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1 종설 알츠하이머병에서임상약물시험의최신동향 강희영박경원 a,b 경상대학교의학전문대학원신경과학교실, 동아대학교의과대학신경과학교실 a, 동아대학교병원인지장애 치매센터 b Recent Update of Clinical Drug Trials in Alzheimer s Disease Heeyoung Kang, MD, Kyung Won Park, MD, PhD a,b Department of Neurology, Gyeongsang National Uninversity School of Medicine, Jinju, Korea Department of Neurology a, Dong-A University College of Medicine, Cognitive Disorders and Dementia Center b, Dong-A University Hospital, Busan, Korea The prevalence of Alzheimer s disease (AD) is increasing as the global population ages. Currently available treatments for AD target cholinergic and glutamatergic neurotransmission. There have been modest symptomatic effects, but disease modifying effects have not been accomplished. This is even true of clinical trials of bapineuzumab and solanezumab, two humanized monoclonal antibodies that bind amyloid. Therefore, innovations in clinical trial designs are necessary, including revised diagnostic criteria and treatment at the earliest stages of AD. Several prevention trials started in 2013, emphasizing these innovative principles of clinical trial design. In this review, we will discuss the paradigm shift for AD clinical treatment trials and ongoing preventative trials. J Korean Neurol Assoc 33(4): , 2015 Key Words: Alzheimer s disease, Disease-modifying treatment, Clinical trial 우리나라의고령인구비율은점차증가하고있는추세이다. 1 65세이상고령인구의비율은 1999년에 7% 를넘어고령화사회에도달한이후, 2013년에는 12.2% 로증가하였고, 2030년에는 24.3% 로높아져초고령사회로들어갈전망이다. 1 고령인구가증가하면서신경퇴행질환을가진환자수도늘어나게되었다. 그중알츠하이머병 (Alzheimer s disease) 은유병률이높을뿐아니라장기간에걸친장애로노인건강에가장중요한영향을미치는질환중하나가되었다. 2 알츠하이머병은노인에서치매를일으키는가장흔한질환이며, 65 세에서 85세범위내에서는나이가 5세증가할때마다발병률이 2배씩높아진다. 2 현재전세계적으로치매를앓고있는환자의수는약 3,600만명에달하며 2020년에는 4,200만명, 2040년에는두배로증가하여약 8,100만명에달할것으로 Received February 17, 2015 Revised May 6, 2015 Accepted May 6, 2015 Address for correspondence: Kyung Won Park, MD, PhD Department of Neurology, Dong-A University College of Medicine, 26 Daesingongwon-ro, Seo-gu, Busan 49201, Korea Tel: Fax: neuropark@dau.ac.kr 추정되고있다. 2 우리나라에서시행한역학연구에의하면 2008년기준으로 65세이상에서약 8.4% 가치매인구이며이중알츠하이머병으로인한경우는전체치매의약 70.7% 로가장많았다. 3 지난 20년간알츠하이머병의치료는주로증상을완화시키고질병진행을지연시킬목적으로아세틸콜린에스테라아제억제제와 NMDA 수용체대항제를사용해왔다. 4 그러나이약물들은약간의증상을일시적으로완화시키지만질병변경효과 (disease-modifying effect) 는입증되지않아병의진행을근본적으로억제하거나예방하는치료제의개발이필요하였다. 4,5 최근아밀로이드와타우단백질을표적으로하거나신경전달물질, 신경염증등알츠하이머병의병리에기반을둔약물들이개발되어임상시험을시행하였으나대부분실패하였다. 4,6 이에연구자들은 3상임상연구의실패원인을분석하고, 앞으로시행될임상약물시험의성공을위해서생물표지자 (biomarker) 를이용한새로운진단기준을도입하는등많은노력을기울이고있다 이고찰에서는최근새로시도되고있는임상약물시험의최신현황과변화양상에대해살펴보고자한다. 252 대한신경과학회지제 33 권제 4 호, 2015

2 알츠하이머병에서임상약물시험의최신동향 본론 1. 알츠하이머병의생물표지자와새로운진단기준 알츠하이머병의발병원인은아직명확하지않으나베타아밀로이드 (beta-amyloid, Aβ) 의비정상적인대사로인해 Aβ판 (plaque) 이형성되어축적되는것과타우 (tau) 의과인산화로인한신경세포손상이가장유력하다. 11 그외에도아포E 단백질유전자, 알파시누클레인침착, 산화스트레스, 뇌세포의염증변화등이뇌세포손상을일으켜알츠하이머병의발생에영향을미치는것으로알려져있다. 11 알츠하이머병의생물표지자 (biomarker) 는체내에서진행되는알츠하이머병의병리적변화를나타내는생리적, 생화학적, 해부적인지표들로병의단계를나누거나병의조기진단에이용될수있다. 가장잘알려진알츠하이머병의생물표지자는뇌척수액 Aβ 42 의감소, 뇌척수액타우의증가, 불소탈산소포도당- 양전자방출단층촬영 (fluorodeoxyglucose-positron emission tomography, FDG-PET) 에서특정뇌부위의당대사의감소, 아밀로이드 -PET에서아밀로이드의축적, 뇌MRI에서관찰되는뇌위축등이다. 12 지난 30년간의연구에서알츠하이머병생물표지자의변화는인지기능이정상일때부터시작되고이런일련의변화들이십여년이상지속된후에비로소임상적으로치매가발현된다는것을알게되었다. 12 이런결과를바탕으로 2011년 NIA-AA (National Institute on Aging-Alzheimer s Association) 에서는알츠하이머병의병리는있으나임상적으로증상이발현되기전상태를전임상단계 (preclinical) 알츠하이머병이라고새로제안하였다. 8 이진단기준에의하면전임상단계알츠하이머병은아밀로이드침착만있는 1단계, 아밀로이드침 착과신경세포퇴행이있는 2단계, 2단계에서경한인지장애를동반한 3단계로나눌수있다 (Fig. 1). 7,8 전임상단계를지나인지장애가나타나기시작하는단계를경도인지장애단계라하고인지장애가진행하여기능적저하를동반한단계를치매단계라정의하였다 (Fig. 1). 9,10 이와같이알츠하이머병은무증상의시기부터증상이나타나진행하는시기까지일련의스펙트럼을가진다. 7 생물표지자는임상증상이나타나기전에진행되고있는알츠하이머병리를확인할수있는방법이며알츠하이머병의일차예방이나이차예방을위한연구에서유용하게사용될것으로보인다. 7,12 2. 임상약물시험현황알츠하이머병의치료제는증상을완화시키는약물과질병변경효과를가진약물로나눌수있다. 질병변경효과란알츠하이머병의근본적인병리에영향을미쳐신경을보호하고병의진행을차단하는것을의미하여환자의관점에서는병리기전과상관없이어떤치료적개입을했을때병의진행을지연시키고그효과가지속적인것을말한다. 13, 년대중반에아세틸콜린에스테라아제억제제가도입되었고 2003년 NMDA수용체대항제가승인되었다. 6 그러나이약물들은알츠하이머병의일부증상을완화시키지만병의진행을억제하는질병변경효과는밝혀지지않았다. 5 질병변경효과를가진약물을개발하기위해최근까지약 80개의후보물질과 200개의임상연구가시행되었으나대부분연구가실패하였다. 4,15-20 또한최근에관심을모았던 Aβ의 N-terminal을인식하는항체인 bapineuzumab 과중간부위 (mid-portion) 를표적으로하는항체인 solanezumab 및면역글로불린기반 (immunoglobulin-based) 약물인 gammagard에대한 3상임상약물시험도모두실패또는부분실패로돌아감으로써알츠하이머병치료제개발의험난함을시사하였다 현재에도질병변경효과를입증하기위한다양한기전의약물이개발중이며그중 Aβ를표적으로하는약물이가장많고, 타우의과인산화와응집을억제하는약물, 27,28 신경전달물질조절을기전으로하는약물, 그외면역기전이나신경염증등과관련된약물등이개발되고있다 (Table 1) Figure 1. Hypothetical clinical spectrum of Alzheimer s disease. The horizontal axis shows clinical stages of Alzheimer s disease from preclinical stage to dementia stage. The vertical axis indicates the changing values of biomarker. Aβ biomarkers become abnormal first, followed by neurodegenerative biomarkers and cognitive symptoms 변화하는알츠하이머병의임상약물시험디자인 1) 질병변경효과입증실패의원인다수의약물이 3상임상연구에서질병변경효과를입증하는것에실패한원인은표적이잘못되었거나, 표적은적절하였지만약물이표적에작용하지않았을경우, 표적과약물작용은 J Korean Neurol Assoc Volume 33 No. 4,

3 강희영박경원 Table 1. Currently proposed disease-modifying therapies for Alzheimer s disease Target pathway Drug mode of action Status of clinical trial Amyloid Aβ production BMS γ-secretase inhibitor Phase II, discontinued EHT0202 α-secretase stimulator Phase II, completed EVP-0962 γ-secretase modulator Phase II, single center Tarenflurbil γ-secretase modulator Failed in phase III Semagacestat γ-secretase inhibitor Failed in phase III TTP488 RAGE inhibitor Phase IIb Aβ aggregation Tramiprosate Aβ aggregation Failed in phase III Aβ clearance Crenezumab Passive immunization Phase II, completed Solanezumab Passive immunization Phase III Gantenezumab Passive immunization Phase II IVIG newgam Passive immunization Phase II Affitope AD02 Active immunization Phase II, completed CAD106 Active immunization Phase II Tau tau aggregation TRx0237 Tau aggregation inhibitor Phase III Epothilone D Microtubule stabilizer Phase I Neurotransmitter Varenicline Nicotine agonist Phase II, discontinued Lu AE HT6 antagonist Phase III Other Simvastatin Immunomodulation Phase II Thalidomide TNF-α inhibitor Phase II Intranasal insulin Synaptic modulation, Regulate Aβ Phase II, completed Aβ; beta-amyloid, RAGE; receptor for advanced glycation end products. Source: 적절하였으나이미신경퇴행이진행되어효과를보지못한경우등이있다. 20,27 현재까지알츠하이머병의표적으로가장많이연구되고있는것은 Aβ이지만이것이신경세포의사멸을일으키는원인인지아니면결과인지에대해서도아직완전히밝혀지지않았으며후기발현알츠하이머병의경우다양한병인이존재하기때문에적절한표적을찾는것은쉽지않다. 27 또한동물실험과달리임상약물시험에서는표적이적절하더라도약물이심각한부작용없이혈액뇌장벽을통과해야표적과작용할수있다. 27 퇴행뇌질환은임상증상이시작되기오래전부터이미병리적인변화가있는상태이므로표적과약물의작용이적절하더라도임상약물시험의시기가늦어효과를입증하지못하는경우도있다. 20,27 따라서임상약물시험에서질병변경효과를입증하기위해서는적절한동물모델을이용하여가능성높은표적을찾고, 새로운효과적인임상시험디자인을이용하여전임상단계에서약물을적용하고, 임상적호전을예민하게측정할수있는적절한도구를사용하여야한다. 20,27 2) 질병변경효과입증임상약물시험최근발표된 bapineuzumab과 solenezumab의 3상임상연구는본래 1차치료목표인중등도환자를포함하는결과는위약과실험약의차이가없는것으로나왔으나, solenezumab의경우경도알츠하이머병환자에서약간의인지기능호전을보였다. 20 이는질병변경효과를입증하기위해서는가능한초기단 계에치료를시작하는것이좋다는것을시사한다. 20 즉알츠하이머병의임상스펙트럼중치매가시작되기전단계, 즉전임상 (preclinical) 단계혹은경도인지장애단계에서가장효과적일가능성이높다. 7 전임상단계에서환자는겉으로드러나는임상증상이없으므로질병변경효과를입증하기위해서는생물표지자 (biomarker) 의변화를통해증명하는방법이있다. 19 하지만현재까지는알츠하이머병임상시험에서임상적인변화를지지할수있는잘표준화된적절한특정생물표지자에대한일치된의견은없는상황이다. 10,28 최근미국식품의약국 (U.S Food and Drug Administration) 은초기알츠하이머병의치료제개발에대한지침을발표였는데, 이보고서에의하면초기알츠하이머병에대한임상시험에서생물표지자만으로효과를평가하는것은아직이르며인지기능과일상생활능력의개선이있는지평가와함께이차평가지표로써생물표지자를활용하는것을권장하고있다. 28 생물표지자를이용하는방법외에도무작위시작또는무작위회수 (randomized-start or randomized-withdrawal) 방식을통해질병변경효과를입증하는방법이있다. 17 무작위시작방식에서는피험자가위약이나시험약에무작위로배정되고일정시점후부터위약을투여받던환자도시험약을투여받게된다. 만약처음에위약을투여받은환자가시험약을투여받고나서적절한시점에처음부터시험약을투여받은피험자와같은정도의인지기능에도달하지못한다면그약제는질병변경 254 대한신경과학회지제 33 권제 4 호, 2015

4 알츠하이머병에서임상약물시험의최신동향 효과가있음을보여준다고할수있다. 28,36 무작위회수방식은시험약을투여받은환자군을특정시점에약을회수하여처음부터위약을투여받은군과비교한다. 처음에시험약을투여받았던군이처음부터위약을투여받았던군에비해지속적으로인지기능이나일상생활수행능력에서더높은점수를유지한다면질병변경효과가있다고평가한다. 28,36 대표적으로파킨슨병치료제인 rasagiline이무작위시작방식을사용하였으며 37 알츠하이머병에서는 DIAN (Dominantly Inherited Alzheimer Network) 연구에서세가지약물에대해무작위회수방식을도입하였다. 38 3) 초기단계의알츠하이머병임상약물시험최근학계에서는알츠하이머병이너무많이진행되어뇌의손상이비가역적인단계에이르기전에초기단계의환자를진 단하고치료하는것에대한중요성이대두되고있다. 8 따라서초기단계의알츠하이머병에대한임상시험이급격히증가하는추세이며, 미국식품의약국에서는초기단계알츠하이머병임상시험에대한지침을공지하였고학계의의견을수렴중에있다. 35 이지침의주목적은임상적으로치매가발현되기전부터다양한병기의알츠하이머병에대한임상약물시험을시행할수있게하기위함이며, 적절한환자선택과임상시험결과측정을어떻게하는것이좋은지에대한내용을제시한다. 초기단계의알츠하이머병환자의경우전반적인일상생활수행능력에는거의문제가없어이전의진단기준으로환자를선택하고결과를측정하는데어려움이있다는것을인정하였다. 즉최근생물표지자를이용한새로제시된알츠하이머병의진단기준을적용하여환자를선택할수있게하였고 8-10,28 임상시험의결과측정에서도인지기능과사회적활동및일상생활기능을종합 Table 2. Characteristics of selected RCTs for prevention of Alzheimer s disease (AD), based on compounds targeting beta-amyloid 39 RCT ADCS-A4 API DIAN Sample size Main inclusion criteria 1,500 older adults with no cognitive impairment Evidence of brain amyloid accumulation (PET). Subjects with no evidence of amyloid burden will also be included 300 members of Colombian families (Antioquia) with early-onset AD. Subjects with no cognitive impairment Carriers of a mutated PSEN1 gene. Non-carriers will also be included, to ensure double-blinding of the genetic status 240 members of families with early-onset AD. Subjects can be asymptomatic or have very mild memory and cognitive problems including mild dementia Carriers (n=120) of mutation in PSEN1, PSEN2 or APP. Non-carrier (n=120) will also be included, to ensure double-blinding of the genetic status Zinfandel-Takeda prevention study 5,000 elderly subjects with no cognitive impairment Subjects at risk of developing MCI due to AD within 5 years. The risk stratification is based on an algorithm including age and TOMM40 and APOE genotype. Subjects with high and low risk will be included Ageat enrolment 70 years 30 years years years Study design Randomized, double blind, placebo-controlled trial Randomized, double-blind, placebo-controlled trial Phase II/III randomized, double-blind, placebocontrolled trial Phase III randomized, double blind, placebo-controlled trial Intervention Anti-amyloid monoclonal antibody: solanezumab (Eli Lilly) Anti-amyloid monoclonal antibody: crenezumab (Genentech) Duration 3 years+2 year extension 5 years (interim analysis at 2 years) Outcomes Primary: cognitive function Primary: cognitive function Secondary: change in AD Secondary: change in AD biomarkers biomarkers, including brain amyloid load and brain atrophy Two anti-amyloid therapies: the anti-amyloid monoclonal antibodies gantenerumab (Hoffmann-La Roche) and solanezumab 2 years+3 year extension 5 years Initial phase (2 years): change in AD biomarkers, including brain and CSF amyloid, to identify the most promising drug candidate Follow-up phase (3 years): cognitive function Pioglitazone, an oral medication already approved for the treatment of type 2 diabetes (Zinfandel-Takeda) Primary: cognitive function (i.e. time to onset of MCI due to AD) Secondary: qualification of the algorithm based on age and TOMM40 and APOE genotype Status Started in 2013 Started in 2013 Started in 2013 Started in 2013 ADCS-A4; Anti-Amyloid Treatment of Asymptomatic Alzheimer s disease, API; Alzheimer s Prevention Initiative, DIAN; Dominantly Inherited Alzheimer Network, MCI; mild cognitive impairment, CSF; cerebrospinal fluid, APOE; apolipoprotein E, APP; amyloid precursor protein, PET; positron emission tomography, PSEN1; presenilin 1, PSEN2; presenilin 2, TOMM40; translocase of outer mitochondrial membrane 40 homolog. J Korean Neurol Assoc Volume 33 No. 4,

5 강희영박경원 적으로평가하는임상치매척도항목합계 (Clinical Dementia Rating- Sum of Boxes, CDR-SB) 점수와같은혼합스케일 (composite scale) 을측정하거나, 미세한인지장애는일상생활기능에변화를주지못하므로적절한인지기능검사를단독으로사용하거나, 치매가발생할때까지의생존분석 (time-to-event survival analysis) 방법으로결과를분석하는방안을제시하고있다 새로운알츠하이머병관련임상시험 1) 알츠하이머병예방임상약물시험알츠하이머병의예방은건강한인구가알츠하이머병의병리가발생하지않도록하는 1차예방과알츠하이머병의병리가시작되었지만아직치매로진단받기전단계에서병의진행을억제하는 2차예방, 임상적으로치매로진단된후증상을완화하고이차적으로발생하는합병증을예방하는 3차예방으로나눌수있다. 39 효과적인예방을위해서는 1차예방혹은 2차예방에해당하는알츠하이머병이발생하기전혹은병리는있으나아직임상증상이발현되기전에중재를하는것이바람직할것으로생각된다. 최근알츠하이머병예방을위한다양한임상약물시험이시도되고있으며, 특히 Aβ를표적으로하는면역억제 제의효과를검증하는이중눈가림위약대조평행군임상시험이 2013년부터시작되고있다 (Table 2). 39 이중 ADCS (Alzheimer s Disease Cooperative Study) 에서시행하는 A4 연구에서는아밀로이드PET에서양성을보이는인지기능이정상인노인을대상으로 solaneuzumab (anti-aβ 16-24) 이인지기능저하를예방할수있는지시험중이며, 40 API (Alzheimer s Preventive Initiative) 연구는 E280A PS1 돌연변이를가진군에서 crenuzumab (Hu IgG4 anti-multiple epitope Aβ 1-40) 의효과를시험하고있다. 41 DIAN 연구에서는보통염색체우성으로유전되는 PSEN1, PSEN2, APP 돌연변이를가진피험자군에서 solaneuzumab, gantenerumab (antibody to fibrillary form, Aβ3-12; 18-27) 의효과를시험한다. 38 이연구들은아직치매로발병하기전의피험자를대상으로하였으며좀더예민하게임상약물시험의효과측정을위해인지기능뿐아니라생물표지자, 정상인지기능에서경도인지장애로진행하는데걸리는시간등을같이측정할예정이다. 39 2) 알츠하이머병예방다영역중재대조군임상시험알츠하이머병의진행을억제하기위한예방적임상약물시험뿐만아니라, 치매로진행되기이전상태인경도인지장애, 고위험군인지장애환자및허약한고령환자를대상으로하는 Table 3. Characteristics of selected RCTs for prevention of cognitive impairment, dementia and Alzheimer s disease based on multi-domain interventions 39 RCT FINGER MAPT PreDIVA Sample size 1,260 community dwellers, from previous population-based observational cohorts 1,680 community dwellers 3,533 community dwellers Main inclusion criteria Dementia risk score>6 and cognitive performance at mean level of slightly lower than expected for age Frail elderly individuals (subjective memory complaint, slow walking speed, limitation in IADL) All elderly within GP practices, non-demented (MMSE>23) Age at enrolment years 70 years years Study design Multi-center, randomized, double blind pursued, parallel-group trial Multi-center, randomized, double-blind controlled trial Multi-site, open, cluster randomized, parallel-group trial Intervention Multidomain: (i) nutritional guidance, (ii) exercise, (iii) cognitive training and social activity, (iv) Monitoring, and management of metabolic and vascular risk factors Multidomain: risk factors assessments, nutritional advice, exercise advice, cognitive training and/or DHA 800 mg/day Multidomain: nurse-led vascular care including medical treatment of risk factors, nutritional advice, exercise advice Duration 2 years+5-year extended follow-up 3 years+2-year extended follow-up 6 years Outcomes Primary: Cognitive performance measured by Neuropsychological Test Secondary: dementia/ad, cognition disability, depressive symptoms, vascular risk factors and outcomes, dietary markers, quality of life, health resource utilization, change in AD biomarkers Primary: change in cognitive function Secondary: cognition (MMSE, CDR), functional status, depression, health resource utilization, change in AD biomarkers Primary: dementia, disability Secondary: cognitive decline (MMSE, VAT), depression, cardiovascular events Status Ongoing, will be completed in 2014 Ongoing, will be completed in 2014 Ongoing, will be completed in 2015 FINGER; Finnish Geriatric Intervention Study to Prevent Cognitive impairment and Disability, MAPT; Multidomain Alzheimer Prevention Study, PreDIVA; prevention of dementia by intensive vascular care, CDR; Clinical Dementia Rating scale, DHA; docosahexaenoic acid, GP; general practitioner, IADL; instrumental activities of daily living, MMSE; mini mental state examination, VAT; visual association test. 256 대한신경과학회지제 33 권제 4 호, 2015

6 알츠하이머병에서임상약물시험의최신동향 대규모다영역중재대조군임상시험도전세계적으로활발히진행되고있다 (Table 3). 39 이연구들은노인에서위험인자를평가하고인지훈련및사회활동강화, 신체운동, 영양인자, 생활습관및혈관위험인자등의조절과개입을통해알츠하이머병을예방이가능한지질병진행의억제효과를시험한다. 39 이중 FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) 연구는나이, 교육, 성별, 혈압, 체질량지수, 총콜레스테롤, 신체운동의정도에따라치매위험점수를매겨 6점이상이면서인지검사 (Consortium to Establish a Registry for Alzheimer's Disease, CERAD) 에서평균혹은나이에비해약간저하된피험자를대상으로 2년간영양, 신체운동, 인지및혈관위험인자를관리하여일차적으로는인지기능에미치는영향을평가하며 5년후에는치매로진행을억제하는효과가있는지를추가로평가할예정이다. 42 MAPT (MultiDomain Alzheimer Preventive Trial) 연구는 70세이상의노인중주관적기억장애를호소하거나하나이상의도구일상생활능력의장애가있는경우, 보행속도가느린경우의피험자에게 DHA (docosahexaenoic acid) 와다영역중재를시행한후인지기능의변화를시험한다. 43 PreDIVA (Prevention of Dementia by Intensive Vascular Care) 연구는 70세이상치매가없는노인에서혈관위험인자를평가하고 4개월마다혈관위험인자를적극적으로관리하는것이이후에치매의발생을예방하는지 6년계획으로시행중이다. 44 이연구들이긍정적인결과를보인다면노년에혈관위험인자를관리하는것이성공적노화에이르게하며치매의발병률을줄이는데중요한방법이될것이다. 결론 알츠하이머병이너무많이진행되어뇌의손상이비가역적인단계에이르기전, 고위험상태혹은초기단계인지장애환자를진단하고치료하는것에대한중요성이최근많은연구에서대두되고있다. 현재생물표지자의발달로뇌척수액생물표지자 (Aβ 42, 타우 ) 혹은아밀로이드 PET 영상을이용한조기발견및질병진행예측등이어느정도가능해졌으며알츠하이머병의진행을억제하는대규모임상약물시험의결과가주목되는시점이다. 결국알츠하이머병은단순히하나의특효약에의해서치료되기는어렵고, 질병의변화가시작되는중년의나이부터다양한치료전략을적용하는다영역중재및예방적치료가무엇보다필요하다. REFERENCES 1. Statistics Korea. Social indicators in Korea Available from URL: ar= Rizzi L, Rosset I, Roriz-Cruz M. Global epidemiology of dementia: Alzheimer's and vascular types. Biomed Res Int 2014;2014: Ministry for Health, Welfare. Nationalwide study on the prevalence of dementia in Korean elders Available from URL: mw.go.kr/front_new/al/sal0301vw.jsp?par_menu_id=04&menu _ID=0403&BOARD_ID=140&BOARD_FLAG=00&CONT_SEQ= &page=1. 4. Nygaard HB. Current and emerging therapies for Alzheimer's disease. Clin Ther 2013;35: Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer s disease. Donepezil study group. Neurology 1998;50: Cummings JL, Morstorf T, Zhong K. Alzheimer's disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res Ther 2014;6: Jack CR Jr, Knopman DS, Weigand SD, Wiste HJ, Vemuri P, Lowe V, et al. An Operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer s disease. Ann Neurol 2012;71: Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7: Albert MS, DeKosky ST, Dickson D, Dubis B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7: McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 2011;7: Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 2002;297: Jack CR Jr, Knopman DS, Jagust WJ, Shaw LM, Aisen PS, Weiner MW, et al. Hypothetical model of dynamic biomarkers of the Alzheimer's pathological cascade. Lancet Neurol 2010;9: Cummings JL. Defining and labeling disease-modifying treatments for Alzheimer s disease. Alzheimers Dement 2009;5: Vellas B, Andrieu S, Sampaio C, Wilcock G. Disease-modifying trials in Alzheimer s disease: a European task force consensus. Lancet Neurol 2007;6: Becker RE, Greig NH. Increasing the success rate for Alzheimer's disease drug discovery and development. Expert Opin Drug Discov 2012;7: Salloway S, Sperling R, Fox NC, Blennow K, Klunk W, Raskind M, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease. N Engl J Med 2014;370: J Korean Neurol Assoc Volume 33 No. 4,

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