Journal of Alzheimer’s Disease 62 (2018) 1067–1077 1067

DOI 10.3233/JAD-170698
IOS Press

Review

The Rationale Behind the New Alzheimer’s

Disease Conceptualization: Lessons
Learned During the Last Decades
José Luis Molinuevoa,b,c,∗ , Carolina Minguillona , Lorena Ramic and Juan Domingo Gisperta,d
a Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
b CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
c Alzheimer’s Disease and Other Cognitive Disorders Unit, Hospital Clı́nic, Institut d’Investigacions

Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain

d Centro de Investigación Biomédica en Red de Bioingenierı́a, Biomateriales y Nanomedicina

(CIBER-BBN), Madrid, Spain

Accepted 31 October 2017

Abstract. In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the charac-
terization of several Alzheimer’s disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a
clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward
a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal
cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or
only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers
and episodic memory impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The
possibility of assessing AD pathophysiology in vivo before the onset of clinical symptoms in the preclinical stage provides
the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large
cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of
AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In
this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual
change.

Keywords: Alzheimer’s disease, biomarkers, continuum, ethical challenges, preclinical, prevention

INTRODUCTION disease (AD). The objective of the present manuscript

is to review how our view of AD has evolved as
This paper is part of the 20th anniversary issue of new biomarker knowledge has emerged during the
the Journal of Alzheimer’s Disease and, following last decades. In addition, the social and ethical impli-
the Editorial Board suggestions, we will review how cations of the new conceptualization of AD will be
our work performed together with a great group of discussed.
professionals has contributed to redefine Alzheimer’s
LATE 1990S: GENETIC
∗ Correspondence to: José Luis Molinuevo, Barcelona␤eta CHARACTERIZATION OF AD
Brain Research Center, Pasqual Maragall Foundation, Barcelona,
Spain. Tel.: +34 93 3160990; E-mail: jlmolinuevo@fpmaragall. More than 95% of affected individuals develop AD
org. after the age of 65, which is known as late-onset AD,

ISSN 1387-2877/18/$35.00 © 2018 – IOS Press and the authors. All rights reserved
This article is published online with Open Access and distributed under the terms of the Creative Commons Attribution Non-Commercial License (CC BY-NC 4.0).
1068 J.L. Molinuevo et al. / The New Concept of Alzheimer’s Disease

while from 1 to 5% develop what is referred to as to decide family planning, and to inform their chil-
early-onset AD (symptom onset in their mid-life). dren. Although preliminary, PICOGEN also showed
Early-onset AD is sometimes genetically determined that predictive testing and disclosure is safe and
due to autosomal dominant mutations whereas late- may be of benefit when performed with a sensitive
onset presents a complex etiology, being mostly approach under strict pre-test counseling protocols
of sporadic origin. Although of different etiology and post-test follow-up programs. Although the dis-
and with distinct genetic profiles, understanding eases, their phenotype, and mutation characteristics
the pathophysiology of autosomal dominant AD were different, emotional reactions were largely
(ADAD) has contributed to the current understanding similar [17].
of the pathologic events that lead to the more common
form of the disease.
In the late 1990s, the genetic characterization of PRE-BIOMARKER ERA CLINICAL
AD and other dementias was an important topic. CHARACTERIZATION OF EARLY AD
Mutations in three genes were identified, the amyloid STAGES
precursor protein (APP), presenilin 1 (PSEN1), and
presenilin 2 (PSEN2), that lead to ADAD. At the time, As mentioned earlier, the vast majority (>95%)
the relative contribution of APP and PSEN mutations of AD patients develop the disease after the
to ADAD was under debate. While a number of stud- age of 65 presenting a complex etiology distinct
ies described that virtually all cases of ADAD could from ADAD, although both share common patho-
be explained by mutations in these three genes [1, physiological hallmarks. Historically, persons with
2], others suggested the involvement of other genes cognitive impairment attending memory clinics,
[3, 4]. already had a full-blown dementia. Nevertheless, in
ADAD research was mainly focused on the char- the late 1990s, efforts from both patients’ associ-
acterization of the clinical features and the genetic ations and public figures disclosing their condition
analysis of families with familial ADAD (e.g., [5–7]) as AD sufferers greatly contributed to increase dis-
since it was fundamental to understand the clini- ease awareness. This resulted in growing numbers
cal characteristics associated with each mutation in of elderly individuals seeking medical advice when
order to offer proper genetic counseling. Clinical, presenting with cognitive complaints that were not
pathological, and genetic overlap among differ- disabling (thus lacking the core feature of dementia).
ent neurodegenerative disorders was also described In this scenario, professionals aimed at characteriz-
[8] and mutations in the MAPT, PGRN,and PRPN ing the ranges between normal aging and dementia,
genes that were associated with familial frontotem- and several terms have been proposed during the last
poral dementia, frontotemporal lobar degeneration decades, such as “Age-Associated Memory Impair-
(FTLD), and familial prion disease were identified ment” (AAMI) [18] or “cognitive impairment no
[9–14]. dementia” (CIND) [19]. From the plethora of terms
Altogether, the experience gathered during this proposed, “mild cognitive impairment” (MCI) has
period allowed us to establish a genetic counsel- clearly gained widest acceptance. Nevertheless, the
ing program for familial dementias: the PICOGEN terms AAMI, CIND, and MCI have some subtle
program [15], which was based on the available differences and thus may not necessarily represent
experience and on the clinical practice guidelines identical populations.
on genetic counselling in Huntington’s disease [16]. As defined by Petersen and colleagues, MCI pre-
Briefly, PICOGEN offered genetic testing and coun- sented the following criteria: 1) subjective concern
selling to patients that were suspected to carry of a memory disturbance (preferably supported by an
disease-causing mutations for AD, FTLD, or prion informant), 2) objective evidence of a memory deficit,
disease. Additionally, asymptomatic subjects who 3) generally preserved cognitive functions, 4) intact
decided to know their genetic status were evaluated activities of daily living, and 5) absence of dementia
within a structured protocol by a psychiatrist and psy- [20]. With these criteria, MCI still constituted a level
chologist prior to entering the program and followed of cognitive decline in which low-functioning normal
up afterwards. PICOGEN participants stated that the older persons and high-functioning early dementia
main reason for their participation in the program patients were hardly distinguishable. In this regard,
was to receive early treatment when available in the research focused in developing sensitive psychome-
future. Secondary reasons were to decrease anxiety, tric tools as well as identifying both genetic and
 J.L. Molinuevo et al. / The New Concept of Alzheimer’s Disease 1069

neuroimaging features capturing MCI patients that 3) age at onset ≥60 years; 4) concerns (worries) asso-
progress to AD [21–27]. ciated with SCD; 5) feeling of worse performance
As initially described, MCI criteria included con- than others in the same age group; 6) confirmation of
cern in the memory domain [20], which was accepted cognitive decline by an informant; and 7) presence
as a limitation of the concept, as other clinical symp- of the APOE ␧4 allele [31, 32].
toms leading to MCI and later on progressing to
dementia were identified [27]. Nevertheless, stud-
ies still showed that while individuals with amnestic THE EMERGENCE OF AD BIOMARKERS
MCI (aMCI) had an increased risk to progress to AND THE NEW CONCEPT OF AD
AD, not all would [28]. Efforts were made to develop
and/or include more specific neuropsychological as Several years ago, a “probable” AD diagnosis was
well as structural and functional neuroimaging mea- defined as a clinical-pathological construct based on
sures to be able to identify patients with prodromal determining the presence of dementia and discard-
AD (patients with suspected AD pathology and a clin- ing other potential etiologies. Therefore, it was a
ical picture with objective cognitive impairment not syndromic diagnosis, that could only be confirmed
fulfilling dementia criteria). Prospective follow up post-mortem [33]. In the last decades, progress in
of amnesic patients at risk for AD, whose features neuroimaging [both magnetic resonance imaging
were intermediate between amnesic MCI and prob- (MRI) and positron emission tomography (PET)]
able AD patients, termed prodromal AD, showed a techniques and cerebrospinal fluid (CSF) assays,
significantly higher progression rate to probable AD has enabled the thorough characterization of sev-
than aMCI patients [29]. eral in vivo AD biomarkers. These include amyloid-␤
The concept of “subjective cognitive decline” (A␤) and tau concentration in CSF [34], hippocampal
(SCD) was first introduced by Reisberg and col- atrophy [35, 36], temporoparietal hypometabolism
leagues in their effort to define AD stages according [37, 38], and cerebral amyloid and tau deposition
to the Global Deterioration Scale (GDS): GDS stage measured by PET) [39, 40], among others. AD
2 was characterized as subjective complaints of mem- biomarkers have recently been divided into three
ory deficit in the absence of objectivized memory binary categories (A, Amyloid biomarker; T, tau
impairment [30]. In the last decade, the relevance biomarker; N, neurodegeneration or neuronal injury
of the identification of this group has been high- biomarker) based on the nature of the pathophysiol-
lighted as a potential indicator of non-normative ogy that each measures [41].
cognitive decline and eventual progression to demen- The initial research criteria that incorporated AD
tia. SCD is currently defined as a “self-experienced biomarkers (see below) distinguished between the so
persistent decline in cognitive capacity in compari- called pathophysiological and topographical mark-
son with a previously normal status that is not related ers, but did not define which ones were more useful
to an acute event” and precludes the presence of to define the disease. Subsequent studies showed
MCI, the predementia stage characterized by objec- which biomarkers presented optimal correlation with
tive cognitive impairment. Similar to the MCI status, underlying AD pathology in post-mortem studies. In
SCD may be related to numerous conditions such this respect, both CSF biomarkers and amyloid PET
as normal aging, personality traits, psychiatric con- imaging showed the highest correlation, making them
ditions, neurologic and medical disorders, substance proxies of AD pathology [42–48]. In addition, several
use, and medication. To develop a conceptual frame- studies have contributed to define the diagnostic per-
work and research criteria for SCD, the Subjective formance of the determination of A␤1-42 , t-tau, and
Cognitive Decline Initiative (SCD-I) Working Group p-tau, establishing a molecular CSF biomarker sig-
was recently established [31]. SCD increases the risk nature of AD through autopsy-confirmed AD cohorts
of cognitive decline, developing dementia and also [49, 50].
the likelihood of being in the preclinical stage of AD The availability through MRI, PET, and CSF anal-
(see below for the definition of the AD preclinical yses of the characteristic and reliable biomarkers of
stage). The SCD-I has proposed a set of specific SCD AD discussed above, enabled the change of AD con-
features, under the name of SCDplus, associated with ceptualization from a clinical-pathological entity to a
an increased likelihood of preclinical AD. These fea- clinical-biological one. AD is currently defined as a
tures are 1) subjective decline in memory, rather than pathologic continuum that can be divided into three
other cognitive domains; 2) onset in the last 5 years; stages: preclinical (abnormal biomarkers and no or
1070 J.L. Molinuevo et al. / The New Concept of Alzheimer’s Disease

only subtle cognitive impairment), MCI or prodromal utility to predict the onset of dementia in predemen-
AD (abnormal pathophysiological biomarkers and tia subjects. In this regard, we showed that, indeed,
episodic memory impairment), and dementia (abnor- an abnormal AD CSF biomarker profile in predemen-
mal biomarkers and clear cognitive and functional tia individuals was a powerful marker of risk for AD
impairment). Furthermore, the possibility of assess- dementia. Only 15% of subjects with a pathological
ing AD pathophysiology in vivo ensued a change in CSF ratio remained free of AD dementia at 5 years of
the research framework of AD. Two sets of criteria follow-up and, conversely, all subjects who reverted
have recently been published, one by the Interna- to normal cognition presented a normal CSF profile at
tional Working Group (IWG; [51]) that has later baseline [56]. In addition, we demonstrated that CSF
been revised (IWG-2; [52]) and the other by working biomarkers were useful in the differential diagnosis of
groups assembled by the National Institute on Aging early-onset cognitive impairment in clinical practice
(NIA) and the Alzheimer’s Association (AA) in the and increased the certainty of AD diagnosis to a high
US (NIA-AA; [53]). Although both define AD as a likelihood in most cases in both amnestic and non-
pathological continuum, the NIA-AA outlines dif- amnestic presentations. Finally, AD CSF biomarkers
ferent clinical syndromes and the preclinical stage, also predicted subsequent impairment and progres-
which are diagnosed with their own specific algo- sion to AD dementia with high accuracy in subjects
rithm, whereas a single diagnostic algorithm that may with early-onset MCI [57].
be applied at any stage of the clinic-biological con-
tinuum is proposed by the IWG. Both sets of criteria
agree in the incorporation of core AD biomarkers RESEARCH IMPLICATIONS OF THE
in the diagnostic process and in the recognition of NEW CONCEPT OF AD
an asymptomatic preclinical stage that can be deter-
mined through these biomarkers. However, whereas Disappointing results from clinical trials per-
biomarker abnormalities are required for diagnosis formed in AD dementia patients made it clear that
according to IWG, the NIA-AA uses biomarker infor- modifying treatments for AD would require ear-
mation (if available) to assess the likelihood (high, lier diagnosis to optimize their potential benefits. In
intermediate, or unlikely) that a clinical syndrome this scenario, the main application of the new AD
is due to AD. Additional differences between these diagnostic research criteria was to allow for an ear-
criteria reside on the fact that NIA-AA support the lier and etiological diagnosis based on a biomarker
diagnosis of AD in asymptomatic individuals with profile [58] which, in turn, would enable earlier
biomarker evidence for A␤ accumulation, whereas interventions in the prodromal stage and secondary
for the IWG-2, these persons are considered to be in prevention in the preclinical one. Non-demented AD
an at-risk state of the disease. Moreover, IWG crite- populations emerged as potential targets for earlier
ria for typical AD require an objective impairment interventions and, therefore, to characterize the rela-
in episodic memory whereas a less strict approach is tionships between their neuropsychological profile,
considered by NIA-AA criteria for the diagnosis of CSF biomarker values, and neuroimaging character-
MCI due to AD. istics stands out as fundamental (e.g., [59, 60] for the
One of the main drawbacks that prevented the prodromal AD stage).
clinical use of CSF biomarkers was the uncertainty In this sense, the concept of preclinical AD rapidly
concerning the lack of comparability of CSF mea- gained attention and work performed by several
surement across different laboratories. Development groups rapidly verified the hypothesis that this stage
of ratios and normalized indices, such as the AD of the disease presents distinct structural and func-
CSF index, increased the diagnostic accuracy of CSF tional imaging characteristics. As mentioned at the
biomarkers. Importantly, the performance of the AD very beginning of this review, familial ADAD pro-
CSF index was very similar when using different vides the opportunity to investigate brain changes
analytical platforms [54]. In addition, collaborative even before symptom onset and we contributed to
efforts were fundamental to demonstrate the validity the topic in performing studies with AD muta-
of the core AD CSF biomarkers for the differen- tion carrier participants recruited throughout the
tial diagnosis of AD dementia even with different PICOGEN program [15]. This allowed us to eval-
pre-analytical conditions [55]. uate cortical thickness, and water diffusivity indexes
A further step to consolidate the use of biomark- in presymptomatic and symptomatic PSEN1 muta-
ers in AD diagnosis was to assess their prognostic tion carriers which were distinct: presymptomatic
 J.L. Molinuevo et al. / The New Concept of Alzheimer’s Disease 1071

carriers displayed increased cortical thickness (espe- protein levels were higher in preclinical AD, although
cially in precuneus and parietotemporal areas) and this increase lost significance when controlled for
decreased mean diffusivity (which may correspond age, and significantly correlated with t-tau and p-tau
to brain swelling due to reactive neuronal hyper- levels, as well as with meaningful neuropsycholog-
trophy and/or inflammatory response to amyloid ical tests. Hence, YKL-40 appeared as a possible
deposition compared to healthy controls), while marker of early pathophysiological changes, poten-
symptomatic subjects had decreased cortical thick- tially linked to an astrocytic inflammatory process, as
ness in the same areas and increased diffusivity well as an early marker to take into consideration in
possibly reflecting predominant neuronal loss, when the pathophysiology of the disease to potentially mea-
compared to controls [61]. Longitudinal studies in sure its progression [66]. Furthermore, we showed
presymptomatic carriers showed accelerated rates that at the earliest stages of AD-related cognitive
of decrease of thickness in the AD-related areas decline, CSF YKL-40 was related to a cerebral struc-
mentioned above, suggesting that brain structure in tural signature that was distinct to that associated with
PSEN1 mutation carriers follows nonlinear trajecto- p-tau neurodegeneration, supporting the presence
ries, with regional increases during the very early of concomitant neuroinflammatory and neurodegen-
presymptomatic period [62]. Strikingly, we could erative processes at the initial stages of cognitive
replicate these findings in the context of sporadic impairment [67]. Similar to what we found with
AD when investigating the relationship between CSF CSF YKL-40, CSF levels of the soluble fragment
A␤ values and cortical thickness in a group of cog- of the innate immune receptor TREM2, sTREM,
nitively preserved subjects. Briefly, an increment in changed dynamically: they are slightly elevated in
cortical thickness in AD-vulnerable areas preceding preclinical AD, peak in MCI due to AD and, in the
cortical thinning that might be related to reactive dementia stage are found reduced versus MCI. We
neuronal hypertrophy and/or inflammation driven by also found that CSF sTREM2 levels were associated
amyloid in very early stages of the disease continuum, with markers of neuronal injury and tau pathol-
was also observed [63]. Similar nonlinear trajectories ogy [68]. In addition, higher CSF sTREM2 values
of AD-related brain atrophy in the AD continuum were associated with increased gray matter volume
ranging from normal cognition to mild AD were in MCI patients in brain areas vulnerable to AD
found when AD-related pathology was tracked with which typically present with atrophy in early AD
the AD-CSF index. In addition, we showed that the in association with increased CSF p-tau levels, sug-
impact of the APOE ␧4 genotype was most evi- gesting a microglial activation and enhanced TREM2
dent in the hippocampus and precuneus with carriers expression in response to incipient neurodegenera-
showing a steeper decline in gray matter volume tion [69]. Finally, we showed that APOE ␧4 allele
after CSF-index values approaching the diagnostic carriers had increased CSF YKL-40 levels particu-
threshold [64]. larly at the preclinical and MCI stages, and showed
Together with the studies performed to char- an inverse association between gray-matter volume
acterize distinct structural and functional imaging and CSF YKL-40 levels, whereas noncarriers dis-
characteristics of the AD preclinical stage, the search played a positive one. Taking into account that the
and validation of novel AD biomarkers that may APOE apolipoprotein is mostly produced in the brain
be useful to further characterize the AD contin- by astrocytes, these results suggested an increased
uum, understand the pathological mechanisms of the astroglial activation in APOE ␧4 carriers. In contrast,
disease, and be used routinely in clinical practice significant differences between APOE ␧4 allele car-
appeared as equally relevant (see a recent meta- riers and noncarriers were not found with respect to
analysis of CSF and blood biomarkers in [65]). CSF sTREM2 [70].
In this line, we contributed characterizing two fac-
tors that may be involved in the neuroinflammatory
mechanisms of the brain triggered by microglia and IDENTIFICATION OF CANDIDATES FOR
astroglia in response to pathological aggregates of SECONDARY PREVENTION TRIALS
amyloid and tau. These are the secreted 40 kDa
glycoprotein YKL-40 (also known as Chitinase 3- The setup of preventive studies requires the iden-
like 1) mostly expressed by astrocytes, and the tification of individuals with an increased risk of
innate immune receptor expressed at the surface of developing AD in the near future that are suitable
microglia TREM2. We showed that CSF YKL-40 to be recruited as asymptomatic subjects in clinical
1072 J.L. Molinuevo et al. / The New Concept of Alzheimer’s Disease

trials [71]. In this context, and aiming at increas- to prevent Alzheimer’s Disease (AMYPAD) project
ing our knowledge of the pathophysiology and will contribute to define the role of amyloid imaging
pathogenic factors emerging at early preclinical AD both in modelling the preclinical stage of the dis-
stages, we established the ALFA (for ALzheimer and ease and its value and efficiency during the diagnostic
FAmilies) program for the prospective follow-up of a process.
cohort of cognitively normal subjects, most of which
are the offspring of AD patients [72]. Within this pro-
gram, the ALFA parent cohort is composed of 2,743 ETHICAL IMPLICATIONS OF AD NEW
cognitively normal participants, most of them first- CONCEPT
degree descendants of AD patients, aged between
45 and 74 years, who have been thoroughly charac- As mentioned before, one of the most relevant
terized from a sociodemographic, clinical, lifestyle, applications of the new concept of AD is to allow
and cognitive point of view. In addition, partici- for secondary prevention strategies in asymptomatic
pants’ APOE haplotype has been also determined. individuals in the preclinical stage, which gives
The ALFA parent cohort will serve as the basis for rise to a variety of novel ethical challenges. In
the establishment of research protocols and studies, clinical research, these ethical issues are mainly
both observational and interventional, of preclini- related to determining appropriate risk/benefit ratios
cal participants at risk of cognitive impairment due and whether or not to disclose information about
to AD, such as the ALFA+ cohort study. On top biomarker status [74].
of a similar characterization as in the ALFA parent With regards to risk/benefit ratios, the earlier in the
cohort (neuropsychological, clinical, etc.), it entails disease continuum, the longer clinical trials aimed
the acquisition of both wet (CSF and blood sample at detecting change will have to last and, therefore,
collection) and imaging (MRI and PET) biomark- asymptomatic participants will be exposed to phar-
ers. The ALFA+ study started in October 2016, will macological agents for an extended period. These
include 500 participants, and complete follow up vis- trials should therefore be designed to ensure that the
its will be performed every three years. In brief, the potential benefits justify participant’s procedural bur-
ALFA+ study will serve to untangle the natural his- den and associated risks. Improving the participant’s
tory of the disease and to model the preclinical stages understanding of the relevant issues, such as the prob-
in order to develop successful trials [72]. abilistic over deterministic nature of biomarkers, will
A fundamental aspect of preclinical AD research be necessary for them to determine the acceptable
resides on the need for collaborative efforts among risk-benefit ratio. In relation to this, one benefit of
research groups and stakeholders involved (fund- conducting trials in preclinical, asymptomatic, indi-
ing agencies, study participants, regulatory agencies, viduals is that they are in a better position to protect
etc.). This is apparent in the recent design of inter- their own welfare and express their values regard-
national initiatives such as the European Prevention ing what risk is acceptable in providing informed
of Alzheimer’s Dementia (EPAD; Europe) and sister consent. A perceived benefit for the participants in
programs upcoming in the US and Canada in which clinical trials is the possibility of receiving an effica-
public-private consortiums are created to speed up cious therapeutic agent and, hence, individuals enroll
the development of better and safer medicines for AD in research because they consider it may be of benefit
prevention. Similar to the ALFA project, these studies to their own health and believe that this outweighs the
are based on research platforms of participants from possible risks. Furthermore, it has been shown that
which specific sub-studies are implemented. The altruism (potential benefit to their relatives, future
EPAD project, funded by the Innovative Medicines sufferers or society) also motivates participating in
Initiative, aims to deliver a standing, adaptive, multi- a clinical trial [75]. In addition, indirect benefits for
arm proof of concept study for early and accurate clinical trial participation may also be perceived. For
decisions on a candidate compound’s (or combination example, participation may yield positive psycholog-
of compounds’) ongoing development for the preven- ical impact on self-confidence, self-worth and the
tion of AD dementia. It also contains an observational perceived benefit of providing societal value [76].
cohort major component (EPAD Longitudinal Cohort With regards to disclosure of biomarker status,
Study) of 6,000 preclinical participants for trial readi- the main risks include placing a cloud of uncer-
ness, run-in data and improved disease modelling tainty over participants that may affect their daily
[73]. The more recently established Amyloid imaging lives and/or performance in specific procedures,
 J.L. Molinuevo et al. / The New Concept of Alzheimer’s Disease 1073

and the complexity of conveying clinically non- risk of developing AD in the near future to be
relevant biomarker status of uncertain prognosis. recruited in these clinical trials, a number of cohort
Main benefits include the protection of biomarker- studies and international collaborative efforts are
negative individuals from risks and harms related being established. In addition, the ethical implica-
to the trial, and the positive impact that this infor- tions of performing clinical research in asymptomatic
mation may have on people’s lives. We recently individuals are being elucidated and addressed. In this
pointed at the relevance of differentiating between scenario, one has reason to feel cautiously optimistic
study types (observational versus interventional) about the future of AD research.
to favor disclosure (transparent enrollment) or not
(blinded enrollment) [74]. Briefly, when considering ACKNOWLEDGMENTS
the prospect of long-term studies, to avoid the impact
of knowing on participants’ performance, together We acknowledge our fellow colleagues at the
with disclosing clinically non-relevant biomarker or Barcelona␤eta Brain Research Center and the
genetic status of uncertain prognosis, blinded enrol- Alzheimer’s Disease and Other Cognitive Disorders
ment was recommended for observational studies. Unit of the Hospital Clı́nic (Barcelona) for their fun-
By contrast, transparent enrollment was favored for damental contributions to the works cited here and
interventional studies, since protecting the subjects their stimulating and inspiring discussions. As the
that are biomarker negative from risks and harms remit of this review was to focus on the implications
related to the intervention prevails over the motiva- of our work in the field during the last years, we would
tions noted above to support blinded enrollment. An like to apologize to our colleagues in the field whose
additional argument for the transparent design is that work could not be cited here.
it better reflects future clinical practice of drug pre- Research conducted by JLM receives support by:
scription to those who learn that they have an altered the EU/EFPIA Innovative Medicines Initiative Joint
AD biomarker which, in turn, would provide informa- Undertaking AMYPAD grant agreement n◦ 115952;
tion about the success of this potential future clinical the EU/EFPIA Innovative Medicines Initiative Joint
practice. New trials currently undergoing, such as Undertaking EPAD grant agreement n◦ 115736;
the Generation S1 with APOE ␧4 homozygotes, will the EU/EFPIA Innovative Medicines Initiative Joint
be disclosing APOE status, through a harmonized Undertaking AETIONOMY grant n◦ 115568; and “la
genetic counseling protocol (NCT02565511). In this Caixa” Foundation. CM is supported by the Spanish
scenario, investigators in transparent research designs Ministry of Economy and Competitiveness (grant n◦
can further protect individuals by assessing if poten- IEDI-2016-00690) and JDG holds a “Ramón y Cajal”
tial participants are emotionally capable of enrolling. programme fellowship (RYC-2013-13054) from the
Data from the REVEAL study showed that those who Spanish Ministry of Economy and Competitiveness.
exhibited a high degree of emotional stress before LR is the recipient of a Miguel Servet grant from the
undergoing genetic testing were more likely to have Spanish Ministry of Science (CP2/00023) as senior
emotional difficulties after disclosure [77]. For those investigator.
included, continuous counseling has been shown to Authors’ disclosures available online (https://
have a direct positive effect on stress and anxiety [78]. www.j-alz.com/manuscript-disclosures/17-0698r1).

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