Elsevier

Neurobiology of Aging

Volume 25, Issue 5, May–June 2004, Pages 619-627
Neurobiology of Aging

Infiltration of the brain by pathogens causes Alzheimer’s disease

https://doi.org/10.1016/j.neurobiolaging.2003.12.021Get rights and content

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-ε4). 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.

Introduction

The early events in the development of Alzheimer’s disease (AD) and its pathological features—amyloid plaques and neurofibrillary tangles (NFT)—remain unclear. Currently, about 20 million people worldwide suffer from AD, and the numbers are increasing with the rise in numbers of those reaching old age. Thus, the need for effective treatments for, and (hopefully) prevention of, AD is becoming ever more urgent.

The possibility of an infectious aetiology of several chronic diseases, including AD, has long been debated. Koch’s postulates, which can in some cases provide absolute proof that a particular microorganism causes a particular disease, have been invaluable in the prevention and treatment of many diseases as well as in advancing microbiology. However, the postulates do not hold for chronic diseases of possible microbial aetiology, particularly those occurring late in life, or for those of possible viral aetiology, or for those that are multifactorial in origin. In diseases of relatively old age, a microbe acting earlier in life might operate by a “hit-and-run” mechanism, or could eventually be present only at an extremely low level, so that searches for the organism might reveal nothing even if it had initiated damage. In viral diseases, the postulates requiring isolation and growth in pure culture cannot be met as viruses reproduce only within living cells. In multifactorial diseases, a causative organism would not be present in those whose disease is due to other factors. However, absence of evidence is not evidence of absence: in several cases when, eventually, overwhelming experimental evidence was obtained, the pathogen concept had to be accepted even though it had met with great opposition initially; two examples are the involvement of viruses in certain types of cancer, and of a bacterium in stomach ulcers.

The detailed research that has been made seeking and detecting two pathogens in brain, herpes simplex virus type 1 (HSV1), and Chlamydia pneumoniae, is described here. The “hit-and-run” theme is not pursued because no such studies have been made in respect to AD and indeed it is obviously very difficult to devise appropriate experiments.

Section snippets

Herpes simplex virus type 1 and AD

A possible viral involvement in the etiopathogenesis of AD was first suggested in 1977 [17]. Later, in 1982, HSV1 was proposed as a likely candidate virus [3] because in herpes simplex encephalitis (HSE), a very rare but extremely serious acute infection of the central nervous system (CNS), the earliest and most severely affected regions are the same as those showing the earliest and most severe pathological changes in AD. Although HSE is a very different disease from AD, it leads to certain

Other herpesviruses and AD

A role for other herpesviruses in AD has been investigated also. Human herpesvirus 6 (HHV6) was found in brain of a much higher proportion of sufferers than aged normals suggesting that this virus might be a risk [36]; however, an equally valid conclusion is that AD brains are more susceptible to the virus. Nevertheless, animal models have shown that HHV6 enhances the damage caused by HSV1, suggesting that HHV6 might enhance the damage caused by HSV1 in AD brain. Other viruses (herpes simplex

Epidemiological studies

Three recent studies of a very different type support a viral role in AD, even if indirectly: (a) AD patients showed a decline in cognitive function for at least two months after a systemic infection, associated probably with microglial cell activation caused by entry of cytokines into the brain [23]; (b) cognitive impairment in elderly cardiovascular patients was associated with viral pathogen burden (HSV1 alone and with HSV2 and cytomegalovirus) [56]; and (c) vaccination against various

Chlamydia pneumoniae and AD

Another organism that has been linked to AD is C. pneumoniae. In this case, the bacterial DNA has been found (in some studies) to be present in brain of a very high proportion of AD patients but in only very few age-matched normals, indicating a greater susceptibility to entry and infection of brain by the bacterium (and possibly also to damage by the latter) in AD patients rather than, as with HSV1, a greater susceptibility to damage of the nervous system.

Other bacteria and AD

In the brains of neuropathologically confirmed cases of AD, bacteria other than C. pneumoniae have been found [44]. In particular, spirochetes were detected in the blood and cerebrospinal fluid from AD patients. Furthermore, these organisms were isolated and cultured from AD patients [44]. Ultrastructural analysis indicated that taxonomically these organisms were in the order of Spirochaetaes. Intriguingly, the tick-borne pathogen Borrelia burgdorferi is the major human spirochetal infection in

Epilogue

There are defined technical difficulties in consistently determining infection associated with chronic disease throughout the body. A relatively primitive understanding of issues of latency of infection, dissemination of infection throughout the body, and strain heterogeneity of a variety of unique microorganisms requires tempered conclusions at this time. Nonetheless, a microbial involvement in AD points to the use of well-established anti-microbial agents for the treatment of the disease. In

Acknowledgements

We thank the Adolph and Rose Levis Foundation for supporting the ongoing development of the C. pneumoniae animal models, and Dr. M. Ball for helpful comments (supported in part from NIH Grant # AG 08017).

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