Delphine Boche - Academia.edu (original) (raw)

Papers by Delphine Boche

Acta neuropathologica communications, Jan 3, 2018

Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulatio... more Alzheimer's disease (AD) is the most common cause of dementia among older adults. Accumulation of amyloid-β (Aβ) in the brain is considered central in AD pathogenesis and its understanding crucial for developing new diagnostic and therapeutic approaches. Recent literature suggests that ageing may induce post translational modifications in Aβ, in the form of spontaneous amino acid modifications, which enhance its pathogenic properties, contributing to its aggregation.In this study, we have investigated whether the isoaspartate (IsoD-Aβ) and pyroglutamate (pE3-Aβ) modified forms of Aβ are significantly associated with AD pathology or represent markers of ageing. Cerebral neocortex of 27 AD cases, 32 old controls (OC) and 11 young controls (YC) was immunostained for pE3-Aβ and IsoD-Aβ, quantified as protein load and correlated with other Aβ forms and p-TAU. IsoD-Aβ and pE3-Aβ were detected at low levels in non-demented controls, and significantly increased in AD (p ≤ 0.001), with a...

Brain pathology (Zurich, Switzerland), Jan 13, 2017

Aβ immunisation of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) tri... more Aβ immunisation of Alzheimer's disease (AD) patients in the AN1792 (Elan Pharmaceuticals) trial caused Aβ removal and a decreased density of neurons in the cerebral cortex. As preservation of neurons may be a critical determinant of outcome after Aβ immunisation, we have assessed the impact of previous Aβ immunisation on the expression of a range of apoptotic proteins in post-mortem human brain tissue. Cortex from 13 AD patients immunised with AN1792 (iAD) and from 27 non-immunised AD (cAD) cases was immunolabelled for pro-apoptotic proteins implicated in AD pathophysiology: phosphorylated c-Jun N-terminal kinase (pJNK), activated caspase3 (a-casp3), phosphorylated GSK3β on tyrosine 216 (GSK3βtyr216 ), p53 and Cdk5/p35. Expression of these proteins was analysed in relation to immunisation status and other clinical data. The antigen load of all of these pro-apoptotic proteins was significantly lower in iAD than cAD (p < 0.0001). In cAD, significant correlations (p < 0.001) ...

Journal of Neuroinflammation, 2016

Background: Genetic risk factors for Alzheimer's disease imply that inflammation plays a causal r... more Background: Genetic risk factors for Alzheimer's disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes. Methods: Using the Medical Research Council Cognitive Function and Ageing Studies resources, we have immunophenotyped microglia to investigate their role in dementia with Alzheimer's pathology. Cerebral cortex obtained at post-mortem from 299 participants was analysed by immunohistochemistry for cluster of differentiation (CD)68 (phagocytosis), human leukocyte antigen (HLA)-DR (antigen-presenting function), ionized calcium-binding adaptor molecule (Iba1) (microglial motility), macrophage scavenger receptor (MSR)-A (plaque-related phagocytosis) and CD64 (immunoglobulin Fcγ receptor I). Results: The presence of dementia was associated positively with CD68 (P < 0.001), MSR-A (P = 0.010) and CD64 (P = 0. 007) and negatively with Iba1 (P < 0.001). Among participants without dementia, the cognitive function according to the Mini-Mental State Examination was associated positively with Iba1 (P < 0.001) and negatively with CD68 (P = 0.033), and in participants with dementia and Alzheimer's pathology, positively with all microglial markers except Iba1. Overall, in participants without dementia, the relationship with Alzheimer's pathology was negative or not significant, and positive in participants with dementia and Alzheimer's pathology. Apolipoprotein E (APOE) ε2 allele was associated with expression of Iba1 (P = 0.001) and MSR-A (P < 0.001) and APOE ε4 with CD68, HLA-DR and CD64 (P < 0.001). Conclusions: Our findings raise the possibility that in dementia with Alzheimer's pathology, microglia lose motility (Iba-1) necessary to support neurons. Conversely, other microglial proteins (CD68, MSR-A), the role of which is clearance of damaged cellular material, are positively associated with Alzheimer's pathology and impaired cognitive function. In addition, our data imply that microglia may respond differently to Aβ and tau in participants with and without dementia so that the microglial activity could potentially influence the likelihood of developing dementia, as supported by genetic studies, highlighting the complexity and diversity of microglial responses.

Brain pathology (Zurich, Switzerland), May 22, 2016

Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk ... more Epidemiological and genetic studies have identified metabolic disorders and inflammation as risk factors for Alzheimer's disease (AD). Evidence in obesity and type-2 diabetes suggests a role for a metabolic inflammasome ("metaflammasome") in mediating chronic inflammation in peripheral organs implicating IKKβ (inhibitor of nuclear factor kappa-B kinase subunit beta), IRS1 (insulin receptor substrate 1), JNK (c-jun N-terminal kinase), and PKR (double-stranded RNA protein kinase). We hypothesized that these proteins are expressed in the brain in response to metabolic risk factors in AD. Neocortex from 299 participants from the MRC Cognitive Function and Ageing Studies was analysed by immunohistochemistry for the expression of the phosphorylated (active) form of IKKβ [pSer(176/180) ], IRS1 [pS(312) ], JNK [pThr(183) /Tyr(185) ] and PKR [pT(451) ]. The data were analysed to investigate whether the proteins were expressed together and in relation with metabolic disorders, d...

Stroke; a journal of cerebral circulation, Jan 14, 2016

Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Fr... more Long-term outcome after subarachnoid hemorrhage (SAH) is potentially linked to cytotoxic heme. Free heme is bound by hemopexin and rapidly scavenged by CD91. We hypothesized that heme scavenging in the brain would be associated with outcome after hemorrhage. Using cerebrospinal fluid and tissue from patients with SAH and control individuals, the activity of the intracranial CD91-hemopexin system was examined using ELISA, ultrahigh performance liquid chromatography, and immunohistochemistry. In control individuals, cerebrospinal fluid hemopexin was mainly synthesized intrathecally. After SAH, cerebrospinal fluid hemopexin was high in one third of cases, and these patients had a higher probability of delayed cerebral ischemia and poorer neurological outcome. The intracranial CD91-hemopexin system was active after SAH because CD91 positively correlated with iron deposition in brain tissue. Heme-hemopexin uptake saturated rapidly after SAH because bound heme accumulated early in the cer...

Acta neuropathologica, 2014

Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increa... more Aβ immunotherapy for Alzheimer's disease (AD) results in the removal of Aβ plaques and increased cerebral amyloid angiopathy (CAA). In current clinical trials, amyloid-related imaging abnormalities (ARIAs), putatively due to exacerbation of CAA, are concerning side effects. We aimed to assess the role of the Aβ transporter apolipoprotein E (apoE) in the exacerbation of CAA and development of CAA-associated vasculopathy after Aβ immunotherapy. 12 Aβ42-immunized AD (iAD; AN1792, Elan Pharmaceuticals) cases were compared with 28 unimmunized AD (cAD) cases. Immunohistochemistry was quantified for Aβ42, apoE, apoE E4 and smooth muscle actin, and CAA-associated vasculopathy was analyzed. Aβ immunotherapy was associated with redistribution of apoE from cortical plaques to cerebral vessel walls, mirroring the altered distribution of Aβ42. Concentric vessel wall splitting was increased threefold in leptomeningeal vessels after immunotherapy (cAD 6.3 vs iAD 20.6 %, P < 0.001), but smoo...

The Journal of Pathology: Clinical Research, 2015

Brain tumour stem cells and microglia both promote the growth of astrocytomas, the commonest form... more Brain tumour stem cells and microglia both promote the growth of astrocytomas, the commonest form of primary brain tumour, with recent emerging evidence that these cell types may interact in glioma models. It is unclear whether microglia and stem cells are associated in human gliomas. To investigate this question, we used the technique of tissue microarrays to perform a correlative study of a large number of tumour samples. We quantified immunostaining of human astrocytic tumour tissue microarrays (86 patients; World Health Organisation grade II-IV) for microglia Ionized calcium binding adaptor molecule 1 (Iba1) and CD68, and stem cell nestin, SOX2 and CD133. Ki67 was used to assess proliferation and GFAP for astrocytic differentiation. Immunoreactivity for both microglial markers and stem cell markers nestin and SOX2 significantly increased with increasing tumour grade. GFAP was higher in low grade astrocytomas. There was a positive correlation between: (i) both microglial markers and nestin and CD133, (ii) nestin and tumour cell proliferation Ki67 and (iii) both microglial markers and Ki67. SOX2 was not associated with microglia or tumour proliferation. To test the clinical relevance, we investigated the putative association of these markers with clinical outcomes. High expression for nestin and Iba1 correlated with significantly shorter survival times, and high expression for nestin, Iba1, CD68 and Ki67 was associated with faster tumour progression on univariate analysis. On multivariate analysis, nestin, CD133 and Ki67 remained significant predictors of poorer survival, after adjustment for other markers. These results confirm previous in vitro findings, demonstrating their functional relevance as a therapeutic target in humans. This is the first report of a novel correlation between microglia and stem cells that may drive human astrocytic tumour development.

The Lancet, 2008

Background Immunisation of patients with Alzheimer's disease with full-length amyloid-β peptide (... more Background Immunisation of patients with Alzheimer's disease with full-length amyloid-β peptide (Aβ 42) can clear amyloid plaques from the brain. Our aim was to assess the relation between Aβ 42 immune response, degree of plaque removal, and long-term clinical outcomes. Methods In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with Aβ 42 (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with Aβ immunostaining (Aβ load) and in terms of characteristic histological features refl ecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model. Findings 20 participants-15 in the AN1792 group, fi ve in the placebo group-died before follow-up started. A further 22 patients-19 in the AN1792 group, three in the placebo group-died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. In the remaining eight participants who received immunisation and who were examined neuropathologically, mean Aβ load was lower than in an unimmunised control group that was matched for age at death (2•1% [SE 0•7] in treated participants vs 5•1% [0•9] in controls; mean diff erence 3•0%, 95% CI 0•6-5•4; p=0•02). Although there was considerable variation in Aβ load and degree of plaque removal among immunised participants, the degree of plaque removal varied signifi cantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0•02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0•93, 95% CI 0•43-3•11; p=0•86) or of an improvement in the time to severe dementia (1•18, 0•45-3•11; p=0•73) in the AN1792 group versus the placebo group. Interpretation Although immunisation with Aβ 42 resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.

The Journal of Pathology, 2015

Amyloid β peptide (Aβ) immunization of Alzheimer's disease (AD) patients has been reported to ind... more Amyloid β peptide (Aβ) immunization of Alzheimer's disease (AD) patients has been reported to induce amyloid plaque removal but with little impact on cognitive decline. We have explored the consequences of Aβ immunotherapy on neurons in post-mortem brain tissue. Eleven immunized (AN1792, Elan Pharmaceuticals) AD patients were compared to 28 non-immunized AD cases. Immunohistochemistry on sections of neocortex was performed for neuron-specific nuclear antigen (NeuN), neurofilament protein (NFP) and phosphorylated-(p)PKR (pro-apoptotic kinase detected in degenerating neurons). Quantification was performed for pPKR and status spongiosis (neuropil degeneration), NeuN positive neurons/field, curvature of the neuronal processes and interneuronal distance. Data were corrected for age, sex, duration of dementia and APOE genotype and also assessed in relation to Aβ42 and tau pathology, and key features of AD. In non-immunized patients, the degree of neuritic curvature correlated with spongiosis and pPKR, and overall the neurodegenerative markers correlated better with tau pathology than Aβ42 load. Following immunization, spongiosis increased, interneuronal distance increased, while the number of NeuN-positive neurons decreased, consistent with enhanced neuronal loss. However neuritic curvature was reduced and pPKR was associated with Aβ removal (p=0.001) in immunized patients. In AD, associations of spongiosis status, curvature ratio and pPKR load with This article is protected by copyright. All rights reserved microglial markers Iba1, CD68 and CD32 suggest a role for microglia in neurodegeneration. After immunization, correlations were detected between the number of NeuN-positive neurons and pPKR with Iba1, CD68 and CD64, suggesting that microglia are involved in the neuronal loss. Our findings suggest that in established AD this form of active Aβ immunization may predominantly accelerate loss of damaged degenerating neurons. This interpretation is consistent with in vivo imaging indicating an increased rate of cerebral atrophy in immunized AD patients.

Neuropathology and Applied Neurobiology, 2015

This article has been accepted for publication and undergone full peer review but has not been th... more This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as

PLoS ONE, 2013

Progress in the development of therapeutic interventions to treat or slow the progression of Alzh... more Progress in the development of therapeutic interventions to treat or slow the progression of Alzheimer's disease has been hampered by lack of efficacy and unforeseen side effects in human clinical trials. This setback highlights the need for new approaches for pre-clinical testing of possible interventions. Systems modelling is becoming increasingly recognised as a valuable tool for investigating molecular and cellular mechanisms involved in ageing and age-related diseases. However, there is still a lack of awareness of modelling approaches in many areas of biomedical research. We previously developed a stochastic computer model to examine some of the key pathways involved in the aggregation of amyloid-beta (Ab) and the micro-tubular binding protein tau. Here we show how we extended this model to include the main processes involved in passive and active immunisation against Ab and then demonstrate the effects of this intervention on soluble Ab, plaques, phosphorylated tau and tangles. The model predicts that immunisation leads to clearance of plaques but only results in small reductions in levels of soluble Ab, phosphorylated tau and tangles. The behaviour of this model is supported by neuropathological observations in Alzheimer patients immunised against Ab. Since, soluble Ab, phosphorylated tau and tangles more closely correlate with cognitive decline than plaques, our model suggests that immunotherapy against Ab may not be effective unless it is performed very early in the disease process or combined with other therapies.

Neuropathology and Applied Neurobiology, 2011

Microglial alterations in human Alzheimer's disease following Ab42 immunization Aims: In Alzheime... more Microglial alterations in human Alzheimer's disease following Ab42 immunization Aims: In Alzheimer's disease (AD), microglial activation prompted by the presence of amyloid has been proposed as an important contributor to the neurodegenerative process. Conversely following Ab immunization, phagocytic microglia have been implicated in plaque removal, potentially a beneficial effect. We have investigated the effects of Ab42 immunization on microglial activation and the relationship with Ab42 load in human AD. Methods: Immunostaining against Ab42 and microglia (CD68 and HLA-DR) was performed in nine immunized AD cases (iAD-AN1792, Elan Pharmaceuticals) and eight unimmunized AD (cAD) cases. Results: Although the Ab42 load (% area stained of total area examined) was lower in the iAD than the cAD cases (P = 0.036), the CD68 load was higher (P = 0.046). In addition, in the iAD group, the CD68 level correlated with the Ab42 load, consistent with the immunization upregulating microglial phagocytosis when plaques are present. However, in two long-surviving iAD patients in whom plaques had been extensively cleared, the CD68 load was less than in controls. HLA-DR quantification did not show significant difference implying that the microglial activation may have related specifically to their phagocytic function. CD68 and HLA-DR loads in the pons were similar in both groups, suggesting that the differences in microglial activation in the cortex were due to the presence of AD pathology. Conclusion: Our findings suggest that Ab42 immunization modifies the function of microglia by increasing their phagocytic activity and when plaques have been cleared, the level of phagocytosis is decreased below that seen in unimmunized AD.

Journal of Neuropathology & Experimental Neurology, 2006

Neuropathologic examination of 3 patients with Alzheimer disease in the Elan Pharmaceuticals tria... more Neuropathologic examination of 3 patients with Alzheimer disease in the Elan Pharmaceuticals trial using antibodies specific for different AA species showed in one case, 4 months after the immunization, evidence of a stage of active plaque clearance with Bmoth-eaten[ plaques and abundant AA phagocytosis by microglia. At 1 to 2 years after immunization, 2 cases showed extensive areas cleared of plaques (69% and 86% of the temporal cortex was plaque-free). Cortex cleared of plaques in all 3 cases had a characteristic constellation of features, including a very low plaque burden, sparse residual dense plaque cores, and phagocytosed AA within microglia. There was resolution of tau-containing dystrophic neurites, although other features of tau pathology (tangles and neuropil threads) remained and cerebral amyloid angiopathy persisted. Although most antibodies generated by AA 42 immunization in humans bind the intact N-terminus, immunohistochemistry with specific antibodies showed clearance of all major species of AA (AA 40 , AA 42 , and N-terminus truncated AA). AA immunotherapy can clear all AA species from the cortex. However, if it is to be used for treatment of established Alzheimer disease, then the residual tau pathology and cerebral amyloid angiopathy require further study.

Clinical Neuropharmacology, 2006

The aim of this article is to review the role of immunotherapy in the removal of proteins which a... more The aim of this article is to review the role of immunotherapy in the removal of proteins which accumulate abnormally in neurodegenerative disorders associated with dementia, in particular amyloid-$ accumulation in Alzheimer's disease. Results: In both transgenic mouse models and in two trials of amyloid-$ immunotherapy for human Alzheimer's disease, active immunization with amyloid-$ 1Y42 results in the removal of amyloid-$ plaques from the cerebral cortex associated with, in the mouse models, improvement in cognitive function. Cerebral amyloid angiopathy and neurofibrillary tangles persist, however, and there is also concern about T lymphocyte immune reactions in the meninges in the human cases. Active immunization schedules are being developed to minimize T lymphocyte reactions and to maximize antibody production and passive immunization protocols are being devised. Immunotherapy for removal of the proteins which accumulate in other neurodegenerative disorders associated with dementia such as prion proteins and "-synuclein are in the early stages of development. Conclusion: Dementias in the elderly are an increasing medical, social and economic problem and current treatments are only effective. In the majority of dementias, proteins accumulate within cells and in the extracellular compartments of the brain. In the most common dementia, Alzheimer's disease, amyloid-$ accumulates as plaques in the extracellular space of the grey matter and in artery walls as cerebral amyloid angiopathy and tau protein accumulates as neurofibrillary tangles within neurons.

Brain, 2013

Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response t... more Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-b immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-b 42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fc receptors I (CD64) and II (CD32); and also immunoglobulin IgG, complement C1q and the T lymphocyte marker CD3 using immunohistochemistry. The data were analysed with regard to amyloid-b and phospho-tau pathology, severity of cerebral amyloid angiopathy and cortical microhaemorrhages. In non-immunized Alzheimer's disease cases, amyloid-b 42 correlated inversely with CD32 and Iba-1, whereas phospho-tau correlated directly with all microglial markers, IgG, C1q and the number of T cells. In immunized Alzheimer's disease cases, amyloid-b 42 load correlated directly with macrophage scavenger receptor A-positive clusters and inversely with C1q. The severity of cerebral amyloid angiopathy and microhaemorrhages did not relate to any of the analysed markers. Overall, the levels of CD68, macrophage scavenger receptor A, CD64, CD32 and the number of macrophage scavenger receptor A-positive plaque-related clusters were significantly lower in immunized than non-immunized cases, although there was no significant difference in Iba-1 load, number of Iba-1-positive cells, IgG load, C1q load or number of T cells. Our findings indicate that different microglial populations co-exist in the Alzheimer's disease brain, and that the local inflammatory status within the grey matter is importantly linked with tau pathology. After amyloid-b immunization, the microglial functional state is altered in association with reduced amyloid-b and tau pathology. The results suggest that, in the long term, amyloid-b immunotherapy results in downregulation of microglial activation and potentially reduces the inflammation-mediated component of the neurodegeneration of Alzheimer's disease.

Brain, 2008

A major feature of Alzheimer's disease is the accumulation of amyloid-b peptide (Ab) in the brain... more A major feature of Alzheimer's disease is the accumulation of amyloid-b peptide (Ab) in the brain both in the form of plaques in the cerebral cortex and in blood vessel as cerebral amyloid angiopathy (CAA). Experimental models and human clinical trials have shown that accumulation of Ab plaques can be reversed by immunotherapy. In this study, we hypothesized that Ab in plaques is solubilized by antibodies generated by immunization and drains via the perivascular pathway, detectable as an increase in cerebrovascular Ab. We have performed a follow up study of Alzheimer's disease patients immunized against Ab42. Neuropathological examination was performed on nine patients who died between four months and five years after their first immunization. Immunostaining for Ab40 and Ab42 was quantified and compared with that in unimmunized Alzheimer's disease controls (n = 11). Overall, compared with these controls, the group of immunized patients had approximately 14 times as many blood vessels containing Ab42 in the cerebral cortex (P_0.001) and seven times more in the leptomeninges (P = 0.013); among the affected blood vessels in the immunized cases, most of them had full thickness and full circumference involvement of the vessel wall in the cortex (P = 0.001), and in the leptomeninges (P = 0.015). There was also a significantly higher level of cerebrovascular Ab40 in the immunized cases than in the unimmunized cases (cortex: P = 0.009 and leptomeninges: P = 0.002). In addition, the immunized patients showed a higher density of cortical microhaemorrhages and microvascular lesions than the unimmunized controls, though none had major CAA-related intracerebral haemorrhages. The changes in cerebral vascular Ab load did not appear to substantially influence the structural proteins of the blood vessels. Unlike most of the immunized patients, two of the longest survivors, four to five years after first immunization, had virtually complete absence of both plaques and CAA, raising the possibility that, given time, Ab is eventually cleared from the cerebral vasculature. The findings are consistent with the hypothesis that Ab immunization results in solubilization of plaque Ab42 which, at least in part, exits the brain via the perivascular pathway, causing a transient increase in the severity of CAA. The extent to which these vascular alterations following Ab immunization in Alzheimer's disease are reflected in changes in cognitive function remains to be determined.

Brain Pathology, 2008

In Alzheimer's disease (AD), there is abnormal accumulation of Ab and tau proteins in the brain. ... more In Alzheimer's disease (AD), there is abnormal accumulation of Ab and tau proteins in the brain. There is an associated immunological response, but it is still unclear whether this is beneficial or harmful. Inflammation in AD, specifically in the form of microglial activation, has, for many years, been considered to contribute to disease progression. However, two types of evidence suggest that it may be appropriate to revise this view: first, the disappointing results of prospective clinical trials of anti-inflammatory agents and, second, the observation that microglia can clear plaques in AD following Ab immunization. Although Ab immunization alters AD pathology, there is limited evidence so far of benefit to cognitive function. Immunization against microorganisms is almost always used as a method of disease prevention rather than to treat a disease process that has already started. In animal models, immunotherapy at an early age can protect against Ab accumulation and it will be interesting to see if this can usefully be applied to humans to prevent AD.

Alzheimer's Research & Therapy, 2010

Evidence for the involvement of infl ammatory processes in the pathogenesis of Alzheimer's diseas... more Evidence for the involvement of infl ammatory processes in the pathogenesis of Alzheimer's disease (AD) has been documented for a long time. However, the infl ammation hypothesis in relation to AD pathology has emerged relatively recently. Even in this hypothesis, the infl ammatory reaction is still considered to be a downstream eff ect of the accumulated proteins (amyloid beta (Aβ) and tau). This review aims to highlight the importance of the immune processes involved in AD pathogenesis based on the outcomes of the two major infl ammation-relevant treatment strategies against AD developed and tested to date in animal studies and human clinical trials-the use of anti-infl ammatory drugs and immunisation against Aβ.