In addition to amyloid beta (Aβ) and tau protein aggregates, the presence of immune-related antigens and cells around amyloid plaques in the brains of patients with Alzheimer's disease (AD) has been reported since the 1980s 123. These initial observations brought about changes to the previously assumed view of the brain as an immunologically isolated organ. In the 1990s, additional findings of activated complement factors, cytokines and a wide range of related receptors in the brain of AD patients led to the concept of neuroinflammation (inflammation within the central nervous system (CNS)), which suggests that immunological processes in the brain are likely to be involved in the pathology of degenerative diseases of the CNS. Table 1 lists signs of an altered immune response reported in AD patients.

The role of aggregated proteins in the pathology of AD had to be re-considered to account for these observations. The inflammation hypothesis emerged relatively recently, when it became clear that the observations of altered immune processes in AD could not be ignored. Neuroinflammation is still considered to be a downstream consequence in the amyloid hypothesis, with Aβ amyloid within the CNS bringing about activation of microglia, initiating a pro-inflammatory cascade that results in the release of potentially neurotoxic substances, including cytokines, chemokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, leading to degenerative changes in neurons 4567. It has also been suggested that activation of microglia may lead to phosphorylation of tau and formation of neurofibrillary tangles (NFTs) 8910. However, the exact role of inflammation in the pathology of AD and its mechanisms in terms of the cells involved - microglia, astrocytes and T lymphocytes - are still debated.

The inflammation hypothesis is also supported by epidemiological retrospective observations that patients with rheumatoid disease who are on long-term anti-inflammatory therapy have a lower prevalence of AD 1112131415. Other largely observational studies have also supported the concept that anti-inflammatory approaches may be protective against the development of AD 1617. Furthermore, transgenic animal studies and human trials have demonstrated that treatment with nitric oxide-releasing non-steroidal anti-inflammatory drugs (NSAIDs) can reduce and/or prevent the AD pathology (reviewed by McGeer and McGeer 18). It has also been shown that a certain drug with anti-inflammatory properties (CNI-1493) suppresses amyloid pathology and improves memory performance in transgenic mice 19. Despite these findings, however, several prospective anti-inflammatory strategies against disease progression in subjects with established AD have failed to show convincingly positive results (see the 'Current treatment strategies based on the inflammation hypothesis' section below). Although these effects did not reach significant levels in large human cohorts 20, interest in the inflammatory processes of AD pathology has persisted 2122. One particularly interesting aspect of these studies was that (at least in animal models) the observed beneficial action of anti-inflammatory drugs was not necessarily attributed to down-regulation of inflammatory processes. Instead, activation of microglia via a route that enhances its phagocytic activity against Aβ was suggested 23.

The inflammation hypothesis also suggests another approach to sporadic AD and associated risk factors for investigation - polymorphism of genes related to induction and regulation of inflammatory processes. Initial studies suggested a role for specific cytokine polymorphisms - for example, in the genes encoding IL-1 and TNFa 2425 - with evidence that IL-1 polymorphism may be associated with differing degrees of microglial activation in AD 26. However, a meta-analysis of genetic influences in AD has not supported the initial findings of cytokine gene variation as a risk factor for AD, but has instead emphasised the over-riding importance of the APOE gene polymorphism as the major genetic risk factor 27. Although many mechanisms for the role of apolipoprotein E (APOE) in AD pathogenesis have been suggested 28, the key mechanism remains unclear. Of particular interest to the inflammation hypothesis is the finding that APOE e4 carriers with AD have more marked microglial activation 29.

Research into the role of inflammation in AD is driven by questions similar to those posed for Aβ and abnormal tau accumulation. Can neuroinflammation be the cause of AD? Are the inflammatory processes in AD contributing to the disease pathology? Alternatively, are they merely the consequence of the disease, initiated and driven by the neurodegeneration? Does inflammation act as a harmless bystander in the disease course? Can the immune processes of the brain be harnessed to fight against the disease pathology?

Inflammation as the sole cause of AD is usually considered as unlikely on the basis that peripheral systemic disorders rarely start with inflammation - there is an initial challenge that is required to stimulate an immune (or inflammatory) response 30. However, it should be noted that being a response to an insult rather than an insult itself, inflammation plays an important role in the reaction of an organism to this insult, with potentially damaging and sometimes fatal consequences (for example, in allergy). Autoimmune diseases can affect the CNS (for example, paraneoplastic syndromes, multiple sclerosis) but there is little evidence to suggest that AD falls into this category.

With respect to whether inflammatory processes in AD contribute to the disease pathology, a lot of evidence has accumulated suggesting that inflammation can contribute to the AD process and exacerbate the course of the disease. It is still unclear exactly how inflammation acts on the diseased brain, as most of the observations about the mechanisms of its action are based on animal models. However, the supportive evidence for inflammation being a contributor to the disease process is as follows. First, the cognitive state of AD patients who also have short-term peripheral infection show signs of sudden decline in cognitive state, and rarely return to the previous level even after recovery from the infection 31. Second, community-based studies suggest that plasma levels of inflammatory proteins, including cytokines, are increased before clinical onset of dementia, including AD 32, which may be exacerbated by the presence of atherosclerosis 33. Third, observed signs of inflammation in the brain of AD patients are comparable to those seen in peripheral inflammatory reactions and are likely to have a strong cytotoxic effect on neurons 530. Fourth, signs of inflammation are particularly localised in the brain areas affected by AD pathology and co-localise with plaques and tau deposits 1234353637383940. Fifth, high pathology controls (individuals who have Aβ and tau aggregates at levels similar to AD patients, but do not develop dementia) show lower signs of inflammation 41. Sixth, Mini Mental State Examination scores of AD patients correlate with the level of cortical microglial activation as observed from in vivo imaging studies 42.

From these observations, inflammation could contribute to the course of AD in two ways. Firstly, as an initial innate immune response to the changes in the AD brain. In the periphery, the innate immune system generates a non-specific response to an invading pathogen or a cell stress stimulus as a general first-line defence mechanism. Inflammation is part of this response, involving signalling via cytokines and via activation of the complement system to recruit the immune cells to the site of stress. In the periphery, this response is also often referred to as an acute, strong, but short-lived immune reaction. In the context of AD, association of microglia - the immune system cells of the CNS - with plaques and NFTs has been observed, suggesting involvement of innate immunity in the reaction to the AD-related stimuli. Observations of acute-phase inflammatory proteins alongside cytokines and chemokines associated with plaques and tangles in AD have been reported, suggestive of multiple ways of interaction between these inflammatory mediators 5. The presence of elements of the complement system and membrane attack complex C5b-9, in particular, has been reported to correlate highly with the level of synaptic loss 41. This engagement of the complement system has not been observed in the brains of high pathology controls, contributing to evidence of the involvement of acute mediators in AD. The C5b-9 complex is known to be very potent at killing or damaging neurons through signalling for production of various cytokines and other complement elements 30. However, most studies refer to inflammation in AD as weak and non-specific. This is explained on the basis of the presence of multiple mechanisms that regulate inflammatory reactions within the brain and minimise them 43. Nevertheless, long exposure to ongoing inflammation signalling, even at low levels, can bring about gradual neurodegeneration that might be more difficult to stop or reverse than acute inflammatory episodes observed in peripheral disorders 30.

Secondly, the low-level ongoing inflammation in AD contributing to the course of the disease can be a sign of impaired adaptive immune responses leading to chronic inflammation. In the periphery, an innate immune response is followed by a switch to an adaptive response with generation of antibodies and overall down-regulation of acute pro-inflammatory signalling. The functions of the adaptive immune response include induction of more specific and stronger defence mechanisms against abnormal stimuli, and engagement of memory T cells that can recognise and eliminate the same stimulus more quickly and efficiently if it is encountered again in the future. The important feature of this type of response is to be able to recognise 'non-self' antigens and distinguish them from 'self'. In the context of AD pathology, Aβ plaques and NFTs persist, accompanied by ongoing inflammation over a long period of time, during which the disease progresses. It is suggested, therefore, that after induction of the initial immune response, when plaques and tangles are recognised as invading stimuli, transition to the adaptive immune response and the mechanism of recognition of plaques and tangles as persisting stress stimuli is impaired. With respect to microglia in AD, this effect is reflected by their inability to transit from an initial classic state (also referred to as pro-inflammatory or Th1-induced) to an alternative (anti-inflammatory or Th2-induced) immune response. Impaired activation of microglial Toll-like receptors in AD brain has also been suggested 444546. The result is that phagocytic activity as well as the neuroprotective function of microglia are impaired 47.

The type of inflammation in the AD brain is not well defined and is often blamed on 'dysfunctional' or 'malactivated' microglia 48. The exact profile of these microglia has not yet been well characterised 4, but the description is often based on observation of a single marker or a dystrophic and apoptotic appearance of the cells 484950.

Some studies report the presence of auto-antibodies against Aβ in older people 51, and possible involvement of T and B cells in the AD process 5253. However, conclusive positive evidence for direct involvement of antibody-mediated response in AD has not yet been presented 30.

One could also suggest that inflammation observed in the brains of AD patients is merely a consequence of the disease, pointing to an inability of microglia to clear ever-growing neuronal debris due to extensive neurodegeneration and synaptic loss. Impaired recruitment of monocytes from the periphery to the site of the disease in AD brain has been suggested in this respect and demonstrated using animal models 545556.

The phagocytic profile of microglia that is often referred to in AD brain is generally non-aggressive, aiming at clearing the damage/debris with minimal further damage to the surrounding tissue, leading to the question: can inflammatory activity in AD brain have a neutral or even beneficial role? However, another perspective comes from studies using a model of neurodegeneration - the ME7 mouse model of prion disease 57. These studies suggest that microglia in the context of a neurodegenerative disease, although generally in an anti-inflammatory state, are 'primed' to switch quickly into an aggressive profile should the opportunity arise. Such an opportunity may be a peripheral infection, as demonstrated in this model 58.

Mixed and often contradictory findings with respect to inflammation in AD indicate the complexity and multi-functional role of the immune system. It became apparent that inflammation in the CNS, as in the periphery, is a mixture of both destructive and rebuilding processes. The balance between these processes determines the overall integrity of the tissue or the whole organism 59. Therefore, inflammation should not be viewed as wholly detrimental or beneficial in AD. Understanding of the whole spectrum of the immune processes involved is necessary to find an optimal solution for the prevention or treatment of the disease.

The possibility of harnessing immune processes to direct the system towards clearance of the disease features has become an actively researched topic of AD. Much AD research is now aimed at modulation of the immune system to direct it away from microglial activation that is pro-inflammatory (or malactivated) towards a more controlled productive and phagocytic antibody-mediated immune response 60.

In summary, the pathological changes associated with AD as described above should not be considered in isolation. It is more likely that their cumulative action results in disruption of the normal work of the CNS through damage to neurotransmitter systems, neuronal dysfunction and death.

Two main treatment approaches addressing inflammatory processes in AD, but from different perspectives, have been investigated so far. The use of anti-inflammatory drugs aims to down-regulate the inflammation in AD brain for a potential beneficial effect, whereas the immunotherapy approach aims to harness the immune system and direct it against the pathological features of the disease, mainly Aβ deposition. The advances in, and limitations of, both approaches are discussed below.

Research into the inflammation in AD so far has demonstrated the complexity of the mechanisms involved, which interact with each other in multiple ways. This web of interactions makes it difficult to isolate any particular inflammatory process, element or cell and pinpoint its individual role in the progress of the disease. Immunisation as one of the AD treatment approaches has led to an increased interest in the immune processes associated with this disease and highlighted their role in AD pathogenesis. The ability to modulate the immune system by active immunisation to generate anti-Aβ antibodies and stimulate clearance of amyloid plaques underlined the potentially beneficial effect that the immune system can have on the pathology of the disease. The inflammatory response side-effect developed by some immunised patients pointed to the complexity of the immune processes acting in the brain and their potential for harmful effects. Microglia, as the main representative of the immune system in the CNS, play an important role in both of these effects. Their mechanism of action in AD pathogenesis and in the context of Aβ immunisation is still not clear. This review aimed to highlight the necessity of approaching current and future research into AD from multiple directions, and the importance of addressing neuro-immune interactions involved in the whole course of the disease when devising potential treatment strategies.

Aβ: amyloid beta; AD: Alzheimer's disease; APOE: apolipoprotein E; CNS: central nervous system; IL: interleukin; NFT: neurofibrillary tangle; NSAID: non-steroidal anti-inflammatory drug; TNF: tumour necrosis factor.

The authors declare that they have no competing interests.