Article
Infectious Burden and Alzheimer Disease: Is There a Link?
It is crucial for practicing psychiatrists to consider that Alzheimer disease can be aggravated by infections of different origin.
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SIGNIFICANCE FOR PRACTICING PSYCHIATRISTS
Figure
Alzheimer disease (AD) is a common chronic neurodegenerative disease that primarily affects people aged 65 or older. According to a report by the Alzheimer Association, about 5.8 million individuals of all ages are suffering from AD in the US alone.1 About 3.5 million women and 2.3 million men have AD.
Disproportionate number of women
New findings from prospective studies were presented at the 2019 Alzheimer’s Association International Conference (AAIC) in Los Angeles.2 Discussions about gender influences on the prevalence and development of AD were particularly relevant.
KEY FACTORS that play vital roles in the understanding of AD’s progression include:
1) Non-employed women have more rapid memory decline compared with women who continue to engage in their careers.
2) The verbal memory of healthy women, as well as that of female patients with AD, surpassed that of healthy men. Women appear to have a comparative verbal advantage that may enable them to compensate more effectively in the early stages of AD.
3) A critical feature of AD is neurofibrillary tangles, which are intracellularly formed by tau protein. Women with mild cognitive impairment had a denser distribution and higher burden of tau. The findings suggest that female brains may have a stronger connection with abnormal tau protein.
4) Using genome sequencing, 11 genes have been found that are related to gender; immune gene (CD1E) in women and the mucolipin gene (MCOLN3) in men appear to be risk factors for AD.
Risk factors for AD include infectious pathogens that can initiate a cascade of chronic neuroinflammatory processes in elderly people. AD can be aggravated by infections of different origin, which implies that it is necessary to accurately diagnose and to provide appropriate treatment based on the impact of an infectious burden on disease progression. Unfortunately, current pharmacotherapy can only reduce the neuropsychiatric symptoms but does not affect the root causes of AD.
Recent research findings also offer hope for developing preventive vaccinations for people. This will reduce the risk of AD rapid progression before it begins because it will eliminate infectious agents that can induce a neurodegenerative process.
The key role of neuroinflammation in AD pathogenesis
Over the past three decades, scientists around the world have been studying the causes of AD. In recent years, various hypotheses have been advanced that propose various mechanisms of pathogenesis and risk factors that are correlated with the disease. The most frequently discussed hypothesis is the amyloid-β hypothesis. It is based on two pathological key aspects in the brains of patients with AD: the neurofibrillary tangles formed with tau-protein inside cells and insoluble clumps of amyloid-β (Aβ) peptide or so-called senile plaques formed outside cells.3
Recent research reveals that Aβ oligomers have antimicrobial properties and, therefore, can be involved in the production and deposition of Aβ that may be indicative of infectious agents.3,4 Three primary contributors have been found in the pathogenesis of AD: neuroinflammatory processes, oxidative stress, and vascular factors.3
As illustrated in the Figure, cumulative infections (bacterial and viral origin), amyloid-β (Aβ) deposits, and an increase in abnormal tau protein lead to a neuroinflammatory process in CNS. Aβ fibrils aggregate into clumps and thereby disrupt the signal transmissions between neurons. Concurrently, neurofibrillary tangles consisting of misfolded tau protein cause the degradation of nerve cells. When resident immune cells such as microglia, macrophages, lymphocytes, and astrocytes are activated, they release pro-inflammatory cytokines (IL-1β, IL-6, IL-18, TNF-α, IFN-γ). This and other inflammatory agents can contribute to additional amounts of Aβ.3,5 As a result of sustained inflammatory insults, a detrimental effect on neurons and the loss of neuronal communication occurs.
The blood-brain barrier can be damaged as a result of oxidative stress caused by microglia and reactive oxygen species. Furthermore, vascular risk factors are known to decline cognitive functions (cerebral hypoperfusion, cerebrovascular lesions, etc) and in combination with an amyloid-relative oxygen species peptide lead to oxidative stress.6 Chronic inflammation may contribute to neurodegeneration and cognitive disorders and it may impair clearance of damaged neuronal proteins in the aged brain.5
Pathogens that contribute to the accumulation of infectious burden
Results published in 2015 in the European Journal of Neurology confirmed a link between infectious burden and AD. Findings suggest that infectious burdens are risk factors pre-onset and responsible for faster progression post-onset.7 Antibody titers of cytomegalovirus herpes simplex virus type 1 (HSV-1) (B burgdorferi, C pneumonia, and H pylori) were assessed using the ELISA serological test in patients with AD and a control group. In all cases, the infectious burden was positively associated with AD. Individuals who had higher infectious burdens and, consequently, increased serum Aβ levels were more affected with respect to cognitive deficits.
Bacteria, viruses, fungi, and, occasionally, protozoa are able to cross through the blood-brain barrier and in turn cause chronic illnesses. Various types of spirochetes (eg, B burgdorferi) and obligate intracellular bacteria (C pneumoniae) are among the most frequently invasive infectious entities that can generate persistent infection in the brain.3 In turn, this finding suggests that these pathogens could enhance the Aβ deposition in AD and trigger peripheral inflammation. Moreover, there is a suggestion that B burgdorferi causes intracellular inflammation in brain tissues, which leads to neurodegenerative and cognitive changes in people with neuroborreliosis and AD. H pylori- specific IgG antibody in serum is thought to be a marker for AD.8 However, further research is needed to detect the availability of these antibodies in the brain.
Viral burden of herpes simplex virus (HSV), human herpesvirus (HHV), and the hepatitis C virus (HCV) is commonly associated with AD by apolipoprotein E-ε4 (APOE-ε4).9 The accumulation of senile amyloid plaques and tau-protein is a significant risk in people with AD due to the combination with APOE-ε4. One of the biomarkers of HSV reactivation detected by ELISA showed a significant link between the presence of anti-HSV-1 IgG, anti-HSV-1 IgM antibodies, and AD.3 According to data from the Center for Disease Control and Prevention, one in three people aged 60 or over suffer from HHV.10 For this reason, shingles indicate a risk for future AD.
There are limited studies to explain the mechanisms that underlay HCV infection and dementia.
Two hypotheses have been advanced:
1) The virus causes the systemic inflammation and thereby contributes to indirect neurotoxicity;
2) The virus is able to disintegrate brain tissues through a direct cumulative neurotoxic effect.
Pharmacotherapy
There is no consensus on the key mechanisms that can trigger a cascade of AD-causing processes. Furthermore, there is no agreement on how to implement specific, strategic pharmacotherapy.4 It is estimated that there were about 146 failed attempts to develop a potential drug for AD treatment between the period of 1998 and 2017. A possible contributing factor to these failures is a focus on a single target approach: the amyloid-β hypothesis.
At present there are no treatments to stop and/or delay underlying disease progression. Current prevalent therapies help to mask the symptoms, but they do not solve the underlying root cause(s).
A fundamental premise for effective treatment is to diagnose AD at the earliest feasible stage. The main symptoms are characterized by cognitive declines across a wide range of abilities: hippocampus-dependent spatial memory, visuospatial agnosia, constructional apraxia, and language and writing problems. Mental status testing, neuropsychological examination to assess patients’ thinking ability, and genetic testing (eg, to detect the presence of APOE-ε4 in serum) should be performed. Subsequent tests used to complement identification of AD include MRI, CT, and PET scans.
The following agents are FDA-approved medications to treat cognitive impairments: cholinesterase inhibitors (donepezil, rivastigmine, galantamine); N-methyl-D-aspartate receptor (NMDA)-antagonists (memantine); and the combination of memantine and donepezil (Namzaric). Donepezil and other cholinesterase inhibitors elevate acetylcholine in the brain. Increased activation of cholinergic receptors on microglia contribute to decreased release of cytokines.11
Glutamate may contribute to AD symptoms because of the over-activation of NMDA-receptors, which leads to neurotoxicity. Memantine blocks NMDA-receptors and inhibits glutamate excitatory neurotransmission.
The effectiveness of these drugs is dependent on individual tolerance. Namzaric, memantine, and donepezil can be prescribed at all stages of AD. Rivastigmine and galantamine are approved to treat mild and moderate conditions. These drugs have common adverse effects, including nausea, vomiting, muscle cramps, headache, and dizziness.
Use of antiviral and anti-inflammatory drugs is off-label for AD. Nevertheless, this kind of treatment supported by evidence-based research may slow the progression of dementia.12,13
Recent findings have shown that not only microtubule-associated protein tau but also amyloid plaques were associated with HSV1 DNA replication. This suggests that HSV-1 promotes the accumulation of toxic Aβ clumps which induces AD-related pathology. Several antiherpetic drugs could be used for treating AD but only for APOE-ε4-carriers. Acyclovir passes through the blood-brain barrier and inhibits viral DNA replication, thereby reducing hyperphosphorylation of p-tau.12,14 The decrease in Aβ deposits reduces levels of HSV1, which minimizes the viral transmission in the brain. Acyclovir has few adverse effects; however, it should be used with caution given its potential for renal failure.
Valtrex (valacyclovir) has shown positive initial results in new indication trials for AD. Compared with placebo, valacyclovir resulted in a decrease in Aβ formation and a smaller increase in 18F-MK-6240 binding to cerebral tau protein. Furthermore, valacyclovir was shown to be effective and safe, which indicates a potential benefit for the future treatment of patients with AD.13
So far, no antimicrobial treatment has been developed for AD. However, it was found that elderly patients with AD frequently have an inflammatory state of gut mucosa because of age-related changes in their gut microbiome (eg, decrease in bacterial diversity.15 In turn, chronic systemic inflammation promote neuroinflammation as result of blood-brain barrier impairment by proinflammatory mediators and bacterial metabolic products.
A team at the University of Chicago utilized a long-term antibiotic mix on experimental rodents.16 The results show a decrease in the growth of amyloid plaques and the activation of microglia. Although, the use of antibiotics for AD may not make sense, the fact of a possible association between gut bacteria and CNS has clinical benefits for further development of new drugs in patients with AD.
Anti-inflammatory drugs also have a role in AD therapy. Nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of AD.3 It is believed that NSAIDs selectively inhibit the isoforms of COX-2 and attenuate prostaglandin synthesis.17 Even though results showed that the risk of Alzheimer dementia was reduced, a wide range of NSAIDS are not therapeutically effective because they require long-term treatment.18,19
Natural immunosuppressive drugs are a possible means to prevent the onset of neurodegeneration. There is considerable evidence that resveratrol possesses an anti-inflammatory effect combined with dietary supplementation. Lipopolysaccharide was used as an inducer of neuroinflammation in response to peripheral infection.20 Moreover, AD is an infectious disease caused by spirochetes, which form biofilms that in turn initiate the innate immune response. The innate immune system is a first responder-the toll-like receptor 2 generates nuclear factor (NF)-κB and TNF-α, which will likely try to kill the spirochetes in the biofilm, but it cannot penetrate the “slime.”21 NF-κB is also responsible for the generation of amyloid-A, which is antimicrobial and cannot penetrate the biofilm either. Consequently, the accumulation of Aβ leads to the destruction of the cerebral neurocircuitry.
Preventive measures
It is significant to note that preventive measures are needed to avoid the risk of premature viral infection in AD patients. There are six pillars of AD prevention: regular exercise, social engagement, healthy diet, mental stimulation, quality sleep, and stress management. These basic health recommendations are associated with maintaining a high-quality life.
Unfortunately, there are no vaccines for HSV-1 or HSV-2, but there is a rich pipeline of candidates. The main difficulties are associated with the virus life cycle and insufficient understanding of the mechanisms of immune control of HSV infection.
Conclusion
At present, AD is a serious global health issue. A large body of evidence shows that infectious pathogens that are responsible for neuroinflammation are observed in elderly people with AD. In-depth studies are needed to determine the root cause of AD. Hopefully, recent discoveries will give rise to effective drug therapies. Eventually, it may be possible to reduce the risk of AD with innovative antiviral therapy and preventive vaccines.
Disclosures:
Dr Aliev is President and Founder, International Research Institute, San Antonio, TX; Professor of Pharmacology, First Moscow State Medical University, Moscow; and Professor, Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Russia. Dr Bachurin is Scientific Director and Professor of Chemistry, Institute of Physiologically Active Compounds, Russian Academy of Sciences. Ms Mikhaylenko is a PhD Student, Department of Pharmacology, Institute of Physiologically Active Compounds, Russian Academy of Sciences. Dr Bragin is President and Founder, Stress Relief and Memory Training Center, Brooklyn, NY. Dr Avila -Rodriguez is Leading Researcher, Health Sciences Faculty, Clinical Sciences Department, University of Tolima, Ibague, Colombia. Dr Somasundaram is Professor, Biology Department, Salem University, Salem, WV. Dr Kirkland is Professor, Biology Department and Executive Vice President, Salem University. Dr Tarasov is Chairman, Department of Pharmacology and Pharmacy, First Moscow State Medical University, Moscow. The authors report no conflicts of interest concerning the subject matter of this article.
Acknowledgments-This research was supported within the framework of the grant provided by CSP Ministry of the Health Russian Federation, and by the IPAC RAS State Targets Project # 0090-2019-0005; the Russian Academic Excellence Project “5-100” for the Sechenov University, in Moscow, Russia, also provided support for the research.
References:
1. Alzheimer’s Association. Alzheimer disease facts and figures. Alzh Dem. 2019;15:321-387.
2. MacKenzie RJ. Quartet of papers provide a fresh look at sex differences in dementia. Technology Networks. July 19, 2019 [Epub].
3. Ashraf GM, Tarasov VV, Makhmutova A, et al. The possibility of an infectious etiology of Alzheimer disease. Mol Neurobiol. 2019;56:4479-4491.
4. Makin S. The amyloid hypothesis on trial. Nature. 2018; 559:4-7.
5. Sochocka M, Diniz BS, Leszek J. Inflammatory response in the CNS: friend or foe? Mol Neurobiol. 2017;54: 8071-8089.
6. Aliev G, Priyadarshini M, Reddy VP, et al. Oxidative stress mediated mitochondrial and vascular lesions as markers in the pathogenesis of Alzheimer disease. Curr Med Chem. 2014;21:2208-2217.
7. Bu XL, Yao XQ, Jiao SS, et al. A study on the association between infectious burden and Alzheimer disease. Eur J Neurol. 2015;22:1519-1525.
8. Doulberis M, Kotronis G, Thomann R, et al. Review: impact of helicobacter pylori on Alzheimer disease: what do we know so far? Helicobacter. 2018;23 [Epub].
9. Lövheim H, Gilthorpe J, Adolfsson R, et al. Reactivated herpes simplex infection increases the risk of Alzheimer disease. Alzh Dem. 2015;11:593-599.
10. Centers for Disease Control and Prevention. About Underlying Cause of Death, 1999-2017. http://wonder.cdc.gov/ucd-icd10.html. Accessed October 1, 2018.
11. Alzheimer Association. Medication for Memory. https://www.alz.org/alzheimers-dementia/treatments/medications-for-memory. Accessed October 1, 2019.
12. Fülöp T, Itzhaki RF, Balin BJ, et al. Role of Microbes in the Development of Alzheimer Disease: State of the Art. Presented at the 2017 IAGG Congress. San Francisco, CA: July 23-27, 2017.
13. U.S. National Library of Medicine. ClinicalTrials.gov. Antiviral Therapy in Alzheimer Disease. https://clinicaltrials.gov/ct2/show/NCT03282916. Accessed October 1, 2019.
14. Wozniak MA, Itzhaki RF. Antiviral agents in Alzheimer disease: hope for the future? Ther Adv Neurol Dis. 2010;3:141-152.
15. Dinan TG, Cryan JF. Gut instincts: microbiota as a key regulator of brain development, ageing, and neurodegeneration. J Physiol. 2017;595:489-503.
16. Dodiya HB, Kuntz T, Shaik SM, et al. Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes. J Exp Med. 2019;216:1542-1560.
17. Szekely CA, Zandi PP. Non-steroidal anti-inflammatory drugs and Alzheimer’s disease: the epidemiological evidence. CNS Neurol Disord Drug Targets. 2010;9:132-139.
18. Yip AG, Green RC, Huyck M, et al for the MIRAGE Study Group. Nonsteroidal anti-inflammatory drug use and Alzheimer disease risk: the MIRAGE study. BMC Geriatr. 2005;5:2.
19. Martyn C. Anti-inflammatory drugs and Alzheimer disease. BMJ. 2003; 327:353-354.
20. Abraham J, Johnson RW. Consuming a diet supplemented with resveratrol reduced infection-related neuroinflammation and deficits in working memory in aged mice. Rejuv Res. 2009;12:445-453.
21. Allen HB. Alzheimer disease: assessing the role of spirochetes, biofilms, the immune system, and amyloid- with regard to potential treatment and prevention. J Alzh Dis. 2016;53:1271-1276.â
