Technological advances in medicine and healthcare over the past decades have increased the life expectancy of the population in industrialized countries, shifting the focus of public attention from communicable to chronic non-communicable diseases, including dementia.

According to WHO data for 2010, the approximate number of people suffering from dementia worldwide is estimated at 35.6 million people, with the figure expected to double by 2030 reaching 65.7 million people and more than triple by 2050 (115.4 million people)[1]. The total number of new cases of dementia each year amounts to 7.7 million, which makes one case every 4 seconds[2]. More recent figures, but in a regional context, are provided by the Alzheimer’s Association, where 5.2 million Americans from all age groups are reported[3] to have Alzheimer’s disease for 2013 in the USA alone. The same report states that 1 in 9 Americans over 65 years of age, respectively, one-third of the persons aged 85 and older suffer from the disease. Among the total number of individuals covering the criteria[4] for AD diagnosis, the distribution is as follows: 4%  - below 65 years of age, 13% - aged between 65 and 74 years , 44% - 75-84 years and 38% - aged 85 and over. In terms of gender distribution, females prevail over males (about two-thirds of women and one third of men).

Dementia is not isolated from individuals alone; rather, it affects their family members, relatives and friends by involving significant healthcare and social care resources for persons with dementia, thus influencing the general public as well. Costs that society bears in health, economic and social  dimensions are substantial, representing a huge burden on the budget. According to the WHO report, the global costs associated with dementia reached the impressive figure of USD 604 billion in 2010 (corresponding to 1.0% of the aggregated worldwide GDP)[5], of which the share of direct medical costs, measured in high-income countries, amounts to only 15%. The rest, being a much more, are indirect costs.

Therefore, the high morbidity of dementia on a global scale, including Alzheimer’s disease, combined with the high cost of this condition in all spheres of public life, the growing need to provide long-term care for the persons with dementia and the related social isolation and stigmatization to cope with, make dementia a global challenge, placing it among public health priorities.

Alzheimer’s disease, the most common cause of dementia, belongs to the group of neurodegenerative diseases characterized by unknown etiology, hereditary predisposition and gradual progression over many years. The disease is of great medical and social importance with unnoticeable onset and irreversible course, being incurable at present, leading to death.

In accordance with the most common description used by clinicians, the disease is known to progress slowly, lasting on average 10-12 years from the time of diagnosis. Early signs are often ignored by the patient and his/her relatives, being mistakenly attributed to aging, thus making it difficult to correctly and adequately diagnose. The most common symptom is the short-term memory loss expressed in difficulties in remembering or reminding recent events and inability to acquire new knowledge and memories. As the disease progresses, the clinical signs become more obvious, being complemented by spatial and temporal disorientation, confusion, mood swings, depression, irritability, aggression, behavioral disturbances, abstract thinking problems, difficulties in speech and loss of long-term memory as well as complete personal degradation with worsening social skills, causing permanent disability and inability to lead full-value life. Finally, organ functions gradually diminish and death occurs.

In order to classify individuals with memory impairment that normally does not progress to dementia, in 1962 V.A. Kral proposed the term “benign senescent forgetfulness”[6]. In addition to the cognitive deficit remaining stable and not deepening in the course of time, these adults show a slight memory decrease when evaluated by memory tests, without significant deviation from age-related norms.

It is this state of gradual transition from norm to pathology that is identified in the literature as “mild cognitive impairment”. MCI is typical of persons without other neurological, psychiatric, vascular, endocrine, communicable and neoplastic diseases, injuries, drug or alcohol intoxication carrying the potential for such diversions, with the MCI individuals exhibiting memory impairment that is more pronounced than what should normally be expected for a certain age and education level with preserved consciousness and cognitions, and routine daily activities remaining undisturbed.

As noted above, the term makes it possible to distinguish between dementia patients and fake dementia ones as well as those characterized by an isolated cognitive deficit due to physiological aging. The first one is an example of irreversible dementia, while in the other mentioned groups memory deficit remains stable or reversal occurs.

It should be emphasized that mild cognitive impairment is not actually a diagnosis (or a distinct nosological unit); rather, it is a concept for which specialized literature has suggested relevant diagnostic criteria that have undergone modifications over time. The MCI term denotes a preclinical, prodromal stage, not automatically presuming the medical diagnosis of Alzheimer’s disease.

To conclude, mild cognitive impairment causes a slight but noticeable and measurable decline in cognitive status, being associated with an increased risk of developing Alzheimer’s disease in the future. Long-term studies have found that in persons aged 65 and above, the frequency of MCI varies from 10 to 20%[7], and in a small percentage of cases mild cognitive impairment may progress to Alzheimer’s disease or other types of dementia, without it necessarily being so. The creation of this term is important in view of its practical importance as far as it is bound to the likelihood to early diagnose that type of degenerative dementia that allows for the application of a more effective treatment.

[1] According to WHO data for 2010, published in “Dementia: A Public Health Priority”, World Health Organization , 2012, p.2, available at: http://apps.who.int/iris/bitstream/10665/75263/1/9789241564458_eng.pdf .

[2] Ibid, p.2., available at: http://apps.who.int/iris/bitstream/10665/75263/1/9789241564458_eng.pdf .

[3] “2013 Alzheimer’s Disease Facts and Figures”, Report of the Alzheimer’s Association, vol. 9, issue 2, 2013, p. 15, available at: http://www.alz.org/downloads/facts_figures_2013.pdf .

[4] The report explicitly states that it is based on estimates and not actual number of cases of dementia diagnosed by a physician, which is due to the impossibility to cover all patients. It is also noted in the report that half of the 5.2 million Americans exhibiting clinical symptoms of Alzheimer’s disease are probably not aware of this fact – author’s note.

[5] See: the WHO Report for 2010: “Dementia: A Public Health Priority”, World Health Organization, p. 25, available at: http://apps.who.int/iris/bitstream/10665/75263/1/9789241564458_eng.pdf .

[6] Kral, V., “Senescent Forgetfulness: Benign and Malignant”, Journal of the Canadian Medical Association, February, 1962, vol. 86 (6): 257-260, available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1848846/pdf/canmedaj00930-0002.pdf .

[7] According to the data of Alzheimer’s Association: http://www.alz.org/dementia/mild-cognitive-impairment-mci.asp .

Although there is no available medication for the treatment of Alzheimer’s disease that may stop or reverse the course of the pathology, the process related to the development and testing of new innovative drugs still continues. Research efforts are primarily devoted to the elucidation of the pathogenetic mechanisms of Alzheimer’s disease and the establishment of a comprehensive theoretical foundation on which modern disease-modifying therapy should be based on, as contrasted to current symptomatic treatment. In this sense, future hopes are associated with immunotherapy, which is believed to limit the development and deposition of abnormal amyloid protein in the brain.

The experimental technology, i.e. intravenous immunoglobulin infusions by maintaining optimal level of antibodies in the patient’s organism constitutes a form of passive immunotherapy with a potential for reduction of beta-amyloid plaques, where the technology is expected to help completely heal or significantly improve the cognitive status of the treated subjects with all subsequent benefits, i.e. improved social interaction and quality of life.

A pilot study examining the efficacy and safety of the treatment of Alzheimer’s disease with immunoglobulins, conducted by Dodel et al.[1] on five patients, who have been treated for over six months with the blood product, reported stabilization of cognitive function as measured by the neuropsychological test “Mini-Mental State Examination” together with reduction in beta-amyloid deposits in the cerebral spinal fluid compared to baseline.

Promising results were also reported by Relkin et al.[2] on a sample of eight patients. The authors found improved cognition and seized cognitive decline in the majority of patients based on MMSE scale following a six-month IVIG administration, suggesting that the method could delay, withhold or even reverse the course of the pathology.

In mid-2013 were announced the results from the phase III of a large-scale randomized double-blind placebo-controlled clinical trial[3] that enrolled 390 patients with mild to moderate Alzheimer’s disease, who have been treated by intravenous immunoglobulins for 18 months. The study, popularly known as “GAP” (“Gammaglobulin Alzheimer’s Partnership”), like in previous clinical trials, traces the biomarkers’ dynamics and the change in the cognitive status of involved individuals. The results to date are contradictory.

Although the above-mentioned data generally demonstrate relatively good tolerability of the blood product, specialized medical literature seems to argue that the potential of the new therapeutic alternative should not be generalized. Despite the somewhat reduced risks associated with passive immunotherapy vs. active one, hazards do exist, being still unknown and unpredictable. The following side effects or complications that may occur during treatment with both active and passive immunotherapy have been reported[4]: autoimmune diseases, brain inflammation (meningoencephalitis), microhemorhages, increased amyloid angiopathy, residual neurofibrillary tangles, brain volume reductions and problems with blood-brain barrier passage of antibodies, posing a threat to patients’ health and worsening their quality of life. Therefore, in view of these considerations very cautious administration of IVIG products is required only after thorough testing on nonmurine animal species (primates) and further validation.

Given that IVIG treatment is still at an experimental stage, it may need additional confirmation based on quite more studies with expanding the number of both the people involved and the time period, with the authors warning that the new approach should not be taken for a universal treatment strategy on the principle “One size fits all.” and therefore not to be viewed as a first-choice therapeutic alternative.

With a view to the above considerations, involved medical personnel needs to be responsible for balancing benefits and risks. In bioethics literature, this is known as a “risk-benefit analysis” where the researcher must weigh and balance the possible benefits and damages occurring in the course of research. One of the main tasks of the medical staff is to ensure that the principle of nonmaleficence has been observed or refrain from causing harm to the subjects in the study by assuring that potential benefits exceed unknown risks. Other negative consequences, such as in the case of patients with compromised decision-making capacity must also be envisaged, for example a decisionally impaired person, who has significantly recovered due to the treatment, might realize his/her deteriorating physical and mental state and as a result become distressed, feel anxiety, hopelessness and despair, thus causing increased suicidal risk among these patients. Physicians should be prepared for timely response to prevent this side effect.

[1] Dodel, R.C., Y.Du, C. Depboylu, H. Hampel, L. Frölich, A. Haag, U. Hemmeter, S. Paulsen, S.J. Teipel, S. Brettschneider, A. Spottke, C.  Nölker, H.J. Möller, X. Wei, M. Farlow, N. Sommer and W.H. Oertel “Intravenous Immunoglobulins Containing Antibodies against β-amyloid for the Treatment of Alzheimer’s Disease” (Short Report), “Journal of Neurology, Neurosurgery and Psychiatry” 2004; 75: 1472-1474, available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1738770/pdf/v075p01472.pdf .

[2] Relkin, N.R., P. Szabo, B. Adamiak, T. Burgut, C. Monthe, R.W. Lent, S. Younkin, L. Younkin, R. Schiff and M.E. Weksler, “18-Month Study of Intravenous Immunoglobulin for Treatment of Mild Alzheimer Disease”, “Neurobiology of Aging”, volume 30, issue 11, November 2009, pp. 1728-1736, available at:  http://www.ncbi.nlm.nih.gov/pubmed/18294736 .

[3] “Updated Results from Phase 3 Trial of IVIG for Alzheimer’s Disease” (Featured Research), Weill Cornell Medical College, July 2013, available at: http://www.sciencedaily.com/releases/2013/07/130716092743.htm .

[4] Foster, J.K., G. Verdile, K.A. Bates and R.N. Martins, “Immunization in Alzheimer’s Disease: Naïve Hope or Realistic Clinical Potential?”, “Molecular Psychiatry” (2009) 14, 239-251, available at:  http://www.nature.com/mp/journal/v14/n3/full/mp2008115a.html .

Similar are the benefits and risks for the family, relatives, friends and caregivers of the patients participating in the experimental therapy. Benefits should be sought with regard to the improved quality of life for the patients as well as the positive impact on the social contacts of the persons concerned, while risks may refer to complications leading to reduced quality of life not only for the patient alone but for his/her kindred, as well (including need of extra care, financial loss, social isolation, stigmatization, etc.). Relatives providing care for persons with MCI should also be completely familiar with the pros and cons of the experiment, which lies within the responsibility of the researchers.

Apart from the direct benefits and risks for the patient and his/her relatives, passive immunotherapy with intravenous immunoglobulins may also produce indirect effects on society as a whole by involving significant health and social resources. If the experimental treatment turns out to be efficient and successful for AD patients in the long run and be approved of the respective regulatory authorities for routine clinical use, patients suffering from other diseases that are usually treated with the same blood product may be deprived of their treatment. Therefore, IVIG priority orientation towards AD patients would lead to a significant reduction in the therapeutic options for the persons suffering from autoimmune diseases, for instance. The high price of the mentioned blood product ranging between USD 3000 and USD 7000 per month[1] must also be taken into consideration – it not only makes treatment extremely expensive, but in light of scant or missing evidence of its effectiveness and safety so far puts its benefits into question.

[1] Foster, J.K., G. Verdile, K.A. Bates and R.N. Martins, “Immunization in Alzheimer’s Disease: Naïve Hope or Realistic Clinical Potential?”, “Molecular Psychiatry” (2009) 14, 239-251, available at:  http://www.nature.com/mp/journal/v14/n3/full/mp2008115a.html .

Due to the still unknown etiology and pathogenesis of Alzheimer’s disease, namely whether beta-amyloid protein is a key cause of the disease or its consequence, currently to both physicians and patients may be unclear if the proposed therapy will affect the specific pathology, i.e. if the new treatment will be etiopathogenetic or only symptomatic. Only by thorough testing of the method will it be possible to check the plausibility of the amyloid hypothesis.

Despite the initial scientific enthusiasm regarding immunotherapy and the very first promising results, medical literature maintains that immunotherapy potential in relation to Alzheimer’s disease should not be generalized. Suspected, however, still unknown are some side effects or complications that may occur during treatment, such as autoimmune diseases, brain inflammation, microhemorhages, increased amyloid angiopathy, residual neurofibrillary tangles, brain volume reductions and problems with blood-brain barrier passage of antibodies. Given that, immunotherapy should not be seen as a universal therapeutic strategy on the principle “One size fits all.” and it is not advisable that IVIG be the first choice for AD patients.

The authors[1] warn that even passive immunization may pose a risk for humans and recommend quite cautious application of the method only after extensive testing on nonmurine animal species such as primates.

[1] Foster, J.K., G. Verdile, K.A. Bates and R.N. Martins, “Immunization in Alzheimer’s Disease: Naïve Hope or Realistic Clinical Potential?”, “Molecular Psychiatry” (2009) 14, 239-251, available at:  http://www.nature.com/mp/journal/v14/n3/full/mp2008115a.html .

The need to test new drugs continues and will continue to be associated with increased demand for clinical trial participants who are vulnerable in a number of ways. First, medicine is a very complex field, not easily understood by the average person. Study participants often have neither sufficient knowledge to determine the best course of action for treating or preventing a disease, nor the necessary expertise to reasonably assess the hazards and risks borne by them in the experiment. Rather, they are placed in a position of dependence – depending on clinician researchers to advise them correctly. A second source of vulnerability is a function of the fact that study participants are often people having problems for which they are seeking a solution. These individuals place their lives in the hands of medical staff, trusting that researchers will act in the participants’ best interest. Third, as far as clinical trials usually take place in a healthcare setting, researchers are in the position to easily gain access to sensitive information that may expose the participants in the study to social or economic risks, such as the presence of diseases that could have a negative impact on the public attitude towards the patient, namely his/her productivity, hence, employability, and, thus, contribute to deepening stigmatization. Fourth, clinician researchers, by virtue of their expertise and status, may abuse their position by exerting pressure on the patient and making him/her agree to the proposed intervention, even through the use of dishonest and unethical methods as coercion, deception, fraud and other forms of manipulation. As a result, patients may be reluctant to exercise their right to autonomy and, consequently, acquiesce to everything required of them – even when it may not be in their best interest. A fifth source of vulnerability when recruiting volunteers to participate in scientific experiments for testing new therapeutic alternatives could be generated by the need to balance between the patient’s right to personal choice, his/her financial needs and the enthusiasm of researchers. Hopeless and desperate patients, not having enough money to pay for expensive treatment, may find it more beneficial to involve in a free trial of the new technology. Such situations normally raise the following ethical issues, i.e. to what extent has voluntary participation been guaranteed by researchers, especially in cases where clinician researchers may be quite enthusiastic and may, therefore, influence the decision of the patient by assuring him/her of the benefits and safety of a completely new, still unproven, therapy as well as how to ensure that potential risks are not to be belittled by the particular individual. Sixth, in the event of early diagnosed patients with anticipation for progressive deterioration over time, the practice of drawing up a legal document called “advance directive” is usually preferred – a written document, in which, while still healthy, a person without prominent cognitive dysfunctions but expected future ones formulates his/her future treatment preferences and desires. In similar situations, where it may take a period of several decades between an individual’s preclinical diagnosis and the onset of clinical symptoms, there is a risk of discrepancy between the present and future “self” of the patient in the changed environment, posing the question how relevant with regard to a particular moment in the future would be the preliminarily given consent/refusal expressed by a person in the advance directive and whether earlier treatment preferences must always be respected by the medical personnel. Here the concept of future-oriented autonomy collides with the welfare of the patient. A seventh source of vulnerability is associated with the adopted practice of legal representation in the event of incompetence, which raises the question if an agent/representative of the patient would always act in the interest of the patient and how this could be ensured. Eighth, patients’ vulnerability may be generated by excessive stereotyping and infantilization of the adults, especially through the application of restrictive procedures, such as the so-called “double consent” where consent is sought by the family, while the subsequent validation/approval of the consent (i.e. “assent”) – by the patient himself/herself, quite analogous to the procedures in children.

In the event of diagnosed with AD individuals stands out the conflict between the right to autonomy of a patient and the limits of his/her capacity/competence – an issue that has been widely discussed in bioethics literature, however, without reaching unanimity. The positions of the authors are diverse, mostly depending on the adopted viewpoint. No universal prescriptions for action exist.

Under the legal doctrine, each subject shall be presumed competent until proven otherwise. For example, in law, unable to make a decision shall be considered the person who is unable to understand the information obtained and cannot hold it long enough (i.e. remember  it), cannot use it or weigh it up as part of the decision-making process and is unable to communicate (express) his/her choice either by speech, or through sign language (for example by blinking eyes or squeezing a hand)[1].

Apart from the purely legal nature of the term “competence”, in the literature prevails the view[2] that the progressive brain damages and ensuing cognitive and emotional disorders, accompanied by sensory impairment and dependence on family and caregivers, require careful and cautious application of the doctrine of competent, voluntary, informed consent in research on adult subjects given the consideration that the mental decline may affect a patient’s ability to understand the medical alternatives by reducing the individual sense of caution and reasonable judgment of the potential risks and burdens associated with the intervention.

Even the prodromal stage of Alzheimer’s disease, popular as MCI, might impair the capacity of patients to give consent. Distinguishing between competent and incompetent subjects is quite a complex process and despite standardized assessment tools, the question remains unresolved as to what upper limit of potential risk should be allowed and whether informed consent should be permitted in high-risk scientific research. Partial answer to this dilemma is contained in the current international codes and guidelines, including the Declaration of Helsinki and the Council for International Organizations of Medical Sciences Guidelines (CIOMS)[3] dealing with issues, such as research in vulnerable populations. They make it obvious that the balance between risks and benefits is especially important in the discussion on non-therapeutic vs. therapeutic research, where only minimal risks are allowed if the research won’t be of benefit to the subjects involved.

Some authors[4] try to distinguish between an ideal, abstract model of autonomy and actual autonomy. Typically, an abstract model assumes the possession of a set of ideal capabilities that an autonomous agent is supposed to have, namely the ability to function as an independent and rational subject in his/her choices and actions, who knows his/her own desires and preferences, being fully competent in the decision-making process. These features, however, present a standard model, difficult to follow in some cases, such as Alzheimer’s disease. The abstract, ideal definition is replaced by a new concept, popular as “actual autonomy” that views the individual as an owner of a particular history of development, personal beliefs, convictions and values, and who does not ​​exist in isolation but in a dynamic relationship with the social world.

In accordance with the above, George Agich notes that although not exhibiting ideal capacity for giving consent due to existing memory deficit, confusion and disorientation, most volunteers participating in clinical trials of drugs are conscious subjects reported to be in excellent or good health, cognizant of everyday life, having their own preferences for specific foods, clothing, persons and activities and demonstrating relatively preserved capacity to interpret information and ask questions.

It would therefore be incorrect for dementia patients to always be deemed completely devoid of decision-making capacity. Moreover, if the information is presented slowly and repeatedly in a non-stressful manner, even people suffering from significant cognitive decline can grasp it. Thus, in compliance with the principle of autonomy, a cornerstone principle of medical ethics, it would be essential that procedures for informed consent be developed sensitive to preserving maximum freedom for the subject over his/her own body. According to the ethical guidelines of the Alzheimer Society of Canada[5], while still intact, the individual’s freedom should not be limited by restrictive measures; rather, he/she should be given a choice and opportunity to decide. This position is shared in other guidance documents[6], adding that a person with preserved competence has the right to make even such a decision that may be perceived by others, including the health personnel, as unreasonable or irrational, with the particular individual not to be categorized as lacking capacity merely because the health professional has deemed his/her decision unwise.

[1] “Reference Guide to Consent for Examination or Treatment”, second edition, Department of Health, United Kingdom, July 2009, p.9, available at:  https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/138296/dh_103653__1_.pdf .

[2] “Dementia – Caring, Ethics, Ethnical and Economical Aspects: A Systematic Review”, Chapter 36 “Ethical and Societal Issues in Dementia”, p. 446, volume 3, June 2008, SBU Statens beredning för medicinsk utvärdering (The Swedish Council on Technology Assessment in Health Care), available at: http://www.sbu.se/upload/Publikationer/Content1/1/Dementia_vol3.pdf .

[3] Ibid, p. 445, available at: http://www.sbu.se/upload/Publikationer/Content1/1/Dementia_vol3.pdf .

[4] Agich, G., “Alzheimer Disease: Therapeutic Strategies”, edited by E. Giacobini and R. Becker, Boston, 1994, available at: http://personal.bgsu.edu/~agichg/Articles/AutAD.pdf .

[5] Sevick, M-A., T. McConnell and M. Muender, “Conducting Research Related to Treatment of Alzheimer’s Disease: Ethical Issues”, Journal of Gerontological Nursing 29(2), February 2003, pp. 6-12, available at: http://www.researchgate.net/publication/7957720_Conducting_research_related_to_treatment_of_Alzheimer%27s_disease._Ethical_issues .

[6] “Reference Guide to Consent for Examination or Treatment”, second edition, Department of Health, United Kingdom, July 2009, p. 10, available at:  https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/138296/dh_103653__1_.pdf .

Patient autonomy is a cornerstone principle of medical ethics and widely discussed issue in specialized literature. In general, patient autonomy can be defined as self-determination, an expression of one’s own will, based on the ability of a person to guide and manage his/her own life in accordance with rational principles and rules, thus allowing him/her to consciously accept or refuse medical interventions.

The right to self-determination is ensured by the presence of valid consent by adherence to the principle of voluntariness and after the patient has been thoroughly introduced to the objective, nature of the procedures, potential risks, duration, anticipated effect of the intervention, etc.

In the context of neurodegenerative diseases particularly stands out the collision between the right to autonomy of a patient and the limits of his/her competence. The altered cognitive status expressed in memory deficit, sensory impairment, confusion, disorientation and compromised capacity to retain long enough and assess information due to brain lesions raises the ethical question about the real boundaries of competence and personal identity of AD subjects.

This faces the preclinically diagnosed individuals with the challenge to make decisions regarding their own future. To what extent do the above-mentioned subjects have the capacity to decide in their own best interest is a disputable issue where the positions of the authors divide and which has been already covered in the answer to the previous question.

Although patient autonomy is considered to be a key point and prerequisite for any medical intervention and has therefore been well debated in the literature on bioethics, data on ethical aspects regarding the application of experimental therapeutic methods in patients with mild cognitive impairment are scarce at best or missing.

Intravenous immunoglobulin therapy is associated with invasive procedures that should be explained in detail to the patients – potential participants in a research. The partially compromised decision-making capacity of MCI persons makes the situation even more complicated as far as it may result in inadequately estimated (belittled) risks. In the context of bioethics, this conflict between the right to autonomy and the limits of competence of the subject needs to be envisaged, with the informed consent process involving a detailed description and clarification of all stages of the therapeutic procedure/experiment/study, including the provision of information on painful interventions, tests and manipulations, data on the effectiveness of the methodology, expected outcome, price, alternative treatments, etc. The information should be presented in an accessible form and in a way that does not hinder patients with a slight cognitive decline to understand the treatment options and make appropriate decisions regarding their quality of life accordingly. With the new experimental strategies, such as the blood product concerned, there is a risk of producing subtle side effects, which can hardly be caught/seen in patients with communication disorders. The potential risk of other unforeseen but serious complications and the harm to persons in the event of being placed into the placebo group in placebo-controlled trials, depriving them of treatment during the experiment, should also be discussed before the patient is asked to give final informed consent.

Involved medical personnel needs to be responsible for balancing benefits and risks. In bioethics literature, this is known as a “risk-benefit analysis” where the researcher must weigh and balance the probable benefits and damages occurring in the course of research. One of the main tasks of the medical staff is to ensure that the principle of nonmaleficence has been observed or refrain from causing harm to the subjects in the study by assuring that potential benefits exceed unknown risks. Other negative consequences, such as in the case of patients with compromised decision-making capacity must also be provided for, for example a decisionally impaired person, who has significantly recovered due to the treatment, might realize his/her deteriorating physical and mental state and as a result become distressed, feel anxiety, hopelessness and despair, thus causing increased suicidal risk among these patients and compromised quality of life. Physicians should be prepared for timely response to prevent this side effect.

These and other issues arising in the course of each experimental therapy and the common belief in the medical community that individuals with compromised capacity belong, by default, to a special class of subjects and should therefore be treated with utmost caution necessitate the provision and development of special protective measures when giving consent so as to properly balance the benefits and risks:

1. Maximum involvement of the persons with mild cognitive impairment in the risk assessment process – a risk that they are willing to take;
2. Providing an inventory of potential risks and burdens for each case study;
3. In light of the vague benefits of experimental drugs and therapies, volunteers must be fully acquainted in advance with the potential risks and burdens of the treatment by providing the individuals with relevant detailed information in the most accessible and understandable manner;
4. Guaranteed opportunity for patients to abstain from participation or reject further participation in the experimental study at any time;
5. Providing indemnity insurance by researchers. The latter are required to insure themselves against potential damage by making best efforts to identify possible adverse effects and determine the likelihood for participants to encounter similar events;
6. Ensuring that patients are aware of the purpose of the randomized controlled trial, whose subject they are, namely, hypothesis testing and providing general knowledge of a medication or therapeutic procedure;
7. Ensuring by researchers that potential participants understand that they may be allocated in the control/placebo group to be randomly determined, with each of them likely to fall into that group;
8. Control over the balancing of study benefits and risks should be carried out by an ethics commission/committee or similar body (it is commonly accepted that such committees approve and coordinate each experimental or epidemiological study with a focus on the population or groups of it).

In order to protect human dignity of dementia patients, in some European and international legal documents, i.e. the Charter of Fundamental Rights of the European Union and the Convention for the Protection of Human Rights and Biomedicine have been stipulated a number of key principles and requirements that must be observed during the intervention, whereas in the field of bioethics they can be summed up into several points as follows[1]:

1. Respect for the dignity of both the persons with dementia and their caregivers and the need for polite and respectful behavior towards them, observing their personality and cultural traditions (ensuring that they are treated tactfully, considerately, carefully and in a good manner);
2. Use by researchers of an appropriate language in the process of communication with dementia patients. Avoiding terms, such as “mad” and “dementia patient”, etc.;
3. Researchers through their own behavior and attitude should ensure the promotion and protection of the dignity of people with dementia;
4. Introducing standardized feedback forms enabling the participants in the experiment to anonymously share opinion, especially in cases when they have some critical remarks on the procedure or wish to express their dissatisfaction or disapproval;
5. Development and implementation of a customized procedure for each individual based on the principle of personal uniqueness and avoiding standardized programmes, except in the cases requiring such standardization;
6. Ensuring the principle of confidentiality when processing the personal data of AD patients by securing the privacy of their personal lives through transparent and legitimate procedures (personal data that have become known to researchers during the experiment);
7. Strict adherence to the principle of voluntariness through the avoidance of deception, fraud, manipulation, coercion and abstaining from unethical behavior on the part of researchers;
8. Viewing informed consent not as a single act but as an ongoing process during which each patient may withdraw whenever he/she wishes to. The informed consent procedure needs to be periodically revised, especially in cases of new information made ​​known to the research team regarding treatment methods;
9. Questioning the need to conduct repeated, painful, stressful or invasive procedures for the patients in the context of missing prevention or efficient etiopathogenetic therapy, i.e. in the event of increased suffering for the patient;
10. Preliminary risk assessment by researchers and allowing only minimum risks in cases where the research does not contribute to the benefit of the subjects;
11. When recruiting volunteers for participation in scientific experiments with unknown risks should be favored the involvement of patients with less severe mental disorders, who are deemed to have basically preserved their competence;
12. Application of methods and techniques simplifying the process of decision-making by reducing the number of possible options and decomposing more complex decisions into a series of simple instructions and step-by-step guidance through the process (compliant with the ethical guidelines of the Alzheimer Society of Canada);
13. Critical use of the legal instrument “advance treatment directive” for expressing consent in advance when the individual is still cognitively intact (typical of early diagnosed patients) due to the possible discrepancy between the present and future “self” of the person;
14. Respect for the patient’s right to autonomy and control over his/her own body and soul, and addressing his/her legal representative only in the event of missing or severely impaired capacity without favoring the second option;
15. Safeguards against stereotyping and infantilizing adults through the practice of restrictive procedures for consent (the so-called “double consent”).

[1] “Ethics”, Alzheimer Europe, available at: http://www.alzheimer-europe.org/Ethics ; Guide to Consent for Examination or Treatment”, second edition, Department of Health, United Kingdom, July 2009, available at:  https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/138296/dh_103653__1_.pdf ; “Dementia – Caring, Ethics, Ethnical and Economical Aspects: A Systematic Review”, Chapter 36 “Ethical and Societal Issues in Dementia”, volume 3, June 2008, SBU Statens beredning för medicinsk utvärdering (The Swedish Council on Technology Assessment in Health Care), available at: http://www.sbu.se/upload/Publikationer/Content1/1/Dementia_vol3.pdf ; Agich, G., “Alzheimer Disease: Therapeutic Strategies”, edited by E. Giacobini and R. Becker, Boston, 1994, available at: http://personal.bgsu.edu/~agichg/Articles/AutAD.pdf .

Traditionally accepted is the notion that in order to be good professionals, healthcare workers besides good qualifications must possess a number of moral virtues and personal qualities, such as compassion, insight, trustworthiness, honesty, integrity and conscientiousness, with the care for patients being based on responsibility, loyalty and mutual trust.

Development of medical science with the invention of new diagnostic and therapeutic procedures poses a number of challenges facing the healthcare workers that could consciously or unconsciously affect their attitude towards patients. The doctors’ wish to find a new effective and successful therapy for treating Alzheimer’s disease prior to the onset of irreversible damages in the brain of patients may cause in healthcare professionals ungrounded optimism, thus obscuring their humane intentions by permitting the enrollment of decisionally impaired persons or subjects deprived of sufficient information in the group for experimental clinical trials. Medical personnel should cautiously balance positive against negative outcomes from the experimental therapy and provide the individuals with accessible, comprehensive factual information on the features, benefits and harms of the new treatment, including the usage of non-verbal methods when needed.

Clinicians should also consider the fact that they are placed in a position intimidating patients in several ways: 1.) Patients do not have enough knowledge to decide for themselves what is good for their own prevention and therefore completely trust the honesty, benevolence and professional advice of physicians/researchers (particularly with regard to incapacitated persons, who, while seeking the best solution for their own health problem, entrust their health and lives in the hands of professionals with the conviction that the latter will act in their best interest.); 2.) Medical staff by virtue of its competence and social status may be intimidating to patients by silently forcing them to agree with everything, thereby depriving them of exercising their right to personal autonomy, even in cases when what is required by the patient may not be in his/her best interest (i.e. an abuse of official position – something that should not be allowed.); 3.) Researchers are obligated to ensure full confidentiality of the data acquired during the experiment since in the course of the study there is a risk of becoming aware of sensitive patient information, whose disclosure would endanger the patient’s social and economic interests.; 4.) The staff must guarantee the principle of voluntariness upon signing the informed consent, bearing in mind that with a view to the patients’ progressive mental deterioration, informed consent should be considered an ongoing process with an option to be potentially revised over time. Coercion, manipulation, fraud and other unethical methods are totally unacceptable or undesirable, with researchers being obliged to envisage measures for protection of the personal data of their patients.; 5.) In an effort to cure or slow disease progression, healthcare professionals might be influenced by the pharmaceutical companies advertising new drugs, without at the same time being sufficiently convinced of the effectiveness of the proposed treatments. Reasonable in this context would be questions such as: How will patients’ quality of life change?; If and how effective are these  drugs?; Do they induce the same side effects?; Is the cost, duration and treatment dose, etc. justified?;  If, moreover, in an experiment involving the testing of new therapeutic methods, medical staff accepts funding from the pharmaceutical industry, a conflict of interest may arise, questioning both the objectivity of the experiment and the expected results.

Despite the common belief that the principles of bioethics are universal and applicable to every culture and society and that have always existed in the religious and moral traditions in various forms, the possibility that some of them may collide with one another at a certain stage of development and/or treatment of AD patients cannot be completely excluded.

Major religions (Christianity, Judaism, Islam and Buddhism) do not differ significantly in terms of their generally positive attitude towards human, with slight variations about prioritizing human body or soul, which might result in minor discrepancies in their opinion as to what extent a person should be allowed to self-decide on issues such as the maintenance or termination of life (for example, the application of euthanasia in AD’s terminal stage). With the mild cognitive impairment phase, however, this dilemma is out of the question, whereas the above-mentioned religions show a positive attitude with respect to all possible methods of treatment of the human body and soul.

Despite the principally expressed considerations, the concrete therapeutic technology under discussion might raise objections among some religious groups in light of the application of whatever therapy, i.e. some religious movements reject medical treatment, while others (such as “Jehovah’s Witnesses”) oppose blood transfusion practices. Therefore, there is a risk that the use of blood products in the form of immunoglobulins may be met with resistance from the supporters of the above-mentioned religious movement[1].

Ethical rules and virtues are likely to come into conflict with the moral of a particular social group. The enrollment of AD subjects or persons with MCI in a clinical trial group to be treated with immunoglobulins presumes these subjects to have already been diagnosed, which would mean that the above individuals are labelled as “mad” or “incurably ill”. This could negatively impact on the individuals and their families, relatives and friends in their future social contacts. Cultural differences linked to the use of information and decision-making in patients suffering from “formidable diseases” may further complicate the situation. In the USA, it is accepted among some groups such as Mexican Americans, Korean Americans and Navajo to inform family members about the health of their significant other before telling the diagnosis to the sick person himself/herself. In Ireland, 83% of the relatives of people suffering from dementia are against the disclosure of the diagnosis to the patients themselves, considering that learning/knowing it may harm the sick person causing him/her anxiety, stress, despair and depression. In this aspect, a conflict may be expected regarding the autonomy of the patient (i.e. his/her autonomy in the treatment decision-making process may be reduced). Therefore, autonomy of an individual depends largely on the people around him/her, their affiliation to a particular social group or community and cultural values, as well[2].

As another prerequisite for a potential conflict between the administered therapy and the pursued social policies in some countries could be mentioned the disparities in the burden between the costs of caring for patients suffering from Alzheimer’s disease and the social costs linked to other public health diseases. In recent years, Alzheimer’s disease has been recognized as a key public health issue because of its significant morbidity, high cost of related care and lack of effective definitive treatment. AD patients, due to their advanced age, are likely to have comorbid chronic diseases, such as diabetes, coronary problems, congestive heart failure and others, making it hard and expensive to treat.

[1] See: Alvargonzález, D. “Alzheimer’s Disease and the Conflict between Ethics, Morality and Politics”, Journal of Alzheimer’s Disease & Parkinsonism, March 2013, available at: http://www.omicsonline.org/alzheimers-disease-and-the-conflict-between-ethics-morality-and-politics-2161-0460.S10-004.pdf ; “Personhood”, Alzheimer Europe, January 2013, available at: http://www.alzheimer-europe.org/Ethics/Definitions-and-approaches/Other-ethical-principles/Personhood ; “Ethical Issues in Practice”, Alzheimer Europe, October 2009, available at: http://www.alzheimer-europe.org/Ethics/Ethical-issues-in-practice .

[2] Ibid.

One of the key principles in bioethics is the principle of justice linked to law and equality. From an ethical point of view, it can be considered in three different ways and subdivided into three distinct categories, respectively: fair allocation of scarce resources (distributive justice); respect for people’s rights (rights-based justice) and compliance with morally acceptable laws (legal justice). Although the right to equal treatment, respectively, equal access to treatment has been formally enshrined in many constitutions, actually, many factors, such as age, place of residence, social status, ethnicity, culture, sexual preference, disability, legal capacity, health budgets, treatment price, insurance coverage, etc. may limit access to treatment. Justice in these cases, without neglecting or underestimating the right of equal access for all, requires that the individual’s needs be balanced with the needs of the general public.

The EU enlargement has brought new opportunities and potential problems in healthcare, while at the same time efforts are underway to harmonize healthcare provisions, including the promotion of cooperation and reaching consensus on a variety of health issues. In 1992, the Maastricht Treaty on the European Union recognized public health as an object of the EU policy. In Europe, bioethics is largely based on the principle of solidarity, freedom of choice, tolerance, equal opportunities, social justice and human dignity. In the European Community, justice and law are seen through the prism of not only the patient alone but also of his/her family members and society as a whole.

Application of passive immunotherapy with intravenous immunoglobulins having still unproven benefits could induce broader effects on society by involving considerable health and social resources. If, in the long run, the experimental treatment turns out to be an efficient and successful strategy for AD patients and, consequently, be approved of the respective regulatory authorities for routine clinical use, individuals suffering from other diseases that are also treated by the same blood product may be deprived of their therapy. Therefore, IVIG priority orientation towards AD patients would lead to a significant reduction in the therapeutic options for the persons suffering from autoimmune diseases, for instance, while the extremely high cost of the blood product may violate the principles of equality, justice and solidarity, resulting in huge over-expenditures. On the other hand, one must take into account the fact that in case of failure to use the new technology, provided that the method has proven to be working and useful, there is a risk of infringing upon the rights of the people with Alzheimer’s disease to reliable and effective treatment providing improved quality of life.

Therefore, in view of the above and in order to ensure fair and reasonable healthcare spending, it is necessary that decisions are made on a case-by-case basis, particularly in situations characterized by limited resources, unequal opportunities and/or other moral discrepancies.

Intravenous immunotherapy is used in a number of diseases, being the only possible alternative in the treatment of primary immunodeficiency conditions (agammaglobulinemia and hypogammaglobulinemia) and secondarily acquired immunodeficiencies. Another major category of pathologies treated successfully with these blood products comprises the following autoimmune diseases: idiopathic thrombocytopenic purpura, Kawasaki disease, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, multifocal motor neuropathy, myasthenia gravis, relapsing-remitting multiple sclerosis as well as other autoimmune disorders: pemphigus, autoimmune uveitis, Graves ophthalmopathy, polymyositis, dermatomyositis, etc. The third class of diseases, in which intravenous infusions have proved their therapeutic effect, are acute infectious diseases.

IVIG production for therapeutic purposes requires vast resources of blood plasma, for the preparation of which are necessary from 3000 to 10000-20000 healthy blood donors.[1] Unreasonable use of immunoglobulins may result in a rapid depletion of quantities produced, depriving a number of patients of the only available treatment for their disease. So as to   distribute and use most efficiently the limited supplies of immunoglobulins in compliance with the ethical principles of justice and interdependence, some countries have established registries regulating the diseases for which IVIG therapy is deemed routine, namely immunodeficiencies in infants and children and diseases with the only possible alternative immunotherapy whose positive effect has been proven in controlled trials. The choice of method should furthermore be consistent with factors, such as patient’s age, opportunities for peripheral venous access, presence of comorbidities (cardiovascular disorders, a history of allergy or renal disease), which may restrict IVIG administration due to expected complications.[2]

Since IVIG administration in AD patients is still at an experimental stage and marked by contradictory intermediate outcomes for the time being, the redirection of the limited quantities of the present blood product to the priority treatment of the huge and rising number of patients with Alzheimer’s disease is likely to disturb the routine therapy of the persons suffering from the  aforementioned autoimmune diseases, which lack another available alternative treatment strategy. Therefore, IVIG administration in AD subjects must not be a first therapeutic choice, whereas each country, depending on the financial capacity of its healthcare system, the available resources of immunoglobulins as well as the number of patients with immunodeficiency conditions and autoimmune diseases, for which no other alternative treatment exists, should determine as to whether to include passive intravenous immunotherapy among the therapies recommended for other groups of diseases (including Alzheimer’s disease).

[1] Gómez-Puerta, J.A., R. Cervera and J. Font, “Clinical Utility of Intravenous Immunoglobulins in Autoimmune Diseases (Utilidad Clínica de las Inmunoglobulinas Endovenosas en las Enfermedades Autoinmunes)”, Inmunología, vol. 22 /Núm 3/Julio-Septiembre 2003: 287-293, Spain. ; Kaveri, S.-V., G. Dietrich, V. Hurez and M. D. Kazatchkine, “Intravenous Immunoglobulins (IVIg) in the Treatment of Autoimmune Diseases”, Clinical and Experimental Immunology (1991) 86, 192-198, available at: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2249.1991.tb05794.x/pdf .

[2] Koski, C.L., J.V. Patterson, “Intravenous Immunoglobulin Use for Neurologic Diseases”, Journal of Infusion Nursing, volume 29, number 3 – supplement, pp. S21-S28, June 2006, available at: http://www.nursingcenter.com/lnc/journalarticle?Article_ID=663755 .

Despite the common belief that the principles of bioethics are universal and applicable to every culture and society and that have always existed in the religious and moral traditions in various forms, the possibility that some of them may collide with one another at a certain stage of development and/or treatment of AD patients cannot be completely excluded.

Major religions (Christianity, Judaism, Islam and Buddhism) do not differ significantly in terms of their generally positive attitude towards human, with slight variations about prioritizing human body or soul, which might result in minor discrepancies in their opinion as to what extent a person should be allowed to self-decide on issues such as the maintenance or termination of life (for example, the application of euthanasia in AD’s terminal stage).

Despite the principally expressed considerations, the concrete therapeutic technology under discussion might raise objections among some religious groups in light of the application of whatever therapy, i.e. some religious movements reject medical treatment, while others (such as “Jehovah’s Witnesses”) oppose blood transfusion practices. Therefore, there is a risk that the use of blood products in the form of immunoglobulins may be resisted against by the supporters of the above-mentioned religious movement.

Ethical rules and virtues are likely to come into conflict with the moral of a particular social group. The enrollment of AD subjects or persons with MCI in a clinical trial group to be treated with immunoglobulins presumes these subjects to have already been diagnosed, which would mean that the above individuals are labelled as “mad” or “incurably ill”, thus leading to depersonalization and other negative consequences for the individuals and their families, relatives and friends in their future social contacts. In the USA, it is accepted among some groups such as Mexican Americans, Korean Americans and Navajo to inform family members about the health of their significant other before telling the diagnosis to the sick person himself/herself. In Ireland, 83% of the relatives of people suffering from dementia are against the disclosure of the diagnosis to the patients themselves, considering that learning/knowing it may harm the sick person causing him/her anxiety, stress, despair and depression. In this aspect, a conflict may be expected regarding the autonomy of the patient (i.e. his/her autonomy in the treatment decision-making process may be reduced). Therefore, autonomy of an individual depends largely on the people around him/her, their affiliation to a particular social group or community and cultural values, as well.

In support of the above is the huge financial, ethical and social burden on the patient’s family and relatives, who, also, consider it moral and ethical to participate in the treatment process options as much as this choice affects their quality of life. Alzheimer’s disease is becoming a key public health issue because of its significant morbidity and duration, high cost of related care and lack of effective definitive therapy. AD patients, given their advanced age, are likely to have additional comorbid chronic conditions such as diabetes and cardiovascular diseases, making treatment harder and more expensive. The choice of therapy should furthermore take into account a number of other factors, such as age, place of residence, social status, ethnicity, culture, health budgets, insurance coverage, opportunities for peripheral venous access, allergy or renal disease, all of which not only make treatment costly but may limit IVIG administration due to expected complications.

In terms of healthcare, the costs of caring for AD patients exceed the social costs, which is also a prerequisite for a conflict between the applied therapy and the social policies in some states.

Each new therapeutic technology is introduced as a routine clinical practice after indisputable evidence in favor of patients and following a detailed economic assessment of the efficiency of various treatment schemes (dose, frequency, duration). In an experimental study on intravenous infusion of immunoglobulins in patients with Alzheimer’s disease were tested different therapeutic regimens for 36 months. The following schemes were applied: 0.2 g/kg every 2 weeks; 0.4 g/kg every 2 weeks; 0.4 g/kg every 4 weeks, and 0.8 g/kg every 4 weeks.[1]

The results from the randomized clinical trials conducted on very few patients, some of whom got complications during the experiment, show a trend towards improvement in the IVIG-treated individuals compared to the placebo group. Although to date no final selection of the most appropriate therapeutic regimen could be made, treatment is known to be quite expensive.

The price is above USD 75 per gram (i.e. approximately USD 15000 per infusion with a patient’s weight about 100 kg and the therapy being administered in the lowest possible dose – 2g/kg).[2] Given the conflicting results of the trials and the small number of treated patients, researchers are too cautious when recommending an official introduction of immunoglobulin therapy for AD patients, highlighting the fact that this would deprive other needy patients of the only possible treatment for their disease.

[1] Gever, J., “IVIG Stops Alzheimer’s in Its Tracks”, published on 17^th July 2012, available at: http://www.medpagetoday.com/MeetingCoverage/AAIC/33780 .

[2] “Intravenous Immunoglobulin”, Wikipedia, available at: http://en.wikipedia.org/wiki/Intravenous_immunoglobulin .

Currently, administration of intravenous immunoglobulins in patients with Alzheimer’s disease is still at an experimental stage marked by contradictory intermediate results. If clinical trials demonstrate indisputably the effectiveness of immunotherapy, its regular usage will be expected to provide improved quality of life for patients.

As already discussed in the previous sections, the reallocation of the limited quantities of immunoglobulins towards the treatment of the increasing number of AD subjects is likely to disturb the therapy of patients with immunodeficiencies or autoimmune diseases, placing IVIG as a treatment option for Alzheimer’s disease in the background. This consideration is with a view to ensuring balanced distribution of healthcare resources for society as a whole, compliant with the principles of justice and interdependence in order to guarantee that they are fairly and rationally exploited by all.