Featured Article The Alzheimer’s Prevention Initiative 

Autosomal-Dominant Alzheimer’s Disease Trial: A study of 

crenezumab versus placebo in preclinical PSEN1 E280A mutation 
carriers to evaluate efficacy and safety in the treatment of 
autosomal-dominant Alzheimer’s disease, including a 
placebo-treated noncarrier cohort 
Pierre N. Tariota,*, Francisco Loperab, Jessica B. Langbauma, Ronald G. Thomasc, Suzanne Hendrixd, Lon S. Schneidere, 
Silvia Rios-Romenetsb, Margarita Giraldob, Natalia Acostab, Carlos Tobonb, Claudia Ramosb, Alejandro Espinosab, William 
Chof, Michael Wardf, David Claytonf, Michael Friesenhahnf, Howard Mackeyf, Lee Honigbergf, Sandra Sanabria Bohorquezf, 
Kewei Chena, Trisha Walsha, Carolyn Langloisa, Eric M. Reimana, on behalf of the Alzheimer’s Prevention Initiative aBanner 
Alzheimer’s Institute, Phoenix, AZ, USA bGrupo de Neurociencias, Universidad de Antioquia, SIU, Medell ́ın, Colombia 
cDepartment of Neurosciences, University of California San Diego School of Medicine, La Jolla, CA, USA dPentara 
Corporation, Salt Lake City, UT, USA eUSC State of California Alzheimer’s Disease Research and Clinical Center, Keck 
Medicine of USC, Los Angeles, CA, USA fGenentech, a Member of the Roche Group, South San Francisco, CA, USA 
Abstract  Introduction:  Autosomal-dominant  Alzheimer’s  disease  (ADAD)  represents  a  crucial  population  for  identifying 
prevention  strategies  that  might  modify  disease  course  for  cognitively  unimpaired  individuals  at  high  imminent  risk  for 
developing  symptoms  due  to  Alzheimer’s  disease  (AD),  that  is,  who  have  “preclinical”  AD.  Crenezumab  is  an  antiamyloid 
monoclonal antibody that binds 
Conflicts  of  interest:  Dr.  Tariot  has  received  consulting  fees  from  Acadia,  Abbott  Laboratories,  AbbVie,  AC  Immune, 
Auspex,  Boehringer  Ingelheim,  Chase  Pharmaceuticals,  Eisai,  GliaCure,  Insys  Therapeutics,  and  Pfizer.  He  has  received 
consulting  fees  and  research  support  from  AstraZeneca,  Avanir,  Eli  Lilly,  Lundbeck,  Merck  &  Co.,  Inc.,  Roche,  and  research 
support  only  from  Amgen,  Avid,  Biogen,  Elan,  Functional  Neuromodulation  (f[nm]),  GE  Healthcare,  Genentech, Novartis, and 
Targacept.  Dr. Tariot has received other research support from the National Institute on Aging and Arizona Department of Health 
Services  and  holds  stock  options  in  ADAMAS.  Drs.  Lopera,  Rios-Romenets,  Giraldo,  Acosta,  Tobon,  Ramos,  and  Espinosa 
report  participation  in  other  projects  financed  by  the  National  Institutes  of  Health,  Comit  ́e para el Desarrollo de la Investigaci 
́on,  and  COLCIENCIAS.  Dr.  Langbaum  has  received  consulting  fees  from  Biogen  and  Lilly.  Dr.  Thomas  has  received 
consulting  fees  from  Toyama,  Avraham,  and  Intel-  Genx.  He  has  received  research  support  from  the  National  Institute  on  Ag- 
ing.  Within  3  years  of  the  beginning  of  this  work,  Dr.  Schneider  has  received  grant  and  research  support  from  Baxter, Biogen, 
Genentech,  Johnson  &  Johnson,  Eli  Lilly,  Lundbeck,  Novartis,  Pfizer,  Roche,  Tau  Rx,  the  State  of California, and the National 
Institutes of Health. Within 3 years of the beginning of the work, he has served as a consultant for and received consul- 
ting  fees  from  Abbvie,  AC  Immune,  Accera,  Allergan,  Allon,  AstraZeneca,  Avraham,  Baxter,  Biogen  Idec,  Biotie,  Boehringer 
Ingelheim,  Bristol-Myers  Squibb,  Cerespir,  Chiesi,  Cognition,  Corium,  Eli  Lilly,  Forum,  General  Electric,  GlaxoSmithKline, 
Insys,  Johnson  &  Johnson,  Lundbeck,  MedA-  vante,  Merck,  Neurim,  Novartis,  Piramal,  Pfizer,  Roche/Genentech, Ste- medica, 
Takeda,  Tau  Rx,  Toyama (FujiFilm), vTv, and Zinfandel. Drs. Cho, Ward, Clayton, Mackey, Honigberg, and Sanabri Bohorquez 
and  Mr.  Friesenhahn  are  all  full-time  employees  of  Genentech,  Inc.,  a  member  of  the  Roche  Group.  Drs.  Cho,  Ward,  and 
Honigberg  own  stock  in  Roche.  Drs. Cho and Ward and Mr. Friesenhahn are inventors on a crenezumab pat- ent. Ms. Walsh and 
Ms.  Langlois  report  no  conflicts.  Dr.  Reiman  has  received  consulting  fees  from  Alkahest,  Alzheon,  Biogen,  Denali,  Pfizer, 
United  Neuroscience,  and  Zinfandel  Pharma.  He  received  research  support  from  Avid/Lilly,  Genentech/Roche,  and 
Novartis/Amgen,  the  National  Insti-  tute  on  Aging,  the  National  Institute  of  Neurologic  Disorders,  Banner  Alz-  heimer’s 
Foundation, Alzheimer’s Association, GHR Foundation, FBRI, NOMIS Foundation, Flinn Foundation, and the State of Arizona. 
*Corresponding author. Tel.: 602-839-6967; Fax: 602-839-6914. E-mail address: [email protected] 
https://doi.org/10.1016/j.trci.2018.02.002 2352-8737/© 2018 The Authors. Published by Elsevier Inc. on behalf of the 
Alzheimer’s Association. This is an open access article under the CC BY-NC-ND license 
(http://creativecommons.org/licenses/by-nc-nd/4.0/). 
Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 
 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 151 
monomeric and aggregated forms of amyloid b, with highest affinity for oligomers; it is in develop- ment for early stages of 
sporadic AD and for ADAD. Methods: This is a prospective, randomized, double-blind, placebo-controlled phase 2 study of the 
efficacy of crenezumab versus placebo in asymptomaticPSEN1E280A mutation carriers from family kindreds with ADAD in 
Colombia. Participants were randomized to receive either crenezumab or pla- cebo for 260 weeks. The study was designed to 
enroll a planned total of 300 participants, including 200 preclinical mutation carriers (approximately 100 treatment, 100 placebo) 
and an additional control group of mutation noncarriers from the same family kindreds included to mask mutation carrier status 
(100 placebo only). The primary outcome is change in the Alzheimer’s Prevention Initiative ADAD Composite Cognitive Test 
Score from baseline to week 260. Secondary outcomes include time to pro- gression to mild cognitive impairment due to AD or 
dementia due to AD; changes in dementia severity, memory, and overall neurocognitive functioning; and changes in 
amyloid–positron emission tomog- raphy, fluorodeoxyglucose–positron emission tomography, magnetic resonance imaging 
volumes, and cerebrospinal fluid levels of b amyloid, tau, and p-tau. Safety and tolerability are assessed. Results: Two hundred 
fifty-two participants were enrolled between December 2013 and February 2017. Discussion: We describe the first large-scale, 
potentially label-enabling clinical trial of a preclinical treatment for ADAD. Results from this trial will inform on the efficacy of 
crenezumab for delaying onset of, slowing decline in, or preventing cognitive impairment in individuals with preclinical ADAD 
and will foster an improved understanding of AD biomarkers and their relationship to clinical outcomes. ©2018 The Authors. 
Published by Elsevier Inc. on behalf of the Alzheimer’s Association. This is an open access article under the CC BY-NC-ND 
license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 
Keywords: Alzheimer’s disease; Autosomal-dominant Alzheimer’s disease; Preclinical Alzheimer’s disease; Prevention; 
Clinical trial; Crenezumab; Alzheimer’s Prevention Initiative 
1. Introduction 
1.1. The Alzheimer’s Prevention Initiative 
In  2010,  Banner  Alzheimer’s  Institute  established  the  Alz-  heimer’s  Prevention  Initiative  (API)  to  (1)  evaluate 
potential  Alzheimer’s  disease  (AD)–modifying  treatments  in  cogni-  tively  unimpaired  people  who  are  at  high  risk 
for  symptoms  of  AD;  (2)  develop  new  cognitive  outcomes;  (3)  assess  whether  biomarker  effects  correlate  with 
clinical  benefit  (“theragnostic”  utility,  i.e.,  the  treatment’s  biomarker  effects  are  “reasonably  likely  to  predict  a 
clinical  benefit,”  a  criterion  that  regulatory  agencies  consider  when  asked  to  qualify a biomarker as a surrogate end 
point;  clinical  end  point,  in  clin-  ical  research,  is  a  disease,  symptom,  or  sign  that  constitutes  one  of  the  target 
outcomes  of  the  trial  or  its  participants),  whether  baseline  biomarkers  are  associated  with  treatment  ef-  fects 
(“predictive”  utility),  and  whether  baseline  biomarkers  predict  clinical  course  (“prognostic”  utility);  (4) help estab- 
lish  the  regulatory  approval  pathway  needed  for  “preclinical”  AD  treatments;  (5)  provide  improved  tests  of  the 
amyloid  hy-  pothesis  than  clinical  trials in clinical or later preclinical (e.g., amyloid-positive only) stages of AD; (6) 
provide  prevention  registries  as  shared  resources;  and  (7)  establish  data  and  sam-  ple  sharing  plans  to  advance  the 
field.  This  is  the  first  of  a  se-  ries  of  API  trials  designed  to  systematically  address each of these aims in addition to 
trial-specific aims. 
1.2. AD and the amyloid hypothesis 
AD is the most common form of disabling cognitive impairment in older people and has a devastating social 
impact 
[1,2].  Postulated  elements  of  the  pathogenic  cascade  include  accumulation  of  amyloid  b  (Ab)  peptides  in 
monomeric,  oligomeric,  and  fibrillar  Ab  species;  aggregation  and  phosphorylation  of  tau;  neuroinflammation; 
synaptic  dysfunction;  and  neuronal  loss.  Accumulation  of  soluble  Ab42  oligomers  and/or  Ab42  fibrils  may  play  a 
critical, early role in the development of AD [3]. 
1.3. Autosomal-dominant Alzheimer’s disease 
Autosomal-dominant  Alzheimer’s  disease  (ADAD)  ac-  counts  for  1%–2%  of  all  AD  cases  [4]. Mutations of the 
pre-  senilin1  (PSEN1),  presenilin2 (PSEN2), and amyloid precursor protein (APP) genes are inherited as fully pene- 
trant,  autosomal-dominant  traits  typically  resulting  in  AD  symptoms  by  age  65  years  [4,5].  Although  there  are 
genetic  and  biological  differences  between  ADAD  and  sporadic  AD,  they  have  similar  neuropathological  and 
clinical  features.  Sporadic  AD  has  been  associated  with  reduced  Ab42  clearance  and  ADAD  with  increased  Ab42 
production;  however,  the  biochemical  consequences  are  similar,  with  brain  accumulation  of  Ab  playing  an  early 
role. Both forms of the disease might respond to treatments affecting Ab [6]. 
1.4. Rationale for preclinical AD trials in ADAD 
Treatments  targeting  this  pathogenic  cascade  include  those  interfering  with  production,  accumulation,  or  toxic 
sequelae  of  Ab  species  [7].  We  hypothesize  that,  to  have their greatest benefit, AD-modifying treatments may need 
to be started before the onset of clinical symptoms, at which 
 
point  fibrillar  Ab  is  plateauing,  tau  pathology  is  apparent,  and  there  is  irreversible  synaptic  or  neuronal  loss  [8,9]. 
Delaying  the  onset  of  symptoms  by  5  years,  at  least  in  sporadic  AD,  could  reduce  dementia  cases  by  50%  [10]. 
Because  progression  to  mild  cognitive  impairment  (MCI)  and  dementia  is  certain,  people  inheriting  ADAD 
mutations  offer  a  compelling  group  for  assessing  the  efficacy  of  puta-  tive  prevention  strategies.  We  sought  to 
conduct  a  study  large  enough  to  address  both  clinical  and  biomarker  outcomes  in  a  relatively  homogeneous 
population  of  cognitively  unim-  paired  mutation  carriers  at  certain  risk  of  developing  AD  de-  mentia  but  lacking 
overt symptoms, that is, with “preclinical AD” [11]. 
1.5. The Paisa mutation and the Antioquia kindreds 
A  Colombian  family  with  early-onset  ADAD  was  described  in  1987  [12]  with  a  PSEN1  mutation  at  codon 280 
(E280A)  [13].  Additional  families  with  this  mutation  have  been  identified  [14],  living  primarily  in  Antioquia, 
Colombia. Analysis of markers surrounding the PSEN1 gene supports the existence of a founder effect [13]. 
The  most  frequent  clinical  presentation  in  this  kindred  is  gradual  memory loss, followed by changes in behavior 
and  language  impairment [15,16]. The cognitive profile of PSEN1 E280A AD does not differ substantially from that 
of  sporadic  AD  [17].  Median  age  of  onset  was  44  years  (95%  CI 43–45) for MCI and 49 years (95% CI 49–50) for 
dementia.  Carriers  died  at  a median age of 59 years (58– 61) [16]. The age at onset of fibrillar Ab deposition was 28 
years  [18]  in  a  pattern  of  deposition  similar  to  that  seen  in  sporadic  AD.  Functional  and  structural  magnetic  reso- 
nance  imaging  showed  characteristic  patterns  of  regional  activation  and  deactivation  as  well  as  reduced  regional 
gray  matter volumes in mutation carriers versus controls (mean age 37 years) [19–21]. These findings suggested that 
we  could  design  a  trial  with  sufficient  power  to  characterize  brain  changes  in  asymptomatic  carriers  of  a  single 
mutation from the same kindred [22,23]. 
1.6. The Neurosciences Group of Antioquia and the API Colombia Registry 
Neurosciences  Group  of  Antioquia  (GNA),  sometimes  together  with  API,  has  conducted  clinical,  cognitive,  ge- 
netic,  postmortem,  and  other  studies  of  families  affected  with ADAD for over 20 years. Planning for the trial began 
in  2008  and  it  was  introduced  to  the  affected  families  in  2010.  Since 2010, GNA has enrolled family members into 
the  API  Colombia  Registry  as  a  research  pre-  enrollment  mechanism  that  was  approved  by  the  local  Ethics 
Committee. 
1.7. Selection of crenezumab 
A Treatment Selection Advisory Committee vetted candi- date agents based on target engagement and safety and 
toler- 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 152 
ability  data. Family members were presented masked profiles of representative agents under consideration and asked 
their  preference  (e.g.,  anti-Ab  or  other  mechanism,  route  of  administration,  known  clinical  effects,  availability). 
They  preferred  an  anti-Ab  agent  with  the  optimal  tradeoff  between  potency  and  safety,  preferably  administered 
orally  or  subcutaneously  (SC).  Crenezumab  was  selected  based  on  its  profile  and  Genentech’s  willingness to share 
API’s general scientific goals. 
Crenezumab  is  a  fully  humanized  IgG4  monoclonal  anti-  body  to  Ab1–40  and  Ab1–42  in  monomeric  and 
aggregated  forms.  In  vitro,  crenezumab  binds with highest affinity to oligomers, inhibits oligomer-induced neuronal 
toxicity,  pro-  motes  oligomer  disaggregation,  and  promotes  removal  via  microglial  phagocytosis,  with  minimal 
inflammatory  activa-  tion  of  microglia  [24,25].  A  murine  antibody  precursor  to  crenezumab  administered 
systemically  reduced  plaque  load  and  improved  memory  performance  in  a  murine  model  of  AD  [25]. Crenezumab 
was  designed  with  an  IgG4  backbone  to  reduce  Fcg  receptor  binding  affinity  compared  to  IgG1  antibodies;  this 
lower  effector  function  was  to  minimize  inflammation  at  brain  vasculature  and  lower  the  risk  of  localized 
microvascular  damage  and  amyloid-  related  imaging abnormalities observed in other anti-Ab tri- als [25–27]. These 
properties  suggested  that  crenezumab  could  offer  clinical  efficacy  with  reduced  risk  of  toxicity  and  potentially 
modify  AD  disease  progression  [25].  Unpub-  lished  data  available  at  the  time  from  two  ongoing  phase  2  trials  in 
patients  with  sporadic  AD  indicated  sufficient  safety  and  tolerability  to  warrant  use  in  this  at-risk population. (The 
phase  2  trials,  as  well  as  a  phase  1  trial, were subsequently completed, confirming the safety and tolerability profile 
known  at  the  time of agent selection, and suggested a signal of efficacy at the higher of the 2 doses tested [15 mg/kg 
intra-  venously  every  4  weeks]  while  also showing lack of benefit of the lower dose of 300 mg SC every 2 weeks in 
persons with AD dementia.) [28–30]. 
2. Methods 
Description  of  this study protocol conforms to the 2013 Standard Protocol Items: Recommendations for Interven- 
tional  Trials  [31,32].  A  checklist  of  Standard  Protocol  Items:  Recommendations  for Interventional Trials items and 
their corresponding page numbers can be found in Supplementary Table 1. 
2.1. Design 
This  is  a  prospective,  randomized,  double-blind,  pla-  cebo-controlled,  parallel-group  adaptive  study  of  the  effi- 
cacy  of  crenezumab  versus  placebo  in  individuals  who  carry  the  PSEN1  E280A  autosomal-dominant mutation and 
do  not  meet  criteria  for  MCI  or  dementia  due  to  AD  [33,34].  The trial is registered in clinicaltrials.gov as “A study 
of crenezumab versus placebo in preclinical PSEN1 
 
 E280A mutation carriers to evaluate efficacy and safety in the treatment of autosomal-dominant Alzheimer’s dis- 
ease, including a placebo-treated noncarrier cohort” (NCT01998841, date of registration: November 22, 2013). The 
study is conducted at a single research site at the Uni- versity of Antioquia in Medellin, Colombia, with satellite sites 
for drug administration and safety monitoring for par- ticipants residing at a distance from Medellin. Enrollment 
began in December 2013 and concluded in February 2017. 
PSEN1  E280A  mutation  carriers  meeting  study  eligi-  bility  criteria  were  randomized  to  one  of  two  treatment 
groups:  crenezumab  or  placebo,  both  administered  SC  at  a  research site every 2 weeks. To maintain genotype blind 
and  to  have  a  genetic  kindred  control,  a  cohort  of  PSEN1  E280A  noncarrier  kindred  family  members  were  also 
enrolled  into  the  study  in  a  double-blinded  fashion  and  administered  placebo  only.  This  is  essentially  a  two-part 
study:  (1)  a  260-week,  double-blind,  randomized,  placebo-  controlled,  clinical  trial  to  study  the  efficacy  of 
crenezumab in an expected total of 200 preclinical individuals with a PSEN1 E280A mutation by comparing change, 
on  drug versus placebo, in a cognitive composite score, other clin- ical outcomes, and biomarker measures; and (2) a 
260-  week,  double-blind,  nonrandomized,  nested,  cohort  study,  including  the  carriers  and  expected  total  of  100 
noncarriers receiving placebo, allowing comparison of cross-sectional and longitudinal data. 
The  study  duration  for  individual  participants  was  planned  to  be  up  to  280 weeks, including a 6-week screening 
period;  a  260-week,  double-blind  treatment  period;  and  a  14-  week  (last  visit  16  weeks  after  the  last  dose of study 
drug)  safety  follow-up  period  to  allow  for  clinical  follow-up  after  treatment  discontinuation.  The  study  design 
originally  incor-  porated  a  decision-making interim analysis after the last participant enrolled received 104 weeks of 
treatment,  continuing  the trial only if specified criteria were met. Based on ongoing review of all data from the field, 
we  decided  sub-  sequently  that  the  interim  analysis  will  be  restricted  to an assessment of overwhelming efficacy or 
reverse efficacy, such as impaired performance on cognitive testing not evident on routine safety review. 
2.2. Objectives 
The  primary  objective  of  this  trial  is  to  evaluate  the  effi-  cacy  of  crenezumab  treatment  compared  with placebo 
for  up  to  260  weeks  on  change  in  cognitive  function  in  preclin-  ical  PSEN1  E280A  autosomal-dominant  mutation 
carriers. 
Secondary  objectives  are  to  evaluate  the  ability  of  crene-  zumab  to  do  the  following in PSEN1 E280A mutation 
car- riers: 
Increase time to progression to MCI or dementia due to 
AD Increase time to progression to a Clinical Dementia 
Rating global score .0 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 153 
Reduce increase in the Clinical Dementia Rating Sum 
of Boxes Reduce cerebral fibrillar amyloid burden using florbe- 
tapir positron emission tomography Reduce decline in regional cerebral metabolic rate of glucose using 
fluorodeoxyglucose–positron emission tomography Reduce brain atrophy as measured by volumetric mag- 
netic resonance imaging Affect cerebrospinal fluid b amyloid, total tau, and 
p-tau 
Safety objectives are to assess the safety and tolerability of crenezumab. 
Pharmacokinetic and pharmacodynamic objectives are to collect sparse pharmacokinetic samples to confirm 
exposure to crenezumab and explore the pharmacodynamic response measured by plasma beta amyloid. Exploratory 
objectives are to: 
Assess the effect of crenezumab on other clinical mea- 
sures of efficacy and AD biomarkers Explore pharmacogenetic influences on crenezumab’s 
effects Explore effects of genetic variation on crenezumab’s 
effects Examine clinical and biomarker changes in noncarriers 
with those seen in carriers treated with placebo Relate crenezumab’s biomarker effects to clinical out- comes and 
examine predictive and prognostic utility of baseline characteristics 
2.3. Treatment group assignments 
At  the  time  the  study  was  implemented,  the  community  standard  was  for  individuals  not  to  learn  their  PSEN1 
geno-  type,  and  there  were  no  options  for  clinical genetic testing or disclosure; provisions will be made to offer this 
information  outside  the  context  of  the  trial  if  community  standards  change.  A  dynamic  randomization  design  was 
used  with  age  (38 or .38), education (,9 or 9 years), apolipoprotein E4 sta- tus, and Clinical Dementia Rating total (0 
or.0)  as  balancing  factors.  Mutation  carriers  were  randomized  to  crenezumab  or  placebo  in  a  1:1  ratio;  mutation 
noncarriers  were  assigned  to  placebo  only.  Efforts  to  promote  adherence  and  retention  include a program to ensure 
ready  access  to  medical  care  in  the  event  of  unanticipated  health  concerns  and  a  program  to  offer  education  and 
support  to  all  affected  family  kindred  members  regardless  of  trial  participation.  Participants who stop treatment are 
invited to continue in the trial. 
2.4. Dosing 
The  original  dose  was  300 mg (2 ! 1 mL SC injections). Treatment is continued in participants who develop MCI 
or dementia due to AD to examine impact of treatment on the overall trajectory of illness. 
 
The Stable doses of maintenance medications are permitted 
Schedule of Events is shown in Table 3. 
Every except for those that may significantly affect cognition. 
6 months, an investigator documents whether the 
participant Intermittent or short-term use of these medications may be 
has progressed to MCI or dementia and, if so, 
whether the allowed if medically necessary. Cholinesterase inhibitors 
pattern is consistent with AD. Where progression 
is judged and/or memantine are prohibited except in participants 
to have occurred, information for that participant 
as well enrolled in the study who develop AD dementia. 
as for a participant who has not progressed is presented in a blinded fashion to the Progression Adjudication 
Commit- 
2.5. Inclusion and exclusion criteria 
tee for review according to a charter. If the investigator and the committee disagree, the committee opinion is used 
for Table 1 indicates pertinent criteria, some of which were amended during the trial (see Section 3.2). 
end-point determination and the investigator’s opinion gov- erns clinical management. 
All data are managed and stored in a secure fashion and reviewed by external study monitors for accuracy and 2.6. 
Clinical outcomes and effectiveness measures 
completeness according to the standards of the International 
The  clinical  and  cognitive  outcome  measures (Table 2) were selected primarily from those used by GNA over 20 
years since the design rested on these data. Change in 
Conference  on  Harmonisation  of  Technical  Requirements  for  Registration  of  Pharmaceuticals  for  Human  Use  and 
health authority requirements. 
the API ADAD Composite Cognitive Test score from base- line to week 260 is the primary outcome measure [49]. 
Sec- 
2.7. Statistical analysis plan 
ondary outcome measures address changes in salient clinical 
Analyses planned for the study include the 
following: A and biomarker measures. Measurement and analysis plans 
limited interim analysis of the cohort of carriers 
will occur for biomarkers will be finalized as late as possible to benefit 
after all participants have completed the week 104 
assess- from new developments in the field, for example, specific re- 
ment. The initially planned primary analysis was 
to occur gions of interest and methods for measuring change in amy- 
after all participants completed week 260. The 
study is loid positron emission tomography measures. Key cognitive 
powered to compare the mean change from 
baseline over and global rating sessions are audio-recorded and monitored 
260 weeks in the API Composite Cognitive 
Battery be- centrally for quality assurance and improvement. 
tween the active group and the placebo. Assuming a 25% 
Table 1 Inclusion and exclusion criteria 
Inclusion criteria 
Membership in PSEN1 E280A mutation carrier kindred PSEN1 E280A mutation carrier or noncarrier status has been confirmed 
by separate laboratory Men and women, age 30 years and 60 years MMSE ‡ 26 (changed to MMSE of 24 for participants with 
,9 years of education, or MMSE of 26 for those with 9 years of education) Does not meet criteria for dementia due to AD [34] 
Does not meet criteria for MCI due to AD [33] as defined by cutoff scores on the Subjective Memory Checklist, CERAD Word 
List Recall, and FAST If female, and not documented to be surgically sterile, willing to undergo pregnancy tests per protocol 
For women who are not surgically sterile, agreement to remain abstinent or use two methods of contraception For men with 
partners of childbearing potential, agreement to remain abstinent or use a condom Study partner who agrees to participate in the 
study and is capable of and willing to accompany the participant to all visits Serum TSH and B12 within normal range (changed 
to also allow values out of range if judged not to be clinically significant) Exclusion criteria 
Has significant medical, psychiatric, or neurological condition or disorder History of stroke Body weight ,40 or .120 kg (lower 
limit changed to 45 kg) Clinically significant depression History of seizures (excluding febrile seizures of childhood or other 
isolated seizure episodes that were not due to epilepsy) Brain MRI results at baseline showing 
B 
evidence of amyloid-related imaging abnormality–edema, infection, significant cerebral vascular pathology, clinically significant 
lacunar infarct, multiple lacunes, cortical infarct, or focal lesions 
B 
more than four cerebral microhemorrhages 
B 
single area of superficial siderosis or prior cerebral macrohemorrhage Clinically significant screening blood laboratory 
abnormalities Positive urine test for drugs of abuse at screening (changed to allow for one additional screening; a second positive 
test [except for cannabinoids] would 
result in exclusion) Use of any other medications with the potential to significantly affect cognition 
Abbreviations: AD, Alzheimer’s disease; FAST, Functional Assessment Staging Test; MCI, mild cognitive impairment; MRI, 
magnetic resonance imaging; PSEN1, presenilin 1; RNA, ribonucleic acid; MMSE, Mini–Mental Status Examination; TSH, 
thyroid-stimulating hormone. 
NOTE. Bolded font criteria represent key amendments. 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 154 
 
dropout  rate,  two-sided  testing  at  the  0.05  level,  a  placebo  group  coefficient  of  variance  of  65%  for  the  week  260 
change  scores  (5100%  !  standard deviation of placebo participant change scores/mean of placebo participant change 
scores),  and  100 participants per arm, the study will have at least 80% power to detect a true effect of 30% reduction 
of  the  mean  decline  in  the  placebo group. The assumed placebo group coefficient of variance of 65% is based on an 
unpublished analysis of the Colombian Registry data. 
Although  the  total  recruitment  of  252  fell  short  of  the  planned  300  participants,  the impact to power is expected 
to  be  offset  by  a  lower-than-planned  attrition  rate  and  the  change  to  a  “common  close”  design.  The common close 
specifies  that  treatment  assigned  at  randomization  and  blinded  study  assessments  are  maintained  until the common 
close,  defined  as  260  weeks  after the last participant is ran- domized. This design will add approximately 25% more 
ob- 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 155 
Table 2 Specific outcome measures and instruments 
Primary outcome measure 
API Cognitive Composite Test (derived from elements of the following) 
B 
Word List: Recall [35–37] 
B 
Multilingual Naming Test [38] 
B 
Consortium to Establish a Registry for Alzheimer’s Disease Constructional Praxis Test [36] 
B 
Mini–Mental State Examination (for Orientation to Time) [39] 
B 
Ravens Progressive Matrices [40] Secondary outcome measures 
Clinical 
B 
Time to progression to mild cognitive impairment or dementia due to Alzheimer’s disease [33] 
B 
Clinical Dementia Rating (global score and sum of boxes) [41] Biomarkers 
B 
Cerebral fibrillar amyloid burden measured by florbetapir positron emission tomography (PET) 
B 
Regional cerebral metabolic rate of glucose using fluorodeoxyglucose (FDG)-PET 
B 
Volumetric magnetic resonance imaging 
B 
Cerebrospinal fluid (CSF) levels of b amyloid, p-tau, and total tau Safety 
B 
Safety laboratories 
B 
Electrocardiogram 
B 
Magnetic resonance imaging 
B 
Suicidality Assessment (Copyright Pfizer Inc. and Janssen Alzheimer Immunotherapy; used with permission) 
B 
Physical and neurological examination 
B 
Vital signs Pharmacokinetic/pharmacodynamic measures (PK/PD) 
B 
PK: CSF and serum crenezumab concentrations at protocol-specified time points (trough serum concentrations are assessed at 
steady state) 
B 
PD: plasma Ab1–40 and Ab1–42 concentrations Exploratory outcome measures 
Clinical 
B 
Trail Making Test [42], Mini–Mental State Examination [39] 
B 
Repeatable Battery for the Assessment of Neuropsychological Status [43] 
B 
Free and Cued Selective Reminding Task (FCSRT) [44] 
B 
Scores of each of the components of the API Composite Cognitive Battery 
B 
Neuropsychiatric Inventory [45,46] 
B 
Geriatric Depression Scale [47] 
B 
Functional Assessment Staging of Alzheimer’s Disease [48] 
B 
Subjective Memory Checklist [16] Fluid biomarkers 
B 
Cerebrospinal fluid levels of other Ab species 
B 
Changes in other blood and cerebral spinal fluid measures Imaging biomarkers 
B 
 Analysis of regions of interest not selected in secondary end point Other 
B 
Changes in primary, secondary, and exploratory outcomes in carriers and noncarriers as function of APOE and genetic variations 
Abbreviations: API, Alzheimer’s Prevention Initiative; Ab, amyloid b; APOE, apolipoprotein E. 
servations toward the primary analysis without delaying the time to primary analysis. 
2.8. Human subjects considerations 
Informed  consent  was  obtained from all participants and study partners for experimentation with human subjects. 
An  approved  companion  guide  to  the  informed  consent  form  was  used,  and  family  members/other  partners  were 
involved  in  the  consenting  process.  Provisions  are  in  place  to  assess  loss  of  capacity  in  individuals  who  develop 
cognitive  impair-  ment,  in  which  case  assent  will  be  used.  Consent  and  assent  procedures  are  conducted  in 
accordance  with  local  ethics  committee  standards.  The  trial  was  approved  by  the  Colom-  bian  Health  Authority, 
Instituto  Nacional  de  Vigilancia  de  Medicamento  y  Alimentos.  An  independent  data  monitoring  committee  that 
includes a representative from the National Institute on Aging (NIA) oversees safety data and will be 
 
responsible for the interim analysis. Safety and tolerability concerns are assessed every 2 weeks for each participant. 
3. Discussion 
3.1. Main aims 
The  study  is  designed to have adequate statistical power to evaluate the impact of crenezumab on cognition using 
a  novel  composite  cognitive  battery  that  was  characterized  in  this  cohort.  We  expect  that  some  participants treated 
with  placebo will progress to MCI, and a smaller number may progress to dementia. We aim to demonstrate whether 
crenezumab  has  the  ability  to  slow  the  progression  of  AD  symptoms  as  well  as  biomarker  measures  of  AD 
pathology and neurodegeneration in ADAD mutation carriers. 
3.2. Study protocol amendments 
Several protocol modifications were made, approved by the ethics committees and Instituto Nacional de 
Vigilancia 
Table 3 Schedule of assessments (abridged) 
Time point Screening 
Q26 weeks afterW52 W104 W260 W274 
Medical history X Physical and neurological examination X X X X X X X X X X Criteria for MCI/AD X X X X X X GDS X X 
X X X X Subjective memory checklist X X X X X X Screening cognitive battery X Composite cognitive battery X X X X X X X 
X Extended cognitive battery X X X X X X CDR X X X X X X FAST X X X X X X NPI X X X X X X Suicidality assessment 
X X X X X X X X Safety laboratories X X X X X X X X X X X DNA (APOE, PSEN1); optional DNA for 
repository 
X 
ECG X X X X X X X X X PK, PD, and exploratory serum, plasma, 
RNA samples 
X X X X X X X X X X X 
ATA sample X X X X X X X Urine screen for drugs of abuse X X X X Serum pregnancy test X Vital signs X X X X X X X X X 
X X X X Dispense study medication X X X X X X X X X X Concomitant medication X X X X X X X X X X X X X Interval 
medical history and adverse events X X X X X X X X X X X X Urine pregnancy test X X X X X X X X X X X X Brain MRI X 
X X X X X X X Lumbar puncture for CSF samples (optional) X X X Fibrillar amyloid PET imaging X X X FDG PET X X X X 
X 
Abbreviations:  AD,  Alzheimer’s  disease;  APOE,  apolipoprotein;  ATA,  antitherapeutic  antibody;  CDR,  Clinical  Dementia 
Rating  Scale;  CSF,  cerebrospinal  fluid;  DNA,  deoxyribonucleic  acid;  ECG,  electrocardiogram;  FAST,  Functional  Assessment 
Staging  Test;  FDG,  fluorodeoxyglucose;  GDS,  Geriatric  Depres-  sion  Scale;  MCI,  mild  cognitive  impairment;  MRI,  magnetic 
resonance  imaging;  NPI,  Neuropsychiatric  Inventory;  PD,  pharmacodynamic;  PET,  positron  emis-  sion  tomography;  PK, 
pharmacokinetic; PSEN1, presenilin 1; RNA, ribonucleic acid. 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 156 
Baseline (W1) 
Q2 weeks after BL W4 
de  Medicamento y Alimentos, and communicated to partic- ipants via revised, approved consent forms. Specifically, 
dur-  ing  enrollment  into  our  trial,  the  phase  2  trials  of  crenezumab  in  persons  with  sporadic  AD  dementia  were 
completed,  after  which  we  increased  the  dose  of  crenezumab  to  720  mg  (2  !  2.4  mL SC injections) to approximate 
the  exposure  levels  of  the  high  intravenous  dose  given  in  phase  2.  The  pro-  tocol  amendment  was  submitted  to 
Instituto Nacional de Vigilancia de Medicamento y Alimentos in August 2014 and approved in May 2015. 
Selected  inclusion/exclusion  criteria  were  amended,  re- flecting pragmatic accommodations to common issues in 
the  community and the need to recruit persons representative of the population at risk. Specifically, the Mini–Mental 
Status  Examination  criterion  was  revised  to  allow an education- adjusted cutoff, based on the observation that some 
prospec-  tive  participants  had  low  Mini–Mental Status Examination scores but no evidence of progressive cognitive 
decline  and  review  of  historical  data  showing  that  such  individuals  did  not  experience  cognitive  decline.  Because 
slightly low 
Q12 weeks after BL uptoW52 W16 W26 W38 W52 
 
vitamin  B12  and  slightly  elevated  thyroid-stimulating  hor-  mone  levels  are  prevalent  in  this  community,  the 
exclusion  criteria  for  these  were  modified  to  allow  inclusion  of  partic-  ipants with clinically insignificant abnormal 
levels.  The  exclusion  criterion  for  a  positive  urine  test  for drugs of abuse at screening was changed to allow for one 
additional  screening;  a  second  positive  test  (except  for  cannabinoids)  would  result in exclusion. Cannabinoid use is 
prohibited  24  hours  before  cognitive  testing  or  scans.  The  use  of  low  doses  of  anticholinergic  antidepressants  for 
depression  and  sleep  disorders,  originally  exclusionary,  was  later permitted, as such drugs are widely used for these 
reasons. 
We  have  sought  permission  to  change  to  a common close study design (see Section 2.7) to enhance the power of 
the study and also maintain the genetic blind until the end of the study. 
3.3. Recruitment 
A  recruitment  campaign  promoted  awareness  of  the  trial  and  the  Registry,  including  earned  media  coverage, 
adver-  tisements,  letters  to  physicians,  educational  programs,  addi-  tional  interviews  of  affected  families,  and 
reviews  of  hospital  and  church  records.  The  Registry  expanded  from  2096 in 2012 to 5846 by 2017, including over 
1100  mutation  carriers.  A  small  team  unblinded  to  genotype  referred  regis-  trants  to  the trial, achieving the goal of 
having  67%  of  trial  participants  being  mutation  carriers,  while  also  averting  the  otherwise-likely  possibility  of  an 
early imbalance of noncarriers to carriers enrolled. 
At  the  time  the  decision  was made to increase the dose, enrollment into the trial was slowed deliberately to allow 
time  for  Health  Authority approval of the higher dose amendment and maximize the number of participants exposed 
to the higher dose. 
3.4. Study population 
The  inclusion  and  exclusion  criteria  limit  the  study pop- ulation to PSEN1 E280A autosomal-dominant mutation 
car-  riers  likely  to  be  in  a  “preclinical”  stage  of  AD  [11].  The  lower  age  limit  of  30  years  will likely be associated 
with  a  high  likelihood  of  brain  amyloid  accumulation,  although  not  all  participants  will  have  moderate  or  greater 
fibrillar  beta  amyloid  accumulation  yet  [19].  Including  individuals  with  less-than-moderate  amyloid  accumulation 
may  help  to  further  probe  the  amyloid  hypothesis  as  well as address the predictive utility of this biomarker. Neither 
participants  nor  investigators  are  provided  information  about  their  biomarker  findings  other  than  clinical  magnetic 
resonance imaging interpretations. 
3.5. Measuring cognitive decline in preclinical AD 
Traditional  cognitive  outcome  measures  used  in  trials  in clinically impaired persons with AD are not appropriate 
in preclinical treatment trials owing to their ceiling effects 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 157 
and  general  lack  of  sensitivity.  Rather  than  selecting  a  single  cognitive  measure  that  has  been  reported  to  measure 
change  in  a  preclinical  stage  of  AD,  or  a measure of cognitive decline that distinguishes between at-risk groups, we 
conducted  lon-  gitudinal  analyses  in  two  independent  cohorts  to  empirically  derive  a  composite  cognitive  battery 
that  is  sensitive  to  pre-  clinical  decline  for  use  in  ADAD  [49]  and  sporadic  AD  treat-  ment  trials  [50],  meeting 
FDA’s  proposed  criteria  for  an  “intermediate  clinical  end  point”  [51].  We  found  that  the  decline  in  our  composite 
cognitive  test  scores  (1)  is  sensitive  to  subsequent  progression  to  clinical  stages  of  sporadic  AD;  (2)  is sensitive to 
preclinical  decline  in  PSEN1  E280A  muta-  tion carriers aged 30 years and older [51] who would not have cognitive 
decline  for  any  other  reason  other  than  ADAD;  (3)  has  the  ability  to  control  for  practice and age effects using data 
from  either  ADAD mutation noncarriers or those who remain cognitively normal during a specified time period; and 
(4) is consistent in independent analyses/cohorts. 
3.6. Theragnostic biomarker development 
Showing  biomarker/efficacy  correlations  in  the  Colombia  ADAD  study  could  provide  a  unique  opportunity  to 
define  specific  biomarker  changes  as  reasonably  likely  surrogate  end  points.  Future  accelerated  approval  using 
biomarker  data  likely  would  have  to  be  confirmed  with  longer  term  clinical  follow-up  as  well  as  showing  that 
biomarker  changes  correlating with cognitive benefit in ADAD are also correlated with cognitive benefit in sporadic 
AD. 
3.7. Process 
Funding  is  provided  by  grants  from  the  NIA,  philanthropy,  and  Genentech/Roche,  a  public-private  partnership 
created  to  maximize  public  benefit  beyond  usual  specific  trial-related  aims.  The  trial  is  jointly  governed  by 
representatives  from  Genentech/Roche,  Banner  Alzheimer’s  Institute,  NIA,  and  GNA.  An  Ethics  and  Cultural 
Sensitivities  Committee  was  created  to  advise  on  issues  such  as  genetic  disclosure,  partic-  ipant  compensation, 
access  to  health  care  or legal assistance, and post-trial plans. The trial design was also vetted by numerous academic 
and  industry  stakeholders,  industry,  pa-  tient  and  family  advocates,  and  community  leaders  in  Colombia  and 
members  of  the  kindred themselves. In the originally funded NIA proposal, a substudy of ADAD muta- tion carriers 
was  proposed  in  the  United  States.  However,  the  subsequent  launch  of  the  Dominantly  Inherited  Alzheimer’s 
Network  trial provided ADAD families in the United States an opportunity to participate in trials, with larger sample 
sizes.  We  decided  to  focus  our  efforts and resources on the kindreds in Colombia and refer any US ADAD kindreds 
known  to  us  to  the  Dominantly  Inherited  Alzheimer’s  Network  trial.  To  optimize  coordination  among  the  various 
preclinical  trials  that  have  emerged  since  API  was  launched,  the  Collaboration  for  Alzheimer’s  Prevention  was 
convened with API as a partner [52]. 
 
3.8. Data and sample sharing 
The  trial  sponsors  have  created  a  precedent-setting  agree-  ment  that  commits  us  to  sharing  trial  data  within  a 
specified  time  frame  after  the  trial  is  completed,  as  well  as  sharing,  to  the  extent  possible,  remaining  biological 
samples.  We  have  committed  to  publishing  full  results  from  the  trial  as well as sharing them with trial participants. 
We  have  endorsed  a  new  principle,  articulated  by  Collaboration  for Alzheimer’s Prevention [53], and are exploring 
the feasibility of sharing prerandomization data. 
3.9. Other considerations 
We  anticipate  further  developments  in  the  field  and  will  respond  accordingly.  If the results warrant approval for 
market-  ing  by Heath Authorities, provisions will be made for all partic- ipants to have post-trial access to treatment. 
A point of contact for public and/or scientific inquiries will be established. 
4. Summary 
We  described  our  preclinical  trial  to  assess  the  impact  of  crenezumab  in  cognitively  unimpaired  persons  with 
ADAD,  designed  to  address  whether  active  treatment  can  delay  the  onset  of,  slow,  or  prevent  cognitive  decline. 
Study  partici-  pants  do  not  meet  criteria  for  MCI  or  dementia  due  to  AD  at  enrollment and are thus in a preclinical 
phase  of  AD  based  on  being  at  high  risk  for  developing  symptomatic  AD  due  to  their genetic status. In addition to 
addressing  a  series  of  spe-  cific  and  exploratory  hypotheses, we intend to maximize the scientific impact of the trial 
through  theragnostic,  predictive,  and  prognostic  biomarker  development  aims,  data  and  sam-  ple  sharing,  and 
development  of  a  large  registry  that  can  be  used  for  other  studies.  This  is  the  first  and  precedent-setting  study in a 
series  of  API  trials  intended  to  provide  a  founda-  tion  for  the  accelerated  evaluation  of  prevention  therapies  in 
unimpaired persons at risk for AD. 
Acknowledgments 
The authors gratefully acknowledge the families with PSEN1 E280A mutations in Colombia. The authors 
acknowledge the contribution of the following additional API contributors, including members of the following 
bodies: Independent Data Monitoring Committee: Karl Kieburtz, M.D., M.P.H. (Chair), Charles Davis, Ph.D., Serge 
Gauthier, C.M., M.D., FRCPC, William Jagust, M.D., Facundo Manes, M.D.; Ethics and Cultural Sensitiv- ities 
Committee: Jason Karlawish, M.D., Scott Kim, M.D., Ph.D., Kenneth Kosik, M.D., Yakeel Quiroz, Ph.D.; Progres- 
sion Adjudication Committee: Howard Feldman, M.D., FRCP, Ronald Petersen, M.D., Ph.D.; Treatment Selection 
Advisory Committee: Paul Aisen, M.D., Steven DeKosky, M.D., David Holtzman, M.D., Kenneth Kosik, M.D., 
Frank LaFerla, Ph.D., Lon S. Schneider, M.D. 
P.N. Tariot et al. / Alzheimer’s & Dementia: Translational Research & Clinical Interventions 4 (2018) 150-160 158 
The authors also wish to acknowledge valuable contributions by former Genentech employees Carole Ho, M.D., 
Robert Paul, M.D., Ph.D., and Shehnaaz Suliman, M.D., and the editorial assistance of Emily A. Kuhl, Ph.D. This 
work is supported by the NIA (1RFAG041705-01A1, 1UF1AG046150, R01 AG055444, P30 AG19610); Banner 
Alzheimer’s Foundation; Fidelity Biosciences Research Initiative; Nomis Foundation; FIL Foundation; Flinn 
Foundation (1862); Colciencias 1115-65741185408-20512, 1115-54531651, CODI 2017 408-20543; the State of 
Ari- zona (Arizona Alzheimer’s Consortium); Genentech/Roche; and Avid/Eli Lilly. BAI, GNA, and 
Genentech/Roche played a leading role in creation of the study design as well as this article and will do so for 
analysis and interpretation of the data. The NIA served in an advisory capacity in the design of the trial and in 
oversight of the DMC. No other sponsor was involved in these activities. 
Supplementary data 
Supplementary data related to this article can be found at https://doi.org/10.1016/j.trci.2018.02.002. 
RESEARCH IN CONTEXT 
1.  Systematic  review:  The  “Alzheimer’s  Prevention  Initiative  Autosomal-Dominant  Alzheimer’s  Disease  (API 
ADAD)  Colombia  Trial”  is  the  first  potentially  label-enabling  trial  with  an  anti-amyloid  therapy  for  prevention  of 
autosomal-dominant Alzheimer’s dis- ease. 
2. Interpretation: Its design and primary outcome may be 
potentially label enabling. 
3.  Future  directions:  Since  it  was  conceived  and  launched,  the  API  ADAD  has  helped  pave  the  way  for  other 
preclinical  trials,  specifically  the  so-called  TOMMORROW  Trial,  the  Anti-Amyloid  Against  Alzheimer’s  (A4) 
Trial, and the two API Generation Program trials. 
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