Elsevier

Neurobiology of Aging

Volume 25, Issue 5, May–June 2004, Pages 629-637
Neurobiology of Aging

Challenges and directions for the pathogen hypothesis of Alzheimer’s disease

https://doi.org/10.1016/j.neurobiolaging.2003.12.022Get rights and content

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.

Introduction

The possibility that infiltration of the brain by pathogens acts as a trigger or co-factor for Alzheimer’s disease (AD) has been proposed repeatedly over the past three decades, with Herpes simplex virus type 1 (HSV1) and Chlamydophila pneumoniae (Cp; previously Chlamydia pneumoniae) being most frequently implicated. The initial impetus for this proposal came from the identification of a slow virus-like agent underlying spongiform encephalopathies and the elucidation of the role of the measles and the JC viruses in causing subacute sclerosing panencephalitis and progressive multifocal leukoencephalopathy, respectively [7], [33], [40]. In the mid-1970s several studies compared the levels of HSV1 neutralising antibodies in the serum [29] and cerebrospinal fluid (CSF) [24] of senile patients with various forms of dementia (including AD), and in other neurologically impaired and non-neurologically impaired control patients. While these studies found higher antibody levels in patients with AD, later studies failed to confirm such increases [44]. In the 1980s, in situ hybridisation was used to examine whether HSV1 is present in AD or control brain tissue. Once again, results were inconsistent, with two studies detecting viral nucleic acid in brain [13], [53] and another reporting higher levels of HSV1 latency-associated transcripts in AD trigeminal ganglia [9], yet other studies found little or no evidence for the presence of HSV1 nucleic acid [36], [42], [57]. With the advent of more sensitive techniques (polymerase chain reaction (PCR)), a high proportion of normal elderly and AD brains have been found to contain HSV1 DNA (discussed in [10]). In addition, an association between Cp and AD has been demonstrated by the Balin group, initially using PCR but with supporting evidence from other techniques [21].

The preceding observations provide a reason for seriously considering the pathogen hypothesis of AD, particularly since the dominant hypothesis in our field (the amyloid hypothesis) is still open to question (see [47]). Nonetheless, the body of data pertinent to the pathogen hypothesis is small and many key questions remain unanswered. In the interests of accelerating progress in the field, the present paper highlights some of the issues that need to be addressed before this hypothesis can either win widespread acceptance or be rejected for rational scientific reasons. We will begin by examining some of the broad implications of the pathogen hypothesis and then examine specific data pertaining to HSV1 and Cp infection of the brain. Throughout this review, we will offer what we consider to be plausible explanations for questions we have raised, in the hope that this will help to guide research into fertile new areas of investigation.

Section snippets

Latency of the pathogen

Viruses and bacteria infect cells by expressing coat proteins that mimic molecules which are commonly bound and internalised by cells. Each cell type expresses a specific range of receptors, so usually only a subset of cells in an organ is vulnerable to infection by a particular pathogen. Isoform differences in these receptors, which vary according to genotype, further influence susceptibility to infection. PCR studies show that during the first two decades of life a significant proportion

Herpes simplex encephalitis

In rare instances, HSV1 causes HSE in immunocompetent individuals. Around 2–4 HSE cases occur per million individuals per annum; if untreated, the disease is fatal in over 70% of cases [60], with death occurring within a few days of manifestation of symptoms. Since HSV1 infection of brain is also postulated to cause AD, it is instructive to compare the clinical and neuropathological symptoms of HSE with those of AD.

Table 1 shows that there are some clinicopathological similarities between HSE

Chlamydophila pneumoniae infection of brain

Unlike HSV1, the challenge to human health posed by the obligate intracellular bacteria C. pneumoniae has become apparent only during the last 20 years, with its possible role in non-respiratory diseases being the object of serious investigation for less than a decade. Cp belongs to the family of bacteria, Chlamydiaceae, that contains members which cause diseases of varied severity and variable pathologic outcome both at the site of initial infection and systemically. Coincidental with its

Summary and conclusions

The pathogen hypothesis of AD was postulated several decades ago but has not yet been subjected to a rigorous attempt at falsification. The fragmentary evidence currently available either provide qualified support for the hypothesis, or at least do not conclusively disprove it. In the spirit of constructive criticism we have highlighted aspects of the hypothesis that require investigation or are represented by contradictory data. Issues of particular concern include:

  • (1)

    paucity of evidence from an

Acknowledgements

We thank Drs. Keith Crutcher and Glenda Bishop for providing constructive suggestions on the manuscript.

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