The Road Ahead to Cure Alzheimer’s Disease: Development of Biological Markers and Neuroimaging Methods for Prevention Trials Across all Stages and Target Populations.
Cavedo E(1), Lista S(2), Khachaturian Z(3), Aisen P(4), Amouyel P(5), Herholz K(6), Jack CR Jr(7), Sperling R(8), Cummings J(9), Blennow K(10), O’Bryant S(11), Frisoni GB(12), Khachaturian A(13), Kivipelto M(14), Klunk W(15), Broich K(16), Andrieu S(17), de Schotten MT(18), Mangin JF(19), Lammertsma AA(20), Johnson K(21), Teipel S(22), Drzezga A(23), Bokde A(24), Colliot O(25), Bakardjian H(26), Zetterberg H(27), Dubois B(28), Vellas B(29), Schneider LS(30), Hampel H(2).
(1)Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de
la Mémoire et de la Maladie d’Alzheimer (IM2A) Hôpital de la Pitié-Salpétrière &
Institut du Cerveau et de la Moelle épinière (ICM), UMR S 1127, Hôpital de la
Pitié-Salpétrière Paris & CATI multicenter neuroimaging platform, France;
Laboratory of Epidemiology, Neuroimaging and Telemedicine, IRCCS San Giovanni di
Dio Fatebenefratelli Brescia, Italy.
(2)AXA Research Fund & UPMC Chair; Sorbonne Universités, Université Pierre et
Marie Curie, Paris 06, Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A)
Hôpital de la Pitié-Salpétrière & Inserm U1127 Institut du Cerveau et de la
Moelle épinière (ICM), Hôpital de la Pitié-Salpétrière Paris, France.
(3)The Campaign to Prevent Alzheimer’s Disease by 2020 (PAD2020), Potomac, MD,
(4)Department of Neurosciences, University of California San Diego, San Diego,
(5)Inserm, U744, Lille, 59000, France; Université Lille 2, Lille, 59000, France;
Institut Pasteur de Lille, Lille, 59000, France; Centre Hospitalier Régional
Universitaire de Lille, Lille, 59000, France.
(6)Institute of Brain, Behaviour and Mental Health, University of Manchester, UK.
(7)Department of Radiology, Mayo Clinic, Rochester, MN, USA.
(8)Center for Alzheimer Research and Treatment, Brigham and Women’s Hospital,
Harvard Medical School, Boston, MA, USA Department of Neurology, Brigham and
Women’s Hospital, Harvard Medical School, Boston, MA, USA Department of
Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA,
(9)Cleveland Clinic Lou Ruvo Center for Brain Health, 888 West Bonneville Avenue,
Las Vegas, Nevada 89106, USA.
(10)Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology,
the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden.
(11)Department of Internal Medicine, Institute for Aging & Alzheimer’s Disease
Research, University of North Texas Health Science Center, Fort Worth, TX, USA.
(12)IRCCS Istituto Centro S. Giovanni di Dio Fatebenefratelli, Brescia, Italy;
University Hospitals and University of Geneva, Geneva, Switzerland.
(13)Executive Editor, Alzheimer’s & Dementia.
(14)Karolinska Institutet Alzheimer Research Center, NVS, Stockholm, Sweden.
(15)Department of Psychiatry, University of Pittsburgh School of Medicine, USA;
Department of Neurology, University of Pittsburgh School of Medicine, USA.
(16)Federal Institute of Drugs and Medical Devices (BfArM), Bonn, Germany.
(17)Inserm UMR1027, Université de Toulouse III Paul Sabatier, Toulouse, France;
Public health department, CHU de Toulouse.
(18)Natbrainlab, Department of Forensic and Neurodevelopmental Sciences,
Institute of Psychiatry, King’s College London, London, UK; Université Pierre et
Marie Curie-Paris 6, Centre de Recherche de l’Institut du Cerveau et de la Moelle
épinière (ICM), UMRS 1127 Paris, France; Inserm, U 1127, Paris, France; CNRS, UMR
7225, Paris, France.
(19)CEA UNATI, Neurospin, CEA Gif-sur-Yvette, France & CATI multicenter
(20)Department of Radiology & Nuclear Medicine, VU University Medical Center, PO
Box 7057, 1007 MB, Amsterdam, The Netherlands.
(21)Departments of Radiology and Neurology, Massachusetts General Hospital,
Harvard Medical School, Boston, MA, USA.
(22)Department of Psychosomatic Medicine, University of Rostock, and DZNE, German
Center for Neurodegenerative Diseases, Rostock, Germany.
(23)Department of Nuclear Medicine, University Hospital of Cologne, Cologne
(24)Cognitive Systems Group, Discipline of Psychiatry, School of Medicine,
Trinity College Dublin, Dublin, Ireland and Trinity College Institute of
Neuroscience, Trinity College Dublin, Dublin, Ireland.
(25)Sorbonne Universités, UPMC Univ Paris 06, UMR S 1127, F-75013, Paris, France;
Institut du Cerveau et de la Moelle épinière, ICM, Inserm, U1127, F-75013, Paris,
France; CNRS, UMR 7225 ICM, 75013, Paris, France; Inria, Aramis project-team,
Centre de Recherche Paris-Rocquencourt, France.
(26)Institute of Memory and Alzheimer’s Disease (IM2A), Pitié-Salpétrière
University Hospital, Paris, France; IHU-A-ICM – Paris Institute of Translational
Neurosciences, Paris, France.
(27)Clinical Neurochemistry Laboratory, Institute of Neuroscience and Physiology,
the Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden; UCL
Institute of Neurology, Queen Square, London, UK.
(28)Sorbonne Universités, Université Pierre et Marie Curie, Paris 06, Institut de
la Mémoire et de la Maladie d’Alzheimer (IM2A) Hôpital de la Pitié-Salpétrière &
Inserm U1127 Institut du Cerveau et de la Moelle épinière (ICM), Hôpital de la
Pitié-Salpétrière Paris, France.
(29)Inserm UMR1027, University of Toulouse, Toulouse, France.
(30)Keck School of Medicine, University of Southern California, Los Angeles, CA,
Alzheimer’s disease (AD) is a slowly progressing non-linear dynamic brain disease
in which pathophysiological abnormalities, detectable in vivo by biological
markers, precede overt clinical symptoms by many years to decades. Use of these
biomarkers for the detection of early and preclinical AD has become of central
importance following publication of two international expert working group’s
revised criteria for the diagnosis of AD dementia, mild cognitive impairment
(MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured
research evidence six AD biomarkers are sufficiently validated and partly
qualified to be incorporated into operationalized clinical diagnostic criteria
and use in primary and secondary prevention trials. These biomarkers fall into
two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque
formation as well as of tau-protein related hyperphosphorylation and
neurodegeneration. Three of the six gold-standard (“core feasible) biomarkers are
neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF
Aβ1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1-40 ratio, T-tau, and P-tau Thr181
& Thr231 proteins have proven diagnostic accuracy and risk enhancement in
prodromal MCI and AD dementia. Conversely, having all three biomarkers in the
normal range rules out AD. Intermediate conditions require further patient
follow-up. Magnetic resonance imaging (MRI) at increasing field strength and
resolution allows detecting the evolution of distinct types of structural and
functional abnormality pattern throughout early to late AD stages. Anatomical or
volumetric MRI is the most widely used technique and provides local and global
measures of atrophy. The revised diagnostic criteria for “prodromal AD” and “mild
cognitive impairment due to AD” include hippocampal atrophy (as the fourth
validated biomarker), which is considered an indicator of regional neuronal
injury. Advanced image analysis techniques generate automatic and reproducible
measures both in regions of interest, such as the hippocampus and in an
exploratory fashion, observer and hypothesis-indedendent, throughout the entire
brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced
tractography as well as resting-state functional MRI provide useful additionally
useful measures indicating the degree of fiber tract and neural network
disintegration (structural, effective and functional connectivity) that may
substantially contribute to early detection and the mapping of progression. These
modalities require further standardization and validation. The use of molecular
in vivo amyloid imaging agents (the fifth validated biomarker), such as the
Pittsburgh Compound-B and markers of neurodegeneration, such as
fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the
detection of early AD pathological processes and associated neurodegeneration.
How to use, interpret, and disclose biomarker results drives the need for
optimized standardization. Multimodal AD biomarkers do not evolve in an identical
manner but rather in a sequential but temporally overlapping fashion. Models of
the temporal evolution of AD biomarkers can take the form of plots of biomarker
severity (degree of abnormality) versus time. AD biomarkers can be combined to
increase accuracy or risk. A list of genetic risk factors is increasingly
included in secondary prevention trials to stratify and select individuals at
genetic risk of AD. Although most of these biomarker candidates are not yet
qualified and approved by regulatory authorities for their intended use in drug
trials, they are nonetheless applied in ongoing clinical studies for the
following functions: (i) inclusion/exclusion criteria, (ii) patient
stratification, (iii) evaluation of treatment effect, (iv) drug target
engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well
as exploratory biochemical, genetic, electrophysiological, and neuroimaging
markers for use in clinical trials are being developed. The current
state-of-the-art and future perspectives on both biological and neuroimaging
derived biomarker discovery and development as well as the intended application
in prevention trials is outlined in the present publication.