Beruflich Dokumente
Kultur Dokumente
Available online at
ScienceDirect
www.sciencedirect.com
Article history: Recent advances in the understanding of Alzheimer’s disease pathogenesis have led to the
Received 24 April 2014 development of numerous compounds that might modify the disease process. Amyloid b
Received in revised form peptide represents an important molecular target for intervention in Alzheimer’s disease.
11 September 2014 The main purpose of this work is to review immunotherapy studies in relation to the
Accepted 3 October 2014 Alzheimer’s disease. Several types of amyloid b peptide immunotherapy for Alzheimer’s
Available online 6 November 2014 disease are under investigation, active immunization and passive administration with
monoclonal antibodies directed against amyloid b peptide. Although immunotherapy
Keywords: approaches resulted in clearance of amyloid plaques in patients with Alzheimer’s disease,
Alzheimer’s disease this clearance did not show significant cognitive effect for the moment. Currently, several
Immunotherapy amyloid b peptide immunotherapy approaches are under investigation but also against tau
Vaccine pathology. Results from amyloid-based immunotherapy studies in clinical trials indicate
Monoclonal antibodies that intervention appears to be more effective in early stages of amyloid accumulation in
Biomarkers particular solanezumab with a potential impact at mild Alzheimer’s disease, highlighting
Amyloid b peptide the importance of diagnosing Alzheimer’s disease as early as possible and undertaking
clinical trials at this stage. In both phase III solanezumab and bapineuzumab trials, PET
Mots clés : imaging revealed that about a quarter of patients lacked fibrillar amyloid pathology at
Maladie d’Alzheimer baseline, suggesting that they did not have Alzheimer’s disease in the first place. So a new
Immunothérapie third phase 3 clinical trial for solanezumab, called Expedition 3, in patients with mild
Vaccin Alzheimer’s disease and evidence of amyloid burden has been started. Thus, currently,
Anticorps monoclonaux amyloid intervention is realized at early stage of the Alzheimer’s disease in clinical trials, at
Biomarqueurs prodromal Alzheimer’s disease, or at asymptomatic subjects or at risk to develop Alzhei-
Peptide b amyloı̈de mer’s disease and or at asymptomatic subjects with autosomal dominant mutation.
# 2014 Elsevier Masson SAS. All rights reserved.
* Corresponding author.
E-mail address: delrieu.j@chu-toulouse.fr (J. Delrieu).
http://dx.doi.org/10.1016/j.neurol.2014.10.003
0035-3787/# 2014 Elsevier Masson SAS. All rights reserved.
740 revue neurologique 170 (2014) 739–748
r é s u m é
Les progrès récents dans la compréhension de la maladie d’Alzheimer ont mené à l’élabora-
tion de nombreuses molécules qui pourraient modifier l’histoire naturelle de la maladie. La
voie amyloı̈de représente une cible importante pour les essais thérapeutiques en cours.
L’objectif principal de ce travail est d’examiner les études d’immunothérapie en rapport
avec la maladie d’Alzheimer. Plusieurs types d’immunothérapie anti-amyloı̈de dans la
maladie d’Alzheimer sont à l’étude, une immunisation active et passive avec l’administra-
tion d’anticorps monoclonaux ciblés sur la voie amyloı̈de. Bien que les approches d’immu-
nothérapie ont donné lieu à une clearance des plaques amyloı̈des chez les patients atteints
de la maladie d’Alzheimer, elles n’ont pas encore montré d’effet cognitif significatif pour le
moment. Actuellement, plusieurs approches d’immunothérapie ciblant la voir amyloı̈de
sont à l’étude, mais aussi contre la pathologie tau. Les résultats des études d’immuno-
thérapie dans les essais cliniques indiquent que l’intervention pourrait être plus efficace
dans les stades plus précoces de la maladie, en particulier le solanezumab avec un impact
potentiel sur la maladie de Alzheimer à un stade léger, ceci soulignant l’importance de
diagnostiquer la maladie d’Alzheimer le plus tôt possible. Dans les 2 récents essais de phase
III avec le solanezumab et le bapineuzumab, l’imagerie TEP a révélé que près d’un quart des
patients n’avaient de phénotype amyloı̈de au départ de l’étude, ce qui suggère qu’ils
n’avaient de maladie d’Alzheimer. Ainsi, une nouvelle phase 3 avec le solanezumab appelé
Expédition 3, chez les patients atteints d’une maladie d’Alzheimer à un stade léger et la
preuve de la présence de lésions amyloı̈des cérébrales a récemment débuté. Ainsi, actuel-
lement, l’intervention est réalisé à un stade précoce de la maladie d’Alzheimer dans les
essais cliniques, à un stade prodromal, ou parfois même chez des sujets asymptomatiques
ou à risque de développer la maladie d’Alzheimer et/ou chez des sujets asymptomatiques
avec mutation autosomique dominante.
# 2014 Elsevier Masson SAS. Tous droits réservés.
involves passive administration with monoclonal antibodies both active and passive immunizations reduce tau pathology
directed against Ab. and prevent cognitive decline in transgenic mice [7]. At this
stage addressing the safety of the tau-immunotherapy is
1.3. Mechanisms of action in immunotherapy highly needed, particularly since it has previously shown the
neurotoxic potential of tau-immunotherapy [8].
Several hypothesis [3] concerning mechanisms of action exist:
1.5. Necropsy data in humans
plaque breakdown: b amyloid plaques are destroyed The authors report a patient with AD without encephalitis
through fragment crystallizable (Fc) mediated phagocytosis who was immunized with AN-1792 [9]. There were no amyloid
by microglial cells. Antibody is able to enter the brain and plaques in the frontal cortex and abundant Ab-immunoreac-
opsonize Ab with resulting Fc receptor-mediated phagocy- tive macrophages, but tangles and amyloid angiopathy were
tosis by microglia. present. The white matter appeared normal and minimal
peripheral sink: the formation of antigen–antibody comple- lymphocytic infiltration in the leptomeninges was observed.
xes in the periphery sequesters amyloid away from the brain This case illustrates the effects of an Ab-based immunization
and prevents the deposition of new plaques. A further on AD pathogenesis in the absence of overt meningoence-
possibility supported by an increase in serum Ab, most of phalitis and leukoencephalopathy.
which is bound to antibody, suggests that Ab may also be
removed from the brain directly into the blood by modifying 1.6. Biomakers and immunotherapy
the Ab brain–blood equilibrium to enhance clearance of
soluble Ab. Clinical tests are currently used as endpoints in AD trials to
aggregation inhibitor: the formation of antigen–antibody measure disease progression based on cognitive, functional,
complexes prevents amyloid from accumulating in plaques. or overall decline [10]. Therapeutic modification of the slopes
of clinical outcome measures is a common outcome metric
Ab oligomers are also a possible simultaneous target for used in clinical trials. A consideration in the use of biomarkers
monoclonal antibodies. A potential mechanism of a direct as co-primary outcome measures is the fact that the rates of
disaggregation of plaques by antibody without glial involve- change over time of different biomarkers vary over the course
ment cannot be excluded. of the disease (Table 1).
In phase II AN1792 study, volumetric magnetic resonance
1.4. Preclinical findings imaging (MRI) was performed pre-dose and at month 12 or
early termination [11]. Two hundred eighty-eight patients had
Preclinical studies showed that immunization against Ab can paired scans (mean interval 10.9 months). Antibody respon-
provide protection and reversal of the pathology of AD in ders (n = 45) had greater brain volume decrease (3.12 1.98 vs
animal models. 2.04 1.74%; P = 0.007), greater ventricular enlargement as a
Several research groups have published preclinical evi- percentage of baseline brain volume (1.10 0.75 vs
dence that supports the validity of active immunization 0.48 0.40%; P = 0.001), and a non-significant greater hippo-
strategy, and improvements in cognitive performance have campal volume decrease (3.78 2.63 vs 2.86 3.19%; P = 0.124)
been reported after immunization with Ab42, in addition to a than placebo patients (n = 57). A dissociation between brain
reduction in Ab neuropathology [4]. These findings provide the volume loss and cognitive function was observed in AN1792/
first direct evidence that an intervention that affects the QS-21 antibody responders. The reasons for this remain
presence of Ab in the brain could lead to an improvement in unclear but include the possibility that volume changes were
cognition [5]. One report of immunization with a fragment of due to amyloid removal and associated cerebral fluid shifts. In
the Ab peptide coupled to polylysines has provided prelimi- the small subset of subjects who had cerebrospinal fluid (CSF)
nary evidence that the immunoconjugate approach is also an examinations [12], CSF tau was decreased in antibody
effective way of mounting an immune response that results in responders (n = 11) vs placebo subjects (n = 10; P = 0.001).
reduced AD-like pathology in amyloid precursor protein (APP) In phase II bapineuzumab study [13], exploratory analyses
transgenic mice. These findings reinforce the idea that showed potential treatment differences on cognitive and
immunization with the entire Ab peptide is not necessary functional endpoints but also on biomarkers in study
for efficacy, and are consistent with the observation that ‘‘completers’’ and APOE4 non-carriers. Exploratory MRI
antibodies directed against the amino-terminal and/or central analyses in the modified intent-to-treat population showed
region of the peptide provide protection against amyloid no treatment differences in brain or ventricular volume
pathology. change. APOE4 non-carriers showed 10.7 mL less brain volume
Several research groups have also investigated a Ab passive loss in the bapineuzumab group compared with placebo (95%
immunization strategy, and initial experiments indicate that a CI 3.4, 18.0; P = 0.004). No difference in ventricular volume was
humoral response alone, in the absence of a cellular response noted. APOE4 carriers showed no treatment difference in brain
to Ab, is sufficient to reduce the amyloid burden in the brain volume. However, greater ventricular enlargement was
and to reverse memory deficits [6]. observed in the bapineuzumab group compared with placebo
Clinical development of tau-immunotherapy is not as (2.6 mL; 95% CI 0.2, 5.0; P = 0.037).
advanced, but preclinical data support its development into In phase II ‘‘proof of concept’’ study, the investigators used
clinical trials. In fact, recent studies have demonstrated that 11C-PiB (Carbon-11-labelled Pittsburgh compound B) PET
742
Table 1 – Biomarkers and immunotherapies in clinical trials.
Study Name of the drug Subjects MRI volumetric Plasma Ab CSF Ab40/42 CSF Tau Amyloid-PET
analyses
Gilman S et al, AN1792 Antibody NA NA No effect Ab42 # NA
Neurology 2005 responders
n = 11
Salloway et al, Bapineuzumab Sub-groups of Carriers study: no NA NA Carriers study: Carriers study: # SUVR
N Engl J Med 2014 carrier and significant difference # p-tau 0.101; P = 0.004
non-carrier Non-carriers study: no Non-carriers Non-carriers study: no
studies significant difference study: no significant difference
significant
difference
Doody R et al, Solanezumab Sub-group of NA " Ab40 # Free Ab40 No effect No effect
N Engl J Med 2014 Expedition 1 " Total Ab40
and 2 studies " Total Ab42
2.2. Vasogenic cerebral edema and passive reported to reduce amyloid plaques, its effect on CAA is less
immunotherapy clear [24]. There was no apparent effect on CAA following
intracerebral application of Ab-specific antibodies in the study
Vasogenic edema is generated by fluid leakage from the blood by Bacskai and colleagues [6]. In the Wilcock and colleagues
vessels into the brain parenchyma via a damaged blood-brain study, after 3–5 months of treatment, cognitive deficits had
barrier. A working group of academic and industry experts, recovered and amyloid plaques were reduced by 90%
established by the Alzheimer’s Association to help guide the compared to controls [25]. By contrast, the severity of CAA
conduct of clinical trials of amyloid-lowering treatments for had increased 3 to 4 folds and the frequency of CAA-associated
AD, renamed abnormalities corresponding to vasogenic microhemorrhages by 6 to 8 folds. These results on CAA-
edema amyloid-related imaging abnormalities ARIA-E. associated microhemorrhage were in line with an earlier
In the phase II bapineuzumab study, 12 of 124 treated report on passive immunotherapy in old APP23 transgenic
patients developed vasogenic cerebral edema [13]. Half of mice. In this study, a mouse monoclonal IgG1 antibody (Ab1)
these developed clinical symptoms, including headache, recognizing the N-terminal residues 3–6 of human Ab
confusion, dizziness and gait disturbance. Bapineuzumab significantly reduced Ab burden while doubling cerebral
was responsible for this adverse event, as it was observed in microhemorrhages. Of note, in this study, bleeding occurred
none of the placebo treated patients, and it exhibited a clear only after treatment of old (21 months-old) but not of young (6
dose-dependence. Interestingly, it also increased in frequency months-old) mice and without apparent change in either
with increasing APOE-e4 gene dose. Clinical manifestations frequency or severity of CAA. The increased rate of micro-
were generally mild and manageable by withholding or hemorrhage appears to require binding of the antibodies to the
delaying further infusions (although one patient did require amyloid plaques as suggested by Racke and colleagues [26].
treatment with dexamethasone to relieve the edema). They found application of the N-terminally directed antibody
In a retrospective analysis [22], 2 neuroradiologists indepen- (3D6), which is known to bind with high affinity to deposited
dently reviewed 2572 fluid attenuated inversion recovery (FLAIR) amyloid, to exacerbate microhemorrhage. By contrast, an
MRI scans from 262 participants in two phase II studies of antibody directed toward the central domain of Ab but
bapineuzumab and an open-label extension study. A total of 210 incapable of binding to it in its deposited form, neither
patients were included in the risk analyses. Thirty-six patients affected frequency nor severity of CAA-associated microhe-
(17%) developed ARIA-E during treatment with bapineuzumab; morrhages. Further support for the notion that microhemor-
15 of these ARIA-E cases (42%) had not been detected previously. rhage depends on antibody binding to plaques was recently
Thirteen of the 15 patients in whom ARIA were detected in this provided by Schroeter et al. [27]. In this study, incidence and
study received additional treatment infusions while ARIA-E severity of this side effect of passive immunotherapy in AD
were present, without any associated symptoms. Occurrence of mouse models appeared to be directly correlated to the
ARIA-E increased with bapineuzumab dose and presence of antibody dose applied. The investigators were able to show
APOE4 alleles. Adverse events, reported in eight symptomatic that there exists a dose range characterized by a reduction of
patients, included headache, confusion, and neuropsychiatric CAA without exacerbation of microhemorrhage. In a recent
and gastrointestinal symptoms. retrospective analysis [22], incident ARIA-H occurred in 17 of
In phase III bapineuzumab studies, the major safety finding the patients with ARIA-E (47%), compared with seven of 177
was ARIA-E among patients receiving bapineuzumab, which (4%) patients without ARIA-E.
increased with bapineuzumab dose (4.2% in the 0.5-mg/kg In phase III solanezumab studies [17], the incidence of ARIA
bapineuzumab group, 9.4% in the 1-mg/kg bapineuzumab was 4.9% with solanezumab and 5.5% with placebo for
group and 14.2% in the 2-mg/kg bapineuzumab group) and hemorrhage (P = 0.49).
APOE4 allele number and which led to discontinuation of the In conclusion, ARIA consists of a spectrum of imaging
2.0-mg/kg dose [15]. findings with variable clinical correlates, and some patients
In phase II gantenerumab study [23], 2 patients in the high with ARIA-E remain asymptomatic even if treatment is
dose group (homozygous for the ApoE4 allele) showed MRI continued. The increased risk of ARIA among APOE4 carriers,
evidence (using a FLAIR sequence) of ARIA-E in the areas of its association with high monoclonal antibodies (which target
highest plaque removal. As with bapineuzumab, ARIA-E fibrillary forms of amyloid) dose, and its time course in relation
occurred more frequently in people carrying ApoE4 as well as to dosing suggest an association between ARIA and alterations
those on the higher dose (200 mg). These abnormalities in vascular amyloid burden.
resolved after the researchers stopped treatment. Theoreti-
cally, gantenerumab is closer to bapineuzumab than solane-
zumab, as it targets both soluble and fibrillary forms of amyloid. 3. Clinical data
In phase III solanezumab studies [17], the incidence of ARIA
was 0.9% with solanezumab and 0.4% with placebo for edema After the successful completion of the 2 phase I studies [28], a
(P = 0.27). phase IIa trial of AN1792 was initiated to learn more about the
immunotherapy approach [12]. In the phase IIa study, 375
2.3. Microhemorrhages patients were enrolled to receive double-blind treatment with
AN1792 or placebo in a 4:1 ratio. Measures of efficacy included
ARIA include MRI signal abnormalities suggestive of ARIA-E cognitive function, brain volume, biomarker concentration
and microhaemorrhages and haemosiderin deposits (ARIA-H) and day-to-day functioning. Signs and symptoms consistent
[22]. While passive AD immunotherapy was consistently with ME were reported in a small percentage of patients who
revue neurologique 170 (2014) 739–748 745
received AN1792, and all study dosing was halted in January it seems that solanezumab presents less central nervous
2002 [19]. Of the 300 AN1792 (QS-21)-treated patients, 59 system adverse events than bapineuzumab.
(19.7%) developed the predetermined antibody response.
Double-blind assessments were maintained for 12 months. In fact, in phase I [16], II and III studies, there was no
No significant differences were found between antibody clinical, CSF, or MRI evidence of ME or vasogenic edema.
responder and placebo groups [12] for Alzheimer’s Disease Analyses of data from 2 phase III solanezumab trials did not
Assessment Scale-Cognitive subscale (ADAS–Cog), Disability show efficacy of this monoclonal antibody. Nonetheless,
Assessment for Dementia (DAD), Clinical Dementia Rating further studies of solanezumab, in patients with mild AD
(CDR), Mini-mental state examination (MMSE), or Clinical (ClinicalTrials.gov Identifier: NCT01900665), in asymptomatic
Global Impression of Change (CGIC), but analyses of the z- persons with biomarker evidence of brain amyloid accumula-
score composite across the Neuro-psychological Test Battery tion (A4 study, ClinicalTrials.gov Identifier: NCT02008357), or
(NTB) revealed differences favoring antibody responders in individuals at risk for or with a type of early onset AD caused
(0.03 0.37 vs 0.20 0.45; P = 0.020). Although immunization by a genetic mutation (DIAN-TU001, ClinicalTrials.gov Identi-
with Ab42 resulted in clearance of amyloid plaques in patients fier: NCT01760005), are necessary for a thorough test of this
with AD, this clearance did not prevent progressive neurode- particular anti-amyloid approach.
generation [29]. Other monoclonal antibodies against Ab reportedly exhibit
In the phase II study of bapineuzumab, 234 patients were properties distinct from bapineuzumab. PF-04360365 targets
enrolled, randomly assigned to bapineuzumab or placebo in 4 the free carboxy-terminus of Ab1–40, specifically Ab33–40.
dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 GSK933776A (which targets the N-terminus of Ab like
infusions, 13 weeks apart, with final assessments at week 78. bapineuzumab) and gantenerumab are respectively in phase
No significant differences were found in the primary efficacy I and III. To the casual observer, gantenerumab may seem to be
analysis (ADAS-Cog and DAD). Exploratory analyses showed just another antibody that aims to clear Ab. In truth, not all of
potential treatment differences on cognitive and functional these antibodies are created equal:
endpoints in study ‘‘completers’’ and APOE4 non-carriers. In
the completer population, treatment differences were obser- gantenerumab is the first human antibody. The adminis-
ved on the ADAS-Cog, NTB, and DAD but not on the CDR-SB, tration of the treatment must be repeated. Thus, it is
and the MMSE showed only a trend [13]. necessary to obtain antibodies with lower immunogenicity.
In phase III bapineuzumab studies, there were no signifi- The production of fully human antibodies could be a
cant between-group differences in the primary outcomes solution;
(ADAS-Cog and DAD). At week 78, the between-group gantenerumab grabs both central and N-terminal portions
differences in the change from baseline in the ADAS-cog11 of Ab;
and DAD scores (bapineuzumab group minus placebo group) currently, there are 3 phase III ongoing studies with
were 0.2 (P = 0.80) and 1.2 (P = 0.34), respectively, in the gantenerumab, for mild AD (ClinicalTrials.gov Identifier:
carrier study; the corresponding differences in the non-carrier NCT02051608), for prodromal AD (ClinicalTrials.gov Identi-
study were 0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg/kg fier: NCT01224106) and for early onset AD caused by a genetic
dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with mutation (ClinicalTrials.gov Identifier: NCT01760005).
the 1.0-mg/kg dose [15].
In phase III solanezumab studies [17], solanezumab failed to MABT5102A (crenezumab) binds to Ab monomers, oligo-
improve cognition (ADAS-Cog) or functional ability (ADCS- mers, and fibrils with equally high affinity. Participants in
ADL). However, in patients with mild AD, based on indepen- crenezumab phase II trial are carriers of a presenilin 1
dent analyses by the ADCS, the modeled between-group mutation, PSEN1 E280A, which is autosomal dominant and
difference in the change in the ADAS-cog14 score from baseline has complete penetrance (ClinicalTrials.gov Identifier:
to week 80 was 1.7 points (95% CI, 3.5 to 0.1; P = 0.06). NCT01998841). Anti-Ab antibodies occur naturally in pooled
Solanezumab could be a potential therapy for patients with preparations of intravenous immunoglobulin (IVIg or IGIV),
mild AD. So, Lilly plans to conduct an additional Phase III study which is already food and drug administration approved for
of solanezumab (Expedition 3 trial) in patients with mild AD. the treatment of a variety of other neurological conditions.
Preliminary work showed that IVIg treatment may be
efficacious in the treatment of AD [30], and advantages to
4. Future perspectives and directions this approach include that IVIg already has a long clinical track
record, it is generally safe and well tolerated, and it
4.1. Drugs in development circumvents the high research and manufacturing costs
associated with monoclonal antibodies [31]. There is one trial
Solanezumab is a monoclonal antibody raised against Ab13–28. currently underway for IVIg in AD (Table 2). Development of
It differs from bapineuzumab in several ways: gammagard is currently stopped [18].
Avoiding both the strong Th1 effects of QS-21 adjuvant and
it recognizes a distinct epitope in the central portion of the the T-cell epitopes at the C-terminus of Ab, CAD106 consists of
peptide; a short N-terminal fragment (sequence predicted not to
whereas bapineuzumab binds amyloid plaques more stron- activate T-cell responses to Ab) of Ab attached to a virus-
gly than soluble Ab, solanezumab selectively binds to like particle (presents repetitively the antigen Ab1–6 to elicit a
soluble Ab with little to no affinity for the fibrillar form; strong B-cell response and stimulates T-cells), with no
746 revue neurologique 170 (2014) 739–748
Epitope Isotype
Bapineuzumab Stopped 1–5 IgG1 Humanized Janssen/Elan/ Cognitive and
(AAB-001, ELN115727) Free N-terminus Pfizer Functional
Solanezumab III 13–28 (central IgG1 Humanized Eli Lilly ADAS-Cog, ADCS-ADL
(LY2062430) portion) in Expedition 3
CSF Ab in DIAN-TU001
Gantenerumab III N-terminus and IgG1 Fully human Hoffman- La ADAS-Cog, ADCS-ADL
central portion Roche in mild AD
Amount of fibrillar
amyloid deposition in
DIAN-TU001
NewGam 10% IVIG II Bind central and NP NP Sutter Health Change in ventricular
C-terminus as well volumetric as
as pathogenic measured by MRI
Gammagard Stopped conformations of Ab NP NP Baxter ADAS-Cog
IGIV, 10% (focus on dimers) Healthcare ADCS-ADL
Corporation
NP: not published; ADAS-Cog: Alzheimer’s Disease Assessment Scale-Cognitive subscale; ADCS-ADL: Alzheimer’s Disease Cooperative Study-
Activities of Daily Living; CDR-SOB: Clinical Dementia Rating scale Sum of Boxes; aa: amino acid.
additional adjuvant. This agent is currently in Phase II these so-called ‘‘affitope’’ peptides, AD01 and AD02, were
trials. Using a novel approach, Affiris is testing short, 6- administered with aluminum hydroxide as adjuvant in
amino peptides that mimic the free N-terminus of Ab and Phase I trials. Other vaccines are currently in development
cause cross-reactivity against the native peptide. Two of (Table 3).
4.2. Targeting pathological tau protein by Alzheimer’s disease: role of pharmacotherapy. CNS Drugs
immunotherapy 2011;25:213–26.
[2] Jack Jr CR, Knopman DS, Jagust WJ, Shaw LM, Aisen PS,
Weiner MW, et al. Hypothetical model of dynamic
Another important target in AD is the NFT, composed
biomarkers of the Alzheimer’s pathological cascade. Lancet
primarily of hyperphosphorylated-tau proteins. Ab immuno- Neurol 2010;9:119–28.
therapy results in a very limited indirect clearance of tau [3] Morgan D. Immunotherapy for Alzheimer’s disease. J
aggregates in dystrophic neurites, showing the importance of Alzheimers Dis 2006;9:425–32.
developing a separate therapy that directly targets patholo- [4] Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido
gical tau. In tangle mouse models, immunization with a T, et al. Immunization with amyloid beta attenuates
Alzheimer disease-like pathology in the PDAPP mouse.
phospho-tau derivative reduces aggregated tau in the brain
Nature 1999;400:173–7.
and slows progression of NFT [32]. Passive immunization with [5] Janus C, Pearson J, McLaurin J, Mathews PM, Jiang Y,
tau antibodies can decrease tau pathology and functional Schmidt SD, et al. A beta peptide immunization reduces
impairments [33]. Indeed, these results must be confirmed in behavioural impairment and plaques in a model of
human studies. AADvac1 is the only vaccine in clinical Alzheimer’s disease. Nature 2000;408:979–82.
development (Table 3). [6] Bacskai BJ, Kajdasz ST, Christie RH, Carter C, Games D,
Seubert P, et al. Imaging of amyloid beta deposits in brains
of living mice permits direct observation of clearance of
5. Conclusion plaques with immunotherapy. Nat Med 2011;7:369–72.
[7] Gu J, Congdon EE, Sigurdsson EM. Two novel Tau antibodies
targeting the 396/404 region are primarily taken up by
As well as its clinical potential, this immunological approach neurons and reduce Tau protein pathology. J Biol Chem
will provide a framework for testing the amyloid hypothesis. 2013;288(46):33081–95.
The idea that the results of immunization against an abnormal [8] Rozenstein-Tsalkovich L1, Grigoriadis N, Lourbopoulos A,
Nousiopoulou E, Kassis I, Abramsky O, et al. Repeated
proteinaceous build-up in the brain of an animal model could
immunization of mice with phosphorylated-tau peptides
translate into a treatment and potentially prevent AD was
causes neuroinflammation. Exp Neurol. 2013 Oct;248:451–6.
initially received with sincere optimism. Active immunization [9] Masliah E, Hansen L, Adame A, Crews L, Bard F, Lee C, et al.
schedules are being developed to minimize T-lymphocyte Abeta vaccination effects on plaque pathology in the
reactions and to maximize antibody production and passive absence of encephalitis in Alzheimer disease. Neurology
immunization protocols are being devised. Results from 2005;64:129–31.
amyloid-based immunotherapy studies in clinical trials [10] Coley N, Andrieu S, Delrieu J, Voisin T, Vellas B. Biomarkers
in Alzheimer’s disease: not yet surrogate endpoints. Ann N
indicate that intervention appears to be more effective in
Y Acad Sci 2009;1180:119–24.
early stages of amyloid accumulation, highlighting the [11] Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins
importance of diagnosing AD as early as possible and L, et al. Effects of Abeta immunization (AN1792) on MRI
undertaking clinical trials at this stage. Thus, currently, measures of cerebral volume in Alzheimer disease.
amyloid intervention is realized at early stage of the AD in Neurology 2005;64:1563–72.
clinical trials, at prodromal AD, at asymptomatic subjects at [12] Gilman S, Koller M, Black RS, Jenkins L, Griffith SG, Fox NC,
et al. Clinical effects of Abeta immunization (AN1792) in
risk to develop AD and at asymptomatic subjects with
patients with AD in an interrupted trial. Neurology
autosomal dominant mutation. This new immunotherapy
2005;64:1553–62.
approach (i.e. to treat early) requires: [13] Salloway S, Sperling R, Gilman S, Fox NC, Blennow K,
Raskind M, et al. A phase 2 multiple ascending dose trial of
early efficient prodromal AD biomarkers; bapineuzumab in mild-to-moderate Alzheimer disease.
to develop different primary outcomes, biomarkers or new Neurology 2009;73:2061–70.
composite cognitive markers. [14] Rinne JO, Brooks DJ, Rossor MN, Fox NC, Bullock R, Klunk WE,
et al. 11C-PiB-PET assessment of change in fibrillar amyloid
beta load in patients with Alzheimer’s disease treated with
The first author is involved in SAR228810 phase I trial. JD is bapineuzumab: a phase 2, double-blind, placebo-controlled,
involved in the writing of the manuscript’s first draft and in ascending dose study. Lancet Neurol 2010;9:363–72.
the review of the subsequent drafts. JD, PJO, TV and BV took [15] Salloway S, Sperling R, Fox NC, Blennow K, Klunk W,
part in the execution of the project and in the review of the Raskind M, et al. Two phase 3 trials of bapineuzumab in
manuscript. mild-to-moderate Alzheimer’s disease. N Engl J Med
2014;370(4):322–33.
[16] Siemers ER, Friedrich S, Dean RA, Gonzales CR, Farlow MR,
Disclosure of interest Paul SM, et al. B. Safety and changes in plasma and
cerebrospinal fluid amyloid beta after a single administration
of an amyloid beta monoclonal antibody in subjects with
The authors declare that they have no conflict of interest Alzheimer disease. Clin Neuropharmacol 2010;33:67–73.
concerning this article. [17] Doody RS, Thomas RG, Farlow M, Iwatsubo T, Vellas B, Joffe
S, et al. Phase 3 trials of solanezumab for mild-to-moderate
Alzheimer’s disease. N Engl J Med 2014;370(4):311–21.
references
[18] Dodel R, Rominger A, Bartenstein P, Barkhof F, Blennow K,
Förster S, et al. Intravenous immunoglobulin for treatment
of mild-to-moderate Alzheimer’s disease: a phase 2,
[1] Delrieu J, Piau A, Caillaud C, Voisin T, Vellas B. Managing randomised, double-blind, placebo-controlled, dose-finding
cognitive dysfunction through the continuum of trial. Lancet Neurol 2013;12(3):233–43.
748 revue neurologique 170 (2014) 739–748
[19] Orgogozo JM, Gilman S, Dartigues JF, Laurent B, Puel M, angiopathy-associated microhemorrhage in amyloid
Kirby LC, et al. Subacute meningoencephalitis in a subset of precursor protein transgenic mice by immunotherapy is
patients with AD after Abeta42 immunization. Neurology dependent on antibody recognition of deposited forms of
2003;61:46–54. amyloid beta. J Neurosci 2005;25:629–36.
[20] Nicoll JA, Wilkinson D, Holmes C, Steart P, Markham H, [27] Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T,
Weller RO. Neuropathology of human Alzheimer disease et al. Immunotherapy reduces vascular amyloid beta in
after immunization with amyloid beta peptide: a case PDAPP mice. J Neurosci 2008;28:6787–93.
report. Nat Med 2003;9:448–52. [28] Bayer AJ, Bullock R, Jones RW, Wilkinson D, Paterson KR,
[21] Winblad B, Andreasen N, Minthon L, Floesser A, Imbert G, Jenkins L, et al. Evaluation of the safety and
Dumortier T, et al. Safety, tolerability, and antibody immunogenicity of synthetic Abeta42 (AN1792) in patients
response of active Ab immunotherapy with CAD106 in with AD. Neurology 2005;64:94–101.
patients with Alzheimer’s disease: randomised, double- [29] Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V,
blind, placebo-controlled, first-in-human study. Lancet Bayer A, et al. Long-term effects of Abeta42 immunization
Neurol 2012;11(7):597–604. in Alzheimer’s disease: follow-up of a randomised,
[22] Sperling R, Salloway S, Brooks DJ, Tampieri D, Barakos J, placebo-controlled phase I trial. Lancet 2008;372:216–23.
Fox NC, et al. Amyloid-related imaging abnormalities in [30] Magga J, Puli L, Pihlaja R, Kanninen K, Neulamaa S, Malm T,
patients with Alzheimer’s disease treated with et al. Human intravenous immunoglobulin provides
bapineuzumab: a retrospective analysis. Lancet Neurol protection against Abeta toxicity by multiple mechanisms
2012;11(3):241–9. in a mouse model of Alzheimer’s disease. J
[23] Ostrowitzki S, Deptula D, Thurfjell L, Barkhof F, Bohrmann Neuroinflammation 2010;7:90.
B, Brooks DJ, et al. Mechanism of amyloid removal in [31] Dodel R, Neff F, Noelker C, Pul R, Du Y, Bacher M, et al.
patients with Alzheimer disease treated with Intravenous immunoglobulins as a treatment for
gantenerumab. Arch Neurol 2012;69(2):198–207. Alzheimer’s disease: rationale and current evidence. Drugs
[24] Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering 2010;70:513–28.
RM, et al. Consequence of Abeta immunization on the [32] Sigurdsson EM. Immunotherapy targeting pathological tau
vasculature of human Alzheimer’s disease brain. Brain protein in Alzheimer’s disease and related tauopathies. J
2008;131:3299–310. Alzheimers Dis 2008;15:157–68.
[25] Wilcock DM, Colton CA. Immunotherapy, vascular [33] Boutajangout A, Ingadottir J, Davies P, Sigurdsson EM.
pathology, and microhemorrhages in transgenic mice. CNS Passive immunization targeting pathological phospho-tau
Neurol Disord Drug Targets 2009;8:50–64. protein in a mouse model reduces functional decline and
[26] Racke MM, Boone LI, Hepburn DL, Parsadainian M, Bryan clears tau aggregates from the brain. J Neurochem
MT, Ness DK, et al. Exacerbation of cerebral amyloid 2011;118(4):658–67.