Alzheimer's June 11

8/8/2019 Alzheimer's June 11

1/13108 | FEBRUARY 2010 | volUmE 6 www.are.cm/rerl

Center or NeurologicDiseases, Departmento Neurology, Brigham

and Womens Hospital,New Research Building636F, 77 Avenue LouisPasteur, Boston, MA02115, USA(C. A. Lemere).Department oNeurosciences,University o Caliornia,San Diego, 9500Gilman Drive, La Jolla,CA 920930624, USA(E. Masliah).

Correspondence to:C. A. [email protected]

Ca Alzheimer isease be prevee

b amli immherap?Cynthia A. Lemere and Eliezer Masliah

Absrac | Alzheimer disease (AD) is the most common orm o dementia. The amyloid (A) peptide has

become a major therapeutic target in AD on the basis o pathological, biochemical and genetic evidence that

supports a role or this molecule in the disease process. Active and passive A immunotherapies have been

shown to lower cerebral A levels and improve cognition in animal models o AD. In humans, dosing in the

phase II clinical trial o the AN1792 A vaccine was stopped when ~6% o the immunized patients developed

meningoencephalitis. However, some plaque clearance and modest clinical improvements were observed in

patients ollowing immunization. As a result o this study, at least seven passive A immunotherapies are

now in clinical trials in patients with mild to moderate AD. Several secondgeneration active A vaccines

are also in early clinical trials. On the basis o preclinical studies and the limited data rom clinical trials,A immunotherapy might be most eective in preventing or slowing the progression o AD when patients are

immunized beore or in the very earliest stages o disease onset. Biomarkers or AD and imaging technology

have improved greatly over the past 10 years and, in the uture, might be used to identiy presymptomatic,

atrisk individuals who might beneit rom A immunization.

Lemere, C. A. & Masliah, E. Nat. Rev. Neurol.6, 108119 (2010); doi:10.1038/nrneurol.2009.219

Introduction

Alzhimr disas (AD) is th lading cas of dmntia,affcting mor than 26 million popl worldwid.1 Clinically,th disas is charactrizd by progrssi mmory loss anda dclin in cogniti abilitis. Sral symptomatic trat-mnts ar in s for AD; howr, no disas-modifying

thrapis ar crrntly aailabl. Th two major pathologicalhallmarks of AD ar xtraclllar amyloid plaqs, whichar formd mainly from th amyloid- (A) pptid, andintraclllar nrofibrillary tangls (NFTs), which containhyprphosphorylatd ta. Othr pathological changs inth brain incld gliosis, inflammation, nritic dystrophy,nron loss, and changs in nrotransmittr lls.2,3 InAD, th dlopmnt of pathology in th brain is thoghtto prcd cogniti symptoms and, hnc, diagnosis of thdisas, by many yars.

Th A pptid, which compriss 4042 amino acids,is gnratd following protolytic claag of th amyloidprcrsor protin (APP).4 Sral findings sggst that A,

particlarly th 42 amino acid form (A142), is a majorfactor in th pathognsis of AD. Mtations inAPPandin th gns that ncod prsnilins 1 and 2, (protinsinold in claag of APP) ar associatd with AD in asmall nmbr of familis. Frthrmor, A is dpositd inplaqs and blood ssls in th brain arly in th disasprocss. Finally, A oligomrs and fibrillar aggrgats artoxic to nrons.57

Th amyloid cascad hypothsis (Box 1) mphasizs acntral rol for A in th pathognsis of AD. Ths, A hasbcom a major thraptic targt, with arios anti-Astratgis bing prsd. Ths stratgis incld lowringth prodction of th pptid by inhibiting th nzyms

rsponsibl for A gnration, prnting th formation ofA aggrgats, and incrasing th rat of A claranc fromth brain. A immnothrapy ss anti-A antibodis,gnratd following accination or introdcd passily,to incras th rat of claranc and prnt aggrgation ofthis pptid (Figr 1).

Or th past 10 yars, A immnothrapy has mrgdfrom prclinical stdis in transgnic mos modls of ADto ntr clinical trials in hmans. Prsntly, at last 13 dif-frnt A immnothrapis ar in clinical trials world-wid.8 Adrs nts, inclding mningoncphalitisand asognic dma, ha bn notd in som of thsclinical trials. Nrthlss, stdis of acti and passi

A immnothrapis ar contining to mo forward,with an stimatd total nrollmnt of >9,000 patints. Onth basis of rslts from prclinical and clinical stdis,w bli that A immnothrapy has strong potn-tial for prnting AD if patints ar immnizd bfordisas onst or in th arlist stags of th disordr.In this Riw, w will proid an oriw of th pr-clinical stdis in animal modls that spportd a rolfor A immnothrapy in th prntion of AD patho-gnsis and cogniti dficits. W also will smmariz thdtails of th AN1792 accin trial and dlir an pdaton th acti and passi A immnothrapis crrntlyin clinical trials. Lastly, w will otlin what w prci

Cmpei ieress

C. A. Lemere declares an association with the ollowingcompanies: Elan, Wyeth. See the article online or ull details othe relationships. E. Masliah declares no competing interests.

REVIEWS

20 Macmillan Publishers Limited. All rights reserved10
mailto:[email protected]:[email protected]://www.nature.com/doifinder/10.1038/nrneurol.2009.219http://www.nature.com/doifinder/10.1038/nrneurol.2009.219mailto:[email protected]:[email protected]


2/13NATuRe RevIeWS|nEuRoLogy vOLuMe 6 | FeBRuARY 2010 | 109

to b important considrations in th dlopmnt of Aimmnothrapy for prnting AD.

Preclinical evidence

In th mid-1990s, Solomon and collags dmonstratdthat anti-A monoclonal antibodis dissold A aggr-gats and prntd A monomrs from aggrgatingin vitro.9,10 Sbsqntly, anti-A antibody-basd thrapisfor AD ha mrgd.

Acive immizai

In 1999, Schnket al. rportd th first idnc that actiA immnothrapy cold rdc A pathologyin vivo.Th rsarchrs accinatd PDAPP mictransgnicanimals that xhibit amyloid plaq pathologywithpr-aggrgatd, synthtic A

142. Th anti-A antibodis

gnratd following immnization both prntd plaqdposition and ld to a rdction of th nmbr of pr-stablishd plaqs in th brains of ths animals.11 In addi-tion, accination attnatd gliosis and nritic dystrophy.Nmros stdis ha confirmd and xtndd ths find-

ings in sral transgnic AD mos modls, sing ariosimmnogns, adjants and rots of administration. Insch modls, acti A immnization initiatd bfor orat th onst of AD-lik pathognsis lowrd brain Alls ffctily1216 and attnatd bhaioral dficits.17,18Ths findings dmonstratd th potntial of acti Aimmnization for prnting crbral A accmlationand cogniti impairmnt.

Th ffcts of acti A immnothrapy on transgnicanimals xhibiting wll-stablishd AD-lik pathologyha bn ariabl. In plaq-baring PDAPP mic (agd1115 or 18 months), accination with A

142prntd

th formation of nw plaqs and, prsmably, ld to

a rdction in stablishd plaqs.11 In Tg2576 mic (aplaq-baring transgnic mos modl of AD), howr,althogh A

142accination in yong, pr-plaq animals

prntd plaq dposition, th sam accin was mchlss ffcti in claring pr-stablishd plaqs in agdmic.14 In 18 month-old 3xTg-AD mictransgnicanimals that xhibit both amyloid plaqs and NFTsacti accination with fibrillar A

142did not rdc

plaq nmbr, or th lls of insolbl A or insolblta. Immnization did, howr, lad to an impromntin bhaioral prformanc and a rdction in solbl Alls in ths animals, sggsting that solbl A spcis(for xampl, oligomrs) might b dirctly linkd to th

bhaioral impairmnt obsrd in th 3xTg-AD modl.19By contrast, in agd bagls that xhibitd diffs plaqsand cogniti dficits, A accination ld to a rdction inplaq brdn bt did not altr crbral A oligomr llsor impro cognition.20

In gnral, th anti-A antibodis dscribd in th stdisabo rcognizd arios B cll pitops within th first15 amino acids of A,12,2125 whras th major T cll pitopswr mappd mainly to th middl rgion and carboxyl tr-mins of th pptid.24,26 An A-spcific T cll pitop has,howr, bn rportd within th first 16 amino acids ofth pptid in Tg2576 mic on a C57BL/6 backgrond andin som hman lkocyt antign transgnic mic.27

Key points

Preclinical studies support the idea that Alzheimer disease (AD) can be

prevented by amyloid (A) immunotherapies

Adverse events, but some eicacy, were observed in clinical trials o the

AN1792 A vaccine and the passive A immunotherapy bapineuzumab

At least 13 A immunotherapies are in clinical trials in patients with mild

to moderate AD

Secondgeneration A vaccines that avoid the adverse events observed withAN1792 and improve antibody generation might improve A immunotherapy

eicacy

A immunization might be considerably more eicacious in AD i administered

beore A aggregation, thereby protecting the brain rom downstreamneurodegenerative eects

Passive immizai

In yong PDAPP mic, passi immnization with ananti-A monoclonal antibody (m266), which rcognizdan pitop in th middl rgion of th pptid (A

1328),

prntd plaq dposition, and ld to a rdction in th

lls of solbl and insolbl A, as wll as an incras inth lls of Aanti-A antibody complxs in th blood.Ths findings spportd a rol for passi A immno-thrapy in th prntion of AD.28 In oldr plaq-baringPDAPP mic, only passi immnization with monoclonalantibodis that rcognizd th amino-trminal pitopsof A (that is, not th mid-rgion or carboxy-trminalpitops) ld to a rdction in pr-stablishd plaqs.29Gnrally, stdis in agd transgnic mic ha rportdthat passi A immnothrapy, whn initiatd aftr thonst of pathology, has lowrd th plaq brdn andcrbral A

142lls,30 rdcd nritic dystrophy,29

and rrsd bhaioral dficits (in som stdis bha-

ioral impromnts occrrd in th absnc of changs inbrain A lls).31,32 Systmic injctions of som anti-Aantibodis, howr, whil lowring A-plaq brdn,ld to an incras in th occrrnc of microhmorrhagsin aras of crbral amyloid angiopathy (CAA).33,34 In onstdy, passi immnization with anti-A monoclonalantibodis dirctd against th carboxyl trmins of thpptid (A

2840) ld to a rdction in plaq brdn

and an impromnt in bhaioral dficits, dspit anincras in microhmorrhag.35 Dirct intrahippocampalinjction of anti-A monoclonal antibodis lowrd thplaq brdn and rdcd th rat of arly aggrgationof phosphorylatd ta in 12 month-old 3xTg-AD mic.36

Box 1 | The amyloid cascade hypothesis

The amyloid cascade hypothesis places the ormation o early, toxic amyloid

(A) oligomers and the accumulation o A aggregates at the center o Alzheimer

disease pathogenesis. This hypothesis states that over time, an imbalance in

A production and/or clearance leads to gradual accumulation and aggregation

o the peptide in the brain, initiating a neurodegenerative cascade that involvesamyloid deposition, inlammation, oxidative stress, and neuronal injury and

loss.3,102,103 Supporting this hypothesis, in vitro and in vivo studies in animal

models have shown that oligomeric and ibrillar orms o A cause longtermpotentiation impairment104,105 and synaptic dysunction,106108 and accelerate

the ormation o neuroibrillary tangles that eventually cause synaptic ailure and

neuronal death.109

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This tratmnt did not, howr, ha any ffct on mor-adancd ta pathology, sch as NFTs, in oldr 3xTg-ADmic,36 sggsting that arly lowring of A might hadownstram ffcts on ta pathology.

Passi A immnization has bn shown to habnficial ffcts on synaptic plasticity and nronalfnction. Intracrbrontriclar infsion of anti-Aantibodis protctd against synaptic loss and gliosis inTg2576 transgnic mic.37,38 Frthrmor, monoclonalanti-A antibodis against th amino trmins and thmiddl rgion of A prntd synaptic plasticity dis-rption indcd by intracrbrontriclar infsionof natrally occrring, cll-drid A oligomrs,39 or of

A dimrs from hman AD crbrospinal flid (CSF).40An anti-A monoclonal antibody (3D6) that rcognizsth fr amino trmins was shown to protct dndriticspins and impro strctral plasticity in th brains ofPDAPP mic.41

Takn togthr, prclinical stdis of A immno-thrapy sggst that th orall fficacy of this trat-mnt approach might b highr whn immnizationoccrs bfor th aggrgation of A and ta, and bforamyloid accmlats in crbral blood ssls. Sralof th first-gnration A immnothrapis that habn tstd in animal modls ha alrady mod intoth latr phass of clinical trials. Frthrmor, nmros

A-specic antibodies bind tothe A peptides and target the

latter for clearance

Active immunization Passive transfer

Delivery by intravenous, subcutaneousor intraperitoneal injection

A-specic antibodies

T cell

Delivery with immune booster (adjuvant) by injection,or intranasal or transcutaneous administration

A-specicantibodies

A-specic antibodies bind tothe A peptides and target the

latter for clearance

Release of TH1-mediated

pro-inammatory and/or

TH2-mediated

anti-inammatory cytokines

B cellepitope

T cellepitope

A peptide(or A B cell epitope plus a foreign T cell epitope carrier protein)

a b

Second signal

Costimulatorymolecules

Naive

T cellsFirst signal

Activated

T cell

APC

B cell

Figure 1 | Active and passive immunization approaches. a | Vaccination (active immunization) activates the bodys immunesystem to produce antigenspeciic antibodies. In AD, ulllength A or a ragment o A conjugated to a oreign T cellepitope carrier protein can be used as an antigen, which is delivered into the body alongside an immune system booster(adjuvant). The humoral immune response is generated when APCs, which take up and process the antigen, present T cellepitopes to naive T

Hlymphocytes, activating the latter (irst signal). Binding o costimulatory molecules on the suraces o

APCs and T cells provides a secondary signal that enhances T cell activation. Meanwhile, the soluble antigen binds toB cell receptors, via the B cell epitope, and this antigen is presented to activated T cells to help the B cell make antibodiesagainst the antigen. Activated T cells also produce cellular immune responses. A T

H1 cellular immune response leads to

the release o proinlammatory cytokines, whereas a TH2 response causes release o antiinlammatory cytokines.

b | Passive immunization bypasses the need or the body to mount an immune response to produce antigenspeciicantibodies. In both active and passive A immunization, antiA antibodies bind A, targeting the peptide or clearance.Abbreviations: A, amyloid; APC, antigen presenting cell; T

H, T helper.

REVIEWS




scond-gnration tratmnts ar ndr instigationin animal modls and arly clinical trials (Box 2). Thmchanisms of A claranc following immnizationmight ary dpnding on th stag of disas (Box 3).

Clinical evidence

the An1792 rials

Design

In th lat 1990s, elan and Wyth dlopd an Aaccin for s in hmans. This accin, AN1792, con-sistd of a synthtic form of th A

142pptid and th

srfac-acti saponin adjant QS-21. To dat, th datafrom th two AN1792 trials ar th only rslts of majoracti A immnization clinical trials that ha bnmad widly aailabl. Th first AN1792 trial, initiatd inDcmbr 1999, was a phas I safty stdy condctdin 80 patints with mild to modrat AD. Ths indii-dals wr randomly assignd to on of for tratmntgrops: AN1792, AN1792 withot QS-21, QS-21 only, orplacbo. Or th sbsqnt 6 month priod, patints inach grop rcid for intramsclar accinations. This

phas I trial did not rport any notabl adrs nts.42

Following th rslts of th phas I stdy, a phas IIa15 month trial was initiatd in Octobr 2001 to al-at th fficacy of AN1792 pls QS-21 in AD. A total of372 patints with mild to modrat AD wr nrolld inthis dobl-blind, placbo-controlld, mlticntr stdy.Of th 300 patints who rcid AN1792 (pls QS-21),223 compltd th stdy. In th othr arm of th trial,53 of th 72 patints who rcid placbo compltdth stdy. This trial was stoppd in Janary 2002 aftr~6% of patints dlopd asptic mningoncphalitisand lkoncphalopathy.43,44 Th trial dsign was sb-sqntly risd to dtrmin th safty and tolrability

of AN1792 at 9 months aftr th last dos of accin. Thrslts of th AN1792 trials ar smmarizd blow.

Immune response

QS-21 strongly indcs T-hlpr (TH

) 1 lymphocyts.Ths, th AN1792 accin was dsignd to indca strong cll-mdiatd immn rspons, which isndd in th ldrly to gnrat a robst antibodyrspons.45In th phas I trial, howr, orall srmanti-A antibody titrs wr low, raching abo 1:1,000in only ~23% of th patints.42 Dring th latr stagsof th phas I trial, th addition of polysorbat 80 tonhanc solbility of th pptid incrasd th nmbr

of antibody rspondrs to almost 60% and modifid thimmn rspons from a prdominantly T

H2 rspons

to a proinflammatory TH

1 rspons.46

In th phas IIa stdy, a slight impromnt in th anti-body titrs following AN1792 immnization was obtaind,with ~20% of th patints showing srm antibody titrsabo 1:2,200 aftr btwn on and thr accinations.In ths patints, immnization rsltd in gnrationof anti-A antibodis targting th amino trmins ofA.47 This trial, as statd arlir, was discontind aftr18 of th 300 patints dlopd mningoncphalitisfollowing btwn on and thr immnizations. Thisfinding ld to th conclsion that AN1792 promotd th

prodction of A-racti atoimmn T clls, whichwas probably rlatd to actiation of T

H1 lymphocyts.

Th TH1 rspons might ha bn rlatd to th adjant

(QS-21) or to th prsnc of T cll and B cll rcognition

Box 2 | Secondgeneration amyloid immunotherapies

Eorts are underway to develop novel active and passive amyloid (A)

immunotherapies that overcome the saety concerns associated with the AN1792

vaccine and exhibit an increase in eicacy. Most o the treatments described

below are currently in preclinical stages o investigation, although some havereached human clinical trials.

An ideal A vaccine would stimulate a Thelper (TH) 2 immune response (rather

than a TH1mediated cellular immune response) to generate robust antiAantibody production that prevents or slows cognitive decline. Examples osecondgeneration active A vaccines include: nontoxic, soluble A derivative

immunogens;15 phage display o A36

;110 short aminoterminal A ragments

that target the B cell epitope while avoiding T cell activation;16,111113 herpes

simplex virus amplicons coding or A;114 the TH2biased aminoterminal UBITh

A vaccine (United Biomedical, Hauppauge, NY, USA);115 nonviral DNA A

vaccines;116 DNA vaccines encoding A aminoterminal ragments, a promiscuous

T cell epitope and molecular adjuvants;117,118 and A retroparticles (A115

displayed on retroviruslike particles used to the transmembrane domain oplateletderived growth actor).119 In addition to the dierent types o vaccines,

various adjuvants and routes o vaccine delivery (such as oral, intranasal and

transcutaneous delivery) are under investigation to improve the saety, eicacy

and ease o use o these immunotherapies.

Passive A immunotherapies are also evolving to include not only sitedirectedhumanized monoclonal antibodies (directed to the amino terminus, carboxyl

terminus or middle region o A), but also conormationspeciic antibodies. The

latter group includes antibodies that recognize toxic, soluble A oligomers120 andAderived diusible ligands.121 This group also comprises shortchain variable

ragment antiA antibodies,122124 antiA intrabodies, which target intraneuronal

A,125 and antibodies directed against toxic, modiied aminoterminal species

o A.126

Box 3 | Mechanisms o amyloid clearance and immunotherapy eicacy

Several mechanisms could explain how antibodies directed at amyloid (A)

promote the clearance o this peptide in vivo. When antiA antibodies orm

complexes with A peptides, the Fc portion o the antibodies might bind the

Fc receptor on microglia, inducing phagocytosis o these complexes.30 Thismechanism would require that antiA antibodies cross the bloodbrain barrier

(BBB) and bind A within the CNS. Some evidence has been reported to support

this mechanism; however, two studies have demonstrated that Fcmediatedphagocytosis is not required or immunotherapyinduced A clearance.127,128

In an alternative mechanism, antiA antibodies in the blood might cause a shit in

the concentration gradient o A across the BBB, thus resulting in an increase

in A elux rom the brain to the periphery.28,129 A antibodies might bind and

remove small A aggregates, thereby neutralizing the eects o toxic A specieson synapses.39 One study suggests that certain antibodies (or example, a mid

region A antibody, m266) sequester monomeric A inside the brain, acilitating

clearance o the peptide and preventing build up o toxic, aggregated orms

o A.130

These proposed mechanisms o A clearance by immunotherapy are not mutually

exclusive and might be disease stagedependent. For example, a preventivevaccine administered beore cerebral amyloid accumulation might not require

that the antibodies cross the BBB to enhance A clearance and maintain A inits monomeric state. By contrast, a therapeutic vaccine (delivered once plaque

deposition is well underway) would probably beneit rom the transpor t o A

antibodies into the CNS to induce A phagocytosis and neutralize local A toxicity.

Circulating antiA antibodies in the periphery might pull A rom brain to blood orclearance, thereby preventing urther deposition.

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pitops in th A pptid. Th B cll pitop (within thfirst 1115 amino acids of A) is considrd to b impor-tant for gnration of anti-A antibodis, whras thmost common T cll pitop (within amino acids 1542of A)48 has bn proposd to ha initiatd th T cllrsponss that triggrd th mningoncphalitis in somAN1792-accinatd patints.

Cognitive, MRI and biochemical outcomes

Th phas I stdy was dsignd to tst th safty of thAN1792 accin; howr, dring th trial, immnizdpatints wr notd to display a tndncy towards slowrcogniti dclin than controls.42 Ths, in th phas IIatrial, th primary nd points incldd safty, tolrability,and pilot fficacy masrsmltipl cogniti ma-srs, olmric MRI, and CSF lls of A

142and phos-

phorylatd ta (phospho-ta). In a singl-cntr analysisof a sbgrop of 30 patints inold in th phas IIa trial,impromnts wr rportd in som masrs of cogni-ti prformanc in six patints with high antibody titrs.49Nrthlss, in th phas IIa trial as a whol, no significant

ffcts on cogniti prformancas masrd by sralnropsychological tstswr rportd in th antibody-rspondr grop.44 A fw of th tsts rlatd to mmory(for xampl,th z-scor across th nropsychologicaltst battry) showd that th antibody rspondrs xhib-itd a slowr rat of mmory dtrioration than did thplacbo-tratd patints (P= 0.02). A follow-p stdy in asbst of patints 4.6 yars aftr AN1792 dosing was haltddmonstratd that most of th antibody rspondrs stillhad dtctabl anti-A titrs (17 of 19 indiidals tstd).Moror, ths indiidals had a markdly rdcd ratof fnctional dclin on th Disability Assssmnt forDmntia Scal and th Dpndnc Scal compard with

placbo-tratd patints.50volmtric MRI stdis rald that antibody rs-

pondrs had incrasd brain olm loss compard withcontrols, and that a dissociation xistd btwn brainolm loss and cogniti fnction in ths indii dals.51On possibl xplanation for this dissociation cold bthat th rmoal of amyloid by immnothrapy mightha occrrd lat in th progrssion of th disas at apoint whn th nrodgnrati pathology and atrophyin th hippocamps was ry adancd. Altrnatily, thMRI rslts might ha indicatd that amyloid rmoalwas accompanid by dynamic changs in flids, which ldto an xtnsi rdction in hippocampal olm. Th

dissociation btwn brain olm loss and cognitiprformanc might also rflct som ngati ffctsof th accination on fibr or whit mattr olm. Ofnot, althogh th hippocampal olm was small in thAN1792 grop, th olm stabilizd aftr sral monthsand did not contin to dcras. In th adjant controlgrop, howr, th hippocampal olm contind todcras or th nxt 4.6 yars.50

In a small sbst of patints assssd at 12 monthsfollowing th last dosing, lls of CSF phosphorylatdta (p-ta) wr fond to b dcrasd in antibody rs-pondrs (11 patints) rlati to patints rciing placbo(10 patints; P



claranc of A), whil othr hallmarks of an AD brain,inclding CAA and NFTs, wr idntifid in th CNS.Similarly, in a singl cas rport of a patint with dmn-tia with Lwy bodis, who xhibitd globally stabl fnc-tional and cogniti fatrs, A immnization rsltdin a markd claranc of amyloid dposits, with ta andsynclin pathology rmaining nchangd.66

A nropathological cas stdy was prformd on thbrain of a 71 yar-old patint with AD who was immnizdwith AN1792 bt did not dlop ncphalitis (Figr 2).67No amyloid plaqs wr notd in th frontal cortx inthis cas, althogh abndant A-immnoracti macro-phags wr obsrd in this rgion. Th prsnc ofNFTs and CAA was an indication that th pathology wasongoing. In this patint, th whit mattr smd normal,and minimal lymphocytic infiltration of th lptomningswas obsrd. Consistnt with th findings from this cas,a sbsqnt stdy of thr immnizd patints raldxtnsi claranc of amyloid and ta-containing n-rits. Howr, othr fatrs of ta pathology (NFTs andnropil thrads) as wll as CAA wr still prsnt.65 In

fact, a prios stdy had showd that althogh parn-chymal amyloid was focally disaggrgatd, asclardposits wr rlatily prsrd or n incrasd in twopatints with AD approximatly 1 yar aftr immniza-tion with AN1792.68 Immnoassays rald that thtotal solbl A lls in th gray and whit mattr wrsharply incrasd in ths accinatd patints compardwith nimmnizd patints with AD and halthy con-trols.68 In anothr stdy, brains wr xamind from ninAD patints 4 months to 5 yars aftr AN1792 accina-tion. Th brains from ths indiidals had markdlyincrasd crbroasclar A

142and A

140dposition

compard with brains from nimmnizd patints with

AD.69 Rmarkably, a complt absnc of both plaqs andCAA was notd in th brains of two patints who did4 and 5 yars aftr th first immnization,69 raising thpossibility that, gin tim, A is ntally clard fromth crbral asclatr.

Crre rials

Passive immunization

At last sn passi AD immnothrapis ar in clinicaltrials in patints with mild to modrat AD (Tabl 1).8In 2008, elan and Wyth rportd that a phas IIa trialof bapinzimab (AAB-001)a hmanizd monoclonalantibody that rcognizs th amino trmins of Ain

patints with mild to modrat AD did not mt thstdys nd points for cogniti fficacy, althogh a trndfor cogniti stabilization was obsrd.70 Post hoc analy-sis, howr, dmonstratd significant cogniti bnfitsfrom this tratmnt in mltipl tsts for patints whodid not carry th apolipoprotin e (APOE) 4 allla major gntic risk factor for AD. By contrast, only atrnd towards bnfit was obsrd inAPOE 4 carrirs,possibly bcas of acclratd pathognsis in thsindiidals. Th otcoms from th post hoc analysisar ncoraging; howr, ths rslts shold b intr-prtd with cation, as th s of mltipl comparisonsin post hoc analyss is controrsial.

Ongoing clinical trials that incld th sparationofAPOE 4 carrirs into diffrnt tratmnt grops, aswll as additional cogniti masrs, shold hlp torsol whthr bapinzimab dmonstrats fficacy inAD. Sral larg phas III bapinzmab trials ar cr-rntly ndrway. In fi of ths stdis, mor than 4,000patints ha bn stratifid according toAPOE 4 statsto s whthr this gntic diffrnc affcts th fficacyof th drg. In ths trials, carrirs ofAPOE 4 ar onlyrciing th lowst dos (0.5 mg/kg) of th tratmnt as arslt of incidncs of transint asognic dma obsrd

in th phas II stdy, particlarly in this sbgrop. Anxtnsion stdy inoling 1,350 patints with AD whoparticipatd in arly bapinzmab trials is also ongoing.Participants in this stdy will rci bapinzmab byintranos injction for 2.5 yars. In April 2009, elan andWyth droppd th highst of th thr bapinzmabdoss (2 mg/kg) inAPOE 4 non-carrirs bcas of thrisk of asognic dma; ths patints ar now bingdosd with 1 mg/kg.71 In addition, sbctanos injc-tion of bapinzmab is bing instigatd in 120 patintswith AD in a phas II clinical trial.

In 2008, eli Lilly rportd that a 12 wk phas II trialof solanzmab (LY2062430)a hmanizd monoclonal

a c

d e

b

Figure 2 | Neuropathological indings in an AN1792immunized patient withAlzheimer disease. A 71 yearold male patient with a 10 year history o dementiawas administered three doses o AN1792. He died a year later due to ailure tothrive, but did not develop meningoencephalitis. a | Gross morphology o the brainshowed preservation o the limbic structures and cortical ribbon. b | In the rontalcortex, although amyloid immunoreactive macrophages were abundant, noamyloid plaques were detected. c | Cortical vessels exhibited persistentamyloidosis despite removal o the surrounding amyloid plaques. d | CD4positiveT cells (indicated by brown staining) were requently located around bloodvessels. e | In areas where amyloid was removed, the neuritic network (labeled

with an antineuroilament antibody) appeared preserved.

foCuS on dEMEntIA




antibody that rcognizs th middl rgion of A and bindssolbl forms of th pptidsccssflly mt th saftyand tolrability nd points. In this stdy, solanzmabwas administrd to 52 patints with mild to modratAD in doss of p to 400 mg pr wk. Th AlzhimrDisas Assssmnt Scal-Cognition scors and CSF ta

lls wr nchangd in ths patints.72,73 Intrstingly,amino-trminal trncatd A spcis (incldingpyrogltamat-modifid A) wr dtctd in patintsblood following, bt not bfor, passi immnization,sggsting a sqstration of A from th brain to thpriphry.74 Two larg phas III stdis of solanzmabin a total of 2,000 patints with mild to modrat ADar ndrway.

Anothr stratgy for passi immnization is th injc-tion of intranos immnogloblin (IvIg), a pooldmixtr of natral hman immnogloblins that incldA antibodis (thos rcognizing A oligomrs andfibrils, among othrs).75 IvIg antibodis ha bn shown

to intrfr with th oligomrization and fibrillization ofA,76,77 protct nrons against A-mdiatd toxicity,76and promot A claranc from th brain.78 In a pilotstdy, IvIg tratmnt ld to a rdction in total A llsin CSF, an incras in srm A lls, and stabilizationof cognition in fi patints with AD.79 In on 18 monthstdy in ight patints with mild AD, IvIg thrapy wasadministrd for 6 months, stoppd for 3 months, andthn rsmd for 9 months. IvIg-tratd patints showdsigns of cogniti impromnt aftr 6 months. Howr,cogniti fnction dclind to baslin dring th washotpriod, and thn stayd at baslin dring th sbsqnt9 months.80 A lls in CSF wr rdcd only dring

th priods of IvIg infsion. In addition, anti-A anti-bodis wr dtctd in th CSF of th patints follow-ing IvIg tratmnt, indicating that IvIg antibodis mightcross th bloodbrain barrir and lowr A lls in thbrain. Baxtr Halthcar and th Alzhimrs DisasConsortim Stdy ha initiatd a phas III IvIg stdy.

On othr IvIg stdy, sponsord by Octapharma, is inprogrss. In addition, sral phas I trials of othr passiA immnothrapis ar ndrway (Tabl 1).

Active immunization

Following halting of th dosing in th phas II AN1792trial for safty rasons, th scond-gnration A ac-cins crrntly in clinical trials ha bn dsignd toaoid stimlating adrs immn rsponss (Tabl 2).8elan and Wyths A accin ACC-001, an A amino-trminal immnoconjgat, was shown to b saf in aphas I stdy and is crrntly in phas II clinical trials in~360 patints with mild to modrat AD. This phas II

trial was pt on hold brifly bcas of a skin lsion in onpatint; howr, non of th adrs ffcts obsrd inth AN7192 trial ha bn obsrd in this nw stdy.81

Noartis also has an A accin (CAD-106) in clini-cal trials. CAD-106 compriss mltipl copis of A

16

copld to Qb irs-lik particls. A first-in-man trial ofCAD-106 was condctd in Swdn in 58 patints withmild to modrat AD. Indiidals in this trial rcidthr 50 g or 150 g doss of th accin.82 Low antibodytitrs wr obsrd with th 50 g dos of CAD-106;howr, at th 150 g dos, antibody titrs wr twofoldhighr. No diffrncs wr obsrd in th xploratoryotcom masrsclinical assssmnt, A CSF lls

Table 1 | Ongoing clinical trials o passive A immunotherapies

therap Spsrs Aib Phase a

mber rials

Esimae

paie

erllme

treame

rai

Primar cme

measres

Esimae

cmplei ae

ial rial

Bapineuzumab(AAB001)*

Elan; Wyeth;JANSSEN AlzheimerImmunotherapy

AntiA aminoterminal MAb

III; one trial 1,350 2.5 years Saety and efcacy July 2012

Bapineuzumab

(AAB001)*

Elan; Wyeth;

JANSSEN AlzheimerImmunotherapy

AntiA amino

terminal MAb

III; fve trials 4,650 18 months Cognit ion and global

unction

April 2011

Solanezumab(LY2062430)

Eli Lilly AntiA midregionMAb

III; two trials 2,000 19 months Cognition and globalunction

July 2012

GammagardIVIg (10%)||

Baxter Healthcare;Alzheimers DiseaseConsortium Study

Pooled humanantibodies

III; one trial 360 18 months Cognition and globalunction

July 2011

Bapineuzumab(AAB001)

Wyeth AntiA midregionMAb

II; one trial 120 6 months Treatmentrelatedadverse eects

March 2010

PF04360365 Pfzer AntiA MAb II; two trials 211 1218months

Saety, tolerability andpharmacokinetics

November 2011

R1450 HomanLaRoche Fully human MAb II; one trial 60 312 months Saety and tolerability May 2009

IVIg (10%) Octapharma Pooled human

antibodies

II; one trial 56 6 months Changes in plasma

A levels

September 2009

GSK933766A GlaxoSmithKline AntiA antibody I: one trial 122 12 months Saety, tolerability andtreatmentrelatedadverse eects

August 2010

*Delivered by intravenous injection. Longterm extension o earlier AAB001 phase II trial. Participants stratiied according to apolipoprotein E genotype.||Gammagard produced by BaxterHealthcare, Deerield, IL, USA. Delivered by subcutaneous injection. Abbreviations: A, amyloid; IVIg, intravenous immunoglobulin; MAb, monoclonal antibody.

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or whol brain olm by MRIbtwn CAD-106-tratd and placbo-tratd patints. A phas II trial ofthis accin is ndrway in ~84 patints with mild AD.

Affiris AG ha rportd that in sparat phas I clinicaltrials, ach condctd in 24 patints with mild to modratAD, two pptid accins mimicking parts of th amino-trmins of th A sqnc, AD01 and AD02, wrfond to b saf aftr for singl-dos accinationswr gin 4 wks apart.83 Long-trm tolrability phas 1bstdis ar ndrway for ths accins. Mrck and unitdBiochmical both also ha acti A accins in phas Itrials (Tabl 2).

Improving amyloid immunotherapyPreici Alzheimer isease

A immnothrapy has a high potntial for lowring

crbral A lls and protcting cognition; howr,as indicatd in animal modls, this approach to thrapysms to b mor ffcti whn administrd arly in thdisas cors. Ths, on of th biggst hrdls to prnt-ing AD by immnization is or ability to idntify poplat risk of dloping th disas byond thos indii-dals baring gntic mtations inAPPor th prsnilingns. Crrntly, a dfiniti diagnosis of AD is madat atopsy, on th basis of nropathological prsncof amyloid plaqs and NFTslsions that accmlator a nmbr of yars bfor nronal loss and clinicaldmntia. Progrss in biomarkrs and imaging tchnology,combind with mor-sophisticatd nropsychological

tsting has incrasd th liklihood that cohorts of halthy,middl-agd and ldrly indiidals at risk of dlopingAD can b idntifid. Th prsnc of anAPOE 4 alllincrass th risk of AD bt dos not dtrmin xactlywhn, or indd if, an indiidal will dlop th disas.Fagan and collags ha shown that in indiidals withry mild or mild AD (Clinical Dmntia Ratings 0.5 and1, rspctily), CSF lls of A

142ar rdcd compard

with halthy agd-matchd controls, whil lls of CSFta and p-ta

181ar both incrasd.84 A similar profil of

CSF changs was rportd in patints with mild cogni-ti impairmnt (MCI) who latr conrtd to AD.85 Inanothr stdy, low CSF A

142lls wr associatd with a

rdction in whol-brain olm, as masrd by strct-ral MRI. This finding sggstd that as A aggrgats andforms crbral plaqs, brain olm ndrgos atrophy.73

In this stdy, incrass in th lls of CSF ta and p-ta181occrrd aftr CSF A lls dcrasd. Moror, thsincrass in ta lls wr mor strongly associatd withnronal damag and cogniti dclin than wr CSFA lls. On stdy has rportd that 2040% of ldrlyindiidals withot dmntia had at last som, if notcomplt, nropathological findings of AD at atopsy.Moror, this stdy rald that th prsnc of ADlsions was associatd with cogniti dysfnction in sp-cific tsts of pisodic mmory, smantic knowldg, isalspatial ability, and/or xcti fnction.87

Brain imaging, whn combind with th aformntiondbiomarkrs, gratly incrass or ability to prdict who is

at risk of dloping AD sral yars bfor disas onst.Brain olm masrmnts by strctral MRI can dis-criminat btwn MCI and AD and prdict conrsionof MCI to AD with high accracy.88 vntriclar olm,as masrd by MRI, was shown to prdict MCI in halthyldrly indiidals followd p for 15 yars.89 Anothradanc in AD brain imaging is PeT with 11C-labldPittsbrgh compond B (PIB), which labls amyloid in thbrains of liing indiidals.90 In AD, PIB binding has bnassociatd with brain atrophy,91 a rdction in CSF A

142

lls,84 and a dcras in glcos mtabolism.92 Somwhatsrprisingly, high PIB binding has bn rportd in halthyldrly indiidals, sggsting that crbral amyloid dpo-

sition prcds cogniti impairmnt in AD.9396 Ths, inth ftr, a combination of imaging (for xampl, MRIand/or PIB-PeT) and biomarkrs (sch as low CSF A

142

lls and high CSF ta and phospho-ta181

lls) mightb sd to idntify and dfin grops of indiidals forAD prntion trials.

Immherap csierais

A immnization looks lik a promising approach for com-bating AD, yt a nmbr of isss prtaining to th trat-mnts thmsls nd to b considrd for this stratgyto sccd, inclding th typ of immnothrapy (Box 4).Indd, long-trm prntion might b mor fasibl with

Table 2 | Ongoing clinical trials o active amyloid immunotherapies

therap Spsrs Vaccie Phase a

mber rials

Esimae

paie

erllme

treame

rai

Primar cme

measres

Esimae

cmplei ae

ial rial

ACC001 Elan; Wyeth A aminoterminalconjugate

II; three trials 360 24 months Saety, tolerabilityand treatmentrelatedadverse eects

May 2012

CAD105 Novartis A15

coupled to Qb

viruslike particles

II; three trials 84 1224

months

Saety and tolerability June 2011

Aftope AD01;Aftope AD02

Afris AG;GlaxoSmithKline

A aminoterminalmimotope adjuvant

Ib; two trials 48 12 months Saety andtolerability*

December 2009

V950 Merck A aminoterminalpeptides conjugatedto ISCOMATRIX

I; one trial 124 48 months Saety and tolerability April 2014

UB311 United Biochemical A114

using UBITh I; one trial 18 7 months Saety and tolerability December 2010

*Longterm extension o previous phase I trial. ISCOMATRIXproduced by CSL Behring,King o Prussia, PA, USA. UBIThproduced by United Biomedical, Hauppauge, NY, USA. Abbreviation:A, amyloid.

foCuS on dEMEntIA




acti than with passi immnization, spcially whnon considrs accinating ry larg poplations or longpriods of tim. Stratgis targting spcific A conforma-tions that ar known to b toxic to nrons might bnfitfrom antibodis dirctd against th amino trmins(immnodominant pitop of A), gin th poor accssi-bility of othr portions of A in aggrgats.25 Whthr dis-soling xisting plaqs will rslt in th rlas of solbltoxic A spcis (for xampl, oligomrs) and, if so, for howlong, rmains nclar. Immnization bfor plaq dposi-

tion might aoid this problm. As a rslt of A immno-thrapy-indcd microhmorrhag in transgnic mosmodls of AD with CAA and asognic dma in hmans(spcially inAPOE 4 carrirs), immnization might ndto b administrd bfor th bild p of amyloid in bloodssl walls to aoid ths adrs ffcts. Intranronal Amight act as a nids for A dposition (intranronally andxtraclllarly) in th soma and along procsss and trmi-nals of affctd nrons. Ths, limiting intranronal Aformation at an arly stag of AD dlopmnt might bprotcti.97,98 An immnological approach for th rdc-tion of A formation by targting th -scrtas claagsit of APP has bn proposd.99

Th ability of th hman body to gnrat a stronghmoral rspons or fight infction dclins with aging,a condition known as immnosnscnc.100,101 In addi-tion, th immn systm might participat in AD patho-gnsis. Chronic xposr of hmans and transgnic micto A aggrgats sms to lad to clllar and hmoralhyporsponsinss to th pptid, which cold, in trn,contribt to th disas procss.26 Ths, a prnti ADaccin startd bfor th bild p of aggrgatd A and/orimmnosnscnc (for xampl, at 5060 yars of ag)might lad to a mor robst and long-lasting hmoralimmn rspons and, hnc, high lls of prodctionof A-lowring antibodis. A prntion trial, howr,

cold tak many yars and incr high costs. Idntifyingindiidals at risk of dloping AD might impro thfasibility of sch trials.

Many halthy middl-agd indiidals with a familyhistory of AD might b willing to participat in a clinicalAD prntion trial; howr, bfor any sch trial coldtak plac, safty and fficacy of th immnothrapy inpatints with AD will probably b rqird. unfortnatly,littl idnc xists that A immnothrapy can rrscogniti impairmnt in patints with mild to modratAD. Indd, stopping th progrssion of nrodgnrationand cogniti dclin onc it is wll ndrway might bdifficlt, n in th contxt of plaq claring,63 sggstingagain that arly immnization might impro th fficacyof A immnothrapy. Ongoing clinical trials shold pro-id som frthr clarification abot whthr A immno-thrapy is ffcti in patints who alrady ha AD. Thstrials, if ngati, will still not dtrmin whthr AD canb prntd if A is lowrd prsymptomatically, bforth onst of sbstantial nrodgnration.

ConclusionsA immnothrapy contins to show promis as a stra-tgy for prnting AD or trating th disas in its arlystags. Prclinical stdis in animal modls ha shownclar idnc that A immnization can prnt cr-bral amyloid pathology, synaptic dgnration and cog-niti dficits. early hman clinical trials of th AN1792A accin wr associatd with adrs ffcts bt alsoshowd som signs of fficacy. Indd, on th basis ofths stdis, at last 13 A immnothrapis ar cr-rntly in hman clinical trials, mostly in patints withmild to modrat AD. If sccssfl, ths trials cold ladto th first idnc of a disas-modifying tratmnt for

AD. Moror, sch an otcom wold indicat sccss-fl translation of prclinical stdis in animal modls toclinical fficacy in hmans.

A immnothrapy might, in th ftr, b an ffctitratmnt for prnting AD. Imaging and biomarkrs haimprod dramatically or th past 10 yars, incrasingth probability of idntifying at-risk indiidals bforclinical symptom onst and allowing th A immno-thrapy rspons to b monitord. If gin arly, bfor ADpathognsis is wll ndrway, A immnization mightb abl to prnt aggrgation of nrotoxic forms of A,thrby prnting downstram ffcts, sch as synapticdysfnction, nronal damag and cogniti impairmnt.

Box 4 | Active versus passive amyloid immunization

Both active and passive amyloid (A) immunotherapies have their advantagesand disadvantages. Active A immunotherapy has the potential to be morecosteective and longlasting, with ewer visits to the doctor, than passiveimmunization, which requires monthly inusions o costly humanized monoclonalantibodies. Active therapies might have additional beneits. One study hasreported that A vaccination in nonhuman primates led to an increase in theproduction o crossreactive, potentially protective A autoantibodies.131 Such

antibodies are typically lower in patients with AD than in agematched healthyindividuals;132 thereore, boosting the levels o these proteins might be beneicial.

Vaccination usually involves delivery o a strong adjuvant to boost antibodyproduction. Such adjuvants could potentially induce an undesirable immuneresponse, especially in elderly individuals in whom proinlammatory cytokines arealready above normal levels.100 In these cases, a passive A immunotherapy mightbe beneicial. One way to circumvent this problem or A vaccines could be to useantiinlammatory T helper 2biased adjuvants, which might help avoid unwantedadverse eects while still increasing antibody production. Another problem oractive therapies is that i an adverse event does occur, the immune response tothe active vaccine can be diicult to stop quickly. Passive A immunotherapies,on the other hand, can be stopped at any time. Another advantage to the passivetherapeutic approach is the use o antibodies that are speciic or particular Aconormations or species thought to be most toxic, thereby avoiding removal o all

A rom the brain. One disadvantage o the passive approach is the potential orpatients to eventually develop neutralizing antibodies against the passive therapy.

Review criteria

Articles or review were identiied rom PubMed and Googlesearches using the ollowing terms: A immunotherapy,immunotherapy and Alzheimers disease, Alzheimersvaccine, A vaccine, A immunization, AN1792,CAD106, bapineuzumab, solaneuzumab,Alzheimers disease clinical trials, aitope, andAlzheimers disease treatments. Only articles publishedin English and rom 1995 were retrieved and consideredor review. Inormation regarding A immunotherapyclinical trials was ound on clinicaltrials.gov and companywebsites. Abstracts and reports rom meetings were usedto ind the most recent results o clinical trials.

REVIEWS




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Ackwlemes

The authors would like to thank Douglas Galasko(UCSD, La Jolla, CA, USA) or his helpul commentsand Anahit Ghochikyan (Institute or MolecularMedicine, Huntington Beach, CA, USA) or her helpin the design o Figure 1. This work was supportedby NIH grants to C. A. Lemere (RO1AG20159)and E. Masliah (AG5131, AG18440, AG02074 andAG10435).

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13/13

CoRRECtIon

Ca Alzheimer isease be prevee b amli immherap?Cynthia A. Lemere and Eliezer Masliah

Lemere, C. & Masliah, E. Nat. Rev. Neurol.6, 108119 (2010); doi:10.1038/nrneurol.2009.219

In the February 2010 issue oNature Reviews Neurology, an entry in Table 1 was

incorrect. In the third entr y or bapineuzumab, the antibody column should have read:

antiA aminoterminal MAb.

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