Alzheimer Mythology: A Time to Think Out of the Box

Article in Journal of the American Medical Directors Association · July 2016

Article Alzheimer Mythology: A Time to Think Out of the Box

Of course, they have NOT been properly evaluated. It's not about "fact or fiction" dilemma, it's rather about trivial PR.

I agree with Ilya Tsyrolov, they prescribe PPI for HP infections.  It's about something other than science whether it is a PR or $$ I am not sure, lawyers may be trying to add on the current PPI law suits.

Caro Pea,

le differenze tra il "mondo" statistico ed il "mondo" reale sono ampiamente note.

Sai bene che alcuni filoni di ricerca, affascinanti sul piano statistico tanto da meritarsi la pubblicazione su riviste "impattanti" , non hanno alcun impatto nel mondo pratico. Non di rado, chi scrive questi articoli NON ha mai visitato un paziente !

Nella mia modesta esperienza (lavoro in un Centro Demenza dalla nascita del c.d. Progetto CRONOS) se qualcuno mi dicesse che curando l'infezione da HP ha ottenuto giovamenti sulla demenza [di quale demenza, poi ? Alzheimer o altro ?], chiederei un TSO per il collega.

Quando non si sa cosa dire [e purtroppo le cure delle Demenze sono insoddisfacenti, modeste o transitorie....], partire con tesi fantascientifiche ricorda ....la volpe che non sapendo cogliere l'uva, si mette a parlare della ....pesca.

Tanto per essere franchi .......

Dimmi pure cosa fai tu nella vita reale........su questo specifico punto.

Un caro saluto. 

Dear Ciro, I do not think HP is related to various forms of dementia. However I am a pathologist and my question was about the method. If you do a search on a drug and deduce that this correlates with anything, then you should consider all, or at least the principal, the factors that are related to the intake of the drug. I put the HP attention only because it is subject I know best. In the question I referred to other possible elements of misinterpretation of data.

"Helicobacter Pylori infection in Western countries is more common in people with problems related to the low quality of life, (poverty but often cognitive / degenerative problems)"

This in the sense that HP nfection is often a consequence and a sign of a disadvantaged life. Disadvantaged life which is medically dealt with the first drug that comes to mind; often the PPI.  There could be a thousand other examples of medicalization of distress: I can think of the thyroid, if some value of thyroid hormones is minimally altered then every event will be the fault of the thyroid. I repeat it is a question of method, and it is unimportant if you have seen people with problems, you have to know things and be intellectually correct.

Maurizio:

You have raised some excellent and highly important concerns, that suggest the need for serious caution in any interpretation of the naively over-celebrated Gomm study.

I will approach the study from a different angel. I have critically appraised the study as to methodological quality, and have  for the following reasons rejected the sufficiency of its conclusions, based as they are on severe methodological limitations:

(1) had poorer health,

(2) were more likely to be taking a greater number of medicines, and

(3) have conditions linked to a higher risk of dementia.

(a) family history of dementia,

(b) alcohol use (including heavy use),

(c) smoking status,

(d) family history of hypertension,

(e) ischemic heart disease,

(f) atherosclerosis,

(g) apolipoprotein E4 allele status (which was not available from the claims data used since such data holds no sociodemographic parameters),

(h) body weight,

(i) use of over-the-counter histamine-2 receptor antagonists/H2RAs which themselves have been linked to dementia risk in prior reports.

Yet clearly these uncontrolled factors can undermine any conclusions as to potential associations, and all of the factors I identified have been shown to have links with Dementia.

This leaves us with a significantly methodologically  compromised study with insufficient power and explanatorily adequacy to support its conclusions.

Clinical Lessons: Case not proven.

Constantine Kaniklidis

Research Director, No Surrender Breast Cancer Foundation (NSBCF)

Reviewer/Curator, Current Oncology

Thank you Constantine for your always valuable and accurate observations.

Maurizio:

Glad to participate in this stimulating discussion. Let me also add my own thoughts and (selective) review findings [and as member, ALZForum] on the specific issue you raised of the potential association between H. pylori infection and neurocognitive compromise. The association is in fact stronger than most researchers have suspected, as I sketch below:

H. PYLORI AND NEUROCOGNITIVE IMPAIRMENTS

The Personnes Agées QUID longitudinal population-based cohort study [Roubaud Baudron 2013] found that after 20 years of follow-up, 28.9% of H. pylori-positive versus 21.1% of H. pylori-negative subjects developed dementia. After correction for confounding factors, the infection was significantly associated with higher risk of developing dementia (P=0.04). Moreover, another large population-based study using one million patients randomly drawn from the Taiwan National Health Insurance Research Database (NHIRD) [Chang 2013] evaluated the effect of H. pylori eradication on the progression of dementia in Alzheimer’s disease patients with peptic ulcer, finding that eradication of the bacterium was associated with a decreased risk of dementia progression compared to persistent infection [Adriani 2014].

Using cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) III, one study [Beydoun  2013] investigated the link between Helicobacter pylori seropositivity and cognitive performance among US adults, finding that H. pylori seropositivity markers were associated with poor cognition among US adults, cross-confirmed in other studies [Han 2015], likely mediated by other factors such as folate and/or Vitamin B12 [Berrett 2016] [Kountouras  2015]. More recently a new update of the NOMAS (Northern Manhattan Study) Prospective cohort study found infectious burden (including H. pylori) may adversely affect cognitive health through variable effects on specific cognitive domains, with a clear association with decline in memory.

These findings have also been confirmed in meta-analyses. A just published (June 2016) Tel Aviv meta-analysis [Shindler-Itskovitch 2016] of seven studies found a significant positive association between H. pylori infection and dementia, with a pooled odds ratio 1.71 and no significant evidence of publication bias, supporting the conclusion drawn that H. pylori may play a significant role in the etiology of dementia.

CLINICAL LESSONS

Given that H. pylori is already decisively implicated in several malignancies including highly challenging pancreatic cancer (including a recent meta-analysis [Schulte 2015] that concluded for strain-specific associations between H. pylori and pancreatic cancer), and given that such eradication interventions can deliver highly favorable benefit/harm ratios in these and other disorders, this suggests a rational strategy of testing elderly patients, especially those at elevated risk of neurocognitive impairments, for H. pylori and if confirmed, initiating eradication therapy, independently desirable.

METHODOLOGY OF THIS REVIEW

A search of the PUBMED, Cochrane Library / Cochrane Register of Controlled Trials, MEDLINE, EMBASE, AMED (Allied and Complimentary Medicine Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, ISI Web of Science (WoS), BIOSIS, LILACS (Latin American and Caribbean Health Sciences Literature), ASSIA (Applied Social Sciences Index and Abstracts), and the SCEH (NHS Evidence Specialist Collection for Ethnicity and Health) databases was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include just-in-time (JIT) medical feed sources as returned from Terkko (provided by the National Library of Health Sciences - Terkko at the University of Helsinki). Unpublished studies were located via contextual search, and relevant dissertations were located via NTLTD (Networked Digital Library of Theses and Dissertations) and OpenThesis. Sources in languages foreign to this reviewer were translated by language translation software.

SELECTIVE REFERENCES

[Adriani 2014] Adriani A, Fagoonee S, De Angelis C, Altruda F, Pellicano R. Helicobacter pylori infection and dementia: can actual data reinforce the hypothesis of a causal association? Panminerva Med 2014; 56(3):195-9.

[Berrett 2016] Berrett AN, Gale SD, Erickson LD, Brown BL, Hedges DW. Folate and Inflammatory Markers Moderate the Association Between Helicobacter pylori Exposure and Cognitive Function in US Adults. Helicobacter 2016 Mar 3.

[Beydoun  2013] Beydoun MA, Beydoun HA, Shroff MR, Kitner-Triolo MH, Zonderman AB. Helicobacter pylori seropositivity and cognitive performance among US adults: evidence from a large national survey. Psychosom Med 2013; 75(5):486-96.

[Chang 2013] Chang YP, Chiu GF, Kuo FC, et al. Eradication of Helicobacter pylori Is Associated with the Progression of Dementia: A Population-Based Study. Gastroenterol Res Pract 2013; 2013:175729.

[Han 2015] Han, M-L, Chen J-H, Liou J-M, Chen T-F, Chen Y-C. Relationship between helicobacter pylori infection and cognitive performance in elders. Alzheimer's & Dementia 2015; 11(7):454.

[Kountouras  2015] Kountouras J, Polyzos SA, Grigoriadis N, Deretzi G. Helicobacter Pylori-Related Vitamin B12 Deficiency: A Potential Contributor in Neuropsychiatric Disorders. Indian J Psychol Med 2015 Oct-Dec; 37(4):475-6.

[Roubaud Baudron 2013] Roubaud Baudron C, Letenneur L, Langlais A, Buissonnière A, Mégraud F, Dartigues JF, Salles N, Personnes Agées QUID Study. Does Helicobacter pylori infection increase incidence of dementia? The Personnes Agées QUID Study. J Am Geriatr Soc 2013; 61(1):74-8.

[Schulte  2015] Schulte A, Pandeya N, Fawcett J, et al. Association between Helicobacter pylori and pancreatic cancer risk: a meta-analysis. Cancer Causes Control 2015; 26(7):1027-35.

[Shindler-Itskovitch 2016] Shindler-Itskovitch T, Ravona-Springer R, Leibovitz A, Muhsen K. A Systematic Review and Meta-Analysis of the Association between Helicobacterpylori Infection and Dementia. J Alzheimers Dis 2016 Apr 15; 52(4):1431-42.

Constantine Kaniklidis

Research Director, No Surrender Breast Cancer Foundation (NSBCF)

Reviewer/Curator, Current Oncology

Member/Contributor, ALZForum

Dear Maurizio and Constantine,

thanks for your considerations and points of discussion. 

There are a lot of important studies published on important scientific journals with high or very high impact factor, as you known.

The point is :

I can have a well completed study with a good statistical picture (as Constatine write : this is not the case of Comm study or others.....)  . But the indications and informations highlighted by these studies have non importance in my clinical activity.

So, when I wrote that statistical word and real life are frequently different, I wanted to highlight this. And this aspect in elderly patients are more and more important ......(usually elderly patient cannot be included in randomized, prospective studies (and not only....).   

As you known, the study having practical consequences are few....... 

In conclusion, even if a study is well completed but has no practical applications , this study is not useful . This point is not original......I known. 

There are colleagues loving numbers and statistics and colleagues loving the patients in front of them, in their outpatient clinics.

Greetings for the day !

CM  

Dear Ciro,

I am sincerely convinced that numbers and statistics serve mainly to those who love the patients. I have, however, some concerns relating to " love the patients" but that's another story.  Loving work one does, do it with seriousness and conscientiousness and intellectual honesty, makes possible that all jobs are valuable and noble; even the most menial jobs.

I enclose one of the many writings possible, only because Lorenzo Tomatis was a teacher for many; whether they were in direct contact with people with medical problems or they worked in laboratories.

“Better health, better environment, better science: 

better use of the precautionary principle”

I mean the "precautionary principle" in the broadest sense, broader than its technical definition.

http://www.iss.it/binary/publ/cont/ANN_08_03_Zapponi.1209032176.pdf

https://www.researchgate.net/search.Search.html?query=%22lorenzo%20tomatis%22&type=publication

Probably we live in ......different worlds.......

You are a pathologist . I am a clinician .

The discussion is very hard and too long.......

Numbers and statistics do not serve if they do not serve in the real life. A lot of numbers and statistics are meaningful but have no utility for the clinician.

If you read some articles on this argument published in the last years on BMJ or JAMA , you can have the same critics than I. Probably.......

Numbers and statistics are useful if respect the Galilean method.......Others considerations are useful for writers and editors, only.

Thanks for your point of view, even if it is completely different from mine.

Ciro  

.

A review article with quotes of some papers about some biological studies.

Neurodegenerative Diseases

Active H. pylori infection appears to induce humoral and cellular immune responses which, via common homologous epitopes (molecular mimicry), cross-react with components of the host's nervous tissue, thereby affecting or exacerbating the nerve cell damage that characterizes the neurodegenerative disorders [30]. In this regard, Baudron et al. [31], by investigating the impact of H. pylori infection on the brain of non-Alzheimer's disease (AD) predisposed mice, showed that H. pylori strain SS1 and Helicobacter felis infection induce gastric inflammation compared to noninfected mice, but without induction of brain neuroinflammation or amyloid-β (Aβ) deposition. Wang et al. [32] demonstrated that injection of H. pylori but not Escherichia coli filtrates induces spatial learning and memory deficit in rats and increases Aβ42 both in the hippocampus and in the cortex, by enhancing the activity of γ-secretase, thereby inducing cognitive impairment via an interruption of the synaptic function. These authors also investigated the effect of H. pylori on tau phosphorylation and showed that H. pylorifiltrates induce tau hyperphosphorylation at several AD-related tau phosphorylation sites in rat brains with glycogen synthase kinase-3β (GSK-3β) activation. Moreover, application of glycogen synthase kinase (GSK)-3 inhibitors attenuates the H. pylori -induced tau hyperphosphorylation, thereby providing evidence for the role ofH. pylori infection in AD-like tau pathology and suggesting that H. pylori eradication may be beneficial in the prevention of tauopathy [33]. These experimental data support relative clinical surveys reporting that H. pylorieradication may positively influence AD manifestations and a 5-year survival rate [30], and suggest that H. pylorimay be a direct causative factor in AD. Apart from experimental data, Bu et al. [34] reported an infectious seropositivity burden including H. pylori, in patients with AD, supporting the possible role of infection/inflammation in the pathophysiology of AD. Using histology for documentation of H. pylori infection, Tsolaki et al. [35] also found positive relationships between H. pylori infection, dementia, and glaucoma, defined as “ocular AD”, as well as between dementia and glaucoma, thereby supporting the hypothesis that neurodegenerative diseases, such as dementia and glaucoma, are linked to each other and to H. pylori infection. Moreover, these authors reported [36] an increased presence of apolipoprotein E (ApoE)4 polymorphism, the strongest genetic risk factor for AD, in H. pylori -positive compared to H. pylori -negative patients with AD (26.9 vs 18.8, p 

Alzheimer Mythology: A Time to Think Out of the Box

Article in Journal of the American Medical Directors Association · July 2016

Article Alzheimer Mythology: A Time to Think Out of the Box

"Heliobacter pylori is a Gram-negative bacteria that grows in the digestive tract and was recently demonstrated to have a significant association with the development of dementia [45]. In older individuals, the presence of H. pylori IgG antibodies was associated with decreased cognitive performance [46], indeed research has shown that AD patients also have increased H. pylori seropositivity in the serum and cerebrospinal fluid (CSF) [47]. Furthermore, Kountouras and colleagues have demonstrated that individuals with AD had an increased incidence of H. pylori infection of the gastric mucosa compared to controls [48]. Within AD patients, those infected with H. pylori had more severe dementia, characterized by lower MMSE scores, with increased proinflammatory cytokines and tau levels in the CSF [49]. A 20-year follow-up study also found H. pylori to be a significant risk factor for the development of dementia, although even at baseline those positive for H. pylori had lower MMSE scores [50]. It has been reported that elimination of H. pylori infection reduced the mortality rate of AD patients when examined 5 years later [51]. Furthermore, AD patients who were treated for their infection and remained H. pylori-free for 2 years had improved cognition than when they were first examined, while those who were still positive for the bacterium had further declined [52]. Animal studies have demonstrated that intraperitoneal injection of H. pylori filtrate into rats increased the concentration of Aβ42 in the cortex and hippocampus, which was associated with memory deficits and impaired spatial learning [53]. This group also reported that H. pylori filtrate significantly increased tau phosphorylation in neuronal cultures in vitro and in the rat hippocampus in vivo [54]. Conversely, infection of C57BL/6 J mice with H. pylori did not affect amyloid deposition when assessed 18 months later [55], however the effect of H. pylori on amyloid pathology in AD-transgenic mice has yet to be examined."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5336609/

Microbiota modulation counteracts Alzheimer's disease progression influencing neuronal proteolysis and gut hormones plasma levels.

Article Microbiota modulation counteracts Alzheimer's disease progre...

Maurizio:

Although the findings are tantalizing, we need to observe caution even with meta-analyses and systematic reviews, and in my own critical appraisal, I am left more with highly intriguing hypothesis generation than high level robust evidence.  Here's why, briefly:

There are currently only seven observational studies (see references below) for which both the exposure variable was H. pylori infection AND the outcome variable was any dementia, and from this heterogeneous data several points here need to be noted:

1.  Each individual observational study has its own methodological weaknesses, with observational studies in general prone to confounding factors, and there is considerable heterogeneity ACROSS these studies.

2.  So it  yet remains unclear yet if association between H. pylori infection and dementia is causal, as there are to date NO RCTs assessing the role of H. pylori eradication therapy on the risk and progression of dementia.

3.  Furthermore, of the observational studies, the large-scale ones [Bu; Huang] did show a positive association between the infection and dementia, BUT with an Odds Ratio (OR) ranging modestly between 1.39 and 1.51, while the Kountouras small-scale studies [Kountouras 2006; 2007] have to be seen as outliers, as they found a rather massive - and highly exceptional and beyond any expected historical controls - OR in excess of 8 (OR > 8)! This is a magnitude of clinical effect rarely seen between exposure variables and outcome variables, and so must be broach with some degree of skeptical posture.

4.  It is interesting to note that in assessing infection, the traditional studies measured H. pylori specific IgG antibodies. However, in contrast,  the Kountouras studies are once again methodological outliers, establishing H. pylori infection status from histological examination of gastric biopsy. Given that H. pylori IgG antibodies can persist in serum for up to one year after the eradication of H. pylori,  this may have caused divergent ORs due to divergent testing technologies.

The upshot: re a true and verifiable causal link between H. pylori infection and the development, risk or progression of Dementia/ALZ, case not proven. We must await well-designed robust and methodologically strong clinical trials, preferably and especially RCTs, before we can legitimately conclude to this etiology, and in the meantime, we need some consensus standard on the optimal diagnosis and measurement of H. pylori before we can even undertake cross-study comparisons, and then determine a methodological quality metric to extract only high methodological quality data to bear on this question, and we are as the above suggests, some considerable distance away from that goal. 

REFERENCES

Baudron CR, Letenneur L, Langlais A, Buissonniere A, Megraud F, Dartigues JF, Salles N, Personnes Agées QUID Study (2013) Does Helicobacter pylori infection increase incidence of dementia? The Personnes Agees QUID Study. J Am Geriatr Soc 61, 74-78.

Bu XL, Yao XQ, Jiao SS, Zeng F, Liu YH, Xiang Y, Liang CR,Wang QH,Wang X, CaoHY,YiX, Deng B, Liu CH, Xu J, Zhang LL, Gao CY, Xu ZQ, Zhang M, Wang L, Tan XL, Xu X, Zhou HD,Wang YJ (2015)Astudy on the association between infectious burden and Alzheimer’s disease. Eur J Neurol 22, 1519-1525.

Huang WS, Yang TY, Shen WC, Lin CL, Lin MC, Kao CH (2014) Association between Helicobacter pylori infection and dementia. J Clin Neurosci 21, 1355-1358.

Kountouras J, Tsolaki M, Gavalas E, Boziki M, Zavos C, Karatzoglou P, Chatzopoulos D, Venizelos I (2006) Relationship between Helicobacter pylori infection and Alzheimer disease. Neurology 66, 938-940.

Kountouras J, Tsolaki M, Boziki M, Gavalas E, Zavos C, Stergiopoulos C, Kapetanakis N, Chatzopoulos D, Venizelos I (2007) Association between Helicobacter pylori infection and mild cognitive impairment. Eur J Neurol 14, 976-982.

NaggaK, Rajani R, Mardh E, Borch K, Mardh S, Marcusson J (2003) Cobalamin, folate, methylmalonic acid, homocysteine, and gastritis markers in dementia. Dement Geriatr Cogn Disord 16, 269-275.

Shiota S, Murakami K, Yoshiiwa A, Yamamoto K, Ohno S, Kuroda A, Mizukami K, Hanada K, Okimoto T, Kodama M, Abe K, Yamaoka Y, Fujioka T (2011) The relationship between Helicobacter pylori infection and Alzheimer’s disease in Japan. J Neurol 258, 1460-1463.

Constantine Kaniklidis

Many thanks Constantine.

I'm almost no fan, perhaps only the right people.

Maurizio:

Yours are some of the most fertile and sophisticated posting I encounter! Always intriguing, a pleasure.

Constantine you're too kind. However, it is always better to receive appreciation rather than kicking in the back. Anyway thanks.

.

Article Microbiome, probiotics and neurodegenerative diseases: decip...

Article Role of neuroinflammation in neurodegeneration: New insights

Heliobacter pylori is a Gram-negative bacteria that grows in the digestive tract and was recently demonstrated to have a significant association with the development of dementia [45]. In older individuals, the presence of H. pylori IgG antibodies was associated with decreased cognitive performance [46], indeed research has shown that AD patients also have increased H. pyloriseropositivity in the serum and cerebrospinal fluid (CSF) [47]. Furthermore, Kountouras and colleagues have demonstrated that individuals with AD had an increased incidence of H. pyloriinfection of the gastric mucosa compared to controls [48]. Within AD patients, those infected with H. pylori had more severe dementia, characterized by lower MMSE scores, with increased proinflammatory cytokines and tau levels in the CSF [49]. A 20-year follow-up study also found H. pylori to be a significant risk factor for the development of dementia, although even at baseline those positive for H. pylori had lower MMSE scores [50]. It has been reported that elimination of H. pylori infection reduced the mortality rate of AD patients when examined 5 years later [51]. Furthermore, AD patients who were treated for their infection and remained H. pylori-free for 2 years had improved cognition than when they were first examined, while those who were still positive for the bacterium had further declined [52]. Animal studies have demonstrated that intraperitoneal injection of H. pylori filtrate into rats increased the concentration of Aβ42 in the cortex and hippocampus, which was associated with memory deficits and impaired spatial learning [53]. This group also reported that H. pylori filtrate significantly increased tau phosphorylation in neuronal cultures in vitro and in the rat hippocampus in vivo [54]. Conversely, infection of C57BL/6 J mice with H. pylori did not affect amyloid deposition when assessed 18 months later [55], however the effect of H. pylori on amyloid pathology in AD-transgenic mice has yet to be examined.

https://www.nature.com/articles/s41598-017-07532-x.pdf

There is epidemiological evidence that H. pylori might predispose to Alzheimer’s disease. To understand the cellular processes potentially linking such unrelated events, we incubated the human gastric cells MNK-28 with the H. pyloripeptide Hp(2-20). We then monitored the activated genes by global gene expression. The peptide modulated 77 genes, of which 65 are listed in the AlzBase database and include the hallmarks of Alzheimer’s disease: APP, APOE, PSEN1, and PSEN2. A large fraction of modulated genes (30 out of 77) belong to the inflammation pathway. Remarkably, the pathways dis-regulated in Alzheimer’s and Leasch-Nyhan diseases result dis-regulated also in this study. The unsuspected links between such different diseases – though still awaiting formal validation – suggest new directions for the study of neurological diseases.

In conclusion, this study presents preliminary evidence of a potential interaction between the availability of serum 5-MTHF and H. pylori seropositivity in predicting decreased cognitive function in US adults aged 60 years and older. This finding might be especially relevant to vulnerable groups such as pregnant women and the elderly.

http://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0190475&type=printable

http://www.pnas.org/content/early/2018/02/20/1721117115

Not in support of the involvement, albeit partial, of the helicobacter pylory in Alzheimer's disease or of the viruses in diabetes. But only to reiterate that, fortunately, science and life are full of counterintuitive surprises.

When I was young, I wrote a report on stomach cancer for a small local convention. Regarding the etiology there was within almost everything (I remember the addatives for salami), but if I had talked about bacteria that caused chronic gastritis followed by intestinal metaplasia and eventually also by an adenocarcinona or lymphoma because of this infectious gastritis, I would probably be fired.

But soon after ...

https://www.nobelprize.org/nobel_prizes/medicine/laureates/2005/press.html

The winner is.......Maurizio Pea .

The Epithelial cell signaling in Helicobacter pylori infection are other pathways associated with AD. Based on AD different subtypes-levels of Aβ, tau hyperphosphorylation, ubiquitination and etc.,- inflammation and immune processes has displayed the different roles since Alzheimer disease patients which use the nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of Alzheimer disease36. Therefore, immune and inflammatory pathways play an important role in modulators of AD36. It can also be inferred that epithelial cell signaling in Helicobacter pyloriinfection has an effect on AD development it is noteworthy that hyperphosphorylation of tau protein is associated with defects in neurons or the loss them37. Infection with Helicobacter pylori (H. Pylori) which is a gram negative bacterium, is related to the AD37. Hyperphosphorylation of tau protein is one of the events seen in the AD patient’s brains37. Studies on the AD patients and normal people showed the significant H. Pylori and anti-H. Pylori IgG antibodies have been observed in cerebrospinal fluid (CSF) and their serum38,39. H. Pylori induced the tau phosphorylation in the AD special sites36 so, it is effective in occurring AD. Here we showed the involvement genes in each pathway with the expression value.

https://www.nature.com/articles/s41598-018-20959-0.pdf

Ai posteri l'ardua sentenza.

In the future, these data and suggestions will give practical considerations.....we hope it.

Hypotheses are hypotheses....and they are not different from hypotheses.

All is possible but it must be demonstrated.

A very valuable review article that emphasizes the issue from a partially different point of view.

"... The utility of antibiotic, antiviral or antifungal drugs in the treatment of AD is an area that deserves further investigation. A small study on this topic had encouraging results, as eradication of H. pylori in infected AD patients was associated with reduced five-year mortality [112]. The antibiotics rifampicin and doxycycline have also shown promise for preventing memory decline in animal models of AD [113, 114], although human trials indicate they have little effect after the onset of symptoms [115]. These results suggest that resolution of the primary infection may be a necessary first step prior to anti-Ab therapy, or even as a preventative measure. The evidence reviewed here supports the view that one of the physiological roles of Ab is to defend the brain and other tissues from microbial invasion. In the light of Ab’s likely function as an AMP, the high incidence of infections among clinical trials that have attempted to deplete Ab is not surprising, as by removing this AMP, the pathogens that triggered the Ab response will be left unhindered to multiply. Perhaps better progress will be made towards a cure for AD if future treatment strategies take into account the likely physiological functions of this enigmatic peptide."

Article Alzheimer’s Amyloid-β is an Antimicrobial Peptide: A Review ...