Most people, despite socio-economic conditions, acquire chronic infections with pathogenic oral bacteria, which quickly adopt the biofilm mode of growth. During biofilm growth and chronic inflammation, they express specific local and systemic inflammatory mediators, which lead to pathology and disease.

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

2. • Amyloid Hypothesis
• Inflammatory Hypothesis
• Pathogen Hypothesis
Alzheimer’s Disease
AdVax solves all
three!

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

4. 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…

5. 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.

6. 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.

7. • 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

8. 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

9. 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

11. 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

12. • “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.

13. • 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;

14. Journal of Alzheimer’s Disease, 2012
Journal 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.

15. “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

16. The Body’s Response to
Oral 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

17. Percentage of people with
these pathogenic oral
bacteria above threshold
% People Above
Threshold
Age

18. Clinical Microbiology Reviews, 2000
American 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

19. • 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

20. 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.

21. 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.

23. • 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.

24. • “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.

25. • 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.

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