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Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 369808, 11 pages doi:10.1155/2012/369808 Review Article Alzheimer’s Disease and the Amyloid Cascade Hypothesis: A Critical Review Christiane Reitz1, 2, 3 1 Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA 2 Gertrude H. Sergievsky Center, College
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  Hindawi Publishing CorporationInternational Journal of Alzheimer’s DiseaseVolume 2012, Article ID 369808, 11 pagesdoi:10.1155/2012/369808 Review Article  Alzheimer’sDiseaseand theAmyloidCascadeHypothesis: ACritical Review  ChristianeReitz  1,2,3 1 Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, College of Physicians and Surgeons,Columbia University, New York, NY 10032, USA  2 Gertrude H. Sergievsky Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA 3 Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA Correspondence should be addressed to Christiane Reitz, cr2101@columbia.eduReceived 28 November 2011; Accepted 3 January 2012Academic Editor: Laura MorelliCopyright © 2012 Christiane Reitz. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the srcinal work is properly cited.Since 1992, the amyloid cascade hypothesis has played the prominent role in explaining the etiology and pathogenesis of Alzheimer’s disease (AD). It proposes that the deposition of   β -amyloid (A  β ) is the initial pathological event in AD leading to theformation of senile plaques (SPs) and then to neurofibrillary tangles (NFTs), neuronal cell death, and ultimately dementia. Whilethere is substantial evidence supporting the hypothesis, there are also limitations: (1) SP and NFT may develop independently, and(2) SPs and NFTs may be the products rather than the causes of neurodegeneration in AD. In addition, randomized clinical trialsthat tested drugs or antibodies targeting components of the amyloid pathway have been inconclusive. This paper provides a criticaloverview of the evidence for and against the amyloid cascade hypothesis in AD and provides suggestions for future directions. 1.Introduction Alzheimer’s disease (AD), which is characterized by pro-gressive deterioration in cognition, function, and behavior,places a considerable burden on western societies. It is thesixth leading cause of all deaths and the fifth leading causeof death in persons aged  ≥ 65 years. To date, an estimated5.4 million Americans have AD, but due to the baby boomgeneration, the incidence in 2050 is expected to reach amillion persons per year, resulting in a total estimatedprevalence of 11 to 16 million a ff  ected persons.Since the first description of presenile dementia by AloisAlzheimer in 1907 [1], senile plaques (SPs) and neurofib-rillary tangles (NFTs) are considered the key pathologicalhallmarks of AD [2]. The identification of   β -amyloid (A  β )in SPs [3] and genetic studies that identified mutationsin the amyloid precursor protein (  APP  ) [4], presenilin 1( PSEN1 ), and presenilin 2 ( PSEN2 ) genes [5, 6] leading to the accumulation of A  β  and early-onset familial dementia[4, 5, 7], resulted in the formulation of the “Amyloid Cascade Hypothesis” (ACH; Figure 1) [8, 9]. According to the ACH, the deposition of A  β  is the initial pathological trigger inthe disease, which subsequently leads to the formationof NFTs, neuronal cell death and dementia. While thereis considerable evidence supporting this hypothesis, thereare observations that seem to be inconsistent. This papersummarizes the current evidence for and against the amyloidcascade in AD. 2.Amyloid CascadeHypothesis As described above, two key observations resulted in theoriginal formulation of the ACH (Figure 1). First, thedetection of A  β  as a main constituent of the SPs [3] andsecond mutations of the  APP   [4],  PSEN1 , and  PSEN2  genes[5, 6], which were found in families with early-onset AD (FAD, disease onset  <  60 years). As a consequence of theseobservations, the presence of A  β  within SPs was interpretedas an e ff  ect of these mutations that subsequently leads tocell death and dementia. Since FAD has—except the earlieronset—a similar phenotype to late-onset AD, it was assumed  2 International Journal of Alzheimer’s Disease  APP  , PSEN  1, PSEN  2 FAD  mutationsSoluble forms of oligomeric A  β APP  ?A  β 42 aggregationAggregate stressDeposited A  β  peptideNeuronal dysfunction and deathDementia  APP FAD  mutations,trisomy 21Tau + NFT Figure  1: Amyloid cascade hypothesis. that this amyloid deposition could explain the pathogenesisof all types of AD. 3.EvidencefromStudieson the FormationofA   β  andTau There are two major objections regarding the ACH assrcinally formulated. First, SPs and NFTs may be reactiveproducts resulting from neurodegeneration in AD ratherthan being its cause, and, second, it remains unclear whetherandhowthedepositionofA  β leadstotheformationofNFTs. 3.1. A  β  and Tau as Reactive Processes.  In persons who suf-fered from head trauma, APP is found with pathologicalfeatures similar to AD in neuronal perikarya and in dys-trophic neurites surrounding A  β  deposits [10]. In addition,there is evidence that neurons in the medial temporal lobesecrete APP and display increased APP immunoreactivity [11]. These findings suggest that increased expression of APPin head trauma cases may be an acute-phase response toneuronal injury [12], which in turn leads to increased A  β deposition. This notion is supported by the observationthat the di ff  erent morphological forms of A  β  deposits,including di ff  use, primitive, and classic deposits, containacute phase proteins such as complement factors and  α -anti-chymotrypsin [13]. Consequently, it has been proposed that,in AD, APP may be a reaction to the disease process in orderto help maintain cellfunction, neuronal growth, and survival[14]. The putative neurotrophic action of APP is supportedby the observation that it shares structural features with theprecursor for epidermal growth factor [14]. Finally, there isalso evidence that NFTs may form as a neuronal response toinjury [15].There are also findings from animal studies suggestingthat the formation of A  β  and NFT may be reactive. In rats,both experimental damage or chemically induced lesions of the nucleus basalis can elevate cortical APP, and intrathecalor intraparenchymal injections of toxins can induce APP inhippocampal neurons, suggesting that the generation of APPcould be a specific response to loss of functional innervationofthecortex[16,17].Denervationofthedopaminepathways and septal lesions a ff  ecting both the cholinergic systemand  γ -aminobutyric acid (GABA) neurons projecting to thedentate gyrus can result in a loss of dendritic microtubule-associated protein 2 (MAP2) and the appearance of tau-immunoreactive dentate gyrus granule cells [18]. Thus, den-ervation can cause transsynaptic changes in dentate gyrusneurons, and these alterations may represent an intermediatestep to NFTs formation. 3.2. Relation of the Formation of NFT to A  β .  SPs and NFTscluster in a significant proportion of cortical areas but they seem to be distributed independently of each other [19]. SPand NFTs also seem to occur temporally separated; in theentorhinal cortex the occurrence of NFTs may in fact precedethe occurrence of SPs [20]. This spatial and temporal separa-tion may suggest that they are pathogenically disconnected.However, evidence for an e ff  ect of A  β  on the formationof NFT comes from transgenic experiments. The presence of   APP   mutations alone or in combination with  PSEN1  muta-tions seems to induce A  β  deposits in normal brain and somedegree of hyperphosphorylated tau in neurites [21] althoughit does not appear to induce tau pathology or a significantinflammatory response. These findings are consistent withstudies in which fetal rat hippocampal neurons and humancorticalneuronstreatedwithfibrielarA  β displayanincreaseddegree of tau phosphorylation [22] providing additionalevidence that amyloid fibril formation might alter thephosphorylation state of tau, which in turn results in the lossof microtubule-binding capacity. Other studies showed thatA  β 25 − 35  can induce the aggregation of tau proteins and that adecrease in aggregation of A  β  was induced by tau peptides[23]. Thus, aggregation of tau may be associated withdisassembly of A  β , which could explain the lack of spatialcorrelation of the SPs and NFTs [19]. Finally, the notion of animpactofA  β  onNFT formationis supported bystudies in  International Journal of Alzheimer’s Disease 3  APP  -transgenic mice reporting that a reduction in endoge-nous levels of tau can ameliorate some of the behavioraland other deficits that are mediated by A  β  [24, 25] and by  the discovery that mutations in the tau gene cause autosomaldominant frontotemporal lobe dementia with a tau pathol-ogy similar to the tau pathology seen in AD but without theappearanceofA  β  plaques[26].Both these observations seemto place tau pathology downstream of amyloid-  β  pathology. 4.EvidencefromGeneticStudies In particular the genes identified in the late-onset form of the disease provide support for the ACH. In general, thesegenesarenotinheritedinaMendelianbutasporadicfashion.However, first-degree relatives of patients with late-onset ADhavetwicetheexpectedlifetimeriskofthisdiseasecomparedto persons without an a ff  ected first-degree relative, and late-onset AD is more frequent among monozygotic than dizy-gotic cotwins, suggesting a substantial genetic contributionto this form of the disease.The apolipoprotein E (  APOE  ) gene, which was identifiedas the first susceptibility gene for late-onset AD, is the majorgenetic risk factor (population attributable risk: ∼ 20%) [27,28]. Each  APOE- ε 4  allele lowers the age at onset in a dose-dependent fashion [27]. How the di ff  erent APOE proteinsmediate their e ff  ects in AD is not fully clarified, but thereis compelling evidence by PDAPP transgenic mice modelsindicating that APOE mediates the clearance of amyloid-  β [29], with the APOE2, APOE3, and APOE4 isoforms beingincreasingly less e ff  ective [30]. Consistent with this notion,the presence of an APOE- ε 4 allele is associated with a higherA  β  burden in the brains of LOAD patients [31, 32], sug- gesting that APOE interacts with A  β  by enhancing its depo-sition in plaques. In various ethnic groups, two haplotypesin the sortilin-related receptor ( SORL1 ) gene associated withLOAD were identified [33–37].  SORL1  is involved in tra ffi ck-ing of APP from the cell surface to the golgi-endoplasmicreticulum complex and  γ -secretase processing of APP [34,38, 39], also in line with the ACH. Recent large-scale GWA studies performed primarily in samples and populations of European ancestry detected genetic variants associatedwith AD in complement component (3b/4b) receptor 1( CR1 )  ,  clusterin ( CLU, APOJ  ), bridging integrator 1( BIN1 ), phosphatidylinositol-binding clathrin assembly pro-tein ( PICALM  )  ,  EPH receptor A1 ( EPHA1 )  ,  CD33 molecule( CD33 )  ,  membrane-spanning 4-domains, subfamily A,members 4 and 6E (  MS4A4/MS4A6E  )  ,  CD2-associated pro-tein ( CD2AP  )  ,  and ATP-binding cassette, subfamily A, mem-ber 7 (  ABCA7  ) [40–42]. While these genes remain to undergo functional validation, they are functionally plausi-ble and also largely consistent with the ACH. Similar andadditive to  APOE  ,  CLU   encodes an apolipoprotein and actsas an A  β  chaperone, regulating the conversion of A  β  toinsoluble forms and A  β  toxicity thereby promoting amyloidplaque formation [43]. ABCA7 is involved in the e ffl ux of lipids from cells to lipoprotein particles, such as APOE andCLU, and in addition regulates APP processing and inhibits  β -amyloid secretion [44]. There is evidence that CR1 may contribute to A  β  clearance by complement activation [45].CD2AP, CD33, BIN1, and PICALM are involved in endo-cytosis (CME), and a recent study [46] showed that severalof these factors involved in endocytosis modify A  β  toxicity in glutamatergic neurons of   Caenorhabditis elegans  and inprimary rat cortical neurons. In yeast, A  β  impaired theendocytic tra ffi cking of a plasma membrane receptor, whichwas ameliorated by endocytic pathway factors identified inthe yeast screen also providing substantial evidence for a link between A  β , endocytosis, and human AD [46]. In summary,convincing evidence for an A  β -related mechanism exists forall of these identified LOAD genes, providing a substantialamount of support for the ACH in AD. 5.EvidencefromClinicalTrialsTargeting  A   β  andTau The drugs currently used to treat AD (i.e., cholinesteraseinhibitors, NMDA receptor antagonists, and antipsychoticdrugs) have limited therapeutic value. New, potentially disease-modifying, therapeutic approaches are targeting A  β and tau protein. Driven by the ACH, there are currently fourmain therapeutic approaches: (a) reducing the generation of A  β , (b) facilitating the clearance of A  β , (c) preventing theaggregation of A  β  and destabilizing A  β  oligomers, and (d)drugs targeting tau [47]. Drugs classes include active andpassive immunization directed against A  β , compounds thatinterfere with the secretases regulating A  β  generation fromAPP, drugs to prevent A  β  aggregation and destabilize A  β oligomers, and drugs targeting tau protein. 5.1. Active and Passive Immunization.  Active and passiveimmunizations were developed to inhibit generation of toxicA  β  aggregates and to remove soluble and aggregated A  β .At least three di ff  erent immune-mediated mechanisms canpromote A  β  removal: solubilization by antibody binding toA  β , phagocytosis of A  β  by microglia, and A  β  extraction fromthe brain by plasma antibodies.In phase II randomized controlled trials (RCTs) of activeimmunization of patients with mild-to-moderate AD withthe anti-A  β  vaccine AN-1792 (QS-21) most but not allparticipantsdevelopedsignificantA  β -antibodytitres[48,49] and there was evidence of memory and function improve-ment and reduced CSF tau concentrations in patients withincreased IgG titres [48, 49]. However, in the first trial patients immunized with AN-1792 had a greater brainatrophy rate on MRI than did patients given placebo possibly because of amyloid removal and cerebral fluid shifts. Inaddition, several patients developed meningoencephalitisdue to a T-cell response. In the follow-up trial, brain volumeloss in antibody responders was not di ff  erent from that inpatients receiving placebo, and no further cases of menin-goencephalitis were found [49]. Responders maintained low,but detectable, anti-AN-1792 antibody titres at about 4.6 yearsafterimmunizationandhadsignificantlyreducedfunc-tional decline compared with placebo-treated patients [49].In addition, immunization with anti-AN-1792 antibody could completely remove amyloid plaques as determined by   4 International Journal of Alzheimer’s Diseasepostmortem assessment although patients still had end-stagedementia symptoms before death.In order to avoid neuroinflammation and neurotoxicity,new vaccines that selectively target B-cell epitopes have beendeveloped. CAD-106, which consists of the immunodrugcarrier Qb coupled with a fragment of the A  β 1 − 6  peptide,could in animal studies induce A  β -specific antibodies andreduce amyloid accumulation without stimulating T cells.In patients with mild-to-moderate AD, CAD-106 induceda substantial anti-A  β  IgG response and was well tolerated[50], confirmatory phase II RCTs are ongoing (NCT01097096, NCT01023685, NCT00795418, NCT00956410, andNCT00733863). ACC-001 isan A  β 1 − 6  fragmentderived fromthe N-terminal B cell epitope of A  β  and conjugated tothe mutated diphtheria toxin protein CRM19. It is beingstudied in phase II RCTs (NCT00479557, NCT01284387,NCT01227564, NCT00498602, NCT00752232, NCT00955409, NCT01238991, NCT00960531, NCT00959192). ACI-24 is a vaccine that contains A  β 1 − 15  closely apposed to thesurface of the liposome. It reduced brain amyloid load andrestored memory deficits in mice [51] and is entering a phaseII RCT. Vaccines that are currently being tested in phase IRCTs are V-950 (NCT00464334; an aluminium-containingadjuvant with or without ISCOMATRIX (CSL Behring, PA,USA, a biological adjuvant of saponin, cholesterol, andphospholipids) and UB-311 (NCT00965588), a vaccine inwhich the immunogen A  β 1 − 14  is associated with the UBIThpeptide (United Biomedical, NY, USA) and a mineral saltsuspension adjuvant [52].A ffi topes, which are short peptides mimicking parts of native A  β 1 − 42 , represent an alternative active immunizationstrategy. The a ffi topes AD-01 and AD-02 target the N-terminal A  β  fragment and both had disease-modifying prop-erties in animal models of AD [53]. Results of recent phaseI RCTs indicate that both are safe and well tolerated(NCT00495417, NCT00633841, and NCT00711139) [53].A ffi topeAD-02recentlyprogressedtophaseIIclinicaltesting(NCT01117818).Passive immunotherapy is based on monoclonal anti-bodies or polyclonal immunoglobulins targeting A  β  topromote its clearance. Animal studies have shown thatanti-A  β  antibodies can prevent oligomer formation andreduce brain amyloid load with improvement in cognitivefunctions [54]. Several monoclonal antibodies are cur-rently being tested: bapineuzumab (AAB-001), solanezumab(LY-2062430), PF-04360365, GSK-933776, R-1450 (RO-4909832), and MABT-5102A. A phase II RCT of bapin-euzumab in patients with mild-to-moderate AD that hada follow-up period of longer than 18 months reported nosignificant e ff  ects on the primary measures of cognitionor activities of daily living, as measured in prespecifiedwithin-dose cohort analyses. However, post hoc anal- ysesof clinical and neuroimaging data from all dose cohortsshowed nonsignificant improvements in cognitive end-points and signs of e ffi cacy in  APOE   ε 4  noncarriers [55].Phase III studies are ongoing, including separate RCTsfor  APOE   ε 4  carriers and non-carriers (NCT00574132,NCT00996918, NCT00998764, NCT00667810, NCT00575055, NCT00676143, and NCT00937352). Solanezumab,a monoclonal antibody that targets specifically soluble A  β ,promotes A  β  clearance from the brain through the blood. Ina phase II RCT, there was a correlation between total plasmaA  β 1 − 42  after treatment (dose-dependent increase), baselineamyloid plaque burden shown by single-photon emissionCT scanning, and a dose-dependent increase in unboundCSF A  β 1 − 42 , suggesting that solanezumab might mobilizeA  β 1 − 42  from plaques and might normalize soluble CSFA  β 1 − 42  in patients with AD [56]. Consequently, two phaseIII RCTs have been initiated (NCT00905372, NCT00904683,NCT01127633). PF-04360365 is a modified IgG2 antibody that binds to the C terminus of A  β 1 − 40 . Preliminary resultson a single-dose regimen indicate that this antibody is welltolerated in patients with AD [57]. Currently, two phaseII RCTs of multiple doses are ongoing (NCT00722046 andNCT00945672). GSK-933776, R-1450 (RO-4909832), andMABT-5102A are monoclonal antibodies that target A  β  andhave been tested in patients with AD in phase I and phaseII trials (NCT01424436, NCT00459550, NCT01224106,NCT00531804, NCT00736775, NCT00997919, NCT01343966, and NCT01397578).Passive immunization [58] can also be achieved by intravenous infusion of immunoglobulins (IVIg), fromhealthydonors,whichincludenaturallyoccurringpolyclonalanti-A  β  antibodies. IVIg is already approved as therapy for immune deficiency, with good safety and tolerability evidence. In two small studies, short-term immunoglobulinadministration in patients with AD was well tolerated,promoted a decrease of total A  β  CSF concentrations, andincreased plasma total A  β  concentrations [59, 60], with evidence of improvement or stabilization of cognitive func-tions. Preliminary data from a phase II RCT confirmedthe positive e ff  ects on cognition [61], a phase III study isongoing (NCT00818662). In summary, the RCTs on activeand passive immunization agents consistently show an e ff  ecton amyloid clearance, and several but not all phase II RCTsshow promising e ff  ects on cognition. 5.2. Drugs to Reduce A  β  Generation from APP.  BACE1 (  β -secretase) initiates the amyloidogenic pathway. Pioglitazoneand rosiglitazone are thiazolidinediones and drugs com-monly used to treat type II diabetes. They happen to act asBACE1 inhibitors through stimulating the nuclear peroxi-some proliferator-activated receptor  γ  (PPAR  γ ). Activationof PPAR  γ  receptors, in turn, can suppress expression of BACE1 and APP and can promote APP degradation by increasing its ubiquitination [62]. In addition to their e ff  ectsonBACE1,therapeutice ff  ectsofPPAR  γ agonistsinADcouldbe caused by their e ff  ect on insulin action. Both rosiglitazoneand pioglitazone increase peripheral insulin sensitivity andreduce concentrations of insulin. Insulin, in turn, competeswith A  β  for degradation by the insulin-degrading enzyme[62].There are only few phase III RCTs, which likely reflectsthe di ffi culty in development of BACE1 targeting agents.BACE1 has many substrates including several with phys-iologically important functions such as neuregulin-1 thatis involved in myelination, and drugs must cross theblood-brain barrier in order to modulate BACE1 function.
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