Common Factors Of Alzheimer’s Disease And Rheumatoid Arthritis—Pathomechanism And Treatment Part 3

In turn, Kao et al. [106], in a case-control study on 2271 patients with AD and 6813 patients in the control group without AD, indicated an inverse relationship between previous AD and RA. 

As you age, do you begin to feel that your memory has declined, or even often forget important things to do or common information such as names and phone numbers? This phenomenon is very common in life, and people often attribute it to the influence of age. However, studies have shown that there is no necessary relationship between AD (Alzheimer's disease) and memory loss.

First of all, we must realize that memory loss is a normal physiological phenomenon. As we age, our brain cells begin to decrease and the function of neurons gradually weakens, which leads to memory loss. But unlike AD, normal age-related memory loss does not reach a serious level, and it is just a relatively slow process, not a sudden occurrence.

Secondly, AD is an age-independent disease that usually occurs in middle-aged and elderly people over 50 years old. People often mistakenly believe that everyone will suffer from AD in their later years, but this is not the case. Most elderly people have very strong memory and cognitive abilities, they can still live healthily, and play an important role in social and family life.

Finally, maintaining good physical and mental health is the best way to prevent AD and memory loss. Paying attention to the shift of attention in life, doing more physical activities, engaging in thinking activities and good social interactions are good ways to keep the brain healthy. In addition, you should maintain healthy eating and sleeping habits, take in the right amount of nutrients, and avoid excessive use of drugs and drinking to keep your body healthy.

In short, AD is not a problem that all elderly people will encounter. Even in old age, memory loss can be prevented and controlled through a healthy and active lifestyle. As long as we maintain good living habits and a positive attitude, we can maintain a healthy brain and a strong memory. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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The mean age of the study group was 76.5 ± 7.9 years, while the mean age of the control group was 76.5 ± 8.3 years. After data analysis, significant differences were identified in geographic region (p < 0.001), level of urbanization (p = 0.002), hypertension (p < 0.001), diabetes (p = 0.027), hyperlipidemia (p < 0.001), stroke (p < 0.001), and coronary heart disease (p < 0.001) between cases and the control group after matching the sex, age group, and year of the index date. 

There was no significant difference in monthly income between the cases and the control group. The study showed that the earlier onset of RA was negatively associated with AD even in people suffering from comorbidities. 

Despite this correlation, the authors note that the study does not take into account several factors. First, the database used by the researchers does not contain information on the presence of inflammatory markers. 

What is more, the database lacked family interviews and indications of possible genetic predisposition. The researchers note that such factors can affect cognitive function and falsify the results of the study. 

The database also has no information on biochemical tests or medical imaging. In addition, the majority of the Chinese population was recruited for the study, which does not allow for generalizing the results and relating them to the general public [106]. 

Similar conclusions were reached by Policicchio et al. [107], who determined that RA was associated with a lower incidence of AD. Researchers have shown that there is no correlation between the use of NSAIDs and AD. The indicated meta-analysis included eight case-control studies and two population studies. The causal relationship was determined based on the MR discussed earlier. 

Previous analysis of the literature showed that RA was associated with a lower incidence of AD. The authors of the study question this hypothesis because MR analysis showed no correlation between AD and RA. Although there is epidemiological evidence to support the validity of the claim, the authors recognize that there are no causal relationships between these disease entities. 

Researchers suggest that a large impact on the validity of the thesis is influenced by factors interfering with research such as selection error or differential diagnosis of RA [107]. 

Therefore, the literature indicates that inflammation is a common feature of both RA and dementia, and this is confirmed by common inflammatory biomarkers found in both diseases (e.g., interleukin-6, interleukin-12, C-reactive protein, engine 3, endothelin-1, resistin, and receptors for the end products of advanced glycation) [108]. 

In addition, by examining the broad relationships between the occurrence of AD, significant relationships between the occurrence of AD and the over-reactivity of the immune system were indicated. 

These studies have indicated the genetic overlap between AD and immune-mediated diseases [109]. Despite the presence of common markers of inflammation, this mention should be treated with great caution. Perhaps the presence of markers of inflammation does not indicate a cause-and-effect correlation between these disorders. 

Perhaps AD and RA are governed by other mechanisms of the formation of an inflammatory reaction, and the only feature that unites them is the presence of indicated markers. This topic requires further work to explain the possible mechanisms of the formation of an immune cascade both in AD in RA and in both disorders.

4. The Role of the Blood–Brain Barrier in AD and RA

The effects of systemic inflammation (infection, pathological conditions, sepsis) affect tissues and organs; however, it should be noted that the blood-brain barrier (BBB) becomes the mediating factor between RA and AD. 

The hyperactivity of the immune system, expressed by an increased concentration of inflammatory mediators, negatively affects the structure and permeability of the barrier [110]. Based on scientific studies, barrier permeability is altered in RA patients. Barrier dysfunction is also associated with neurodegenerative diseases, including AD [111]. 

Among the mediators of the immune system, inflammatory cytokines deserve special attention, as they show the ability to easily exceed the BBB [112]. The barrier is crossed with the use of various structures, that is: by passing through the periventricular organs [113], by stimulating the vagus nerve [114], and by direct binding to the endothelium, which results in the opening of tight junctions, penetration of the cytokine, and its activity within the brain tissue [82]. The relationship between RA and AD has been studied in rats with collagen-induced arthritis (CIA) [115]. 

This model is characterized by a clinical picture of RA. In addition to immune system activity in the disease, the integrity of the BBB was also studied by measuring the expression of Aβ transport proteins in the blood vessels of the brain. The study showed an increase in astrogliosis, the level of peripheral and brain cytokines, and activation of microglia in the brain in CIA rats compared to the control group. 

It should be mentioned here that astrogliosis is observed at the time of neuronal degradation in response to injury, infection, or the presence of a neurodegenerative disease. During the study, barrier permeability was measured using sodium fluorescein, and found that it was significantly increased in CIA rats. 

The vascular changes observed were associated with increased expression of matrix metalloproteinase and decreased expression of tight junction proteins. Occludin is one such protein. Increased expression of the RAGE receptor in the hippocampus, which is involved in the influx of Aβ from the blood to the brain, was also observed during the study. 

To visualize the transport of Aβ via the BBB in CIA rats, animals were administered Aβ42 intravenously. It was shown that the concentrations of Aβ42 in the cortex and the whole brain were compared between the CIA rats and the control group. 

However, it was shown that in the hippocampus, the Aβ level of the CIA rats was approximately 1.8 times higher than that of the control. This relationship indicates an increased influx of Aβ from the blood to the hippocampus of CIA rats [115]. 

It was also suggested that RA patients are a group predisposed to disturbances of homeostasis within the blood vessels, heart, and cerebral vessels. The studies were conducted in CIA rodents and investigated endothelial dysfunction induced by chronic inflammation in RA. The expression of strict proteins was determined by immunoblotting and occludin immunofluorescence. 

Reduced expression of the protein involved in the formation of tight junctions (occludins) has been reported. The study concludes that barrier integrity is impaired in the pathophysiology of RA [116].

5. Therapeutic Strategies Targeting Aggregates or Oligomers, Which Are the Most Dangerous Amyloid Forms

The amount of discovered amyloidogenic proteins continues to increase, which makes it difficult to diagnose patients suffering from amyloidosis. 

In the first stages of treatment, it becomes necessary to identify the amyloidogenic protein to make a proper diagnosis and implement appropriate treatment. Correct diagnosis is based on the use of histochemical tests [117], biochemical tests [118], genetic analyses [119,120], and functional imaging studies. 

At the present stage, the most effective approach to the treatment of systemic amyloidosis is to stop or reduce the synthesis of the amyloid precursor [121]. It is indicated that disruption of the expression of the corresponding gene using antisense oligonucleotides and small interference RNA can significantly reduce the amount of amyloidogenic precursor. 

Such a solution had a positive effect in the form of reduction of the synthesis of amyloidogenic light chains [122]. Despite the promising effect, the application of the present method in clinical trials faces some difficulties, including modulation of the intracellular concentration of interfering RNA [123]. The first innovation in the treatment of amyloidosis was achieved by inhibiting proteases, which are responsible for the generation of amyloidogenic fragments. It is estimated that this strategy would also find application in the treatment of Alzheimer's disease. 

This is because the therapeutic target in AD is to inhibit β- and γ-secretases that produce the amyloidogenic peptide [120]. In addition, the new clinical approach points to the positive importance of lipid-lowering drugs from the statin group, which can prevent the progression of AD through a mechanism related to the modulation of the ability of secretases to cleave the amyloid precursor [124]. 

In addition, anti-inflammatory drugs used in the treatment of AD may have a direct influence on secretase activity [125]. The use of secretase inhibitors in therapy has some limitations. For example, one of the γsecretase inhibitors, R-flurbiprofen (Flurizan TM), had a limited effect on patients with mild AD and did not affect patients with moderate AD [126]. 

In addition, a significant limitation of such treatment is the fact that γ-secretases take part in many physiological functions in humans. Therefore, it is an enzyme not specific to APP, because it participates in the regulation of cell growth and the transformation of proteins. This insufficiency contributes to the toxic effects in humans [127]. 

This adverse effect creates harmful defects in-memory processing, myelination, and motor coordination [128]. The limitation of using secretase inhibitors is also the BBB because the endothelial cells of this barrier restrict the diffusion of large or hydrophilic molecules. 

The secretase inhibitor needs to cross the BBB and neuronal membranes, because the process of modification of APP runs in the endosomes of neurons within the brain. It is also known that the largest molecular size that can cross the BBB is approximately 550 DA, so in the development of new drugs, the size of the molecule is important [126]. 

It is also considered that for AD therapies, it is necessary to treat individuals in the "preclinical" (presymptomatic) stage [129]. Progress in science was brought by the recently described therapy with the use of mesenchymal stem cells (MSC) [130]. 

These cells are isolated from bone marrow, adipose tissue, and the umbilical cord [131]. They are pluripotent and can transform into any type of cell: osteoblasts, chondrocytes, and adipocytes. MSCs exhibit a wide range of activities and influence the function and activity of the immune system by modulating the proliferation of key mediators of innate and acquired immunity. 

The injection of MSC into the brain in AD and intra-articular in RA is beneficial because inflammation is reduced, cell proliferation is stimulated, and behavioral indicators are improved [132]. 

Currently, great hopes are placed on aducanumab, which in amyloid PET imaging limited the pathology of amyloid and was effective at reducing dementia in patients in phase III clinical trials [133]. If subsequent assumptions are met, aducanumab may become the first drug to modify the course of the disease, thus confirming the validity of the anti-amyloid strategy [133]. 

Aducanumab therapy is associated with adverse reactions known as Amyloid Related Imaging Abnormalities (ARIA). During therapy, in a mice model, bleeding and swelling of the brain were observed, which consequently caused headaches, confusion, or convulsions. 

For comparison, Xiong et al. [134] in 2021 did not notice these adverse effects after therapy with a new antibody targeting APOE. This antibody is determined as HAE-4. 

In studies in mice treated with HAE-4, amyloid plaques were removed from brain tissue and blood vessels without increasing the risk of bleeding into the brain. What is more, the researchers pointed out that the brain's blood vessels showed a greater ability to expand and narrow on demand, and inflammation within the brain was significantly reduced [134]. 

A monoclonal antibody targeting amyloid is also a candidate for treatment-it is BAN240, developed by Eisai and Biogen [135]. However, it is highly probable that when used alone, these agents will not be able to limit or cure such a complex pathology of amyloidosis. There is great hope in the use of combination therapy [135].

6. Conclusions

Systemic inflammation affects the appearance of neurodegenerative changes. 

The similarity of AD and RA pathomechanisms is visible in the activity of the immune system, which, under the influence of appropriate factors, produces inflammatory biomarkers (e.g., interleukin-6, interleukin-12, C-reactive protein, engine 3, endothelin-1, resistin, and receptors for the end products of advanced glycation). 

Cytokines mediate many processes in the body that affect the tightness of the blood-brain barrier, including its integrity, and strictly reduce the expression of occluding-forming junctions. In addition, AD and RA are disorders associated with the pathology of amyloid. 

In AD, Aβ plaques increase the susceptibility of neurons to excitotoxicity, loss of synaptic protein, and cholinergic transmission, while in RA, cytokine-stimulated amyloid contributes to the degradation of the bone–joint bond. 

The incidence of AD is much higher in RA patients than in healthy people. The existence of a complex network of connections is explained by demonstrating the correlation between the nervous, skeletal, and immune systems as well as the aging mechanisms of the organism. Despite the presence of common factors, this mention should be treated with great caution. 

The presence of inflammatory markers may not indicate a cause-and-effect relationship between these disorders. It is possible that AD and RA have different inflammatory mechanisms and the only trait that they have in common is the presence of the markers indicated. 

This topic requires further work to elucidate possible mechanisms of the immune cascade in both AD in RA and both diseases simultaneously. 

Currently, the treatment of systemic amyloidoses involves stopping or reducing the amyloid precursor synthesis, inter alia, by disrupting the expression of the relevant gene using antisense oligonucleotides and small interfering RNA. 

Innovation in the treatment of amyloidosis has also been achieved by inhibiting proteases, which may also be effective in the treatment of AD. Innovative therapies using mesenchymal stem cells and monoclonal antibodies targeting amyloid are of particular importance. 

As these treatments are unsatisfactory and have numerous side effects, the search for therapeutic strategies with greater efficacy and a higher safety profile is still ongoing.

Author Contributions: Writing: P.T. and M.H., review and editing: M.H. and J.D. All authors have read and agreed to the published version of the manuscript.

Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: Not applicable.

Conflicts of Interest: The authors declare no conflict of interest.

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