The Infectious Cause And Preventive Of Down Syndrome And Alzheimer’s Disease

Leslie C. Norins, et al

Abstract

Advances in medicine and a corresponding increase in longevity have revealed an unexpected and startling phenomenon: as they age, individuals with Down syndrome are at an increased risk for developing Alzheimer's disease. It also tends to appear in them earlier than is typically seen in classic cases. There is also rising evidence to suggest that the root cause of Alzheimer's disease is infection from viral, bacterial, or parasitic microorganisms (e.g. Herpes Simplex Virus, Toxoplasma gondii, and more). The cause of Down syndrome is widely accepted to be “Trisomy 21,” but the root cause of that is unknown. I hypothesize that Down syndrome itself is caused by an Alzheimer’s-capable microbe, which in certain susceptible individuals is followed by Alzheimer's disease, and the two illnesses proceed together. Understanding the relationship between Down syndrome, Alzheimer's disease, and infections could be a critical step toward the prevention of both diseases.

Keywords: Alzheimer's disease, Down syndrome, Infectious agents, Pathogens, Susceptibility

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Introduction

Alzheimer's disease (AD), accounts for 60–80% of dementias in seniors (those age 65 and older), and Down syndrome (DS) is the most common chromosomal disorder in children. Both have serious consequences for the individuals impacted. Within the United States, DS affects approximately 8 in every 10,000 live births [1]. Worldwide, 44 million people have developed AD or a related form of dementia [2]. Yet to date there is no preventive or cure for either condition.

Better medical care in recent decades has been enabling children with DS to live longer than did those in the early 1900s. However, this additional longevity has revealed an unexpected and startling phenomenon. After they passage 30 years, 50% or more of these DS individuals develop Alzheimer's disease (DS-AD), and by age 60 years, at least 70% will develop the disease [3]. This suggests there likely is some link or relationship between DS and AD, but exactly what it has thus far escaped detection [4].

The hypothesis

My hypothesis is that infection by viral, bacterial, and parasitic microorganisms are responsible for both DS and AD, and I further predict that if it can be eliminated early, both conditions may be preventable.

The five chief components of these contentions are (a) the neurodegeneration in DS-AD is almost identical to that in classic AD, (b) pathogens (viruses, bacteria, and parasites) are increasingly suspected of having a role in AD, (c) infectious agents acquired early in life may apparently disappear but resurface years later as a disease different than the initial one, (d) certain infectious agents, or immune reactions against them, are detected at higher-than-expected levels in DS children or their mothers, and (e) microbes can cause changes in chromosomes.

The neurodegeneration in DS-AD is almost identical to that in classic AD

Post-mortem studies of DS and AD brains reveal critical pathological similarities, particularly regarding amyloid-β (Aβ). The Aβ protein plays a critical role in the progression of AD. In fact, the amyloid cascade hypothesis has been the prevailing theory behind the development of AD [5]. The Aβ protein is formed from the larger amyloid precursor protein (APP). Importantly, the APP gene is located on chromosome 21, and the hallmark feature of DS is an extra copy of this chromosome (also known as Trisomy 21). Although the APP gene may not occur in the DS critical region, there still exists an extra copy of the gene. This may be why Aβ proteins begin to accumulate earlier in individuals with DS [6].

Aβ is found within the extracellular plaques and blood vessel walls of both DS and AD patients, with Aβ build-up occurring earlier in life for DS patients [7]. DS and AD patients have similarly elevated levels of plaque-associated proteins, and a similar distribution of plaques and neurofibrillary tangles, with a greater density in DS patients [8]. Structurally, the Aβ protein found in AD is almost identical to that found in DS [9].

Pathogens are increasingly suspected of having a role in AD

Microbes reported harbored in the brain of AD patients include herpes simplex virus (HSV) [10,11], spirochetes [12-15], Chlamydia pneumonia [16,17], the parasitic protozoan Toxoplasma gondii [18,19], Porphyromonas gingivalis [20], Helicobacter pylori and others of this genus [21,22], and prions [23,24]. The oral bacteria associated with periodontal disease (Fusobacterium nucleatum and Prevotella intermedia) have also been shown to be increased in AD patients compared to controls [25].

HSV provides a compelling example of the infectious agent theory of AD. There are over a hundred publications associating this virus with dementia e.g. [26-28]. In a retrospective cohort study of 33,448 subjects, a 2.5-fold increased risk of developing dementia was found in patients with either HSV-1 or HSV-2 infections, and a decreased risk of dementia was associated with the use of anti-herpetic medication to treat these infections [29]. Additionally, in a study of 229,594 individuals, patients with Herpes zoster had a 12% higher risk of dementia than controls, whereas such patients treated with antivirals had a 24% lower risk of dementia [30].

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Illnesses appearing in later life may be caused by organisms invading years earlier

It is well established that certain organisms acquired in early life appear as one ailment initially, but then decades later evidence themselves again as a different condition. A well-known example of this is varicella-zoster; chickenpox in a juvenile apparently self-cures, becomes invisibly latent in nerves, and then years later produces shingles in that same person, now elderly. Treponema pallidum, upon first infecting a young adult, produces a cutaneous chancre and secondary rash, but then becomes latent, sometimes appearing decades later as damaging neurosyphilis [31].

Congenital cytomegalovirus (CMV) is another infection that occurs in infancy or early childhood [32]. While many people remain asymptomatic throughout their lives, chronic and sometimes severe health problems develop in approximately one in five people that harbor this organism [32,33]. Similarly, the parasitic protozoan Toxoplasma gondii, which infects one-third of the population in developed countries, is often asymptomatic but can be transmitted from mother to fetus (congenital toxoplasmosis) during or just before pregnancy, potentially causing miscarriage (or stillbirth) or serious visual, hearing, motor, cognitive, visual, or hearing problems in a child [18,34].

Transmission of infectious agents may start as early as conception or even before. Twenty-seven viruses that cause viremia have been found in human semen or sperm, some of which may cause acute infections (e. g., Zika and Ebola viruses), and others that may cause latent or chronic infection (e.g., CMV and HIV) [35]. Zika virus can cause congenital microcephaly, which can also be contracted after birth. Other viruses, such as Hepatitis B, C, HPV, and HIV, can be transmitted to the fetus as well [35]. It is important to keep in mind that not all infectious agents suspected of playing a causal role in the development of AD are acquired during childhood, such as HSV-1 and P. gingivalis. However, infections, in general, remain a risk factor for AD, and these infections during childhood may be exacerbated when they resurface by the extra copy of the APP gene responsible for producing beta-amyloid proteins on chromosome 21.

DS children and their mothers have evidence of certain infectious agents

The HSV-1 virus has been detected in the brain of patients with DS [36]. However, it is worth noting in this study that viral antibodies are also detected in controls. DS individuals also frequently have higher antibody titers to Epstein-Barr virus than control children [37]. In another study of 19 DS individuals with periodontal lesions, subgingival sampling revealed that 32% harbored Epstein-Barr virus type 1, 26% had CMV, 16% had HSV, and 11% had a viral co-infection [38].

In a study examining anti-Toxoplasma IgM and IgG antibody levels in 120 children with neurological disorders as compared to 120 healthy control children, DS children had a statistically significant elevation in anti-Toxoplasma IgG and IgM seropositivity [39]. Another study examined the serum obtained from 53 mothers of DS children and 154 mothers of healthy control children during pregnancy or during delivery; here, IgG antibodies to HSV-2 were significantly higher in mothers of DS children as compared to mothers of healthy control children [40]. Although not definitive, these results may indicate that HSV-2 (or other viruses) may be transmitted from mothers to children and cause Trisomy 21, particularly if the individual with Trisomy 21 (and, thus, DS) has a specific susceptibility to the pathogen.

One method for surveying microbes (bacteria and fungi) in a sample, 16S rRNA sequencing, has been conducted to examine the gut microbiota of DS individuals as compared to controls. In a small study of DS individuals, aberrations have been reported, especially including an abundance of Parasporobacterium, Veillonellaceae, and Sutterella, the latter of which is significantly correlated with the Aberrant Behavior Checklist (ABC) total score, indicative of a potential role for this genus in behavior [41]. Interestingly, Sutterella has also been found to be differentially abundant in AD patients versus controls [42].

Infectious agents can affect chromosomes

Once viruses are transmitted congenitally, they may also cause chromosomal aberrations. Human viruses, upon infecting a host, can integrate their genome into that person’s chromosomes [43]. This may occur incidentally or as part of the viral lifecycle, potentially leading to long-term persistence as well as detrimentally impacting the host cells. One such virus that causes DNA breaks is CMV [44]. Additionally, CMV can infect cells in fetuses, inducing chromosome aberrations that result in congenital abnormalities [45]. Chromosomes from DS patients also seem to be more sensitive to breakage than chromosomes from control subjects after varicella-zoster/chickenpox infection [46].

One of the most well-established occurrences of viral integration into host chromosomes involves human herpesvirus 6 (HHV-6) [43]. Research suggests that at least 90% of children are infected with HHV-6 before 2 years of age [47]. HHV-6 viral DNA can even be passed through the germline; in fact, about one percent of people in the U.S. have HHV-6 viral DNA integrated into their chromosomes, specifically within their telomeres [48]. The integrated genomes can later emerge as functional infectious viruses within the host and have also been implicated in encephalitis, multiple sclerosis, idiopathic cardiomyopathy, myocarditis, and mesial temporal lobe epilepsy [48].

One of the types of HHV-6, HHV-6A, has also been indicted in dysregulation of autophagy in both neurons and astrocytoma cells, which has been associated with increased production of Aβ protein as well as tau protein hyper-phosphorylation, both of which are associated with AD pathophysiology [49]. If HHV-6 or another virus is integrated into chromosome 21 in children with DS, it could conceivably emerge years later to trigger AD. Thus, microbes and pathogens, such as HHV-6, may both trigger Trisomy 21 and reappear later as the causal agent in DS-AD.

Discussion

The appearance of AD in so many aging DS individuals is distressing. But is also a research challenge. Could some of the answers to the causation of AD-DS reveal the root cause of classic AD in seniors? Or even illuminate a malleable root cause of Trisomy 21 itself? Unfortunately, investigations to date are relatively few.

The discovery of the extra chromosome indicative of Trisomy 21 was a major discovery and diagnostic aid. It has drawn much attention and publicity and is frequently said to be the “cause” of DS. However, there is still no clear understanding of how this chromosomal aberration translates into the signs and symptoms of DS itself. Researchers are well aware that correlation does not equal causation. Thus, despite its fame, trisomy of the 21st chromosome itself may not be the root cause of DS. So far, it is only proven to be a valuable laboratory marker with intriguing characteristics.

A comprehensive analysis of the microbiota that differentiates DS individuals from normal controls would likely be very informative. Metagenomics sequencing, which detects the full spectrum of microbes, including bacteria, viruses, fungi, and parasites found in a single sample, would be highly useful for this application [50]. To my knowledge, it has not been applied previously.

There are a variety of other experimental studies that could lend support to this hypothesis. For instance, DNA sequencing could be performed in DS and controls early in life to examine if there is viral DNA present. It would also be helpful to utilize animal models for this hypothesis. Specifically, it could provide direct causal evidence that viruses can induce DS, a point that is difficult, if not impossible, to make with human subjects and clinical data. These are areas of research prime for exploration. It is also an interesting point that as women age, they increase the chances of Trisomy 21 in their children [51], and this could be due to increased pathogen exposure. This too could be examined in a research setting.

One limitation of the current hypothesis is that viral-induced DNA aberrations have not been directly observed on chromosome 21. Future studies would be helpful in determining in cellular models if the viruses or microbes associated with the development of AD can cause chromosomal aberrations, specifically on chromosome 21. If an infectious agent is indeed implicated in generating Trisomy 21, and possibly DS-AD later, then there may be viable preventives already available. I have outlined some such preventives elsewhere [52].

All these areas warrant further evaluation and research. The suspicion that an infectious agent is likely involved in the development of DS and AD opens the doors for the exploration of possible preventive measures and therapies.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Disclosure of Support
Dr. Norins is the founder and principal of Alzheimer's Germ Quest, a Florida-based charity to encourages deeper investigation of the possible role of microbes in Alzheimer's disease. It is independent, self-funded, and does not seek or accept outside donations. It has no commercial activities and no interactions with the pharmaceutical industry.

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