text: Alzheimer’s disease could be caused by viruses like herpes, a group of renowned dementia experts have warned, as they call for urgent investigation into the link. 
   
   The worldwide team of 31 senior scientists and clinicians, which include specialists from Oxford, Cambridge, Edinburgh and Manchester Universities and Imperial College, have written an editorial which suggests that microbes are the major cause of dementia. 
   
   The herpes virus - the type which causes cold sores - and chlamydia bacteria are named as the major culprits, as well as a type of corkscrew-shaped bacteria called spirochaete. 
   
   “There is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component. We can’t keep ignoring all of the evidence” 
   
   “There is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component. We can’t keep ignoring all of the evidence” Professor Douglas Kell, Manchester University 
   
   Currently most scientists are trying to find treatments which prevent the build of sticky amyloid plaques and misfolded tau proteins in the brain which prevent neurons from communicating with each other, leading to memory loss and cognitive decline. 
   
   But in an the editorial in the Journal of Alzheimer’s Disease, it is suggested that it is a viral or bacterial infection which triggers the plaque build-up in the first place. Targeting them specifically with antimicrobial drugs could halt dementia. 
   
   Professor Douglas Kell of the University of Manchester’s School of Chemistry, said “We are saying there is incontrovertible evidence that Alzheimer’s Disease has a dormant microbial component. We can’t keep ignoring all of the evidence.” 
   
   There are currently 850,000 people living with dementia in Britain which is due to rise to one million by 2025 and two million by 2050. But despite 412 drugs trials taking place between 2002 and 2012, nothing has been shown to combat the disease. 
   
   The authors say that viruses and bacteria are common in the brains of elderly people, and although they are usually dormant, they can ‘wake up’ after stress or if the immune system is compromised. Around two thirds of people will acquire the herpes virus at some point in their lives, and many will not realise they have it. 
   
   Photo: ALAMY 
   
   The herpes virus in particular is known to damage the central nervous system, and the limbic system in the brain which regulates mood and instinct and is associated with mental decline and personality changes. 
   
   They also point to the fact that a gene mutation - APOEe4 - which makes one in five people more susceptible to Alzheimer’s disease, also raises their susceptibility to infectious disease. Viral infections in the brain are already known to cause symptoms similar to Alzheimer’s and the experts say the link has been ‘neglected’ for too long. 
   
   “Alzheimer’s disease causes great emotional and physical harm to sufferers and their carers as well as having enormously damaging economic consequences,” they write. 
   
   “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 Alzheimer’s disease progression. 
   
   “We refer to the many studies, mainly on humans, implicating specific microbes in the elderly brain, notably herpes simplex virus type 1, chlamydia pneumoniae and several types of spirochatete. 
   
   “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.” 
   
   They say new findings could also have implications for the future treatment of Parkinson’s Disease, and other progressive neurological conditions. 
   
   Professor Resia Pretorius of the University of Pretoria, who worked with Prof Kell on the editorial, said “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 plaque formation.” 
   
   Dementia charities said they had noticed that viruses and bacteria were more common in people with Alzheimer's disease. 
   
   Dr James Pickett, Head of Research at Alzheimer’s Society said: “A large number of different microbes including viruses, bacteria and fungi have been found in the brains of older people - but there do appear to be more of them in the brains of people who have died with Alzheimer’s disease. 
   
   "While these observations are interesting and warrant further research, there is currently insufficient evidence to tell us that microbes are responsible for causing Alzheimer’s disease in the vast majority of cases. We would like to reassure people that there remains no convincing evidence that Alzheimer’s disease is contagious or can be passed from person to person like a virus. 
   
   “Given the enormous global impact of dementia, there is intense interest from the research community to understand all the potential contributing factors. We welcome research that explores all possible avenues and have committed £100 million over the next decade to more fully understand the causes of dementia and to improve diagnosis, treatment and prevention of the condition.” 
   
   Last year, researchers found that the 'seeds' of Alzheimer's could be passed through blood transfusions and medical accidents. 
   
   Prof John Hardy, Professor of Neuroscience, UCL, said: “This is a minority view in Alzheimer research. There had been no convincing proof of infections causing Alzheimer disease. We need always to keep an open mind but this editorial does not reflect what most researchers think about Alzheimer disease.” 
   
   Dr Simon Ridley, Director of Research at Alzheimer’s Research UK, said: “There is growing evidence for the role of the immune system in Alzheimer’s and active ongoing research looking at how an inflammatory response might contribute to the disease. There is some evidence to suggest that infections in general could ramp up the immune system and contribute to the progression of Alzheimer’s, but there isn’t conclusive evidence to suggest that a particular infectious agent or microbe could be directly responsible for causing the disease. 
   
   "There are many avenues being explored to understand the initial events that trigger the development of Alzheimer’s and this is an important part of the research process for ruling in and out particular hypotheses. There is no evidence that Alzheimer’s can be passed from person to person like a virus. Continued research funding into diseases like Alzheimer’s is important to build a clearer picture of the genetic and lifestyle risk factors for the disease and use this knowledge to develop preventions or treatments.” ||||| A worldwide team of senior scientists and clinicians have come together to produce an editorial which indicates that certain microbes - a specific virus and two specific types of bacteria - are major causes of Alzheimer’s Disease. Their paper, which has been published online in the highly regarded peer-reviewed journal, Journal of Alzheimer's Disease, stresses the urgent need for further research - and more importantly, for clinical trials of anti-microbial and related agents to treat the disease. 
   
   
   
   This major call for action is based on substantial published evidence into Alzheimer's. The team’s landmark editorial summarises the abundant data implicating these microbes, but until now this work has been largely ignored or dismissed as controversial - despite the absence of evidence to the contrary. Therefore, proposals for the funding of clinical trials have been refused, despite the fact that over 400 unsuccessful clinical trials for Alzheimer's based on other concepts were carried out over a recent 10-year period. 
   
   
   
   Opposition to the microbial concepts resembles the fierce resistance to studies some years ago which showed that viruses cause certain types of cancer, and that a bacterium causes stomach ulcers. Those concepts were ultimately proved valid, leading to successful clinical trials and the subsequent development of appropriate treatments. 
   
   
   
   Professor Douglas Kell of The University of Manchester’s School of Chemistry and Manchester Institute of Biotechnology is one of the editorial’s authors. He says that supposedly sterile red blood cells were seen to contain dormant microbes, which also has implications for blood transfusions. ||||| 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 vitro block 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 CH25 H 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 (APOE ɛ4 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 APOE ɛ4 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.
target: – Roughly two-thirds of American adults have been exposed to the herpes type 1 virus (oral; type 2 is the genital one), and they could be predisposed to developing Alzheimer's disease later in life. So writes a group of 31 international scientists and clinicians in an editorial in the Journal of Alzheimer's Disease, stating that "substantial published evidence" suggests such a link and calling on researchers elsewhere to take action. They claim that some microbes—the virus and two types of bacteria, chlamydia and spirochete—are linked to the progressive neurological disease. "We are saying there is incontrovertible evidence that Alzheimer's disease has a dormant microbial component," writes lead author Douglas Kell in a University of Manchester statement. "We can't keep ignoring all of the evidence." The authors propose that the named microbes "reach the [central nervous system] and remain there in latent form." They can then essentially wake up during the course of aging, under stress, or as the immune system declines. "The consequent neuronal damage ... occurs recurrently, leading to ... ultimately AD," the authors posit. They point to the failure of 413 Alzheimer's drug trials conducted between 2002 and 2012 and "express our concern that one particular aspect of the disease has been neglected," as "antiviral/antimicrobial treatment of AD patients ... could rectify the 'no drug works' impasse." Meanwhile, not all are convinced, with one neuroscience professor framing theirs as a "minority view"; he tells the Telegraph there has "been no convincing proof of infections causing" the disease. (This 38-year-old's form of Alzheimer's is genetic.)