Posts Tagged ‘Herpes virus’

Role of infectious agent in Alzheimer’s Disease?

Larry H. Bernstein, MD, FCAP, Curator



Role of Infection in Alzheimer’s Ignored, Experts Say

Nancy A. Melville

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 theJournal of Alzheimer’s Disease.

Antiviral Treatment

“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, toldMedscape 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.

Causative Role?

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 areAPOE 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.

Microbes and Alzheimer’s Disease


  • Herpes simplex virus 1 (HSV-1) encephalitis predominantly involves the orbital surface of the frontal lobes and medial surface of the temporal lobes, resulting in areas of increased T2 signal on MRI
  • Herpes simplex virus 2 (HSV-2) is the primary cause of recurrent meningitis
  • After varicella, the varicella zoster virus (VZV) becomes latent in ganglia along the entire neuraxis; its reactivation can lead to herpes zoster, vasculopathy, myelitis, necrotizing retinitis or zoster sine herpete
  • The neurological complications of Epstein–Barr virus are diverse, and include meningitis, encephalitis, myelitis, radiculoneuropathy, and even autonomic neuropathy
  • The most common neurological complication of cytomegalovirus (CMV) is poly-radiculoneuropathy in immunocompromised individuals
  • Virological confirmation of neurological disease relies on the detection of herpesvirus-specific DNA in bodily fluids or tissues, herpesvirus-specific IgM in blood, or herpesvirus-specific IgM or IgG antibody in cerebrospinal fluid
  • HSV-1, HSV-2, VZV and CMV are the most treatable herpesviruses

Most HHVs can cause serious neurological disease of the PNS and CNS through primary infection or following virus reactivation from latently infected human ganglia or lymphoid tissue. The neurological complications include meningitis, encephalitis, myelitis, vasculopathy, acute and chronic radiculoneuritis, and various inflammatory diseases of the eye. Disease can be monophasic, recurrent or chronic.


The researchers also add that a gene mutation – APOEe4 – which appears to makes some of the population more susceptible to Alzheimer’s disease, could also increase these people’s susceptibility to infectious diseases.

 As a counter view, Professor John Hardy, Teacher of Neuroscience, UCL, told the website Journal Focus he was doubtful about the claims: “This is a minority sight in Alzheimer research study. There had actually been no convincing evidence of infections triggering Alzheimer disease. We require constantly to maintain an open mind however this editorial does not show exactly what many scientists think of Alzheimer disease.”

However, another of the researchers, Resia Pretorius of the University of Pretoria, told Bioscience Technology: “The microbial presence in blood may also play a fundamental role as causative agent of systemic inflammation, which is a characteristic of Alzheimer’s disease. Furthermore, there is ample evidence that this can cause neuroinflammation and amyloid-β plaque formation.”

The possibility of transfer has been reported to the journal Nature. The paper is titled “Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy.”

The report explains that during the period from 1958 to 1985, 30,000 people worldwide — mainly children — were administered injections of human growth hormone. This was designed to treat short stature. The hormone was extracted from thousands of human pituitary glands, with the source material being recently deceased people.

It now appears, The Economist summarizes, that some of these hormonal extracts contained prions. Around one in 16 of the children developed the brain disorder Creutzfeldt-Jakob disease (CJD). The concern with CJD centered on prions.

Read more:

Chain reaction

Evidence emerges that Alzheimer’s disease, and other neurodegenerative disorders such as Parkinson’s, may be transmissible



Reporting from the frontiers of health and medicine

A rare disease killed her mother. Can this scientist save herself?

CAMBRIDGE, Mass. — Five years ago, after watching her 51-year-old mother descend quickly into dementia, disability, and then death, Sonia Vallabh learned she was destined for the same fate. They both shared an extremely rare genetic mutation that leads a protein in the brain to turn toxic.

Vallabh, then a recent Harvard Law School graduate working as a consultant, decided to quit her job to spend time learning more about the mutation and nascent efforts to understand and treat it.

Now, she and her husband, Eric Minikel, a former transportation planner, are first authors on a paper about so-called prion diseases. Published Wednesday in Science Translational Medicine, the paper found that not all prion gene mutations are an early death sentence — though Vallabh’s variation is.

The husband-and-wife team, now both PhD students working in the same lab at the Broad Institute, also found that people can survive with only one copy of the prion gene, suggesting that a treatment to block the mutated version can be delivered safely.

Prion diseases were made famous by “mad cow disease,” outbreaks of which have led to mass killings of cattle. Eating sick cows can cause the fatal neurodegenerative illness known as Creutzfeldt-Jakob disease. But there are genetic versions of prion diseases that account for about 15 percent of cases. They come from mutations to the prion protein gene PRNP, which causes a protein in the brain to fold the wrong way, forming toxic clumps. Once these proteins get a foothold in the brain, they can cause extremely rapid damage.

Vallabh’s mother, who seemed completely normal at Christmastime in 2009, showed the first symptoms of disease in January 2010 and was demented and unable to speak clearly by March. She last recognized her daughter in May, Vallabh said, and died two days before Christmas that year, shortly after doctors finally identified the cause of her bizarre symptoms.

Vallabh, Minikel, and their coauthors compared a data set — painstakingly collected over decades — of gene sequences from 16,000 prion disease patients from all over the world, with two data sets of sequences from healthy people: more than 60,000 collected by the Broad-led Exome Aggregation Consortium and 530,000 from 23andMe, a consumer genetics company that invites clients to volunteer their gene sequences for research.

The size of the data sets allowed the researchers to draw conclusions even with a condition as rare as prion disease. Doctors had previously only known about 63 possible mutations in people with disease, so they had thought that all the mutations necessarily caused problems. But the researchers found 141 healthy people in the 23andMe dataset who had mutations to the PRNP gene — a rate far higher than the incidence of prion disease. That means some of the mutations must be harmless or at least not always cause disease, said J. Fah Sathirapongsasuti, a computational biologist at 23andMe and a study coauthor.

Out of 16 mutations for which there was evidence in the larger populations, they concluded that three were likely benign, three caused somewhat increased risk of disease, and four others, including Vallabh’s mutation, definitely do cause the fatal illness, they found.

They also discovered three older, healthy people who carried only one functional copy of the PRNP gene. That means that knocking out the mutated version of PRNP with gene therapy, or tamping down its activity with drugs, should be an effective way to eliminate the risk of disease without causing life-threatening problems.

Their paper has already helped at least one person, according to Dr. Robert Green, a medical geneticist at Brigham and Women’s Hospital, who cowrote an opinion piece published alongside the new study.

One of Green’s patients, whose mother died of prion disease, had been told her mom’s mutation — which she didn’t inherit, but her sister did — was always fatal. After seeing the new study, Green was able to inform the sister that her mutation was most likely harmless.



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