The potentially critical role of infection in the etiology of Alzheimer's disease is largely neglected, despite decades of robust evidence from hundreds of human studies, as well as the possible therapeutic implications, experts say.
"Despite all the supportive evidence, the topic [of linking infections to Alzheimer's disease] is often dismissed as 'controversial,' " the authors of an editorial, signed by an international group of 33 researchers and clinicians, write.
The editorial was published online March 8 in the Journal of Alzheimer's Disease.
"One recalls the widespread opposition initially to data showing that viruses cause some types of cancer, and that a bacterium causes stomach ulcers," the authors write.
The implications could be just as important with regard to Alzheimer's disease, coauthor Ruth F. Itzhaki, PhD, of the Faculty of Life Sciences at the University of Manchester, United Kingdom, told Medscape Medical News.
"The implications are that patients could be treated with antiviral agents. These would not cure them, but might slow or even stop the progression of the disease," she said.
The evidence points to herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochetes, which make their way into the central nervous system (CNS), where they can remain in latent form indefinitely, the authors note.
The link with HSV1 is supported by as many as 100 studies. Only two studies oppose the association; both were published more than a decade ago, the authors state.
Under the prevailing theory, agents such as HSV1 undergo reactivation in the brain during aging and with the decline of the immune system, as well as when persons are under stress.
"The consequent neuronal damage ― caused by direct viral action and by virus-induced inflammation ― occurs recurrently, leading to (or acting as a cofactor for) progressive synaptic dysfunction, neuronal loss, and ultimately AD [Alzheimer's disease]," the authors write.
Importantly, that damage includes the induction of amyloid-β (Aβ) peptide deposits, considered a hallmark of Alzheimer's disease, which initially appears to be only a defense mechanism, the authors add.
In outlining some of the strongest evidence behind the theory, the authors note that although viruses and other microbes are common in the elderly brain and are usually dormant, influences such as stress and immunosuppression can cause reactivation.
"For example, HSV1 DNA is amplified in the brain of immunosuppressed patients," they write.
In addition, herpes simplex encephalitis is known to damage regions of the CNS linked to the limbic system, and therefore to memory as well as cognitive and affective processes, the same regions affected in Alzheimer's disease.
HSV infection is known to be significantly associated with the development of Alzheimer's, and the disease is known to have a strong inflammatory component that is characteristic of infection, the authors say.
On a genetic level, research has shown that polymorphisms in the apolipoprotein E gene (APOE) that are linked to the risk for Alzheimer's also control immune function and susceptibility to infectious disease.
In terms of evidence of a causative role of infection in Alzheimer's disease, the authors cite studies indicating that brain infection, such as HIV or herpes virus, is linked to pathology similar to Alzheimer's.
Notably, infection with HSV1 or bacteria in mice and cell culture studies has been shown to result in Aβ deposition and tau abnormalities typical of Alzheimer's disease.
In addition, the olfactory dysfunction that is an early symptom of Alzheimer's disease is consonant with a role of infection: The olfactory nerve leads to the lateral entorhinal cortex, where Alzheimer's pathology spreads through the brain, and it is the likely portal of entry of HSV1 and other viruses into the brain, the authors note.
"Further, brainstem areas that harbor latent HSV directly irrigate these brain regions: brainstem virus reactivation would thus disrupt the same tissues as those affected in Alzheimer's disease," they write.
In terms of mechanisms, the authors cite mounting evidence that virus infection selectively upregulates the gene encoding cholesterol 25-hydroxylase (CH25H), and innate antiviral immunity is induced by its enzymatic product 25-hydroxycholesterol (25OHC).
The human CH25H polymorphisms control susceptibility to Alzheimer's as well as Aβ deposition.
Consequently, "Aβ induction is likely to be among the targets of 25OHC, providing a potential mechanistic link between infection and Aβ production," the authors write.
Considering the devastating toll Alzheimer's disease takes on individual lives and society, the need to reconsider the collective evidence of a role for infection is pressing, the authors note.
"Alzheimer's disease causes great emotional and physical harm to sufferers and their carers, as well as having enormously damaging economic consequences," they write.
"Given the failure of the 413 trials of other types of therapy for Alzheimer's disease carried out in the period 2002-2012, antiviral/antimicrobial treatment of Alzheimer's disease patients, notably those who are APOE ɛ4 carriers, could rectify the 'no drug works' impasse.
"We propose that further research on the role of infectious agents in Alzheimer's disease causation, including prospective trials of antimicrobial therapy, is now justified."
Chicken or the Egg?
Commenting on the editorial for Medscape Medical News, Richard B. Lipton, MD, Edwin S. Lowe Professor, vice chair of neurology, and director of the Division of Cognitive Aging and Dementia at Albert Einstein College of Medicine in New York City, applauded the effort to raise awareness of the issue.
"The authors are to be commended for reminding us of the hypothesis that infection may contribute to Alzheimer's disease," he told Medscape Medical News.
He noted the variety of genetic and environmental factors that can influence onset and progression of complex disorders such as Alzheimer's disease.
"For Alzheimer's disease, most people would agree that cardiovascular risk factors, traumatic brain injury, and stress increase risk of disease," he said.
"It is entirely plausible that infectious agents may be one of many factors that contribute to the development of Alzheimer's disease. Infectious agents could operate through several mechanisms."
The evidence does not necessarily prove a causative role, he added.
"Temporality means that infection precedes disease," he said. "The studies showing infectious and inflammatory markers in the Alzheimer's brain don't tell us which came first. Alzheimer's disease could be a state which predisposes to infection."
The editorialists' financial disclosures are available online. Dr Lipton has disclosed no relevant financial relationships.
J Alzheimers Dis. Published online March 8, 2016. Editorial