide another clue. Chlamydia pneumoniae steals ATP from mitochondria and has been proven to induce a state of inflammation and elicit mitochondrial damage.
Time to test antibacterial therapy in Alzheimer’s disease
Abstract- “Alzheimer’s disease is associated with cerebral accumulation of amyloid-β peptide and hyperphosphorylated tau. In the past 28 years, huge efforts have been made in attempting to treat the disease by reducing brain accumulation of amyloid-β in patients with Alzheimer’s disease, with no success. While anti-amyloid-β therapies continue to be tested in prodromal patients with Alzheimer’s disease and in subjects at risk of developing Alzheimer’s disease, there is an urgent need to provide therapeutic support to patients with established Alzheimer’s disease for whom current symptomatic treatment (acetylcholinesterase inhibitors and N-methyl d-aspartate antagonist) provide limited help. The possibility of an infectious aetiology for Alzheimer’s disease has been repeatedly postulated over the past three decades. Infiltration of the brain by pathogens may act as a trigger or co-factor for Alzheimer’s disease, with Herpes simplex virus type 1, Chlamydia pneumoniae, and Porphyromonas gingivalis being most frequently implicated. These pathogens may directly cross a weakened blood-brain barrier, reach the CNS and cause neurological damage by eliciting neuroinflammation. Alternatively, pathogens may cross a weakened intestinal barrier, reach vascular circulation and then cross blood-brain barrier or cause low grade chronic inflammation and subsequent neuroinflammation from the periphery. The gut microbiota comprises a complex community of microorganisms. Increased permeability of the gut and blood-brain barrier induced by microbiota dysbiosis may impact Alzheimer’s disease pathogenesis. Inflammatory microorganisms in gut microbiota are associated with peripheral inflammation and brain amyloid-β deposition in subjects with cognitive impairment. Oral microbiota may also influence Alzheimer’s disease risk through circulatory or neural access to the brain. At least two possibilities can be envisaged to explain the association of suspected pathogens and Alzheimer’s disease. One is that patients with Alzheimer’s disease are particularly prone to microbial infections. The other is that microbial infection is a contributing cause of Alzheimer’s disease. Therapeutic trials with antivirals and/or antibacterials could resolve this dilemma. Indeed, antiviral agents are being tested in patients with Alzheimer’s disease in double-blind placebo-controlled studies. Although combined antibiotic therapy was found to be effective in animal models of Alzheimer’s disease, antibacterial drugs are not being widely investigated in patients with Alzheimer’s disease. This is because it is not clear which bacterial populations in the gut of patients with Alzheimer’s disease are overexpressed and if safe, selective antibacterials are available for them. On the other hand, a bacterial protease inhibitor targeting P. gingivalis toxins is now being tested in patients with Alzheimer’s disease. Clinical studies are needed to test if countering bacterial infection may be beneficial in patients with established Alzheimer’s disease.”
Chlamydia pneumoniae: An Etiologic Agent for Late-Onset Dementia
Frontiers in Aging Neuroscience, 2018.
Dr. Balin and colleagues review the work surrounding the correlation between CpN infection and the development of dementia. To quote the authors:
“Over the last 15 years, current and ongoing work has implicated infection in the etiology and pathogenesis of late-onset dementia. Infectious agents reported to be associated with disease initiation are various, including several viruses and pathogenic bacterial species. We have reported extensively regarding an association between late-onset disease and infection with the intracellular bacterial pathogen Chlamydia pneumoniae. In this article, we review previously published data and recent results that support involvement of this unusual respiratory pathogen in disease induction and development. “
Herpes viruses and Alzheimer’s disease: new evidence in the debate
Lancet Neurology, 2018.
Dr. Balin and Dr. Hudson were asked by Lancet Neurology to draft a response to the recent work by Dr. Tanzi and colleagues correlating LOAD to HSV-1 infection. Here is the most powerful message from the article.
“With the focus having been on amyloid-β and tau for the past 30 years and more, we contend that answers to the questions of Alzheimer’s disease, and possibly other neurodegenerative conditions as well, does not reside solely in the pathology, but rather in the route to that pathology, for which infectious agents provide biologically and pathologically relevant solutions.”
Chlamydia Pneuominae as an Etiologic Agent for Late-Onset Alzheimer’s Disease
IOS Press, 2017.
This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a “trigger or initiator” in the pathogenesis of this disease.
Microbes and Alzheimer’s Disease
Journal of Alzheimer’s Disease, 2016.
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 type1(HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology ofAD. Fungal infection of AD brain[5,6]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.”
Herpes Simplex Virus Type 1 and Other Pathogens are Key Causative Factors
in Sporadic Alzheimer’s Disease
Journal of Alzheimer’s Disease, 2015
This review explores the relationship between pathogens, including Herpes simplex virus type 1 (HSV-1), Cytomegalovirus, and other Herpesviridae, Chlamydophila pneumoniae, spirochetes, Helicobacter pylori, and various periodontal pathogens and sporadic Alzheimer’s Disease. It examines the correlation of infection with the release of pro- inflammatory cytokines that may cross the blood-brain barrier and promote neurodegeneration.
Infectious Agents and Neurodegeneration
Molecular Neurobiology, December 2012.
Abstract- “A growing body of epidemiologic and experimental data point to chronic bacterial and viral infections as possible risk factors for neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Infections of the central nervous system, especially those characterized by a chronic progressive course, may produce multiple damage in infected and neighboring cells. The activation of inflammatory processes and host immune responses cause chronic damage resulting in alterations of neuronal function and viability, but different pathogens can also directly trigger neurotoxic pathways. Indeed, viral and microbial agents have been reported to produce molecular hallmarks of neurodegeneration, such as the production and deposit of misfolded protein aggregates, oxidative stress, deficient autophagic processes, synaptopathies and neuronal death. These effects may act in synergy with other recognized risk factors, such as aging, concomitant metabolic diseases and the host’s specific genetic signature. This review will focus on the contribution given to neurodegeneration by herpes simplex type-1, human immunodeficiency and influenza viruses, and by Chlamydia pneumoniae.”
Historic evidence to support a causal relationship between spirochetal infections and Alzheimer’s disease
Frontiers In Aging Neuroscience, 2015.
Abstract- “Following previous observations a statistically significant association between various types of spirochetes and Alzheimer’s disease (AD) fulfilled Hill’s criteria in favor of a causal relationship. If spirochetal infections can indeed cause AD, the pathological and biological hallmarks of AD should also occur in syphilitic dementia. Historic observations and illustrations published in the first half of the 20th Century indeed confirm that the pathological hallmarks, which define AD, are also present in syphilitic dementia. Cortical spirochetal colonies are made up by innumerable tightly spiraled Treponema pallidum spirochetes, which are morphologically indistinguishable from senile plaques, using conventional light microscopy. Local brain amyloidosis also occurs in general paresis and, as in AD, corresponds to amyloid beta. These historic observations enable us to conclude that chronic spirochetal infections can cause dementia and reproduce the defining hallmarks of AD.”
Chlamydophila pneumoniae and the etiology of late-onset Alzheimer’s disease.
Journal of Alzheimers Disease, 2008.
Abstract- “Sporadic, late-onset Alzheimer’s disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD (∼5% of all cases) and LOAD (∼95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the “trigger” events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a “trigger or initiator” in the pathogenesis of this disease.”
Infiltration of the brain by pathogens causes Alzheimer’s disease.
Neurobiology of Aging, 2004.
Abstract- “Despite very numerous studies on Alzheimer’s disease (AD), especially on amyloid plaques and neurofibrillary tangles, little information has been obtained thus on the causes of the disease. Evidence is described here that implicates firstly herpes simplex virus type 1 (HSV1) as a strong risk factor when it is present in brain of carriers of the type 4 allele of the gene for apolipoprotein E (APOE-4). Indirect support comes from studies indicating the role of APOE in several diverse diseases of known pathogen cause. A second putative risk factor is the bacterium, Chlamydia pneumoniae. This pathogen has been identified and localized in AD brain. Current studies aimed at “proof of principle” address the entry of the organism into the CNS, the neuroinflammatory response to the organism, and the role that the organism plays in triggering AD pathology. An infection-based animal model demonstrates that following intranasal inoculation of BALB/c mice with C. pneumoniae, amyloid plaques/deposits consistent with those observed in the AD brain develop, thus implicating this infection in the etiology of AD.”
Challenges and directions for the pathogen hypothesis of Alzheimer’s disease.
Neurobiology of Aging, 2004.
Abstract- “This paper critically reviews the possibility that infiltration of the brain by pathogens (e.g. Herpes simplex virus type 1 (HSV1) or Chlamydophila pneumoniae (Cp)) acts as a trigger or co-factor for Alzheimer’s disease (AD). The evidence currently available is limited and in some cases inconsistent, but it does justify the need for more vigorous investigation of this hypothesis. An issue of particular concern is the paucity of experimental evidence showing that pathogens can elicit the neuropathological changes and cognitive deficits that characterise AD. Other weaknesses include a failure to obtain independent confirmation of Cp in AD brains, and a lack of evidence for HSV1 proteins or intact virions in AD brain tissue. Future avenues of investigation that might prove fruitful include epidemiological investigations of the incidence of AD in individuals who are either immunosuppressed or have received chronic antiviral or antibiotic therapy. There is also a need to consider systemic infections as potential contributors to the pathogenesis of AD.”
Alzheimer’s disease and infection: do infectious agents contribute to progression of Alzheimer’s disease?
Alzheimers and Dementia, 2009.
Abstract- “Infection with several important pathogens could constitute risk factors for cognitive impairment, dementia, and Alzheimer’s disease (AD) in particular. This review summarizes the data related to infectious agents that appear to have a relationship with AD. Infections with herpes simplex virus type 1, picornavirus, Borna disease virus, Chlamydia pneumoniae, Helicobacter pylori, and spirochete were reported to contribute to the pathophysiology of AD or to cognitive changes. Based on these reports, it may be hypothesized that central nervous system or systemic infections may contribute to the pathogenesis or pathophysiology of AD, and chronic infection with several pathogens should be considered a risk factor for sporadic AD. If this hypothesis holds true, early intervention against infection may delay or even prevent the future development of AD.”
What is the relationship between Chlamydia pneumoniae and Late-onset Alzheimer’s Disease?
Laboratory Medicine, 2001.
Abstract- “Beginning with the demonstration of Helicobacter pylori as an etiologic agent for ulcers, the notion that microbial pathogens can play an initiating and/or exacerbatory role in chronic disease has gained increasing credence. Indeed, studies have suggested associations between Chlamydia trachomatis and cervical cancer, Nocardia asteroides and Parkinson’s disease, and Chlamydia pneumoniae and atherosclerosis, among many others. While most such associations are controversial, these lines of research remain under active investigation. In this article, evidence for and against the association between late-onset Alzheimer’s disease (AD) and persistent infection with C. pneumoniae will be reviewed.”
Are the Infectious Roots of Alzheimers Buried Deep in the Past?
Journal of Molecular Pathological Epidemiology, 2017.
Abstract- “Recent literature shows a controversial new push to tie microorganisms to Alzheimer’s disease (AD). Study after study, in which scientists have injected human Alzheimer-diseased brain tissue into mice and other laboratory animals that later developed the disease have left little doubt that Alzheimer’s disease (AD) arises from an infectious process. By 2013 Mawanda and Wallace’s “Can Infections Cause Alzheimer’s Disease” struck down some of the commonly entertained pathogens for AD such as herpes simplex virus type 1, Chlamydia pneumoniae, and several types of spirochetes. Instead, they pointed to two prime suspects for Alzheimer’s amyloid-beta deposition: “especially chronic infections like tuberculosis and leprosy.” To be sure, it was German neuropathologist Oskar Fischer of the Prague school of Neuropathology, Alzheimer’s great rival, who was the first to suggest that infection might be causative for Alzheimer’s. Fischer’s credentials: he was the co-discoverer of Alzheimer’s disease. His suspected germ was the Streptothrix, today classified as Actinomycetes, a rare central nervous system pathogen which at the time was so constantly and consistently mistaken for tuberculosis that Choppen- Jones suggested that TB be called tuberculomycosis. And Just ten years before Oskar Fischer found Actinomycosis-like forms in Alzheimer’s cerebral plaque, BabèÅ and immunologist Levaditi reported in “On the Actinomycotic Shape of the Tuberculous Bacilli” that Fischer’s typical Actinomyces-like clusters (Drüsen) with clubs appeared in the tissue of rabbits inoculated with tubercle bacilli beneath the dura mater of their brains. Investigators who supported and subsequently followed up on Fischer’s Alzheimer’s germ are also discussed.”