Live Discussion: The Pathogen Hypothesis

Updated 12 March 2009

We held this live discussion with discussants Brian Balin, Denah Appelt, Joseph Lyons, Ruth Itzhaki, and Curtis Dobson on 1 July 2004.

See Transcript—Posted 6 August 2004
See comment by Stephen R. Robinson—Posted 1 July 2004
See Q&A—Updated 30 July 2004

Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging 2004;25(4);419-429. Abstract

Robinson SR, Dobson C, Lyons J. Challenges and directions for the pathogen hypothesis of Alzheimer's disease. Neurobiol Aging 2004; 629-637. Abstract

Moderator’s summary: Pathogens as a cause of Alzheimer’s disease
By June Kinoshita

The notion that microbes such as herpes simplex virus 1 (HSV1) and Chlamydophila pneumoniae (Cp) could be a causal factor in Alzheimer’s diseases would probably be viewed by the main stream of AD researchers as being beyond the pale. Although a small body of recent findings has reported strikingly strong associations between these pathogens and AD [1,7], subsequent attempts to replicate the findings have met with mixed results (discussed in [10]). At this juncture, it might be convenient to dismiss the hypothesis, but as both sides of this debate session agreed, there are plausible reasons for these discrepancies that deserve to be resolved through further research. While opinions diverged on the strength of evidence for and against the hypothesis, there was a consensus that the possibility of common infectious agents causing such a widespread scourge of old age is one that is too important to ignore.

It may be of interest to step back from the specific merits and future challenges of the pathogen hypothesis (which the participants cover thoroughly in this issue) to ponder changes in the medical culture that may have contributed to the willingness of the debate participants and audience alike to weigh the evidence dispassionately rather than to dismiss the whole idea as being implausible on the face of it. Most researchers today grew up in an era when microbes were presumed to have been brought under human control. The 19th and 20th centuries saw the microbial perpetrators of the great killer diseases tracked down one by one and vanquished with drugs and vaccines. Events over the past two decades have rudely awakened medical science to the reality that we have not, after all, advanced into the post-infectious era. The AIDS pandemic and emergence of drug-resistant tuberculosis, malaria and other scourges shocked us into realizing that microorganisms have been far from conquered. These devastating setbacks have driven home the fact that we are engaged in an evolutionary arms race in which our science and wits are pitted against the ability of microbes to adapt to our most clever weapons.

In the same period, a microbe, Helicobacter pylori, came to be accepted as causing duodenal ulcers and gastric cancers [3]. Previously, ulcers were viewed as a classic degenerative condition, the result of some toxic combination of stress, chemical irritants and bad genes. The discovery of a bacterial origin was greeted initially with hostility, but was eventually hailed as marking a paradigm shift in the pathogenesis of chronic diseases. More recently, another microbe, C. pneumoniae, has come under suspicion for playing a role not only in AD, but in atherosclerosis [2,5], the preeminent chronic killer disease.

These may not be flukes, argues biologist Paul Ewald. Ewald has championed a theory, first suggested by physicist Gregory Cochran, that most, if not all, of the chronic degenerative diseases of aging are microbial in origin [4]. While a great deal of effort is currently being invested in pinpointing genes for late-onset Alzheimer disease, the evolutionary argument holds that deleterious genetic mutations, even those that are expressed late in life, cannot persist in a population. Pathogens, in contrast, can persist indefinitely because the host’s ability to evolve resistance to pathogens is matched by the pathogens’ ability to keep shifting their strategy for living off the host. Thus, Ewald writes, “If we see chronic diseases that have commonly been causing damage for a long time, the best bet is that they have infectious causes” [6].

Evolutionary theory has yet to make inroads into the thinking of most Alzheimer researchers. For the majority, it is safe to assume that the idea that microorganisms can cause Alzheimer’s stretches credulity. If pathogens were responsible, one might well wonder how the culprits could have escaped the scrutiny of generations of pathologists. Microbes, however, are capable of astounding stealth. They can insinuate themselves into host cells and genomes, where they may lie latent and be very challenging to detect. Microbes can also leave a trace in the host’s immune memory, exerting lethal effects not through acute infection but by triggering autoimmune responses through molecular mimicry between microbial proteins and host proteins [12].

While these are some compelling theoretical arguments for taking the pathogen hypothesis seriously, the burden lies with proponents to prove the theory, rather than with the indifferent majority to disprove it. In this issue of Neurobiology of Aging, Itzhaki et al. [7], present arguments in support of the pathogen hypothesis, reviewing not only the positive and negative studies that have sought evidence for HSV1 and Cp in Alzheimer brains, but also discussing how pathogens might interact with other known risk factors for AD, such as APOE-α 4 genotype [8], aging, the immune system and trafficking of pathogens into the central nervous system. The companion article by Robinson et al. [10], points out some important discrepancies in these studies and discusses major arguments that could be made against the hypothesis, such as whether it is compatible with the existence of inherited forms of AD. The authors also make constructive suggestions regarding future research. Clinical trials of antibiotics or antiviral drugs, for example, could test whether removing a putative pathogen has any effect on disease progression.

As these articles make clear, these are still early days for the pathogen hypothesis, and the proponents have their work cut out for them. Both HSV1 and Cp are highly challenging to detect, and disputes over their association with AD are clouded by methodological issues. A rigorous effort to test the hypothesis would profit from standardizing methods, for example by distributing a uniform set of tissues with positive and negative controls to determine whether all of the laboratories involved are achieving equal levels of sensitivity. The standard protocol should also require multiple testing of each brain [11], preferably using diverse methods.

An animal model that develops AD pathology and behavioral deficits upon exposure to pathogens would help establish the credibility of the hypothesis. The Balin laboratory presented a mouse model that develops amyloid-beta deposits in the brain following intranasal infection with Cp [9]. That study awaits publication and independently replication. Finally, the hypothesis might be more readily accepted if its advocates could clarify whether the two pathogens implicated to date are acting through independent pathways, or are involved in a common mechanism.

At the end of the day, one might ask, so what? Suppose that microbes cause Alzheimer’s, how will that change strategies for treating the disease? Proponents of the hypothesis suggest that antimicrobial drugs or vaccines can be marshaled to nip the disease in the bud. However, if microbes turn out to work harm through amyloid-beta or non-specific inflammatory responses, would not these remain the better therapeutic targets? These questions probably cannot be answered until more is known about whether and how pathogens contribute to AD. Readers of Robinson et al., and Itzhaki et al., in this issue, are invited to consider the facts and issues and decide whether it is worth enlarging their imaginations to include microbes as potential players in causing Alzheimer’s disease.

Note on Permissions: The background text for this live discussion, "Moderator’s summary: Pathogens as a cause of Alzheimer’s disease," by June Kinoshita, originally appeared in Neurobiology of Aging 25 (2004) 639–640. (See Science Direct). Articles by Robinson et al., Itzhaki et al., and Little et al. reprinted from Neurobiol Aging, 25, with permission from Elsevier.

[1] Balin BJ, Gerard HC, Arking EJ, Appelt DM, Branigan PJ, Abrams JT, et al. Identification and localization of Chlamydia pneumoniae in the Alzheimer’s brain. Med Microbiol Immunol (Berl) 1998;187:23– 42. Abstract

[2] Campbell LA, Kuo CC. Chlamydia pneumoniae and atherosclerosis. Semin Respir Infect 2003;18(March (1)):48–54. Abstract

[3] Cilley RE, Brighton VK. The significance of Helicobacter pylori colonization of the stomach. Semin Pediatr Surg 1995;4(November (4)):221–7. Abstract

[4] Cochran GM, Ewald PW, Cochran KD. Infectious causation of disease: an evolutionary perspective. Perspect Biol Med 2000;43 (Spring (3)):406–48. Abstract

[5] de Boer OJ, van der Wal AC, Becker AE. Atherosclerosis, inflammation, and infection. J Pathol 2000;190(3):237–43. Abstract

[6] Ewald P. Plague time. Anchor Books; 2002. p. 56.

[7] Itzhaki RF, Wozniak MA, Appelt DM, Balin BJ. Infiltration of the brain by pathogens causes Alzheimer’s disease. Neurobiol Aging 2004; this issue. See .pdf above.

[8] Itzhaki RF, Dobson CB, Lin WR, Wozniak MA. Association of HSV1 and apolipoprotein E-varepsilon4 in Alzheimer’s disease. J Neurovirol 2001;7(December (6)):570–1. Abstract

[9] Little CS, Hammond CJ, MacIntyre A, Balin BJ, Appelt DM. Chlamydia pneumoniae induces Alzheimer-like amyloid plaques in brains of BALB/c mice. Neurobiol Aging 2004;25(4), in press. See .pdf above.

[10] Robinson SR, Dobson C, Lyons J. Challenges and directions for the pathogen hypothesis of Alzheimer’s disease. Neurobiol Aging 2004; this issue. See .pdf above.

[11] Smieja M, Mahony JB, Goldsmith CH, Chong S, Petrich A, Chernesky M. Replicate PCR testing and probit analysis for detection and quantitation of Chlamydia pneumoniae in clinical specimens. J Clin Microbiol 2001;39(May (5)):1796–801. Abstract

[12] Zhao ZS, Granucci F, Yeh L, Schaffer PA, Cantor H. Molecular mimicry by herpes simplex virus-type 1: autoimmune disease after viral infection. Science 1998;279(February (5355)):1305. Abstract

Additional References

Higuchi Md et al. Trypanosoma cruzi trans-sialidase as a new therapeutic tool in the treatment of chronic inflammatory diseases: possible action against mycoplasma and chlamydia. Med Hypotheses. 2004 Jan 1;63(4):616-23. Abstract

Hill JM, Steiner I, Matthews KE, Trahan SG, Foster TP, Ball MJ. Statins lower the risk of developing Alzheimer's disease by limiting lipid raft endocytosis and decreasing the neuronal spread of Herpes simplex virus type 1. Med Hypotheses. 2005;64(1):53-58. Abstract

Mori I, Kimura Y, Naiki H, Matsubara R, Takeuchi T, Yokochi T, Nishiyama Y. Reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease. J Med Virol. 2004 Aug ; 73(4):605-11. Abstract

Perry VH. The influence of systemic inflammation on inflammation in the brain: implications for chronic neurodegenerative disease. Brain Behav Immun. 2004 Sep 1;18(5):407-13. Abstract

Comment by Stephen R. Robinson, Monash University, Australia—Posted 1 July 2004

When will the pathogen hypothesis catch on?

The idea that Alzheimer's disease is caused by a pathogen which invades the brain has been around for decades, but this notion has never attracted serious attention from mainstream researchers. It is often dismissed because "if AD was really caused by a virus or bacteria, they would have found it by now, and in any case everyone knows that AD is not contagious—it only affects the aged". This reasoning overlooks the fact that the vast majority of diseases known to humanity are caused by pathogens, including quite a few that affect cognitive function, either directly (eg. HIV-1) or indirectly (eg. hepatitis). That the pathogen has not yet been identified is hardly surprising. After all, it took thousands of researchers, two decades and many billions of dollars to reach the conclusion that amyloid deposition does not cause AD. The marginalization of the pathogen hypothesis has stymied research in this area, and much of the supporting data which exists was generated on a pauper's budget, doing credit to the tenacity of proponents such as Ruth Itzhaki, Brain Balin and Mel Ball.

Since the leading proponents of the amyloid deposition hypothesis capitulated (Hardy and Selkoe, 2002), the Alzheimer's field has been left in a vacuum. Sure we still have the 'oligomeric amyloid hypothesis' the 'inflammation hypothesis' and the 'oxidative stress hypothesis' but when one looks beyond the hype it is clear that they merely describe a facet of AD, not its cause. They cannot explain for example, the spatiotemporal spread of plaques and tangles, why certain neurotransmitter types are preferentially affected, or why particular pathways in the brain are selectively targeted. They cannot account for the non-cognitive behavioural disturbances (eg sundowning), or the predilection for old age, and they struggle to explain why ApoE4 is the major genetic risk factor.

The pathogen hypothesis by contrast, offers explanations for all facets of AD, and for this reason it deserves serious consideration. The pathogen hypothesis was showcased in a debate at the second Challenging Views of Alzheimer's Disease conference in July, 2003. As an 'outsider' I was astounded to discover that despite three decades of publications by its proponents, not a single skeptic had taken the pathogen hypothesis seriously enough to write a critique. With colleagues Curtis Dobson and Joseph Lyons, we have now written that critique (Robinson et al., 2004). It is clear to us that much research remains to be done before a strong case can be established, yet it is equally evident that many important questions and issues are ripe for investigation. Certainly there are enough indirect observations to pique the interest of any objective researcher, including reports in the past few months of HSV-1 in the brain tissue of AD patients (Denaro et al., 2003; Mori et al., 2004).

Who knows, perhaps one day we will be able to immunize against AD!

References

Denaro, F.J., Staub, P., Colmer, J. and Freed, D.M. (2003) Coexistence of Alzheimer disease neuropathology with herpes simplex encephalitis. Cell Mol Biol (Noisy-le-grand). 49: 1233-40.

Hardy, J., and Selkoe, D.J. (2002) The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science. 297: 353-6.

Mori, I., Kimura, Y., Naiki, H., Matsubara, R., Takeuchi, T., Yokochi, T. and Nishiyama, Y. (2004) Reactivation of HSV-1 in the brain of patients with familial Alzheimer's disease. J. Med. Virol., 73: 605-11.

Robinson, S.R., Dobson, C. and Lyons, J. (2004) Challenges and directions for the pathogen hypothesis of Alzheimer's disease. Neurobiol. Aging, 25: 629-637.

Has anyone tested the use of antibiotics for Alzheimer's patients? My mother was diagnosed with the disease more than seven years ago. Although she quit after the diagnosis, she was a heavy smoker most of her life, which resulted in congestion problems. Over the last seven years she was given antibiotics several times. Each time her condition improved dramatically. When she stopped the medication she reverted back to the way she was before. She is now in the last stages of her disease and refuses to eat or drink. She was sent to the emergency room and not expected to survive the night. They gave her and antibiotic drip and by the next day she was fighting to go home. She recognized us, was able to put three words together, and understood and responded to everything we said to her. She even played a little joke on my sister, pretending to be dead and then jump up laughing because she scared her.

Remarkably, this is something that has been recognized by clinicians for many, many years. I have innumerable accounts from individuals who have reported on exactly the same response. There have been reports back to me of individuals who have not spoken for years that have "recovered" this ability following antibiotic therapy. Is the response specific to treating an infection systemically or in the brain, or does it have to do with an anti-inflammatory action of the antibiotics? We just don't have the answers to these questions at this time. In my estimation, there has to be a mandate in this for performing clinical trials based on the antibiotic approach. Hopefully, we can convince the NIH or big pharma that these trials would be worthwhile.

Q. by Donna Walraven, MSW—Posted 23 January 2009

When my father was alive there was an occasion where he had a serious bladder infection that was finally treated by a urologist outside of the nursing home where he stayed in Port Lavaca, Texas. The urologist gave him powerful antibiotics. After a few days on these antibiotics my father became lucid for over a week. He did not know my name before; now he was calling me by name again, and not just responding to questions, but actually carrying on a conversation with me.

It was a gift because soon after this episode he was overfed again and had to be resuscitated for the third time, but this time something happened to his throat and he was unable to eat again. He died about 10 days later.

I just thought that someone should know because it did seem to help him for a time.