Key Symposium | doi: 10.1111/j.1365-2796.2010.02315.

Immunotherapy for Alzheimer’s disease

D. Morgan
From the Alzheimer’s Institute, University of South Florida, Tampa, FL, USA

Abstract. Morgan D. (Alzheimer’s Institute, University of
South Florida, Tampa, FL, USA) Immunotherapy for
Alzheimer’s Disease (Key Symposium). J Intern Med
2011; 269: 54–63.
In the year1999, a vaccine approach was found to
reduce amyloid deposits in transgenic mice overpro-
ducing the amyloid precursor protein. This was
followed closely by demonstrations that vaccines or
passive immunotherapy could rescue memory defi-
cits in these mice. Initial human clinical trials re-
vealed apparent autoimmune reactions in a subset of
patients, but also some cases of cognitive benefit and
amyloid clearance. Further work with passive immu-
notherapy in mouse models confirmed exceptional
clearing abilities of anti-amyloid antibodies even in
older mice. However, in parallel with parenchymal
amyloid clearance was the appearance of micro-
haemorrhages and increased vascular amyloid
deposition. Additional clinical trials with passive
immunotherapy confirmed occasional appearance of
microhaemorrhage and occurrence of vasogenic
oedema in some patients, particularly those with the
apolipoprotein E4 genotype. Recent data with posi-
tron emission tomography demonstrates trial partici-
pants passively immunized with anti-Aß antibodies
have reduced signals with amyloid binding ligands
after 18 months of therapy. Several anti-Aß immu-
notherapies have reached phase 3 testing, and
immunotherapy is likely to be the first test of the
amyloid hypothesis of Alzheimer’s disease. Identify-
ing antibody variants that retain amyloid clearance
with fewer adverse reactions remains a major focus of
translational research in this area.
Keywords: Alzheimer’s disease, antibody, microhaem-
orrhage, transgenic mice.

Introduction Although debated intensely for the past 25 years,

there is now a reasonable consensus emerging
Alzheimer’s disease is the most common form of or-
regarding the pathogenesis of Alzheimer’s disease.
ganic dementia. It affects roughly10% of the popula-
The initiating factor, which appears necessary but
tion over 65 and 40% of those over 85 years of age. In
not sufficient for Alzheimer’s disease, is the accumu-
the US, 7–8% of all medical costs are related to
lation of amyloid aggregates consisting of the Aß pep-
dementia. Unlike other leading causes of death, mor-
tide. The genetics of familial forms of Alzheimer’s dis-
tality from Alzheimer’s disease is increasing. The
ease and Down’s syndrome cases (which result in
number of cases is predicted to escalate dramatically
precocious Alzheimer pathology) have as a common
over the next 2–3 decades as success in treating heart
element overproduction of a longer C-terminal form
disease and cancer permit more individuals to reach
of the Aß peptide (42 amino acids in length). This form
the age of risk for dementias.
is more prone to form beta sheet structures and
aggregate into oligomers and fibrils [3]. Evidence is
The definition of Alzheimer’s dementia is based on a
now emerging that these amyloid deposits may be
case report by Alois Alzheimer (1907) based on a pla-
present up to a decade prior to the initiation of cogni-
que and tangle pathology within the brain of a women
tive symptoms of the disorder [4, 5].
succumbing to the disorder in her fifties. Until re-
cently, the definitive diagnosis of Alzheimer’s re-
A second step in the pathogenesis of the disease is the
quired either biopsy or postmortem histopathology
formation of intraneuronal neurofibrillary tangles
[1]. The introduction of ligands labelling amyloid pla-
formed from hyperphosphorylated forms of the
ques with positron emitting isotopes and spinal fluid
microtubule binding protein tau. Other neurodegen-
measurements of specific molecules combined with
erative disorders can be formed by the tau pathology
cognitive testing now permits more definitive diagno-
in the absence of amyloid deposits, but these differ
ses to be ascertained without requiring histopathol-
from Alzheimer’s both in clinical presentation and in
ogy [2].

54 ª 2010 The Association for the Publication of the Journal of Internal Medicine
 D. Morgan
| Key Symposium: Immunotherapy for Alzheimer’s disease
the location of the pathology regionally in the brain.
In tau transgenic mouse models, the tau deposits can
be precipitated by intracranial injection of amyloid [6]
or breeding with mice producing Aß deposits [7].
Moreover, interrupting the amyloid deposition with
anti-Aß immunotherapy can diminish the progres-
sion of tau pathology in mice expressing multiple
transgenes [8]. Moreover, the tau pathology appears
to be more closely correlated with cognitive status
than the amyloid pathology, consistent with it being
more proximal cause of the mental dysfunction [9].
By uncertain mechanisms, these pathologies result
in the loss of synaptic function, synapses and ulti-
mately a loss of neurons leading to considerable brain
atrophy. There are multiple hypotheses regarding the
mechanistic steps involved, some of which argue the
intermediate sized aggregates of amyloid and ⁄ or tau,
referred to as oligomers, may be more directly causing
the toxicity, but demonstrations in vivo are still lack-
ing. Even in the mildest stages of the disorder, the so-
called ‘‘mild cognitive impairment’’ phase, there ap-
pears to be considerable accumulation of plaque and
tangle pathology, and neuron loss [10]. Increasingly
these observations suggest that treating the disorder
at the earliest possible stages, much as is performed
with cardiovascular disease, will be essential to con-
trolling Alzheimer’s disease.
Studies of active immunotherapy in animal models
The gene responsible for the protein containing the
Aß peptide is the amyloid precursor protein (APP).
APP was cloned in the late 1980s following the
sequencing of the vascular Aß deposits by Glenner
et al. [11]. Several years later, it was identified that
some families inheriting Alzheimer’s disease in an
autosomal dominant fashion had mutations in APP
near the cleavage sites releasing the Aß peptide [12].
This led to a very substantial number of largely failed
attempts to develop transgenic mice overexpressing
mutant forms of human APP [13]. Finally, two models
emerged [14, 15] which demonstrated amyloid depo-
sition in locations and with features common to that
found in Alzheimer’s disease. Although some claim
that certain of these APP transgenic models are supe-
rior and other APP models lacking, the remarkable
feature is that the patterns of Aß deposition are lar-
gely the same in all models in spite of different muta-
tions and promoters (cortical and hippocampal dif-
fuse Aß deposits, compacted neuritic plaques and
vascular amyloid are found in most APP models and
Alzheimer’s tissue [16]). These transgenic mice are
superb representations of amyloid deposition.
Unfortunately, many authors argue that they are
ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63
‘‘Alzheimer’s mice’’ and that treatments effective in
the mice should be effective in Alzheimer patients.
Unfortunately, the APP mice lack a number of critical
features of Alzheimer’s, including hyperphosphory-
lated tau pathology and significant neuron loss. At
best they resemble an early preclinical phase of the
disease, nonetheless one which may be the optimal
phase in which to initiate therapy that prevents the
disorder.
The seminal paper in the field of immunotherapy for
Alzheimer’s disease was published in 1999. Schenk
and his collaborators at Elan Pharmaceuticals (nee
Athena Neuroscience) demonstrated that treating
mice with a vaccine against the Aß peptide in an APP
mouse model prior to the formation of deposits was
effective in blocking amyloid accumulation as the
mice aged. Within weeks of this publication, our re-
search group in Tampa, Florida began treating APP
mice at a later age, when amyloid deposits had al-
ready become manifest. One pathogenic component
of Alzheimer’s disease pathology was argued to be the
inflammation associated with amyloid deposits, and
we had concerns that the immune activation associ-
ated with the vaccine might aide in clearing the amy-
loid plaques, but may also cause destructive bystan-
der effects to the surrounding tissue. We also had
recently detailed the time course of memory deficien-
cies developing in our APP + PS1 mouse model [17]
as the amyloid accumulated [18]. After several
months of repeated immunization, we tested the mice
for behavioural deficiencies, but found no deficits in
either the treated or untreated mice. However, when
we continued the treatment to an age when we ex-
pected memory deficits to be present, we found the
vaccinated mice were protected from these deficits,
whilst mice given a control vaccination were unable
to learn the task [19]. A second research group work-
ing independently found qualitatively similar effects
on memory in a different mouse model [20]. These
observations that vaccines or antibodies against the
Aß peptide can rescue the memory deficits in these
models have been replicated extensively, in some
cases demonstrating that rescue can be seen within
days of treatment (before clearance of plaque deposits
can be detected; [21, 22].
Importantly, the efficacy of the vaccine in reversing
amyloid deposits is not only found in transgenic mice.
Nonhuman primates also develop amyloid deposits
like Alzheimer patients and associated memory defi-
cits (although like the mice, they do not develop tau
pathology) [23]. These can be reversed within months
using vaccination against the Aß peptide [24]. Beagle
55
 D. Morgan
| Key Symposium: Immunotherapy for Alzheimer’s disease
dogs also develop diffuse amyloid deposits and mem-
ory dysfunction with age. Two years of active immuni-
zation were found to clear these diffuse (not com-
pacted) deposits, but not have impact on the age-
associated memory impairments in these animals
[25]. It is important to recognize that most mammals
develop age-associated memory impairments and
the majority lack amyloid deposition of any type.
Hence, memory deficiencies with age are not always
associated with amyloid deposits.
The development of novel vaccine strategies and ad-
juvants against the Aß peptide has been an area of in-
tense creativity. In most instances, the goal has been
to develop B-cell activation and antibody production,
with minimal T-cell involvement (at least against Aß),
because of the adverse events found in human trials
with vaccines against Aß (see below). These impres-
sive approaches have been carefully described in a
recent review [26] and are outside the scope of
the present review. However, long-term, assuming
immunotherapy is successful against Alzheimer’s
pathology, these may become standard approaches
to preventing the disease.
Mechanisms of immunotherapy action in reducing Aß deposits
The success of the immunotherapy approach to brain
disorder surprised a number of investigators given
the dogma that the brain is an immune-privileged or-
gan with minimal immune surveillance. Nonetheless,
the normal range of CSF IgG (5–50 mg L)1) is roughly
0.1% of the plasma IgG concentration, with an aver-
age concentration of 0.1 lmol L)1. Studies in rodent
with iodinated anti-Aß antibodies confirm that
0.11% of the circulating antibody enters the CNS
[27]. This has led to several proposed mechanisms
regarding the reduction in Aß deposition associated
with anti-Aß immunotherapy.
The first proposed mechanism relied upon the tradi-
tional role of antibody to opsonize antigens leading to
macrophage phagocytosis and complement activa-
tion [28] (Fig. 1). This approach assumes that suffi-
cient antibody enters the brain and binds to the amy-
loid to trigger this phagocyte action of either resident
microglia, or infiltrating monocytes ⁄ macrophages.
Certainly, our own work and that of others have dem-
onstrated decoration of amyloid deposits after sys-
temic administration of anti-amyloid antibodies [29].
One advantage of this mechanism is that the stoichi-
ometry to the antibody to Aß can be considerably
<1 : 1 and still have a meaningful impact on deposi-
tion. It also may explain how antibodies selective to
56 ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63
Fig. 1 Opsonization and Phagocytosis. Anti-Ab antibodies
bind to Ab aggregates within the CNS. The immune complex
then stimulates phagocytosis by Fc-gamma receptor bearing
macrophages. The ingested Ab is then digested and ⁄ or
exported from the CNS. Reprinted from Ugen, K. and Morgan,
D. DNA and Cell Biology 20:677–678.
one form of Aß can clear other forms, assuming that
heteromeric fibrils containing these different forms
are present [30, 31].
A second proposed mechanism assumes that the
penetration of the antibodies into CNS is not a critical
step and that the presence of circulating antibodies
creates a ‘‘peripheral sink’’ which alters the equilib-
rium across the blood brain barrier for Aß to favour ef-
flux owing to the reduced free Aß concentration in
blood [32] (Fig. 2). Certainly, many antibodies with
high affinity for Aß do dramatically elevate circulating
concentrations. There also appear to be mechanisms
by which circulating Aß does cross into the CNS,
which would be expected to decline as free Aß
dropped [33]. However, it has also been argued that
the major cause of increased Aß in circulation with
antibody administration is owing to the reduced rates
of clearance from the blood [34]. A variant of this idea
is that the antibodies in the brain ventricular fluid
might bind Aß and act as a sink within the central
nervous system.
A third option is that antibodies act catalytically to
modify the secondary structure of the Aß monomers
into a conformation that is less likely to form the
aggregates associated with oligomeric or fibrillar
forms (Fig. 3). This was first proposed by Beka Solo-
mon et al. before the capacity of antibodies to affect
Aß in vivo was demonstrated [35, 36]. She has dem-
onstrated that stoichiometries of antibodies as low as
1 : 10 effectively blocked Aß fibril formation in vitro.
 D. Morgan
| Key Symposium: Immunotherapy for Alzheimer’s disease
Fig. 2 Peripheral Sink. Circulating anti-Ab antibodies bind
free Ab in the blood and increase the efflux of Ab down its con-
centration gradient and ⁄ or block the influx of Ab from the cir-
culation and back into the brain. Reprinted from Ugen, K. and
Morgan, D. DNA and Cell Biology 20:677–678.
Fig. 3 Catalytic Modification of Conformation. Antibody
binds Ab and modifies the secondary structure to one which
minimizes the formation of aggregates. Reprinted from Ugen,
K. and Morgan, D. DNA and Cell Biology 20:677–678.
We have confirmed this and extended the results to
indicate that stoichiometries of antibody to Aß as low
as 1 : 1000 can specifically modify the secondary
structure of Aß and block fibril formation using ATR-
FTIR and atomic force microscopy [37]. Obviously,
this catalytic modification hypothesis benefits from
being active at low stoichiometries and may be active
in the absence of macrophage activation, a circum-
stance that might still lead to adverse bystander ef-
fects.
A fourth mechanism has been suggested to be active
at least for intracranially administered antibody.
That is neonatal Fc receptor (FcRn) medicated efflux
of antibody antigen complexes across the blood brain
barrier [38]. This mechanism was shown to be
ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63
saturable and inhibited by Fc fragments. One possi-
ble consequence is that excess antibody may lead to
competition within this efflux mechanism by increas-
ing transport of antibody without bound antigen. Our
own work and that of others has found that excess
anti-Aß monoclonal antibody administered systemi-
cally can inhibit clearance of amyloid plaques [39,
40].
Critically, none of these mechanisms are mutually
exclusive. Moreover, different antibodies may utilize
different mechanisms to different degrees. For exam-
ple, antibodies not binding fibrillar amyloid may be
less able to induce phagocytosis, yet function excep-
tionally as a peripheral sink. Some antibodies upon
binding Aß may not modify the secondary structure,
but still activate macrophages and FcRn-mediated
transport. The extent to which different antibodies
utilize different mechanisms may also confer differ-
ent adverse event profiles for each of the antibodies.
Active immunization (vaccine) clinical trials
Given the remarkable success of vaccination in ani-
mal models and the absence of any alternative dis-
ease modifying therapy for Alzheimer’s disease, Elan
partnered with Wyeth to initiate an active immuniza-
tion trial against the Aß peptide in Alzheimer pa-
tients. The vaccine consisted of the full length pep-
tide, which contains both B- and T-cell epitopes,
aggregated into fibrils. Initially, about 60 patients
were treated with one or more doses of the vaccine
and the cases monitored in a phase 1 safety trial. One
of the initial observations was a variable antibody re-
sponse, with many patients failing to develop detect-
able titres against the antigen. Approximately half
way through the trial, there was a change in the adju-
vant to QS-21 in an attempt to enhance this response.
There were no adverse responses detected during the
trial portion of the phase I study [41].
This led Elan and Wyeth to pursue a phase 2a trial
with the AN1792 formulation including the QS-21
adjuvant. The goal was to immunize patients to a pre-
set antibody titre using multiple inoculations. Within
a short time of initiating the trial, however, the immu-
nizations were halted as a result of a fraction of the
patients developing aseptic meningoencephalopa-
thy, an inflammatory reaction in the CNS, which in
most instances responded well to steroid therapy.
Subsequently, one case from the phase 1 trial also
developed these symptoms of CNS inflammation and
died from pulmonary embolism a short time later
[42]. A second case from the phase 2a study was also
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| Key Symposium: Immunotherapy for Alzheimer’s disease
collected [43]. In both cases, a T-cell infiltrate of the
CNS was apparent with signs of meningeal inflamma-
tion. The T cells did not appear directed to the amyloid
deposits, and there was no relationship between anti-
body titre and incidence of the adverse event, but it
was concluded the response was an autoimmune
reaction caused he vaccine [44].
In spite of the interruption of the trial, some cases did
develop significant antibody titres. In the cohort eval-
uated in Zurich, these titres were measured using a
brain amyloid histology assays (TAPIR) without
breaking the blind [45]. Cognitive function tests in
this cohort (35 overall) indicated that those patients
with the highest titre declined less over the ensuing
year than those without detectable antibody titres.
Some of these cases remained stable for years after
the original treatments. Whilst admittedly anecdotal,
these observations implied that the immunotherapy
approach may have benefits in spite of the adverse
events observed.
A more complete follow-up of the patient cohort stud-
ied in the truncated phase 2a vaccination trial has
been conducted at 4–5 years postimmunization. This
study examined cognitive test performance of 25 ori-
ginal cases that responded to the immunization
(reaching a titre of 1 : 2200) and had 129 cases over-
all. A significant difference in Disability Assessment
for Dementia (an activities of daily living measure)
and the Dependence Scale was found in the initial
responders indicating a benefit of the treatment.
Although no differences in the rate of brain shrinkage
by MRI or cognitive performance were observed, these
results are encouraging that some benefit could be
obtained from a trial that was suspended before
reaching the intended duration of therapy.
Studies of passive immunotherapy in animals
The combination of low responsiveness to vaccines
and the appearance of T-cell dependent adverse
events with active immunization quickly led multiple
groups to evaluate monoclonal antibody treatments
to clear brain amyloid deposits. The first publication
of the success of this approach [28] was followed
shortly by others [32]. Our own work in this area was
facilitated by a collaboration with a small biotechnol-
ogy start-up in the San Francisco Bay area, Rinat
Neurosciences. Rinat shared with us antibodies they
had developed against specific Aß epitopes which we
then tested in our murine models of amyloid deposi-
tion (using research support from the NIA ⁄ NIH). Our
first studies examined the effects of intracranially
58 ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63
applied antibodies and detailed a rapid time course of
changes in amyloid deposits and microglial activa-
tion. In a series of papers, we found that diffuse amy-
loid was cleared within 1 day, whilst congophilic
deposits, associated with microglial activation, were
cleared within 3 days. By 1 week, the regions infused
with antibody were largely cleared of deposits and free
of antibody [46, 47]. We further found that systemic
administration of antibodies in aged amyloid deposit-
ing APP mice (18–22 months; analogous to 65- to 75-
years-old humans) caused a time-dependent clear-
ance of pre-existing deposits that after 3 months re-
duced the congophilic compacted plaques by 90%
compared to mice given a control antibody[29]. How-
ever, a prior brief report had indicated that passive
immunotherapy caused appearance of microhaem-
orrhage in aged amyloid depositing mice [48]. When
we stained sections for haemosiderin, we found a
time-dependent increase in the number of micro-
haemorrhages associated with the antibody-medi-
ated removal of the parenchymal amyloid deposits
[49]. Moreover, we were the first to report an increase
in the number of vascular amyloid deposits and asso-
ciation of the haemorrhages with these deposits.
However, remarkably, these aged mice that had held
amyloid in their brain from over half their lifetimes
and endured microhaemorrhages, still obtained the
benefit of restored memory performance with the
antibody treatment. Subsequently, others confirmed
that treatment with anti-Aß antibodies in older mice
that already possess deposits when treatment is initi-
ated (a therapeutic rather than prophylactic model)
leads to microhaemorrhage development [50, 51].
After confirming our observation that Rinat’s anti-
body caused microhaemorrhage, we cautiously ad-
vised them of this significant concern. This led them
to modify the antibody to minimize interaction with
effector proteins such as Fc-gamma receptors and
complement proteins (by enzymatic deglycosylation).
When we tested this antibody using intracranial
administration, it was capable of removing amyloid
deposits without causing activation of microglia [52].
Further tests using systemic administration showed
dramatically reduced formation of microhaemor-
rhages and a smaller increase in vascular amyloid
deposition with the modified antibody. Although
there was a slight reduction in amyloid clearance,
both the modified and native antibodies rescued the
memory deficits in the aged amyloid depositing trans-
genic mice [53].
One potential explanation for the increase in micro-
haemorrhage is that antibodies capable of binding
 D. Morgan
| Key Symposium: Immunotherapy for Alzheimer’s disease

amyloid fibrils in the vasculature can cause a local
inflammatory reaction. Ultimately this may weaken
the endothelial cell barrier and result in vascular
leakage. A second possibility is that the opsonization
of parenchymal Aß deposits leads to macrophage
phagocytosis which then redistributes the phagocy-
tosed material to the vasculature. Fiala and col-
leagues used an in vitro blood brain barrier to demon-
strate that macrophages with engulfed amyloid die
when attempting to pass through the endothelial cell
barrier [54]. This leads to local deposition of the amy-
loid material they have phagocytosed. By reducing
the activation of effector proteins, the deglycosylated
antibody used in our mouse work may diminish the
formation of vascular deposits and microhaemor-
rhages by reducing the extent of microglial ⁄ macro-
phage activation and phagocytosis. However, effects
mediated by the peripheral sink and the catalytic
modification of Aß would be retained. Our results
with Rinat’s modified antibody led to their acquisition
by Pfizer. A humanized version of this antibody is
presently in phase II clinical testing (ponezumab;
Table 1).
Passive immunization in Alzheimer patients
Given the issues associated with active immuniza-
tion, several companies have started clinical trials
using monoclonal antibodies against the Aß peptide.
By far the most advanced of these is an N terminal-
specific antibody from Elan-Wyeth referred to as
bapineuzimab (now in development by Wyeth-Pfizer
and Janssen). The phase 1 trial of this antibody used
single administrations of 0.5, 1.5 or 5 mg kg)1 of the
antibody[55]. Patients were tested cognitively both
before administration and 16 weeks later. With re-
spect to safety, 3 of 10 patients at the highest dose
developed vasogenic oedema by MRI. One patient
developed a punctuate MRI hyperintensity that was
not present prior to the treatment and remained
12 months later. This was interpreted as a micro-
haemorrhage. Although not designed to measure effi-
cacy, exploratory analyses found that the MMSE val-
ues improved in the 0.5 and 1.5 mg kg)1 doses, with
no benefit found in the highest dose. This is similar to
our dose–response data mentioned above, with bene-
fits to APP mice at 3 and 10 mg kg)1 of antibody and
no benefit at 30 mg kg)1 [39]. The causes for these
atypical dose responses are not clear, although satu-
ration of FcRn transport is one option. A similar inac-
tivity at high doses was also reported previously in ab-
stract form [40].
A phase II clinical trial with bapineuzimab has also
been completed. The study included 230 patients
and four doses of the drug (0.15, 0.5, 1 or 2 mg kg)1)

Table 1 Immunotherapeutic approaches in clinical development

Company Approach Abeta Epitope Biological Stage

Janssen ⁄ Wyeth (Elan) Passive N-terminus Bapineuzumab Phase III
Eli Lilly Passive Central domain Solanezumab Phase III
Baxter Passive IVIg – mix Gammaguard Phase III
Janssen ⁄ Wyeth (Elan) Active N-terminus ACC-001 Phase II
Novartis Active N-terminus CAD106 Phase II
Pfizer Passive C-terminus Ponezumab Phase II
GSK ⁄ Affiris Active Abeta mimetic Affitope AD1 and AD2 Phase II
Roche Passive N-terminus + central domain Gantunerumab R1450 Phase I
Merck Active Conformational V950 Phase I
GlaxoSmithKline Passive GSK933776A Phase I
Janssen ⁄ Wyeth (Elan) Passive N-terminus Bapineuzumab s.c. Phase I
Eisai ⁄ BioArctic Passive Protofibrils BAN2401 Phase I
Abbott Passive Conformational Preclinical
Elan ⁄ Wyeth Passive Conformational AAB-002 Preclinical
Genentech ⁄ ACImmune Passive Conformational Preclinical
BiogenIdec ⁄ Neurimmune Passive Preclinical
Boehringer ⁄ Ablynx Nanobodies Abeta Preclinical

ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63 59
 D. Morgan
| Key Symposium: Immunotherapy for Alzheimer’s disease
receiving six infusions 13 weeks apart [56]. Vasogen-
ic oedema was found in roughly 10% of the cases trea-
ted with bapineuzimab, with half of these being
symptomatic. There was propensity for the vasogenic
oedema to be more common in the higher dose groups
and in apolipoprotein E4 carriers. Intention to treat
analysis failed to identify a significant cognitive bene-
fit of bapineuzimab (all dose groups combined), but
there were significant benefits in patients that com-
pleted all six antibody infusions and in patients that
were nonapolipoprotein E4. Thus, in spite of the ab-
sence of a dose–response effect, a phase III trial is
presently underway, with a separate analysis of E4
carriers and noncarriers. It should be noted that prior
studies also identified less efficacy of treatments in
apolipoprotein E4 carriers for tacrine [57] or rosigli-
tizone [58].
Pathological analyses of vaccinated patients
Roughly 8 years have passed since the first patients
received anti-Aß vaccines. A number of these cases
have now come to autopsy. The Southampton group
led by James Nicoll have collected tissue from a num-
ber of patients (up to 12 at present) who were in the
phase I trial and have issued multiple reports on anal-
yses from these specimens [59–62]. Based upon the
time postvaccination, they describe the following se-
quence of events in the small patient population they
have. At relatively short intervals (<1 year), they ob-
serve the presence of ragged ‘‘moth-eaten’’ amyloid
deposits and the presence of microglia with ingested
immunopositive amyloid. Between 1 and 3 years po-
stimmunization, they report a partial clearance of
amyloid deposits (compared to age-matched Alzhei-
mer samples that were not part of the study), and the
appearance of increased numbers of vascular amy-
loid deposits and increased microhaemorrhage. By
4–6 years of postimmunization, they identified two
cases that have a virtually complete removal of amy-
loid deposits, including vascular deposits, and no evi-
dence of residual microhaemorrhage. Nonetheless,
there was no resolution of tau pathology. Perhaps
most disturbing was that no cognitive benefits of the
amyloid clearance could be detected in these end
stage cases [59]. This implies that (i) amyloid has no
direct impact on cognitive status in humans, (ii) these
patients had some other form of dementia to begin
with or (iii) that the damage is so extensive by the time
that cognitive symptoms are apparent and that res-
cue is not feasible. In any event, if these two cases are
representative, this does not bode well for any anti-
amyloid approach in patients that already have the
disease. It should be noted that even in the MCI
60 ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63
phase, prior to overt clinical dementia, considerable
neuron and synapse loss is evident [10].
The way forward
One of the more exciting developments of the last
2 years in Alzheimer’s disease research is the identifi-
cation of methods to positively identify Alzheimer de-
ments from other disorders without requiring au-
topsy. One method to achieve this is positron
emission tomography (PET) using amyloid binding li-
gands. The first of these was a [11C]-labelled com-
pound referred to as Pittsburgh compound B [63].
Additional ligands are in various stages of develop-
ment using [18F] labelling, a longer-lived isotope per-
mitting a broader application of the methods (i.e. not
requiring an adjacent cyclotron and radiochemistry
facility). An increasing number of publications dem-
onstrate a reasonable correlation of the PET ligand
signals and amyloid deposition in brain. Perhaps
most important, there now appear to be individuals
who are cognitively normal, but carry positive PET
amyloid ligand signals. A recent report monitoring
these individuals has found a high predictability of
the PET signals in normals and subsequent conver-
sion to dementia [4]. In addition, there are now cere-
brospinal fluid analyses that appear to specify Alzhei-
mer cases, and these also appear in some individuals
that do not yet have dementia. Together these raise
the possibility of defining, with some precision, a set
of individuals with dramatically increased risk of
dementia. At the recent ICAD meeting in Honolulu, it
was suggested these signals may precede disease on-
set by up to a decade [5].
This raises the possibility of attempting to prevent the
development of Alzheimer’s dementia. Screening
high-risk populations for these amyloid signatures
using PET scans and spinal fluid analyses may iden-
tify those with amyloid deposits before substantial
neural damage has occurred. Treatments could then
be attempted which reduce the amyloid in anticipa-
tion of slowing the onset of the disorder or preventing
the disease altogether. In this context, a subset of the
patients in the phase 3 bapineuzimab trial were
screened for amyloid deposits using PET scans before
and after the 18 months treatment with the
agent[64]. The antibody treatment significantly re-
duced the intensity of the amyloid signals over the
18 months of the trials compared to patients receiv-
ing placebo therapy. Even if the issue of vasogenic oe-
dema complicates the use of bapineuzimab, there are
a large number of other immunotherapy approaches
also in clinical or preclinical development (see
 D. Morgan
| Key Symposium: Immunotherapy for Alzheimer’s disease
Table 1). We remain hopeful that one or more of these
will succeed in reducing amyloid presymptomatically
and that this will be sufficient to avert the onset of the
cognitive problems associated with Alzheimer’s
dementia, permitting us to prevent Alzheimer’s dis-
ease from occurring.
Acknowledgements
This work was supported by NIH grants AG-04418,
AG 15490 and AG18478. We thank Karen Ashe and
Karen Duff for early access to their transgenic mouse
models of amyloid deposition.
Conflict of interest statement
In the past decade, Dr Morgan has consulted with the
following pharmaceutical companies on issues re-
lated to Alzheimer’s Immunotherapy. Pfizer, Wyeth,
Rinat Neuroscience, Merck, Astra-Zeneca, Bristol-
Myers-Squibb, Eisai, Forest, Lundbeck, Neurim-
mune, Elan and Baxter. Dr Morgan does not have
current research support from any of the above-men-
tioned companies.
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Correspondence: Dave Morgan, Byrd Alzheimer Institute, 4001 E
Fletcher Ave, MDC 36, University of South Florida, Tampa, FL
33613, USA.
(fax: 1 813 396 1601; e-mail: scientist.dave@gmail.com).

ª 2010 The Association for the Publication of the Journal of Internal Medicine Journal of Internal Medicine 269; 54–63 63