Opinion: Amyloid-β immunotherapy for Alzheimer's disease: the end of the beginning

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P E R S P E C T I V E S

21. Chakrabarti, S. et al. Comparison of the extent andpattern of family burden in affective disorders and schizophrenia. Indian J. Psychiatry 37, 105–112(1995).

22. Banerjee, G. & Roy, S. Determinants of help-seekingbehaviour of families of schizophrenic patients attending a teaching hospital in India: an indigenousexplanatory model. Int. J. Soc. Psychiatry 44, 199–214(1998).

23. Prince, R. The use of Rauwolfia for the treatment ofpsychoses by Nigerian native doctors. Am. J. Psychiatry117, 147–149 (1960).

24. Giel, R., Gezahegn, Y. & Van Luijk, J. N. Faith-healing andspirit-possession in Ghion, Ethiopia. Soc. Sci. Med. 2,63–79 (1968).

25. Korkeila, J., Lehtinen, V., Sohlman, B. & Tuori, T. Patients’expectations from their psychiatric community care inFinland. Nordic J. Psychiatry 52, 513–517 (1998).

Online links

DATABASESThe following terms in this article are linked online to:OMIM: http://www.ncbi.nlm.nih.gov/Omim/schizophrenia

FURTHER INFORMATIONEncyclopedia of Life Sciences: http://www.els.net/schizophreniaWorld Health Organization: http://www.who.int/Access to this interactive links box is free online.

9. Heinrichs, D. W., Hanlon, E. T. & Carpenter, W. T. Jr. The quality of life scale: an instrument for measuring theschizophrenic deficit syndrome. Schizophr. Bull. 10,388–398 (1984).

10. Leff, J., Trieman, N., Knapp, M. & Hallam, A. The TAPSProject. A report on 13 years of research, 1985–1998.Psychiatr. Bull. 24, 165–168 (2000).

11. Pickard, l. et al. Evaluating the Closure of Cane HillHospital (Research and Development for Psychiatry,London, UK, 1992).

12. Reda, S. Public perceptions of former psychiatric patientsin England. Psychiatr. Serv. 47, 1253–1255 (1996).

13. Wolff, G., Pathare, S., Craig, T. & Leff, J. Public educationfor community care. A new approach. Br. J. Psychiatry168, 441–447 (1996).

14. Levy, C. 2 accused of looting home for the mentally ill inQueens. New York Times (28 June 2002).

15. Levy, C. J. For mentally ill, death and misery. New YorkTimes (28 April 2002).

16. Levy, C. J. Here, life is squalor and chaos. New YorkTimes (29 June 2002).

17. Levy, C. J. Voiceless, defenseless and a source of cash.New York Times (30 April 2002).

18. Crepet, P. A transition period in psychiatric care in Italyten years after the reform. Br. J. Psychiatry 156, 27–36(1990).

19. Lelliot, P. & Wing, J. A national audit of new long-staypsychiatric patients II. Impact on services. Br. J.Psychiatry 165, 170–178 (1994).

20. Salokangas, R. K. R. Community care and need fortreatment of schizophrenic patients in Finland. Br. J.Psychiatry 164 (Suppl. 23), 115–120 (1994).

The future of psychiatric careThe closure of the asylums is an irreversibleprocess. If governments were to reverse thepolicy, the resources required to re-establishthe old institutions would be phenomenal.However, as is evident from the scandaloussituation in some community homes in theUnited States, it is possible to perpetuate theworst of the asylum abuses outside their walls.Community care can be provided on thecheap, but this usually means that it is grosslysubstandard. If it is well resourced, it costs atleast the same as care in the old psychiatrichospitals4. Although never publicly acknowl-edged as policy, there is a strong suspicion thatsome governments have promoted commu-nity care in the expectation of saving money. Itis clear that providing a community servicethat is at least as good as the hospital-basedservice it replaces does not lead to financialsavings. Indeed, if all the functions of the oldasylums are satisfactorily reprovided in thecommunity, it is likely to cost more thanhospital care. Consequently, the future patternof psychiatric services worldwide will dependon the willingness of governments to investin their development.

The increasing recognition in the Westthat users or consumers of health servicesneed to be able to influence their develop-ment has been taken very seriously by plan-ners of psychiatric services25. This willinevitably alter the direction of change. Ifusers are listened to, the demise of psychiatrichospitals will be hastened, as a huge majorityof them prefer life in the community3.

Julian Leff is at the Institute of Psychiatry,King’s College London, De Crespigny Park,

London SE5 8AF, UK.e-mail: [email protected]

doi:10.1038/nrn937

1. Jones, M. Social Psychiatry in Practice: the Idea of theTherapeutic Community (Penguin, Harmondsworth, UK,1968).

2. Bennett, D. in Theory and Practice of PsychiatricRehabilitation (eds Bennett, D. H. & Watts, F. N.) 15–42(John Wiley & Sons, Chichester, UK, 1983).

3. World Health Organization. Atlas: Mental HealthResources in the World (WHO, Geneva, 2001).

4. Hallam, A., Beecham, J., Knapp, M. & Fenyo, A. TheTAPS project 23. The costs of accommodation and care.Community reprovision for former long-stay psychiatrichospital patients. Eur. Arch. Psychiatry Clin. Neurosci.243, 301–310 (1994).

5. Jones, D. The TAPS Project 11. The selection of patientsfor reprovision in evaluating community placement oflong-stay psychiatric patients. Br. J. Psychiatry 162(Suppl. 19), 36–39 (1993).

6. Leff, J. & Trieman, N. The TAPS Project 46. Long-staypatients discharged from psychiatric hospitals: social andclinical outcomes after five years in the community. Br. J.Psychiatry 176, 217–223 (2000).

7. Harding, C. et al. The Vermont longitudinal study ofpersons with severe mental illness: I. Methodology, studysample, and overall status 32 years later. Am. J.Psychiatry 144, 718–726 (1987).

8. Angermeyer, M. C. & Kilian, R. in Quality of Life in Mental Disorders (eds Katschnig, H., Freeman, H. &Sartorius, N.) 19–30 (John Wiley & Sons, Chichester, UK,1997).

Amyloid-β immunotherapy for Alzheimer’s disease: the end ofthe beginningDale Schenk

O P I N I O N

The agents that are available at present forthe management of Alzheimer’s disease treatonly the symptoms of neurodegenerationand, at best, result in modest, short-termimprovements in cognitive function.Immunotherapy represents one of the firsttests of the amyloid hypothesis in the clinic,and is an evolving approach to thetreatment of Alzheimer’s disease that offersa genuine opportunity to modify diseaseprogression. Although initial clinical trials ofone approach met with some setbacks,active or passive immunization holds greatpotential for treating or even preventingAlzheimer’s disease.

The idea of harnessing the power of theimmune system to treat a neurological dis-order as complex as Alzheimer’s disease (AD)has captured the imagination and interest ofmany who have witnessed the devastationcaused by this condition. It is believed that abnormal accumulation of amyloid-β

peptide (Aβ) into extracellular toxic plaquesis responsible for the neurodegeneration andresulting dementia in AD (BOX 1). Therefore,Aβ represents an important molecular targetfor intervention in AD, and agents that canprevent its formation and accumulation orstimulate its clearance might ultimately be oftherapeutic benefit. Potential inhibitors of theβ- and γ-secretase enzymes (which are requiredfor the production of Aβ) are under investiga-tion, but an alternative strategy involving Aβimmunotherapy is attracting much attention.As well as its clinical potential, this immuno-logical approach will provide a framework fortesting the amyloid hypothesis.

Preclinical studies showed that immuniza-tion against Aβ can provide protection and, insome cases, reversal of the pathology of AD inanimal models. The idea that the results ofimmunization against an abnormal protein-aceous build-up in the brain of an animalmodel could translate into a treatment andpotentially prevent AD was initially received

© 2002 Nature Publishing Group


immunoconjugate approach is also an effec-tive way of mounting an immune responsethat results in reduced AD-like pathology inamyloid precursor protein (APP) transgenicmice12. These findings reinforce the idea thatimmunization with the entire Aβ peptide isnot necessary for efficacy, and are consistentwith the observation that antibodies directedagainst the amino-terminal and/or centralregion of the peptide provide protectionagainst amyloid pathology.

Several research groups have also investi-gated a passive immunization strategy13–18,and initial experiments indicate that ahumoral (antibody) response alone, in theabsence of a cellular response to Aβ, is suffi-cient to reduce the amyloid burden in thebrain and to reverse memory deficits. In otherwords, as antibodies themselves were admin-istered to the mice, and no T cells against Aβwere generated, these studies show that anti-bodies alone can elicit a protective effect.Interestingly, they also show that peripherallyadministered antibodies can have protectiveeffects in the brain. Consistent with thisobservation, it has been shown that antibod-ies not only bind to plaques in the brain13,but can also be found complexed to Aβ inplasma14 and at low levels in the cerebro-spinal fluid (CSF) of immunized animals9.Not all anti-Aβ antibodies can effectivelyreduce pathology in the brain13. Those thatcan reduce pathology share the characteristicof binding to the first 16 amino acids of Aβ,and this coincides with the ability of suchantibodies to bind to native plaques in brainsections13. The reasons for this are not clear,but one possibility is that only the first 16amino acids of Aβ are accessible either insolution or on the surface of the plaques, sothat only antibodies directed against thisregion are effective.

Mechanisms of actionAlthough active or passive administration ofanti-Aβ antibodies seems to be effective inreducing AD-like pathology in transgenicmouse models, the means by which theyachieve this effect, whether by stimulatingmicroglial activity, sequestering free Aβ, dis-rupting its aggregation, or by a combinationof these mechanisms, has yet to be deter-mined (BOX 3). Investigations using mono-clonal antibodies directed against differentregions of Aβ have indicated that, whereasamino-terminal antibodies were effective inreducing plaque burden, those directedagainst the carboxyl terminus were not13.Moreover, neuropathological analyses showthat anti-Aβ antibodies seem to triggerphagocytosis of Aβ plaques from PDAPP

with sincere optimism. However, scientificand public scepticism of the approach hasarisen recently after reports of encephalitis insome patients who were immunized with theentire amyloid peptide in a Phase IIa study1.

In this article, I briefly review our currentknowledge of Aβ immunotherapy and iden-tify challenges for the future. As with any pro-posal for a radically new medical therapy, itwill be some time before the approach is fullyevaluated as a potential treatment for AD.

Strategies for Aββ immunotherapySeveral types of immunotherapy for AD areunder investigation (BOX 2). The first, directimmunization with synthetic intact Aβ

42(the

predominant form of Aβ in the amyloidplaques of AD) has been evaluated in trans-genic mouse models and has recently providedthe first clinical experience of Aβ immuno-therapy. This approach stimulates T-cell, B-celland microglial immune responses. A secondmethod of active immunization involves theadministration of synthetic fragments of Aβ(which preferentially stimulate B cells andhence antibody production) conjugated to acarrier protein that provides helper-T-cellepitopes (stimulating T cells to provide the necessary cytokines to allow the B cells to mature and generate antibodies), thus

avoiding the potential problems associatedwith mounting a T-cell response directlyagainst Aβ. The third type of immuno-therapy under investigation involves passiveadministration with monoclonal antibodiesdirected against Aβ. This approach circum-vents the need for the patient to mount animmunological response to the Aβ peptide.

Preclinical findingsTransgenic animals expressing the AD-linkedgene mutations that are implicated in familialAD2,3 and result in overproduction of Aβ

42

(REFS 4–8) have become a valuable tool for eval-uating the feasibility of therapeutic strategiesfor AD. Several research groups have pub-lished preclinical evidence that supports thevalidity of the different Aβ immunotherapyapproaches (TABLE 1) and, in several studies,improvements in cognitive performance havebeen reported after immunization with Aβ

42,

in addition to a reduction in Aβ neuropathol-ogy9–11. These findings provide the first directevidence that an intervention that affects thepresence of Aβ in the brain could lead to animprovement in cognition — a predictionthat is consistent with the amyloid hypothesis.

One report of immunization with a frag-ment of the Aβ peptide coupled to polylysineshas provided preliminary evidence that the

NATURE REVIEWS | NEUROSCIENCE VOLUME 3 | OCTOBER 2002 | 825

Box 1 | The amyloid hypothesis

Amyloid-β peptide (Aβ) is derived from a much larger precursor protein, termed amyloidprecursor protein (APP), which is cleaved sequentially, first by β-secretase (forming the solubleectodomain APPβ and the β-stub) and then by γ-secretase (see panel a of the figure). Aβ is thenthought to self-associate under certain circumstances to form proteinaceous aggregates calledamyloid plaques (panel b, stained with Bielschowsky’s silver stain; panel c, stained with anti-Aβantibody). These plaques occur at a high density in many parts of the brain in patients withAlzheimer’s disease (AD) and, on the basis of the amyloid hypothesis, are thought to lead to abroad spectrum of neuropathologies that ultimately result in the neurotoxicity and neuronaldeath (panel d, the brain of a patient with AD showing enlarged sulci) that underlie thesymptoms of dementia observed in these patients.

NH2

COOH

β-secretase γ-secretase

β-stub

APPβ

Aβ42

a b

cd




effector functions (including Fc receptors or complement), which might also affecttheir efficacy.

Clinical experienceOn the basis of extensive preclinical safetyand efficacy data from several species (mice,rabbits, guinea pigs and monkeys), Aβ

42

(under the name of AN 1792), plus theadjuvant QS-21 (adjuvants are nearly alwaysused in immunization or vaccine formula-tions and serve to stimulate an immuneresponse), entered clinical trials for possibletreatment of AD. A small, single-dose PhaseI study was carried out in 24 patients andgood tolerability data were reported.Consequently, a multiple-dose Phase I studythat monitored more than 70 patients wascarried out to evaluate immunogenicity andfurther safety measures. This second studyshowed that AN 1792 was well toleratedand, in a subset of patients, a good immuno-logical response was obtained, although thestudy was too small to determine possibleefficacy. After the successful completion ofthe two Phase I studies, a Phase IIa trial ofAN 1792 was initiated to learn more aboutthe overall immunotherapy approach and to support further immunotherapeuticefforts, such as Aβ immunoconjugates andmonoclonal antibodies, that are also beingpursued.

indicated that monoclonal antibodies thatare directed against specific Aβ epitopesmight protect against neurotoxicity byinhibiting the fibrillar aggregation of Aβin vivo17,18,20. These results indicate that sev-eral forms of Aβ, both plaque-derived formsand oligomers in solution, might contributeto cognitive decline in transgenic models,and it is possible that a similar situationcould occur in vivo in patients with AD.These contrasting findings have led to adebate about whether, to be effective, it ismore important for an antibody to capturesoluble forms of Aβ, or to bind to the plaque-derived component and clear it. This is anactive area of investigation, and various Aβantibodies can selectively facilitate clearanceby either one or both of these mechanisms.The complexity of the situation is increasedby the ability of various antibody isotypes to interact with different immunological

mice or AD brain sections by isolated micro-glial cells in an ex vivo assay13. The availableevidence indicates that this occurs through amechanism termed ‘Fc-mediated phago-cytosis’. This is a biological phenomenonthat occurs when antibodies bind to foreignobjects (or in this case plaques), allowingengagement of microglial or monocyticcells through a specific interaction betweenFc receptors on the phagocytic cell and theFc region of the bound antibody complex.This triggers the microglial cell to engulfand digest the object that has been recog-nized by the antibody. Confocal microscopystudies have showed the presence of inter-nalized Aβ in microglia after anti-Aβ admin-istration13. This type of analysis has alsoshown that the Fc region of the antibody isnot absolutely required to clear plaques inthe brain19.

Alternatively, an antibody termed 266,which is directed against the central domainof Aβ, has been reported to act as a ‘periph-eral sink’, capturing Aβ in the bloodstreamand indirectly reducing the Aβ burden inthe brain, theoretically by driving the equi-librium of the peptide from brain to plasmacompartments14,15. However, antibody 266can also be found in CSF, indicating that,like antibodies to other regions of Aβ, 266can move into the brain and might exert itseffects centrally. In vitro studies have also

Box 2 | Antibody strategies

Three different approaches to generating antibodiesdirected against amyloid-β peptide (Aβ) are depicted.The first strategy involves immunization with full-lengthAβ, which contains 42 amino acids (see panel a of thefigure). After injection, the peptide is taken up byantigen-presenting cells, and fragments of the peptide arepresented to T cells. Subsequently, various B cells that canrecognize epitopes on Aβ

42are engaged and proliferate.

These eventually produce anti-Aβ antibodies. It isthought that these antibodies are key to effecting thereduction in Aβ pathology that has been seen in anumber of APP transgenic mouse models after Aβ

42

immunization. The second type of active-immunizationapproach involves the administration of small fragmentsof Aβ conjugated to an unrelated carrier protein (panel b).This immunoconjugate approach is similar to the firststrategy with the exception that the T cells are stimulatedby the carrier protein rather than the Aβ fragment (whichlacks T-cell epitopes). This approach also yields a strongantibody response to a region of the Aβ peptide. Thethird strategy is to administer anti-Aβ antibodies directly(panel c). This approach does not require any type ofimmunological response from the host and, as such, hasthe potential to be useful in individuals that might nototherwise generate an immune response to Aβadministration.

NH2

COOH

Carrier protein

NH2

COOH

Active immunization Passive immunization

Immunization withintact Aβ42 peptide

Immunization withAβ fragments

Immunization withanti-Aβ antibodies

Anti-Aβ antibodies

Immuneresponse

B cell

T cell

Antigen-presenting cell

Aβ fragmenta b c

“Cautious optimism aboutthe future of AD treatmentis warranted, but it will besome time before we knowwhether such optimism is justified.”



which will aid in the future design of second-generation approaches. For example, anautopsy case from a patient enrolled in oneof the Phase I studies who had received mul-tiple doses of AN 1792 (who died as a resultof pulmonary embolism about one year afterthe trial was completed) is under analysisand should be useful in interpreting the pos-sible effects of AN 1792 on AD-like brainpathology (J. Nicoll, personal communica-tion). Interestingly, preliminary findingsshow that not all of the affected individualsin the Phase IIa study had a measurable antibody titre against Aβ, indicating that the presence of immunoglobulin-γ was not a prerequisite for the development ofmeningoencephalitis.

In the Phase IIa study, 375 patients wereenrolled to receive double-blind treatmentwith AN 1792 or placebo in a 4:1 ratio.Measures of efficacy included cognitive func-tion, brain volume, biomarker concentrationand day-to-day functioning. Although thestudy was not designed to have the statisticalpower to show that treatment altered the rateof cognitive decline in patients with antibodyresponses to AN 1792, it was anticipated thatmeaningful information on brain-volumedecline might be available. Given the interestsurrounding Aβ immunotherapy, the studywas fully enrolled within weeks (300 of 375patients received the active treatment).Unfortunately, signs and symptoms consis-tent with meningoencephalitis werereported in a small percentage of patients(17 cases to date) who received one to threedoses of AN 1792, and all study dosing washalted in January 2002 (REF. 1). Informationon the clinical reports of each of the patientsthat experienced side effects is being col-lected and will be reported in detail else-where (J.-M. Orgogozo, personal communi-cation). Briefly, the symptoms, duration andseverity of the meningoencephalitis variedconsiderably among the affected patients.Typical symptoms included transientchanges on magnetic resonance imaging

(MRI) scans, in addition to elevated countsof white blood cells in the CSF, indicatingcentral inflammation in the subset ofpatients affected. Although dosing has beenterminated, coding on the remainingpatients in the trial remains unbroken andmonitoring for MRI changes, cognitivedecline, immune function and safety willcontinue into 2003. Further tests are under-way to investigate the pathological mecha-nisms that underlie the syndrome, althoughdata are not yet available.

It is anticipated that further data fromboth of the Phase I studies in addition to thePhase IIa study will provide importantinsights into possible efficacy, safety issuesand the mechanism of action of AN 1792,

NATURE REVIEWS | NEUROSCIENCE VOLUME 3 | OCTOBER 2002 | 827

Table 1 | Overview of preclinical studies

Authors (year) Immunization Model Key findings Reference

Active immunization with synthetic AββSchenk et al. Aβ42 PDAPP mice Generation of high-titre anti-Aβ antibodies; development of Aβ plaques, neuritic 9(1999) dystrophy and astrogliosis almost completely prevented in young animals; marked

reduction in extent and progression of AD-like neuropathology in older animals

Janus et al. Aβ42 protofibrillar TgCRND8 Generation of anti-Aβ antibodies; reduction in Aβ plaque deposition without 10(2000) assemblies mice reducing overall Aβ levels; improvements in cognitive function in Morris water maze

Morgan et al. Aβ42 APP/PS1 Generation of high-titre anti-Aβ antibodies; modest reduction in Aβ deposits; 11(2000) mice improved performance in radial-arm water-maze model of learning and memory;

no deleterious behavioural effects of any inflammatory response resulting fromimmunization

Active immunization with Aββ peptide fragments

Sigurdsson Tg2576 mice Reduction in brain amyloid burden and slightly smaller reduction in soluble Aβ42 12et al. (2001) level; absence of inflammatory markers associated with plaques

Passive immunization with monoclonal anti-Aββ antibodies

Bard et al. 3D6 (anti-Aβ1–5) PDAPP mice Presence of anti-Aβ antibodies in CNS after peripheral administration; antibody 13(2000) 10D5 (anti-Aβ1–16) binding to Aβ plaques; reduction in amyloid plaque burden

DeMattos et al. m266 (anti-Aβ13–28) PDAPP mice Reduction in brain Aβ deposition without binding to Aβ plaques; increase in 14(2001) plasma Aβ levels

DeMattos et al. m266 (anti-Aβ13–28) PDAPP mice Correlation of plasma Aβ levels with Aβ load and amyloid load after immunization 15(2002)

Dodart et al. m266 (anti-Aβ13–28) PDAPP mice Presence of Aβ–anti-Aβ antibody complex in plasma but not CSF sample; reversal 16(2002) of memory defects in object-recognition task and holeboard learning-and-

memory task

Solomon et al. Anti-Aβ1–28 In vitro Prevention of Aβ self-aggregation and preservation of Aβ solubility 17(1996)

Solomon et al. Anti-Aβ1–16 In vitro Restoration of solubility of preformed fibrillar Aβ by disruption of fibrillar structure; 18(1997) protective effect on Aβ neurotoxicity

Aβ, amyloid-β peptide; AD, Alzheimer’s disease; APP, amyloid precursor protein; CNS, central nervous system; CSF, cerebrospinal fluid; PS1, presenilin 1.

Box 3 | Possible mechanisms of action of anti-Aββ antibodies

Plaque breakdownPlaques formed by the accumulation of amyloid-β peptide (Aβ) are destroyed through Fc-mediated phagocytosis by microglial cells.

Peripheral sinkThe formation of antigen–antibody complexes in the periphery sequesters amyloid away fromthe brain and prevents the deposition of new plaques.

Aggregation inhibitorThe formation of antigen–antibody complexes prevents amyloid from accumulating in plaques.




11. Morgan, D. et al. A β peptide vaccination preventsmemory loss in an animal model of Alzheimer’s disease.Nature 408, 982–985 (2000).

12. Sigurdsson, E. M., Scholtzova, H., Mehta, P. D.,Frangione, B. & Wisniewski, T. Immunization with a non-toxic/nonfibrillar amyloid-β homologous peptide reducesAlzheimer’s disease-associated pathology in transgenicmice. Am. J. Pathol. 159, 439–447 (2001).

13. Bard, F. et al. Peripherally administered antibodiesagainst amyloid β-peptide enter the central nervoussystem and reduce pathology in a mouse model ofAlzheimer’s disease. Nature Med. 6, 916–919 (2000).

14. DeMattos, R. B. et al. Peripheral anti-Aβ antibody altersCNS and plasma Aβ clearance and decreases brain Aβburden in a mouse model of Alzheimer’s disease. Proc. Natl Acad. Sci. USA 98, 8850–8855 (2001).

15. DeMattos, R. B., Bales, K. R., Cummins, D. J., Paul, S. M.& Holtzman, D. M. Brain to plasma amyloid-β efflux: ameasure of brain amyloid burden in a mouse model ofAlzheimer’s disease. Science 295, 2264–2267 (2002).

16. Dodart, J. C. et al. Immunization reverses memorydeficits without reducing brain Aβ burden in Alzheimer’s disease model. Nature Neurosci. 5, 452–457(2002).

17. Solomon, B., Koppel, R., Hanan, E. & Katzav, T.Monoclonal antibodies inhibit in vitro fibrillar aggregationof the Alzheimer β-amyloid peptide. Proc. Natl Acad. Sci.USA 93, 452–455 (1996).

18. Solomon, B., Koppel, R., Frenkel, D. & Hanan-Aharon, E.Disaggregation of Alzheimer β-amyloid by site-directedmAb. Proc. Natl Acad. Sci. USA 94, 4109–4112 (1997).

19. Bacskai, B. et al. Non-Fc mediated mechanisms areinvolved in clearance of amyloid-β in vivo byimmunotherapy. J. Neurosci. 22, 7862–7872 (2002).

20. Frenkel, D., Katz, O. & Solomon, B. Immunization againstAlzheimer’s β-amyloid plaques via EFRH phageadministration. Proc. Natl Acad. Sci. USA 97,11455–11459 (2000).

21. Lopez, J. C. The comeback of immunization. Nature Rev.Neurosci. 3, 330 (2002).

22. Hock, C. Vaccination therapy for Alzheimer’s disease.Neurobiol. Aging 23, S143 (2002).

23. Monsonego, A. et al. Immunogenic aspects of amyloid β-peptide: implications for pathogenesis and treatment of Alzheimer’s disease Neurobiol. Aging 23, S112 (2002).

AcknowledgementsI thank J. Callaway, M. Koller, R. Black and C. Gombar for carefulreading of the manuscript. I would also like to acknowledge themany contributions of my other colleagues at Elan and Wyeth tomany aspects of the Aβ immunotherapeutic efforts.

Online links

DATABASESThe following terms in this article are linked online to:LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/APPOMIM: http://www.ncbi.nlm.nih.gov/Omim/Alzheimer’s disease

FURTHER INFORMATIONEncyclopedia of Life Sciences: http://www.els.net/Alzheimer disease | amyloidosis | microglia | neuroimmunologyAccess to this interactive links box is free online.

systems. The success of the immunotherapyapproach in preclinical models of AD gar-nered much excitement, but this hope hasrecently been partially dashed by the occur-rence of meningoencephalitis in some patientswho received the first available form. However,setbacks with new forms of therapy are notunusual; in fact, they tend to be the rule ratherthan the exception. Fortunately, the scientificbasis of Aβ immunotherapy is well founded,and a series of biologically distinct clinicalapproaches are now under consideration.Cautious optimism about the future of ADtreatment is warranted, but it will be sometime before we know whether such optimismis justified. At the very least, there is still muchwork to be undertaken to refine the approachand unlock its full potential for the treatmentand prevention of AD.

Dale Schenk is at Elan Pharmaceuticals,800 Gateway Boulevard, South San Francisco,

California 94080, USA.e-mail: [email protected]

doi:10.1038/nrn938

1. Senior, K. Dosing in phase II trial of Alzheimer’s vaccinesuspended. Lancet Neurol. 1, 3 (2002).

2. Tanzi, R. E. et al. The gene defects responsible for familial Alzheimer’s disease. Neurobiol. Dis. 3, 159–168(1996).

3. Hardy, J. New insights into the genetics of Alzheimer’sdisease. Ann. Med. 28, 255–258 (1996).

4. Citron, M. et al. Mutation of the β-amyloid precursorprotein in familial Alzheimer’s disease increases β-proteinproduction. Nature 360, 672–674 (1992).

5. Citron, M. et al. Mutant presenilins of Alzheimer’s diseaseincrease production of 42 residue amyloid β-protein inboth transfected cells and transgenic mice. Nature Med.3, 67–72 (1997).

6. Suzuki, N. et al. An increased percentage of long amyloidβ protein secreted by familial amyloid β protein precursor(β APP717) mutants. Science 264, 1336–1340 (1994).

7. Borchelt, D. R. et al. Familial Alzheimer’s disease-linkedpresenilin I variants elevate Aβ1–42/1–40 ratio in vitro andin vivo. Neuron 17, 1005–1013 (1996).

8. Scheuner, D. et al. Secreted amyloid β-protein similar tothat in the senile plaques of Alzheimer’s disease isincreased in vivo by the presenilin 1 and 2 and APPmutations linked to familial Alzheimer’s disease. NatureMed. 2, 864–870 (1996).

9. Schenk D. et al. Immunization with amyloid-β attenuatesAlzheimer-disease-like pathology in the PDAPP mouse.Nature 400, 173–177 (1999).

10. Janus, C. et al. A β peptide immunization reducesbehavioural impairment and plaques in a model ofAlzheimer’s disease. Nature 408, 979–982 (2000).

Future perspectives and directionsOne question about the adverse eventsobserved in the AN 1792 Phase IIa study iswhether the syndrome was mediated byantibodies, T cells or microglia. A secondquestion is whether patients who developedantibody responses to AN 1792 experiencedbenefit; that is, did they show a reduction inplaque pathology? Such a question is likelyto be answered only by MRI, Aβ-imagingstudies or, ultimately, at autopsy.

The adverse effects reported in the AN 1792 Phase IIa trial were greeted withconsiderable disappointment by both the medical field and the lay press, and theevents were interpreted by some as signallingthe end of the entire Aβ immunotherapyapproach. However, several research articlesand commentaries have recently adopted a more long-term view of the topic21,22. At apreclinical level, more evidence exists for thepotential efficacy of Aβ immunotherapythan for any other current approach to ADtreatment. Moreover, it is not at all clear, oreven likely, that the side effects seen in thePhase IIa study will occur with the protocolsfor passive antibody administration that aresoon to enter the clinic, as the entire cellularcomponent of the immune response is cir-cumvented by this approach. Even theimmunoconjugate approach with amino-terminal Aβ fragments will prevent a T-cellresponse, as T-cell epitopes to Aβ have beenreported to reside in the mid-to-carboxy-terminal region of the peptide23. As a resultof these considerations, recent scientificgatherings have concluded that Aβ immuno-therapy is very much alive, although we stillhave much to learn about harnessing thepower of the immune system to tackle a targetas multifaceted as AD.

ConclusionAβ immunotherapy for AD brings togethertwo of the most complex biological systems inthe human body: the immune and nervous


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