“Microbiome-sparing solutions for Alzheimer’s & cardiovascular disease”

•Amyloid Hypothesis• Inflammatory Hypothesis•Pathogen Hypothesis

Alzheimer’s Disease

AdVax solves all three!

More than a century ago, Alzheimer himself suggested that senile plaque formation in the brain was likely the result of microbial infection.

And the answer was right under our noses.

ADVAX DOES!

…But he didn’t have the right TOOLS

He had it right about the BUGS…

BMC Geriatrics, 2014

• “We postulate that Alzheimer’s disease and atherosclerosis are both caused by chronic immunologic challenge to protect against particular infectious agents, at the expense of longer-term pathology.”

Lathe R, Sapronova A, Kotelevtsev Y. Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr. 2014;14:36.

PLoS ONE, 2010

• “Recent independent findings show that Aβ (the precursor of β-amyloid) is an antimicrobial peptide (AMP) and is the first evidence that the molecular species responsible for amyloidosis may have a normal function in the brain. This stands in stark contrast to current models, which assume β-amyloid deposition to be an accidental process resulting from the abnormal behavior of an incidental product of catabolism. Our data suggest increased Aβ generation, and the resulting AD pathology, may be part of the innate immune response to a bacterial infection of the brain.”

• Thus, these results independently suggest the involvement of infectious agents in AD pathology

Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, et al. (2010) The Alzheimer’s Disease-Associated Amyloid b-Protein Is an Antimicrobial Peptide. PLoS ONE 5(3): e9505. doi:10.1371/journal.pone.0009505.

• Oral spirochetes - Increased amyloid beta precursor protein levels- Increased amyloid beta deposition- Induced tau phosphorylation- Able to escape destruction by the host immune

reactions- Established chronic infection and sustained

inflammation.

Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation. 2011;8(1):90.

AdVax

Neurospirochetosis and Alzheimer’s disease

• Oral pathogens found at the site of beta amyloid deposits in 98% of Alzheimer’s brains and non-existent in all but 7% of the non-Alzheimer’s brains.

Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation. 2011;8(1):90.

AdVax

AdVax

Miklossy J. Alzheimer's disease - a neurospirochetosis. Analysis of the evidence following Koch's and Hill's criteria. J Neuroinflammation. 2011;8(1):90.

•The outcome of these infections determined by:

- Genetic predisposition of the patient

- Virulence of the infecting agent

- Lifestyle triggers

- Stress, nutrition, exercise

Travel to entorhinal cortex (first site of AD destruction and beta

amyloids)

Pathways of Pathogens

Oral origin

Travel to olfactory bulb (first symptom of AD is loss of smell)

First cranial nerve

• “Additional research shows the presence of metabolic byproducts of specific oral pathogens present in Alzheimer’s brains, but not in the brains of those without Alzheimer’s. “LPS from periodontal bacteria can be found in the AD brain suggesting a role for oral-pathogen-related virulence factors in AD dementia”

• P. gingivalis LPS found at the site of beta amyloid

Journal of Alzheimer’s Disease, 2013

Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer's disease brain tissue. J Alzheimers Dis. 2013;36(4):665-77.

• Oral pathogens have been demonstrated to be able to penetrate the brain of even ApoE-/- mice following which they contribute to complement activation with bystander neuronal injury.

• In murine studies, specific oral pathogens were present in 9 out of 12 brains at 24 weeks.

• Amyloid does not form until after infection by the oral pathogens.

• Pathogen, inflammation, amyloid.

Journal of Alzheimer’s Disease, 2014

Poole S, Singhrao SK, Chukkapalli S, et al. Active Invasion of Porphyromonas gingivalis and Infection-Induced Complement Activation in ApoE-/- Mice Brains. J Alzheimers Dis. 2014;

Journal of Alzheimer’s Disease, 2012Journal of Neuroimmunology, 2009

• When periodontal disease is present, a person is seven times more likely to fail the cognitive health test

• Periodontal disease is as significant a factor for Alzheimer’s disease as age.

• Periodontal disease is associated with amyloid accumulation.

• Periodontal disease is associated with lower cognitive performance.

• TNF-α and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects.

Kamer AR, Morse DE, Holm-pedersen P, Mortensen EL, Avlund K. Periodontal inflammation in relation to cognitive function in an older adult Danish population. J Alzheimers Dis. 2012;28(3):613-24.

Kamer AR, Craig RG, Pirraglia E, et al. TNF-alpha and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects. J Neuroimmunol. 2009;216(1-2):92-7.

“We have known for sometime that what is good for your heart

is good for your head.”

— Clare Watson, Alzheimer’s Society Research Committee Manager

The Body’s Response toOral Biofilm

Mouth•Oral inflammation•Bleeding gums•Bone loss•Loose/lost teeth•Cavities Heart

•Foam cells•Ox-LDL•hs-CRP•Lp-PLA2•MPO

Brain•Neuroinflammation•Amyloid beta•Cognitive decline•Alzheimer’s disease

Percentage of people with these pathogenic oral bacteria above threshold

% People Above Threshold

Age

Clinical Microbiology Reviews, 2000American Journal of Periodontology,

2001

1. Invasion of gram negative bacteria through epithelial lining of periodontal pockets

2. Effects from the circulating toxins of periodontal pathogens.

3. Inflammation caused by the immunologic response to the pathogens & their toxins.

3 Pathways:

Li X, Kolltvei KM, Tronstad L, et al. Systemic diseases caused by oral infection. Clin Microbiol Rev. Oct 2000, p 547-558

Iacopino, AM. Periodontitis and diabetes interrelationships: role of inflammation. Am Periodontal 2001, 6: 125-137

• AdVax has sequenced and developed supragenome modeling for the key virulent pathogens:– Treponema denticola– Porphyromonas gingivalis

• AdVax uses our existing patented technology, developing monoclonal antibodies and first-in-man vaccines for P. gingivalis & T. denticola

AdVax

P. gingivalis and T. denticola

• P. gingivalis and T. denticola act together• They sense and respond to each other• Increased virulence together

Journal of PLoS ONE, 2014

Tan KH, Seers CA, Dashper SG, et al. Porphyromonas gingivalis and Treponema denticola exhibit metabolic symbioses. PLoS Pathog. 2014;10(3):e1003955.

Infection & Immunology, 2014

Invasion of oral and aortic tissues by oral spirochete Treponema denticola in ApoE(-/-) mice causally links periodontal disease and atherosclerosis.

“Specific oral pathogen closely associated with periodontal disease and the rapid progression of atheroma in ApoE-null mice. These studies confirm a causal link for active oral pathogen infection with both atheroma and periodontal disease.”

Chukkapalli SS, Rivera MF, Velsko IM, et al. Invasion of oral and aortic tissues by oral spirochete Treponema denticola in ApoE(-/-) mice causally links periodontal disease and atherosclerosis. Infect Immun. 2014;82(5):1959-67.

• Pathogen-directed treatment of periodontal disease has just been found to lower patients’ Lp-PLA2 from 30% to 37%.

• Lp-PLA2 is the only test recognized by the FDA to determine who will develop atherosclerosis, have a heart attack or stroke as it is an enzyme involved with LDL cholesterol forming foam cells, which form plaque in the arteries

Cardiovascular Systems, 2014

Duane C. Keller. Systemic Lp-PLA-2 cardiovascular marker response to direct medication delivery periodontal treatment. Cardiovascular System. 2014;2(1):8.

• “Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT at 3 years.”

• Increase in oral pathogens associated with increased atherosclerosis and CVD

• Decrease in oral pathogens associated with decreased incidence of atherosclerosis and CVD

Journal of the AHA, 2013

Desvarieux M, Demmer RT, Jacobs DR, Papapanou PN, Sacco RL, Rundek T. Changes in clinical and microbiological periodontal profiles relate to progression of carotid intima-media thickness: the Oral Infections and Vascular Disease Epidemiology study. J Am Heart Assoc. 2013;2(6):e000254.

• Increase presence of P. g. → decreases Tregs (regulatory T cells)

So...• Increase P.g. → Decrease Tregs →

Increase Atherosclerotic Plaque!• (especially P.g. FimA Genotype ll)

Journal of PLoS ONE, 2014

Yang J, Wu J, Liu Y, et al. Porphyromonas gingivalis infection reduces regulatory T cells in infected atherosclerosis patients. PLoS ONE. 2014;9(1):e86599.

“Microbiome-sparing solutions for Alzheimer’s & cardiovascular disease”