For those interested in infectious agents and Alzheimer’s disease (AD), this year’s Alzheimer’s Association International Conference (AAIC) represented a landmark in that the Alzheimer’s Association, the second leading provider of funding for research on the disease, and the organizer of the largest AD conference in the world, organized with enthusiasm a session comprising a discussion on infectious agents and AD. This was the first time that the word ‘viruses’, and probably the first time ‘bacteria’ too, had been heard at a major session of an Alzheimer’s Association conference. Gratifyingly, Dr. Maria Carillo, chief science officer of the Alzheimer’s Association, made a declaration of support for furthering research on this topic, stating that “Ideas in this area of research are still evolving; there is now growing evidence that microbes1 such as bacteria and viruses may play a role in degenerative brain diseases such as Alzheimer’s.” She emphasized that
“new research suggests infectious agents may be triggering immune reactions related to plaques and tangles … and that loss of cognitive function in Alzheimer’s disease may stem from several different disease processes in the brain, not just one”.
Five talks were arranged for the infection-AD session: three of the speakers supporting a role for microbes and two opposing it. The talks were (in theory) restricted to 10 minutes each, which obviously allowed only the briefest presentation of evidence for or against a microbial role, and precluded that of any new, unpublished work.
The first talk, by Rob Moir (Massachusetts General Hospital and Harvard Medical School), started with a reminder of the eponymous Dr. Alois Alzheimer and his seminal observations on the unusual features of a previously unrecognized disease of the brain. Moir stated the main objections that have been raised to the concept that amyloid-β (Aβ) is an antimicrobial peptide (AMP) produced to combat infection—and then demolished them. The first objection was that that the current amyloidogenesis concept obviates the need for an infectious agent. His answer to this was that amyloid formation is in fact a response to infection. To the point that no single microbe has been closely associated with the disease, Moir argued that many different types of infection can stimulate amyloidogenesis and that its fibrilization results in its encaging the microbe . (Interestingly, the concept of entrapment of microbes was raised many years ago in the flocculation hypothesis of Robinson and Bishop (2002) , but was ignored, as was the discovery a few years later, though ignored to a lesser extent, that most of HSV1 DNA in AD brains is located within amyloid plaques .) Moir voiced also that none of us was suggesting that Aβ was unimportant, but instead, that it has indeed a major role in AD, but not as a cause of the disease.
The second talk, by the present author (University of Manchester), gave a more or less potted history of the discoveries that led to the formulation of the HSV1-AD concept; this maintains that HSV1 is likely a major cause of the disease, though the take-home message stressed that the concept does not preclude the likelihood that specific bacteria too are involved in the development of the disease. The slides displayed the evidence for HSV1 presence in brain and its reactivation there, its association with AD, including its causing an accumulation of Aβ and P-tau in infected cell cultures and mouse brain, its co-localization in AD amyloid plaques, and also the protective effects of the antiviral, acyclovir, on HSV1-infected cells in culture . Further, the importance of understanding that infected does not necessarily mean affected—hence the existence of infected, but asymptomatic, “controls”—was stressed. Finally, the striking population epidemiological data from Taiwan were described, showing the association of HSV infection and AD, and the success of antivirals in preventing (or possibly delaying) the disease, the latter result supporting a causal role for HSV1 in AD [5, 6].
The 3rd supportive talk, by Ben Readhead (ASU-Banner, Neurodegenerative Disease Research Center), described the usage of large multiomic next-generation sequencing studies for exploring the role of the brain microbiome in AD, aiming to find whether microbes in the brain were causal, accelerants, or opportunistic. The main discovery of the study was the importance of HHV6 and 7 as well as HSV1 in AD brains, including positive correlations between viral abundance, clinical dementia rating, and neuropathology . (In fact, HHV6 was first detected in AD brains at a much higher frequency than in age-matched controls, in 2002 , though its level was not quantified; indeed frequency/prevalence needs to be distinguished from the abundance/level/amount of a microbe, the latter but not the former being reported in the paper by Readhead et al. ). The conclusion of Readhead et al.  was that virus-host regulatory networks indicate complex interactions between several species of herpesvirus and host genes, including perturbation of host networks related to the pathogenesis of AD; these suggest that infections are at least capable of accelerating disease, and also indicate testable hypotheses for further evaluating the pathogen hypothesis of AD.
The two dissenting voices were then heard, not so much refuting any points raised by the proponents or even the involvement of microbes in AD but instead, questioning the significance of their presence and the possible mechanisms of microbial action. The talk by Todd Golde (University of Florida) stressed the important point, on which all the speakers agreed, that association does not prove causality, and also that some of the studies described were carried out with insufficient care. More importantly, the results might be an indication of “reverse causation”, i.e., neurodegeneration might lead to some degree of reactivation of dormant viruses present (although by saying this, he tacitly acknowledged at least the presence of viruses in brain). However, his main concern was that such research might distract from more impactful work (such as amyloid studies).
The concerns of the last speaker, Michael Heneka (University of Bonn Medical Center), were partly based on the role of microglia, including the likelihood that microbial pyroptosis (a highly inflammatory form of programmed cell death that occurs most often because of infection by intracellular pathogens) seeds the deposition of Aβ . He posited also that bacteria, rather than being involved at the initial stage of AD, might invade the brain during the terminal stage of the disease as a result of local chronic brain inflammation compromising the integrity of the blood-brain barrier. He considered too the possibility that peripheral bacterial infection might accelerate disease pathogenesis without the bacteria actually infiltrating the brain . (In fact, the HSV-AD concept suggests that reactivation of HSV1 existing in brain might well occur as a result of peripheral infections leading to brain inflammation.)
The audience was estimated as some 700 people, filling completely the large auditorium. Whether or not anyone present changed sides because of the arguments is unknown; taking a vote before and after the discussion (as in the Controversies in Neurology congresses) might have revealed that. However, no objections of any type were raised, suggesting that as in the past, there are no true arguments against the putative role of microbes. In fact, the extreme hostility to the concept that existed for almost three decades although ludicrous, as the opponents never voiced any scientific objections, precluded any appreciable funding for the work and caused great difficulties in publication of results. It was therefore gratifying that microbial studies are now described by the AAIC as one of the “currently hot topics in neuroscience”, and also that Dr. Richard Hodes, director of the National Institutes of Health (NIH)’s National Institute on Aging, told STAT (the health-oriented online news produced by Boston Globe Media) , “We’ve brought together pharma, biotech, philanthropies, and multiple academic departments to work together to identify new targets for intervention,” and “We’ve learned from the unfortunate failures in this space … the culture shift is really remarkable … .” He said of the viral theory that “People thought it was unreasonable, crazy, had no evidence, … but the level of evidence has reached a point where we think it’s important to research.” Further, at the end of the session, Dr. Mackiewicz, of the National Institutes of Aging (NIA), announced that the NIA had heard the pros and cons of this debate and was of the view that Infectious Etiologies should be a high priority target.
Proof of causality in a non-contagious disease of humans can be provided either by prevention of a disease by a drug that targets specifically the putative agent or, in those already suffering from the disease, by slowing their rate of deterioration, or else by vaccination specifically against the putative agent. A clinical trial of valacyclovir (VCV), the biodrug of acyclovir, is being run by Dr. DP Devanand at the New York State Psychiatric Institute, and colleagues; they hope it will show whether or not VCV reduces the rate of deterioration in HSV1- or HSV2-seropositive patients with mild AD: 65 patients will be treated with oral VCV (2 to 4 g per day) and will be compared with 65 patients with placebo, in a 78-week Phase II proof of concept trial . Assessments at baseline and after 78 weeks will include tests of cognition and activities of daily living (ADAS-Cog and ADCS-ADL), usage of 18F-Florbetapir PET and 18F-MK-6240 imaging to detect amyloid and tau accumulation, changes in cortical thinning on structural MRI, olfactory identification deficits, and antiviral antibody titers. APOE genotypes will be investigated also. The results will not be known until 2022, but it seems wise to stress that if the trial proves negative, and sufferers are helped only minimally or not at all by the antiviral, the HSV1-AD concept would not be disproved: possibly, an anti-inflammatory is needed in combination with the antiviral, or there might be some other factor in the disease that we are currently unaware of, and which, therefore, has not been combated.
A clinical trial supported by the company Cortexyme is investigating treatment for the oral bacterium Porphyromonas gingivalis, the main bacterium involved in the pathogenesis of periodontitis, which has been implicated in AD. P. gingivalis bacteria produce major virulence factors, gingipains, which are cysteine proteases, and the trial is based on the discovery of P. gingivalis DNA in the brains of over 90% of people with AD (consistent with earlier studies detecting the bacterial DNA in brain of infected mice ) and the finding that gingipain levels correlate with tau and ubiquitin pathology . Dominy et al.  found also that after oral P. gingivalis infection of mice, the bacteria, on entering the brain, caused AD-like changes, including the formation of amyloid plaques, inflammation, and the death of hippocampal neurons. A gingipain inhibitor COR388, produced by Cortexyme, prevented these AD-like changes and was found to be well-tolerated in Phase Ib human studies. Initial results of a large Phase II/III trial supported by Cortexyme will be revealed at the end of 2021.
What of the future? Probably, the most pressing needs are, firstly, data on the type(s) of microbe present in individual brains, so that an appropriate regimen of treatment can be devised, and secondly, detailed mechanisms of viral damage that lead to the development of the disease. Research on microbes and AD has expanded greatly during the last year or so, one or more relevant articles being published every month, and it will expand further in view of the funding that NIH has promised (followed by the American Society for Infectious Diseases). To those of us who endured two or more decades of baseless opposition, it is heartening to read the NIA’s “Notice of Special Interest [which] specifies a high-priority topic of interest”: “Taking into consideration the strong links between microbial pathogens and AD and the emergence of the antimicrobial protection hypothesis of AD, this high-priority topic invites research on mechanisms underpinning neurodegeneration in AD associated with microbial pathogens in the CNS” . One can only hope that funding bodies in other countries will take note of the changing attitudes of US funders, and will open their minds and resources to aspects such as infection. Certainly, the future is starting to look brighter for research on microbes, and hopefully will look brighter also for AD patients and their carers.