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Role of infectious agent in Alzheimer’s Disease?

March 21, 2016 by larryhbern

Role of infectious agent in Alzheimer’s Disease?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

Role of Infection in Alzheimer’s Ignored, Experts Say

Nancy A. Melville http://www.medscape.com/viewarticle/860615

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

Authors: Itzhaki, Ruth F.^{a; *} , et al Article type: Editorial DOI: 10.3233/JAD-160152

Journal: Journal of Alzheimer’s Disease, 8 March 2016; pp. 1-6, 2016 http://content.iospress.com/articles/journal-of-alzheimers-disease/jad160152

We are researchers and clinicians working on Alzheimer’s disease (AD) or related topics, and we write to express our concern that one particular aspect of the disease has been neglected, even though treatment based on it might slow or arrest AD progression. We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1 (HSV1), Chlamydia pneumoniae, and several types of spirochaete, in the etiology of AD [1–4]. Fungal infection of AD brain [5, 6] has also been described, as well as abnormal microbiota in AD patient blood [7]. The first observations of HSV1 in AD brain were reported almost three decades ago [8]. The ever-increasing number of these studies (now about 100 on HSV1 alone) warrants re-evaluation of the infection and AD concept.

AD is associated with neuronal loss and progressive synaptic dysfunction, accompanied by the deposition of amyloid-β (Aβ) peptide, a cleavage product of the amyloid-β protein precursor (AβPP), and abnormal forms of tau protein, markers that have been used as diagnostic criteria for the disease [9, 10]. These constitute the hallmarks of AD, but whether they are causes of AD or consequences is unknown. We suggest that these are indicators of an infectious etiology. In the case of AD, it is often not realized that microbes can cause chronic as well as acute diseases; that some microbes can remain latent in the body with the potential for reactivation, the effects of which might occur years after initial infection; and that people can be infected but not necessarily affected, such that ‘controls’, even if infected, are asymptomatic [2].

EVIDENCE FOR AN INFECTIOUS/IMMUNE COMPONENT

(i) Viruses and other microbes are present in the brain of most elderly people [11–13]. Although usually dormant, reactivation can occur after stress and immunosuppression; for example, HSV1 DNA is amplified in the brain of immunosuppressed patients [14].
(ii) Herpes simplex encephalitis (HSE) produces damage in localized regions of the CNS related to the limbic system, which are associated with memory, cognitive and affective processes [15], as well as personality (the same as those affected in AD).
(iii) In brain of AD patients, pathogen signatures (e.g., HSV1 DNA) specifically colocalize with AD pathology [13, 16, 17].
(iv) HSV infection, as revealed by seropositivity, is significantly associated with development of AD [18–21].
(v) AD has long been known to have a prominent inflammatory component characteristic of infection (reviewed in [22, 23]).
(vi) Polymorphisms in the apolipoprotein E gene, APOE, that modulate immune function and susceptibility to infectious disease [24], also govern AD risk (reviewed in [25, 26]). Genome-wide association studies reveal that other immune system components, including virus receptor genes, are further AD risk factors [27–32].
(vii) Features of AD pathology are transmissible by inoculation of AD brain to primates [33, 34] and mice [35, 36].

EVIDENCE FOR CAUSATION

(i) In humans, brain infection (e.g., by HIV, herpesvirus, measles) is known to be associated with AD-like pathology [37–42]. Historical evidence shows that the clinical and pathological hallmarks of AD occur also in syphilitic dementia, caused by a spirochaete [4].
(ii) In mice and in cell culture, Aβ deposition and tau abnormalities typical of AD are observed after infection with HSV1 [43–52] or bacteria [16, 53–55]; a direct interaction between AβPP and HSV1 has been reported [56]. Antivirals, including acyclovir, in vitroblock HSV1-induced Aβ and tau pathology [57].
(iii) Olfactory dysfunction is an early symptom of AD [58]. The olfactory nerve, which leads to the lateral entorhinal cortex, the initial site from where characteristic AD pathology subsequently spreads through the brain [59, 60], is a likely portal of entry of HSV1 [61] and other viruses [62], as well as Chlamydia pneumoniae, into the brain [63], implicating such agents in damage to this region. 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 AD [64].

GROWING EVIDENCE FOR MECHANISM: ROLE OF Aβ

(i) The gene encoding cholesterol 25-hydroxylase (CH25H) is selectively upregulated by virus infection, and its enzymatic product (25-hydroxycholesterol, 25OHC) induces innate antiviral immunity [65, 66].
(ii) Polymorphisms in human CH25H govern both AD susceptibility and Aβ deposition [67], arguing that Aβ induction is likely to be among the targets of 25OHC, providing a potential mechanistic link between infection and Aβ production [68].
(iii) Aβ is an antimicrobial peptide with potent activity against multiple bacteria and yeast [69]. Aβ also has antiviral activity [70–72].
(iv) Another antimicrobial peptide (β-defensin 1) is upregulated in AD brain [73].

Regarding HSV1, about 100 publications by many groups indicate directly or indirectly that this virus is a major factor in the disease. They include studies suggesting that the virus confers risk of the disease when present in brain of carriers of the ɛ4 allele of APOE [74], an established susceptibility factor for AD (APOEɛ4 determines susceptibility in several disorders of infectious origin [75], including herpes labialis, caused usually by HSV1). The only opposing reports, two not detecting HSV1 DNA in elderly brains and another not finding an HSV1–APOE association, were published over a decade ago [76–78]. However, despite all the supportive evidence, the topic is often dismissed as ‘controversial’. One recalls the widespread opposition initially to data showing that viruses cause some types of cancer, and that a bacterium causes stomach ulcers.

In summary, we propose that infectious agents, including HSV1, Chlamydia pneumonia, and spirochetes, reach the CNS and remain there in latent form. These agents can undergo reactivation in the brain during aging, as the immune system declines, and during different types of stress (which similarly reactivate HSV1 in the periphery). 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. Such damage includes the induction of Aβ which, initially, appears to be only a defense mechanism.

AD causes great emotional and physical harm to sufferers and their carers, as well as having enormously damaging economic consequences. Given the failure of the 413 trials of other types of therapy for AD carried out in the period 2002–2012 [79], antiviral/antimicrobial treatment of AD patients, notably those who are APOEɛ4 carriers, could rectify the ‘no drug works’ impasse. We propose that further research on the role of infectious agents in AD causation, including prospective trials of antimicrobial therapy, is now justified.
(http://j-alz.com/manuscript-disclosures/16-0152).

Essential Science: Pathogenic organisms may trigger Alzheimer’s

By Tim Sandle Mar 14, 2016 in Science

Read more: http://www.digitaljournal.com/science/essential-science-are-pathogens-a-cause-of-alzheimer-s/article/460147#ixzz43Y

Alzheimer’s disease is a common pathology of the modern world, especially with ageing populations. This is generally regarded to be due to both hereditary components and as a result of numerous injuries to neuronal structures and components of the central nervous system. There may also be an environmental connection.

With the neurodegenerative disease, the majority medical opinion is that a protein called amyloid-beta forms sticky “plaques” in the brains of people with Alzheimer’s disease, ultimately killing the surrounding neurons and causing memory loss and other cognitive problems. The protein forms over many years, possibly beginning in childhood. The theory runs that an amyloid-related mechanism, designed to control neuronal connections in the brain in early life, is again triggered by the ageing-related processes in later life.

[The core focus of Wenk’s work is the study of the consequences of chronic brain inflammation as a result of normal aging and of Alzheimer’s disease. His current research centers on how Alzheimer’s disease is caused by inflammation to the brain.

As he explains: “Inflammation is now thought to underlie most age-associated neurological diseases. Chronic brain inflammation does not cause these diseases; it simply magnifies the pathology and induces it to progress. The inflammatory process is likely initiated by mutant proteins that appear soon after birth. Alzheimer’s disease is now thought to begin very early in life; it simply takes many decades for the symptoms to appear.”

Current medical opinion is that, over many years, a protein called amyloid-beta (Aβ) forms sticky “plaques” in the brains of people with Alzheimer’s disease, ultimately killing the surrounding neurons and causing memory loss and other cognitive problems.

In his search for a way to stop the condition’s progress, Wenk is exploring the ability of cannabinoids to reduce inflammation inside the brain.]

http://medireview.com/2014/02/study-medical-marijuana-may-prevent-alzheimers-disease/

In an alternative research stream, the 31 international scientists have written an opinion-led editorial in The Journal of Alzheimer’s Disease (titled “Microbes and Alzheimer’s Disease“.) This editorial puts the case for the herpes virus and Chlamydia bacteria causing Alzheimer’s disease.

Herpes is a family of viruses, of which herpes simplex virus 1 and 2 (HSV-1 and HSV-2), are examples, and these are the cause of a common, easily transmitted diseases. HSV-1 (which produces most cold sores) and HSV-2 (which produces most genital herpes) are ubiquitous and contagious.

Chlamydia infection is a common sexually transmitted infection in humans caused by the bacterium Chlamydia trachomatis. Chlamydia is a major infectious cause of human genital and eye disease. C. trachomatis is a Gram-negative bacterium. It is ovoid in shape and non-motile.

The reason why there may be an association, the researchers suggest, is because viruses have been linked with certain cancers and some bacteria are associated with stomach ulcers; the connection between microorganisms and types of diseases is not uncommon. It follows that viruses or bacteria (or both) are responsible for the build-up of the plaque that ultimately leads to Alzheimer’s disease. The researchers are of the opinion that microbial infections trigger neuroinflammation and, in turn, this leads to plaque formation.

The reason for this assertion, the researchers contend, is because viruses and bacteria are common in the brains of elderly people in higher numbers than young people. While these organisms are usually dormant, they can ‘wake up’ after stress or if the immune system is compromised. This is particularly so with a type of herpes virus, which about two-thirds of people pick up during their lifetime. A link between herpes and damage to the nervous system has previously been established.

Herpesvirus infections of the nervous system

Donald H Gilden*, Ravi Mahalingam, Randall J Cohrs and Kenneth L Tyler

Nature Clinical Practice Neurology (2007) 3, 82-94 http://dx.doi.org:/10.1038/ncpneuro0401

There are eight human herpesviruses (HHVs). Primary infection by any of the eight viruses, usually occurring in childhood, is either asymptomatic or produces fever and rash of skin or mucous membranes; other organs might be involved on rare occasions. After primary infection, the virus becomes latent in ganglia or lymphoid tissue. With the exception of HHV-8, which causes Kaposi’s sarcoma in patients with AIDS, reactivation of HHVs can produce one or more of the following complications: meningitis, encephalitis, myelitis, vasculopathy, ganglioneuritis, retinal necrosis and optic neuritis. Disease can be monophasic, recurrent or chronic. Infection with each herpesvirus produces distinctive clinical features and imaging abnormalities. This Review highlights the patterns of neurological symptoms and signs, along with the typical imaging abnormalities, produced by each of the HHVs. Optimal virological studies of blood, cerebrospinal fluid and affected tissue for confirmation of diagnosis are discussed; this is particularly important because some HHV infections of the nervous system can be treated successfully with antiviral agents.

Herpesviruses are large double-stranded DNA viruses. Approximately 130 different herpesviruses have been identified, not only in mammals, but also in frogs, lizards, birds, fish and mosquitoes. There are eight human herpesviruses (HHVs): herpes simplex virus (HSV-) 1, HSV-2, varicella zoster virus (VZV or HHV-3), Epstein–Barr virus (EBV or HHV-4), cytomegalovirus (CMV or HHV-5), HHV-6, HHV-7, and HHV-8. A characteristic feature of all herpesviruses is their ability to become latent, primarily in ganglia of the nervous system and lymphoid tissue. For example, HSV and VZV become latent in neurons of ganglia, whereas EBV is latent in B lymphocytes. Most of the HHVs are neurotropic and infrequently cause serious acute and chronic neurological disease of the PNS and CNS that might be monophasic, recurrent or chronic. Infection with each herpesvirus produces different clinical features and imaging abnormalities, and many HHV infections can now be treated. This Review focuses on the neurological complications of the HHVs, and discusses optimal virological tests to identify the etiological agent, along with state-of-the-art treatments for these disorders.

KEY POINTS

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.”

In related news, and as reported earlier on Digital Journal, a review of medical records suggests that it could be possible to transmit Alzheimer’s through certain medical procedures. Here the causative agent is a prion. Prions (“proteinaceous infectious particles”) are types of protein folded in atypical and complex ways.
Alzheimer’s and Parkinson’s diseases may be transmissible

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: http://www.digitaljournal.com/science/alzheimer-s-and-parkinson-s-diseases-may-be-transmissible/article/444338#ixzz43Y

Chain reaction

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

WHEN Auguste Deter was admitted to hospital in 1901, her medical records described her helpless expression and problems remembering her husband’s name. It was only after her death, in 1906, that an autopsy revealed a number of brain abnormalities. The doctor who discovered them was Aloysius Alzheimer and the two proteins he found in her brain are today thought to be an integral part of the disease named after him. These days Alzheimer’s is recognised as a progressive neurological condition that mostly arises in the old. Now scientists have uncovered evidence that it may be possible to transmit Alzheimer’s through certain medical procedures.The story, reported in Nature this week, starts with the fact that medical and surgical procedures can transmit prion diseases, which are progressive neurodegenerative disorders first seen in animals. From the late 1950s to 1985, about 30,000 people worldwide, mostly children, received injections of human growth hormone to treat their short stature. This hormone had been extracted from thousands of human pituitary glands taken from cadavers. Unfortunately some extracts contained prions, abnormal infectious proteins. A small percentage of these patients—up to 6.3%, in one national sample—eventually went on to develop Creutzfeldt-Jakob disease (CJD), a neurological disorder.

At the Medical Research Council’s Prion Unit, which opened in London in 1998, Sebastian Brandner conducts post-mortem examinations of people who have died from prion diseases. During an autopsy of several patients who died from CJD acquired through injections of human growth hormone, he noticed something so surprising that he called his colleague, John Collinge, a professor of neurology at University College London, to take a look. What he found were substantial deposits of the amyloid beta protein, one of the two key proteins that Alzheimer discovered in Mrs Deter that are tied to the development of this disease. After conducting eight autopsies, only one patient was found to be entirely free of the protein.

What makes this discovery particularly unusual is that Alzheimer’s is rare in people below the age of 60 and all the patients examined were between 36 and 51 years old. Moreover, the sort of brain pathology the researchers observed is not found in patients who have died from CJD that was inherited or acquired spontaneously. Dr Brandner and Dr Collinge are therefore proposing that when these patients were injected with human growth hormone, it was contaminated not only with prions but also small fragments, or seeds, of the amyloid beta protein—which then spread, rather like CJD, through their brains.

Folding wrongly

An observational study such as this cannot prove that deposits of amyloid beta were caused by seeds of the protein in contaminated hormone injections. Nonetheless, it is by no means an outlandish theory. In recent years it has become apparent that degenerative brain disorders such as Alzheimer’s, Parkinson’s and motor neurone disease, like prion disease, result from the spread of misfolded proteins.

Proteins are made up of chains of molecules, and to do their job as part of the body’s metabolism they must fold into a precise shape. But sometimes a protein misfolds. Usually misfolded proteins will simply fail to work; occasionally they will work, but wrongly. In CJD, prions misfold and are able to transmit their conformation to other properly folded proteins. In Alzheimer’s it is becoming clear that amyloid beta deposition can also be induced through a prion-like means: misfolded proteins beget more misfolded proteins.

KAREN WEINTRAUB

Reporting from the frontiers of health and medicine

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

http://www.statnews.com/2016/01/20/prion-disease-genes/

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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