Dementia is an overall term for a decline in mental ability severe enough to reduce a person's ability to perform everyday activities. Alzheimer's disease is the most common type of dementia, which accounts for 60 to 80 percent of cases {76}.

Alzheimer's is a progressive disease, where dementia symptoms gradually worsen over time. In ICD-10-CM the code is G30 and in the ICD-10 classification of mental and behavioral disorders, diagnostic criteria for research the code is F00. According to DSM-IV criteria for Alzheimer’s disease memory deficit must be objectively demonstrated plus at least one other cognitive deficit: aphasia (abnormal speech), executive function impairment (difficulty with planning, judgment, mental flexibility, abstraction, problem-solving, etc.), agnosia (impaired recognition of people or objects), or apraxia (impaired performance of learned motor skills). These cognitive deficits must result in impairment in performance of daily activities. In the newest Diagnostic and Statistical Manual of Mental Disorders (DSM-5)  “dementia” is replaced by “major neurocognitive disorder” {3} {75}.The diagnosis is confirmed by post mortem evidence of neurofibrillary tangles and neuritic plaques in excess of those found in normal ageing of the brain (ICD-10).

Those with Alzheimer's live an average of 3.6 to 6.6 years after the diagnosis, depending on age and other health conditions {78}.

Mild cognitive impairment (MCI) describes a transitional state between normal aging and pathological decline {10} {49} {81}. Many terms and definitions have been used to describe mild forms of cognitive impairment. According to Petersen et al. {63} mild cognitive impairment is classified as 1) MCI that primarily affects memory is known as "amnestic MCI, aMCI" and 2) MCI that affects thinking skills other than memory is known as "nonamnestic MCI, A person with MCI is at an increased risk of developing Alzheimer's disease and other dementias, however, many individuals revert to normal or do not progress {81}. The conversion rate from MCI to Alzheimer's is low, about 7% in community based samples and 15% in specialized care samples {49}. Therefore MCI diagnosis alone cannot be equaled with a pre-dementia stage {48}. In order to allow treatments like medication, MCI diagnosis should be supplemented with predictors of a rapid cognitive decline, such as older age, vascular risk factors, neurological symptoms, apoE ɛ4genotype, etc.) {48}. In the DSM-5 a term “mild neurocognitive disorder” is used instead of mild cognitive impairment {3} {75}.

The most important risk factor for Alzheimer’s disease is age {43}. Up to 5 percent of people with the disease have early onset Alzheimer's, which often appears when someone is in their 40s or 50s. Many of the risk factors for cognitive impartment, Alzheimer’s disease and dementia are similar as the cardiovascular disease risk factors: Smoking, hypertension, hypercholesterolemia and overweight {75}. Midlife diabetes is associated with elevated risk {43} {75}. Some of the risk factors are modifiable through life style changes or with medical treatment.  Risk factors that cannot be modified include family history of dementia, genetic factors (APOE ԑ4), traumatic brain injuries and male sex. Other factors proposed to be related to increased AD risk include: low educational level, lack of cognitive activities, loneliness and lack of social networks, depression, low physical activity and heavy drinking {15} {43} {75}. Risk scores have been developed to predict risk of dementia {43}. It is not clear to what extent risk factors for clinically diagnosed AD increase the risk of developing neuropathological changes in AD or how comorbid conditions increase the risk of onset and progression of AD {75}. The role of modifiable life styles is also putative since the quantification of lifestyle factors varies largely in terms of intensity, frequency and duration of exposure.

The possible risk factors for minor cognitive impairment are partly the same as for dementia and Alzheimer’s disease, such as age, hypertension and ApoE ԑ4 {48}. Many other risk factors of dementia and Alzheimer’s disease have so far failed to show significant effect on MCI risk, such as gender, cardiovascular diseases, serum total cholesterol, cerebrovascular diseases, stroke, diabetes, smoking, psychiatric illness {48}.

The major issue with MCI is that subjects with this disorder may progress to dementia in higher proportions than do cognitively normal people. A challenge in assessing the outcome of MCI – as in the case of the incidence and prevalence of MCI – is the non-uniform criteria applied in the diagnosis of the disorder. Furthermore, the symptomatology in the subjects is variable and in addition to Alzheimer’s disease, MCI may appear in patients with other neurodegenerative disorders such as Parkinson’s disease an also in  cerebrovascular disorders. According to a meta-analysis of eight studies that examined the risk of  dementia or Alzheimer’s disease annual conversion rate (ACR) to dementia was 13.8 (95% 8.44–22.6), higher in subjects with MCI compared to healthy controls {56}. However, most of the individuals with MCI may not develop dementia. Studies report a wide variation in the risk of conversion after a one year follow-up (10.2 to 33.6%, median 19.0%), and after two years conversion frequency has varied from 9.8 to 36.3% (median 18.6%) {81}. A meta-analysis, based on the data of 41 studies with at least three years of follow-up concluded that about 30% of the MCI patients convert to dementia within 5 years after the diagnosis of MCI, and that the cumulative conversion rate to dementia in subjects followed up 5 years or more may not exceed 38% {56}. In general, population based studies show lower conversion rates of MCI to dementia: in the meta-analysis, the proportion of MCI subjects with conversion to dementia was 39.2% in the clinic based studies and 21.9% in community studies {56}. The ACR of MCI to dementia varies 2% to 31% across the studies {9}. Meta-analysis of community based studies reported an ACR of MCI to Alzheimer type dementia to be 6.9% (95% CI 4.1–10.4%) {56}. Several predictive factors for the risk of conversion from MCI to dementia have been identified. Multivariate analyses have shown that at baseline lower Mini Mental State Examination (MMSE), diastolic blood pressure, BMI {66}, ApoE ԑ4 allele {22}, temporal lobe /hippocampal volume in MRI {33} {37} {80}, abnormal FDG- or BIB PET {44} as well as CSF concentration of TAU and ApoE ԑ4 {33} {50} {54} {80} predict the risk of conversion to dementia. According to the meta-analysis of follow-ups studies, the ACR to dementia is similar in subjects with amnestic MCI and multiple-domain MCI (11.7% and 12.2%, respectively) and higher than in subjects with non-amnestic MCI {56}. Assessment of the risk of mortality associated with MCI is difficult due to limited number of population based studies as well as due to varying criteria for the diagnosis of MCI {34}. However, several studies have reporter increased mortality in subjects with MCI compared with cognitively non-impaired controls with hazard ratios varying from 1.2 to 2.2 {34} {35} {39} {83}. The mortality may be higher in subjects with multiple-domain amnestic MCI compared to those with single-domain amnestic MCI {39}. AD is characterized by insidious onset and progressive deterioration of cognitive function, functional abilities, behavior and mood. The progression varies inter-individually. Several scales are being used in clinical practice for the assessment of the severity of cognitive and functional decline in dementia. Most commonly used are MMSE, Clinical Dementia Rating (CDR), and Global Deterioration scale (GDS) {38} {68}. For clinical assessment and treatment consideration purposes, AD dementia is categorized as mild (MMSE 18–26, GDS 3–4, CDR 0.5–1), moderate (MMSE 10–22, GDS 4–6, CDR 1–2), and severe (MMSE 0–2, GDS 6–7, CDR 2–3). The decline in MMSE scores varies between 2.6 and 4.5 points in various studies, slower in community based studies than in clinic based surveys {1}. Some studies have suggested a non-linear decline in cognition in AD so that the progression is slower in patients with mild disease and on the other hand in severe disease but faster in patients with moderate disease {19} {57}. Functional decline is a prerequisite for the diagnosis of dementia and it is manifested already in early AD dementia. With the progression of cognitive symptoms in AD, social and occupational functioning continue to deteriorate {40}. Also behavioral and psychic symptoms correlate with the severity of cognitive deficits {47} {57}. Functional decline in patients with AD eventually leads to institutionalization. It has been estimated that approximately 50% of the demented patients of Northern Europe and North America are in institutionalized care but the percentage is lower in Southern European countries {1}.

The mortality risk in patients with AD is 1.5 to 5-fold compared with cognitively normal subjects {78}. Median survival time in AD ranges from 3.3 to 11.7 years {78}, and the annual mortality rate is 5.95% (95% CI 4.56–7.34) {18}. Predictive factors for mortality in patients with AD are age, male sex, increased disease severity and functional impairment {78}.

The hallmark of MCI is cognitive decline that is greater than expected for an individual’s age and education level. The cognitive decline does not, however, interfere notably with activities of daily life {31}. Thus, the subjects with MCI have subjective cognitive complaints, which can be objectively verified, but no dementia. In most cases MCI is associated with isolated memory impairment (so called amnestic MCI) but also non-amnestic MCI (impairment in executive, language or visuospatial functions) may occur {63}. The impairment can be restricted to one cognitive domain or to multiple domains {63}.

In addition to its core features, i.e. cognitive symptoms, MCI can be associated with various behavioral symptoms. Systematic reviews of studies addressing neuropsychiatric manifestations in MCI have revealed that many patients with MCI have depression, anxiety, apathy and irritability {4} {58}. In fact, neuropsychiatric symptoms in MCI have similar pattern as in AD {58}. In caregivers and the family MCI may cause depression, stress, and burden {73}.

In AD dementia, there is a progressive decline in cognition. In mild dementia, the most prominent deficit is in the ability to recall new information. Other symptoms include impairment in language and visuospatial functions as well as involvement of attentional and executive domains {40}. Neuropsychiatric symptoms include depression, anxiety and irritability. Also sleep problems, apathy, delusions and paranoia may appear {40}. The patients may be able to do shopping, simple hobbies, bathing and dressing but they may have difficulties in complex financial arrangement {40}.

Patients with moderate AD dementia have impairment of all major cognitive domains. Also behavioral and psychic symptoms progress and frank hallucinations and delusions may appear. Behavior may involve socially inappropriate issues, and motor restless may occur. Behavioral and psychic symptoms may emerge as primary issues for caregivers {40}. Most of the ADL functions begin to be significantly affected e.g. cooking, cleaning and simple financial actions are impaired. The patients require daily help in dressing and daily hygiene, and eating may be involved. The patients may need 24 hour supervision {40}.

In severe AD dementia the patients may be disoriented to place and time and they may have difficulties in identifying close relatives. They may be able to conduct a casual conversation.  Functionally the patients are dependent of others for almost all of their daily care and they suffer from incontinence. At the latest stages of the disease the patients become bedridden. Psychic symptoms include worsening hallucinations, agitation, or on the other hand, progressive apathy {40}.

Personality changes may accompany AD. Increased neuroticism, decreased extraversion and conscientiousness, and stable or slightly decreased openness and agreeableness have been observed in patients with AD {69}. These symptoms may be associated with social dysfunction due to AD. Literature suggests that high neuroticism or low conscientiousness may be early signs of dementia of the Alzheimer type as well as the best predictors of subsequent personality change in dementia {69}.

Alzheimer’s disease has great consequences not only for the patient and the family members, but also for the health care system and the society. The direct medical costs (hospital care, medication, visits to clinics) are highest in the Western Europe and North America, however, majority of the costs are related to direct social care costs (homecare, food services, residential and nursing home care) and  informal care (input of families) (CUR-5 Table 1). According to World bank data 42.3% of the total costs are direct social costs, 41.7% informal care and 16% direct medical costs {84}.

In the United Kingdom, the annual societal costs of dementia (£23 billion) were estimated to match those of cancer (£12 billion), heart disease (£8 billion) and stroke (£5 billion) combined {84}. Therefore early diagnosis and evidence-based interventions are in greater focus. Delaying the onset by just a year or two could reduce the burden of AD on society and health care system.

CUR-5 Table 1. Estimated number of people with dementia and prevalence of dementia in population > 60 years (2010) {65} and the burden of disease (in billions US$) by WHO {84}.

Key: ADLs, activities of daily living.

Intravenous immunoglobulins (IVIG) are expected to have potentially beneficial effects on the pathogenetic process of Alzheimer’s disease by stabilizing cognitive functioning in patients with mild-to-moderate Alzheimer’s disease {20} {46}. The benefits of IVIG in AD are believed to be related to fact that they contain both anti- tau and anti-Aβ natural antibodies and can help in reducing the misfolding, aggregation and deposition of amyloid-β, and deposition of misfolded tau protein in neurofibrillary tangles {Kayed}. The neuroprotective mechanisms of IVIG are not well known {82}.

If mild cognitive impartment would be identified early this would allow earlier treatment to slow progression of AD or even prevent it. Early interventions are likely to be more effective than if the disease is already advantaged. Slowing the progression of AD with IVIG or other therapies could have major impact on the need for care and burden of the disease.

At the moment it is not possible to assess impact of IVIG on AD mortality or other impacts on patients since we lack clinical studies.

A problem can arise in the supply of IVIG. IVIG is prepared from the plasma immunoglobulins of over 10 000 donors and the processing of plasma into IVIG takes about 9 months. IVIG treatment is therefore expensive. Supply could become a major problem if IVIG products would be used for AD unless new manufacturing processes are developed. {46}.

Target populations for IVIG therapy are {Appendix SAF-1}:

• Patients with Mild Cognitive Impairment (ICD-9-CM Diagnosis Code 331.83; ICD-10-CM G31.84) as defined by validated criteria;
• Patients with mild-to-moderate Alzheimer’s disease (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria and with MMSE score between 15 and 26;

Patients with moderate-to-severe Alzheimer’s disease (ICD-9-CM Diagnosis Code 331.0; ICD-10-CM G30.9), as defined by validated criteria and with MMSE score less than or equal to 14.

The worldwide prevalence estimates are given usually for dementia than for Alzheimer’s disease since the possibilities to make correct diagnosis can vary. Also estimates vary between studies.

The age-standardised prevalence of dementia among populations > 60 years is 5-7% {65}. In 2010 it was estimated that there are over 35 million people worldwide living with dementia. These numbers are expected to double every 20 years to 65.7 million in 2030 and to 115.4 million in 2050 {65} {Table CUR-5}. In 2010 over half (58%) of people with dementia lived in low or middle income countries, this proportion is expected to rise to 71% in 2050. China has more cases of Alzheimer’s disease than any other country; in 2010 there were 919 million (95% CI 5.92–12.48) people with dementia and the prevalence was 2.6% (0.0–28.2) at age 60-65 years and 60.5% (39.7–81.3) at age 95-99 year olds {12}. The incidence of dementia in China was 9.87 per 1000 person-years and that of Alzheimer’s disease 6.25/1000 person-years {12}. The increase in numbers of people with dementia will occur much rapidly in low or middle income countries and faster than assumed {12} {84}.

According to worldwide meta-analysis of studies between 1984-2008, the prevalence of mild cognitive impairment was 24.6% but varied between 21.5–71.5%, and the prevalence of amnestic MCI (aMCI) alone was 4.6% (range 8.5–25.9%). For people > 65 years the MCI incidence varied between 21.5–71.3/1000 person-years. For aMCI the rates ranged from 8.5 to 25.9 per 1000 person-years {81}. In another systematic review the incidence rates were 51–76.8/1000 person-years and for aMCI between 9.9 and 40.6/1000 person-years {48}.

There are no established treatments for MCI.

In contrast to MCI, there are several pharmacological possibilities for the treatment of AD. Currently available drug treatments for AD are considered symptomatic. It is recommended that patients with AD and mild to moderate dementia are initially treated with one of the cholinesterase inhibitors (ChEIs), i.e. donepezil, galantamine, or rivastigmine {30} {38} {89}. These drugs have been shown as having efficacy on cognitive function, global outcome, and ADL functions {38}. ChEIs can be used also in the severe form of AD either alone or in combination with the glutamate antagonist memantine {38}. Memantine can also be used alone in patients with severe AD and in patients who have contraindications or who are intolerant to ChEIs {38}. See also {CUR12}.

IVIG is considered as an experimental therapy in AD. Thus, the alternatives to IVIG in AD are the three ChEIs and memantine. It is recommended that patients with AD and mild to moderate dementia are initially treated with one of the cholinesterase inhibitors (ChEIs), i.e. donepezil, galantamine, or rivastigmine {30} {38} {89}. See {CUR12}.

MCI was introduced as a clinical entity more than 20 years ago, and during this time, multiple definitions for the syndrome have been proposed {63}. MCI is defined as a syndrome with cognitive decline greater than expected for an individual’s age and education level but in the absence of significant effect on instrumental activities of daily living (ADL) {31}. The subjects with MCI have thus subjective cognitive complaints which can be objectively verified but no dementia. Subjects with MCI have most commonly isolated memory impairment (so called amnestic MCI) but also non-amnestic MCI (impairment in executive, language or visuospatial functions) may occur {63}. The impairment can be restricted to one cognitive domain or to multiple domains {63}. In considering this clinical and cognitive syndrome, it is important to emphasize that sharp demarcations between normal cognition and MCI and between MCI and dementia are difficult, and clinical judgment must be used to make these distinctions {2}.

Current definition and diagnostic criteria for MCI are present in {CUR-11 Table 2}. There are no specific operational criteria for the diagnosis of MCI that are applied in the clinical daily routine {63}. In the clinical diagnosis of MCI the first step is history taking followed by physical examination including cognitive assessment {32} {38} {85}. Information from spouses, other relatives and caregivers are important in assessing possible behavioral symptoms and ADL functions. For the demonstration of cognitive impairment, measures such as the Mini Mental State Examination (MMSE) score or Montreal Cognitive Assessment (MoCA) test can be used {13}. However, the evidence of the sensitivity of MMSE in the identification of MCI is not good and the value of MMSE in the diagnosis of MCI is very limited {53}. The clinician should also determine whether the impairment involves only one cognitive domain such as memory or are other cognitive domains impaired {63}. Thereafter, the etiology of MCI should be evaluated with neuroimaging and possibly by biomarkers {64}.

The key element in the diagnosis of AD is clinical history which needs to be supplemented with information impairment in ADL functions {38}.  Diagnosis of AD requires an assessment of cognitive function in all patients {38}. Quantitative neuropsychological testing should be performed in subjects with questionable or very early dementia {38}. The proposed diagnostic criteria for probable and possible AD are presented in {CUR-11 Table 3} {51}. AD can be definitely diagnosed only post mortem {5}. Brain imaging studies are an essential part of diagnostic setup of bot MCI and AD and magnetic resonance imaging (MRI) is preferred because it is superior to computed tomography (CT) in demonstration of cerebral atrophy {28} {30} {38}. Hippocampal atrophy, as demonstrated by coronal T1-weighted MRI images is the best established and validated imaging marker of AD {28}. Functional neuroimaging, i.e. positron emission tomography (PET) with [18]-fluorodeoxyglucose (FDG) or [11C]PIB may increase the accuracy of separating subjects with MCI from healthy individuals {14} {28} {38}. Furthermore, MRI and PET may help to predict which cases of MCI will convert to AD {14} {28} {38}. A meta-analysis of MRI studies, using voxel-based morphomery in MCI patients, found that the left medial temporal lobe (especially hippocampus and parahippocampal gyrus) is the most affected region in MCI subjects who will convert to AD {27}. In addition to neuroimaging, the value of chemical biomarkers in the diagnosis of AD has been investigated. Low cerebrospinal fluid (CSF) concentration of amyloid-b (Ab1 – 42), in combination with high total CSF tau and phosphorylated tau, can discriminate AD patients from healthy subjects with reasonable sensitivity  and specificity {7} {26} {54}.  Due to issues such as variation in the results for different laboratories and cut off values, more validation work has to be done before the measurements can be considered mandatory in the diagnostics of dementia {5} {7} {27}. Subjects with cognitive problems usually see first their general practitioner (GP). Studies have shown that GPs correctly identify less than 50% of the individuals with MCI and they also have difficulties in identifying mild dementia {55}.

CUR-11 Table 2. Core clinical criteria for the diagnosis of MCI. Adapted from {2}.

CUR-11 Table 3. Diagnostic criteria for probable and possible Alzheimer’s disease dementia. Adapted from {51}.

There are no effective interventions available for MCI {16}. Two meta-analyses of the three studies reporting  conversion MCI to dementia gave no clear evidence of a beneficial effect of cholinesterase inhibitors (ChEI) on the progression to dementia at one, two or three years {70} {79}. The risk ratio (RR) for conversion at two years was significantly different from unity (0.67; 95% CI 0.55–0.83), but this is based on only two studies reported in the same article. There were essentially no clinically meaningful symptomatic effects of ChEI on cognitive test scores {70}. Other pharmacological interventions, such as huperzine A {88}, a chemical derived from a type of club moss (Huperzia serrate), vitamin E {24}, piribedil, nicotine, gingko biloba, B vitamins, nonsteroidal anti-inflammatory drugs, and omega-3 polysaturated fatty acids {16} have failed to reduce the risk of conversion to AD.

Non-pharmacological interventions physical activity and cognitive exercise may improve memory and executive functions in older people with MCI {67} {77}. Cognitive training interventions may improve some cognitive aspects in patients with MCI such as memory performance, executive functioning and attention but effects of these improvements on ADL functions is unclear {67}. Physical exercise may also have some positive effects {63} {77}. Treatment of modifiable risk factors in MCI, such as hypertension, diabetes mellitus, and hyperlipidemia, is recommended although there are no data of positive effects of interventions against these disorders {23}.

Currently available drug treatments for AD are considered symptomatic. It is recommended that patients with AD and mild to moderate dementia are initially treated with one of the cholinesterase inhibitors (ChEIs), i.e. donepezil, galantamine, or rivastigmine {30} {38} {89}. These drugs have been shown as having efficacy on cognitive function, global outcome, and ADL functions {38}. The effects of ChEis have been demonstrated mainly in studies lasting up to six months and the magnitude of the effects seems to be at the best modest {21} {38}. ChEIs have generally shown no meaningful improvement in the quality of life in patients with AD. The most common adverse effects of ChEIs are nausea, vomiting, diarrhea, abdominal pain, malaise, fatique, dizziness and headache. There is no conclusive evidence of any differenced in the efficacy or safety of the three ChEis {30} {38}. There are some discrepancies in the conclusions of different guidelines in respect to the use of ChEIs in severe AD: The NICE guidance {89} limits the use of ChEIs for mild to moderate AD whereas the European Federations of Neurological Sciences (EFNS) guideline and a Canadian guideline recommend the use of ChEIs also in the severe AD {30} {38}.

Memantine is a non-competetive N-methyl-D-aspartate receptor agonist which has been approved for use in moderate to severe AD. Evidence for the efficacy of memantine monotherapy in mild AD is lacking {71}. Recently, its efficacy as monotherapy in moderate to severe AD has been challenged {45}. The benefits of adding memantine to ChEI treatment are not clear {38} {61}. Systematic reviews suggest that the combination treatment with memantine and ChEIs may have beneficial effects on cognition, functional outcome and neuropsychiatric symptoms in patients with moderate to severe AD but the clinical relevance of the effects is unclear {25} {60}. The NICE guidance recommends the use of memantine in patients moderate AD who are intolerant or have a contraindication for ChEIs or for patients who have severe stage of AD {89}. The Canadian guideline concludes that there is insufficient evidence to recommend for or against the combined use of ChEIs and memantine {30}. Behavioral and psychic symptoms are prevalent in patients with AD the symptomatology tends to worsen with the progression of the disease. ChEIs have been shown to reduce behavioral and psychological symptoms in patients with mild to severe AD but the clinical relevance of the effects us unclear {11} {38}. ChEIs may have beneficial effects on psychosis and apathy {38}. Memantine may have efficacy on delusions, agitation, aggression and irritability in patients with severe AD {38}. Antidepressants may reduce agitation in patients with AD {74}. Risperidone and olanzapine are useful in reducing aggression in AD, and risperidone reduces psychotic symptoms in AD patient, but these drugs are associated with serous adverse cardiovascular events and extrapyramidal as well as with a small increase in the risk of death symptoms {6} {72}. Guidelines suggest that atypical antipsychotics can be used for severe agitation, aggression and psychosis at low doses and with careful monitoring {30} {38}. Mood stabilizers are ineffective or even harmful in AD {87}.

It has been shown that occupational therapies and exercise interventions may slow functional decline in AD but the clinical significance of the findings is uncertain {52}.

Since their introduction, IVIG have been proposed as a treatment for an array of disorders, including primary and secondary immune deficiency states, and a variety of autoimmune and inflammatory disorders.

It is suggested that IVIG (0.2 g to 2.0 g per kg bodyweight, any regimen) might have beneficial effects on the pathogenic processes of Alzheimer’s disease {20}, also at the stage of Mild Cognitive Impairment, by interfering positively with metabolism of amyloid β that seems to be reduced in subjects at risk for Alzheimer’s disease. It is hypothesised that IVIG use for passive immunotherapy in Alzheimer’s disease could slow the disease progression {20} {46} and use in patients with Mild Cognitive Impairment could avoid or delay the onset of Alzheimer’s disease {Appendix SAF-1}.

IVIG are currently used as first line therapy for various condition {90}. However, some new indications are emerging and extensions in the indications could be proposed {91}. At time of writing, no manufacturers have submitted requests to EMA for the market approval of the IVIG for Alzheimer’s disease including Mild Cognitive Impairment {Appendix CUR-3}.

IVIG are not used for Alzheimer’s disease including Mild Cognitive Impairment in any of the EUnetHTA partners answered the survey. However, while some partners explicitly excluded the use of IVIG for the mentioned indications, some others stated that, given the characteristics of the internal monitoring and reimbursement system, it’s impossible exclude the off-label use of IVIG {Appendix CUR-3}.

As IVIG have not been approved for Alzheimer’s disease including Mild Cognitive Impairment, IVIG therapy does not have a formal prescription pathway for such indications. Considering the contextual differences among the countries, a generalisation of the off-label prescription strategies of the IVIG therapy is not possible and remains out of the scope of the present results card.

The current setting for the administration of IVIG therapy (for any condition) is use within hospitals {Appendix CUR-3}.

Individual manufacturers are exploring the feasibility of developing IVIG therapy for Alzheimer’s disease including Mild Cognitive Impairment but, at time of writing, no manufacturers applied for market authorisation to EMA {Appendix CUR-3}. No data are available regarding the monitoring of off-label or compassionate use of IVIG for Alzheimer’s disease including Mild Cognitive Impairment {Appendix CUR-3}.

IVIG is presently very widely used for the treatment of a variety of immunologic disorders. IVIG is being used as a treatment in many different conditions, including mainly primary and secondary antibody deficiency states, haematology (acquired red cell aplasia, alloimmune thrombocytopenia, autoimmune haemolytic anaemia, haemolytic disease of the newborn, immune thrombocytopenic purpura), neurology (Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculneuropathy, inflammatory myopathy, Myastenia gravis, multifocal motor neuropaty) and other conditions (Kawasaki disease, transplantation, toxic epidermal necrolysis, staphylococcal or streptococcal toxic shock syndrome, autoimmune congenital heart block, autoimmune uveitis). See {TEC2}.

For more than thirty years, IVIG has been used for the treatment of post-exposure to infectious diseases, immune disorders and the management of patients with neurological conditions. IVIG treatment is used routinely for some immune-mediated neurological disorders such as Guillain-Barre syndrome, and recently IVIG has been investigated for the treatment of neurodegenerative disorders.

IVIG has not been approved for prevention or treatment of AD and mild cognitive impairment.

IVIG treatment of AD patients was first reported in a pilot study in 2004 {20}. Five patients with mild to moderate AD – Mini Mental State Examination (MMSE) mean score 19.4 – received Octagam (Octapharma; dose = 0.4 g/kg) on 3 successive days, every 4 weeks for 6 months. MMSE scores improved slightly in four of the AD patients and were unchanged in the fifth one, while their Alzheimer's Disease Assessment Scale-Cognitive sub-scale (ADAS-cog) scores decreased, suggesting increased cognitive functioning, in four patients and did not change in the fifth one. In 2009 results were published from a pilot study in which eight AD patients (mean MMSE score 23.5) were administered Gammagard S/D (Baxter Healthcare). After 6 months of treatment the mean MMSE score increased to 26.0, reflecting increased scores for six patients and no change in scores for two patients. After a 3-month washout period, the mean MMSE score returned to baseline (23.9). Following an additional 9 months of treatment, MMSE scores were essentially unchanged (mean 24.0).

Before publishing these results, in 2006 Baxter began a double-blind Phase II AD trial with Gammagard. Improved outcomes were noted in the Gammagard-treated subjects compared to those initially treated with placebo at 3, 6, and 9 months.

The results of a double-blind, placebo-controlled, 24- week phase II AD trial with Octagam were published in January 2013 {20}. Octagam had no apparent effects on cognitive or functional scores in the AD patients. No increase was found for plasma Aβ1-40; this had been reported in the pilot studies and suggested that IVIG products might increase efflux of Aβ from the brain. The only positive finding reported in this study, less reduction in glucose metabolism in some brain regions in the Octagam-treated individuals, was of uncertain significance. In conclusion, this trial showed favourable safety and tolerability of intravenous immunoglobulin and the absence of severe autoimmune reactions. Longer studies of larger populations are needed to assess effects on cognition and function in patients with Alzheimer’s disease.

In May 2013, the results of a placebo-controlled phase III AD trial with Gammagard were announced. Three hundred ninety patients had been treated every 2 weeks for 18 months with 200 mg/kg Gammagard, 400 mg/kg Gammagard, or placebo. No significant differences were found for the rate of cognitive decline between the Gammagard-treated group and placebo group.

Two AD-related IVIG trials are still in progress. Flebogamma (Grifols Biologicals) is being evaluated, together with albumin, in an AD phase III trial, and NewGam (Octapharma) is being investigated by Sutter Health in a phase II trial to determine its effects in patients with amnestic mild cognitive impairment (MCI) and its influence on the risk for these patients to develop AD. A possible reason for the failures in the most recent IVIG trials is that by the time AD’s clinical features become evident, its pathology, including extensive neuronal loss, is already well established. The trial with MCI patients should provide an indication of whether earlier IVIG treatment may be beneficial.

Newer research and developing human trials are becoming established for the use of intravenous immunoglobulins (IVIG) for the treatment and prevention of Alzheimer’s disease.

The IVIG trials reported to date in AD patients have produced conflicting findings. Because the most recent trials produced negative results, enthusiasm for IVIG as a treatment for AD has been reduced. Polyvalent antibody therapy for AD, as typified by IVIG, should have advantages over administration of individual monoclonal antibodies. To identify which antibodies should be included in an AD-specific IVIG preparation, more must be known about the range of anti-AD antibodies in IVIG and their effects on AD pathology in animal models. 

IVIG therapy is proposed as a new mode of care for Alzheimer’s disease including Mild Cognitive Impairment. Current management involves the treatment of cognitive, non-cognitive and behavioural symptoms. Non-pharmacological treatment includes social support, increasing assistance with day-to-day activities, information and education, carer support groups, community dementia teams, home nursing and personal care, community services such as meals-on-wheels, befriending services, day centres, respite care and care homes {89}. At the current stage of development, it is not possible to state whether the IVIG therapy will be proposed alone or in combination with the current management solutions.

Immunoglobulins (IVIG) are authorised in Europe as {Appendix CUR-3}:

Replacement therapy in adults, and children and adolescents (0-18 years) in the following conditions:

• Primary immunodeficiency syndromes with impaired antibody production;
• Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed;
• Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation;
• Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT);
• Congenital AIDS and recurrent bacterial infections;

Immunomodulation in adults, and children and adolescents (0-18 years) in the following conditions:

• Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count;
• Guillain Barré syndrome;
• Kawasaki disease;
• Multifocal Motor Neuropathy (MMN).

IVIG are reimbursed across countries for a list of approved indications. As IVIG are not formally used for Alzheimer’s disease including Mild Cognitive Impairment, no specific reimbursement schemes have been developed. Reimbursement of the IVIG therapy for off-label use cannot be excluded {Appendix CUR-3}.