Table Of ContentDEVELOPING
THERAPEUTICS
FOR ALZHEIMER’S
DISEASE
PROGRESS AND CHALLENGES
Edited by
Michael S. Wolfe
Ann Romney Center for Neurologic Diseases
Brigham and Women’s Hospital and Harvard Medical School
Boston, MA, United States
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Dedication
Dedicated to the memory of my father,
Donald Wolfe, and to all those for whom effective
Alzheimer prevention and treatment
will have come too late.
List of Contributors
J. Avila CIBERNED, Madrid, Spain P. Davies Litwin-Zucker Center, Feinstein Insti-
C. Ballatore Department of Chemistry, School of tute for Medical Research, Manhasset, NY,
Arts and Sciences; Center for Neurodegenerative United States
Disease Research, Institute on Aging, Univer- N. Gertsik Memorial Sloan-Kettering Cancer
sity of Pennsylvania;, Philadelphia, PA, United Center, New York, NY, United States; Weill
States Graduate School of Medical Sciences of
G. Bitan Neurology, UCLA, Los Angeles, CA, Cornell University, New York, NY, United
United States States
K. Blennow Clinical Neurochemistry Lab, Neu- T.E. Golde Center for Translational Research
roscience and Physiology, University of Gothen- in Neurodegenerative Disease; Department
burg, Mölndal, Sweden of Neuroscience, University of Florida Col-
lege of Medicine, Gainesville, FL, United
K.R. Brunden Center for Neurodegenerative
States
Disease Research, University of Pennsylvania,
Philadelphia, PA, United States L.T. Haas Cellular Neuroscience, Neurodegen-
eration and Repair Program, Department of
F. Cabezas-Opazo Laboratory of Neurodegen-
Neurology, Yale University School of Medicine,
erative Diseases, Biomedical Research Center,
New Haven, CT, United States
University of Chile, Santiago, Chile
C.R. Harrington School of Medicine and Den-
M.C. Carlson Mental Health; Center on Aging
tistry, College of Life Sciences and Medicine,
and Health; Center for Innovative Care in
University of Aberdeen, Aberdeen, United
Aging, Johns Hopkins Bloomberg School of
Kingdom
Public Health, Baltimore, MD, United States
D.M. Holtzman Neurology, Washington Uni-
R.J. Castellani Department of Pathology, Univer-
versity, St. Louis, MO, United States
sity of Maryland, Baltimore, MD, United States
A.S. Chesser Department of Anesthesiology, B. Hooli Neurology, Massachusetts General
University of Rochester Medical Center, NY, Hospital; Neurology, Harvard Medical School,
United States Boston, MA, United States
S.C. Correia CNC—Center for Neuroscience J.-Y. Hur Memorial Sloan-Kettering Cancer
and Cell Biology; Institute for Interdisciplin- Center; Weill Graduate School of Medical Sci-
ary Research, University of Coimbra, Coimbra, ences of Cornell University, New York, NY,
Portugal United States
H. Crehan Ann Romney Center for Neurologic D.S. Johnson Pfizer Worldwide Research and
Diseases, Brigham and Women’s Hospital; Development, Neuroscience Medicinal Chem-
Neurology, Harvard Medical School, Boston, istry and Chemical Biology, Cambridge, MA,
MA, United States United States
J.L. Cummings Cleveland Clinic Lou Ruvo G.V.W. Johnson Department of Anesthesiology,
Center for Brain Health, Cleveland Clinic, Las University of Rochester Medical Center, Roch-
Vegas, NV, United States ester, NY, United States
xiii
xiv List of Contributors
V.M.-Y. Lee Center for Neurodegenerative Dis- G. Perry College of Sciences, The University of
ease Research, Institute on Aging, University of Texas at San Antonio, San Antonio, TX, United
Pennsylvania, PA, United States States
C.A. Lemere Ann Romney Center for Neuro- R.A. Quintanilla Laboratory of Neurodegen-
logic Diseases, Brigham and Women’s Hos- erative Diseases, Biomedical Research Center,
pital; Neurology, Harvard Medical School, University of Chile, Santiago, Chile
Boston, MA, United States
F. Rahimi Research School of Biology, the
C.B. Lessard Department of Neuroscience, Australian National University, Canberra,
Center for Translational Research in Neurode- Australia
generative Disease, McKnight Brain Institute,
Y. Ran Department of Neuroscience, Center for
University of Florida, Gainesville, FL, United
Translational Research in Neurodegenerative
States
Disease, McKnight Brain Institute, University
H. Li Bio-Nano Research Facilities, West V irginia of Florida, Gainesville, FL, United States
University, Morgantown, VA, United States
A.P. Sagare Department of Physiology and Bio-
Y.-M. Li Chemical Biology, Memorial Sloan Ket- physics and the Zilkha Neurogenetic Institute,
tering Cancer Center, New York, NY, United Keck School of Medicine of the University of
States Southern California, Los Angeles, CA, United
F. Liao Department of Neurology, Hope Center States
for Neurological Disorders, Knight Alzheim- M.E. Schmidt Neuroscience Experimental Med-
er’s Disease Research Center, Washington icine, Janssen Research & Development, Beerse,
University School of Medicine, St. Louis, MO, Antwerpen, Belgium
United States
L.S. Schneider Psychiatry, Neurology, and Ger-
F.M. Longo Neurology and Neurological Sci-
ontology, Keck School of Medicine of USC, Los
ences, Stanford University, Stanford, CA, United
Angeles, CA, United States
States
D.J. Selkoe Neurology, Harvard Medical School;
S.M. Massa Department of Neurology and
Ann Romney Center for Neurologic Diseases,
Laboratory for Computational Neurochemis-
Brigham and Women’s Hospital, Boston, MA,
try and Drug Discovery, San Francisco Veter-
United States
ans Affairs Medical Center, and Department
D.A. Simmons Department of Neurology and
of Neurology, University of California San
Neurological Sciences, Stanford University,
Francisco, San Francisco, CA, United States
Palo Alto, CA, United States
D.C. Matthews ADM Diagnostics, LLC, C hicago,
S. Sinha Institute of Nano Science and Technol-
IL, United States
ogy, Habitat Centre, Mohali, Punjab, India
M. Medina CIBERNED, Madrid, Spain
A.B. Smith III Department of Chemistry, School
P.I. Moreira CNC—Center for Neuroscience and
of Arts and Sciences, University of Pennsylvania,
Cell Biology; Laboratory of Physiology, Faculty
PA, United States
of Medicine, University of Coimbra, Coimbra,
Portugal S. Staelens Molecular Imaging Center Ant-
werp, Antwerp University, Wilrijk, Antwerp,
A.R. Nelson Department of Physiology and
Belgium
Biophysics and the Zilkha Neurogenetic Insti-
tute, Keck School of Medicine of the Univer- J.M.D. Storey TauRx Therapeutics Ltd., Singa-
sity of Southern California, Los Angeles, CA, pore; Department of Chemistry, University of
United States Aberdeen, United Kingdom
S.P. Pallo Department of Anesthesiology, Uni- S.M. Strittmatter Neurology; Cellular Neuro-
versity of Rochester Medical Center, NY, United science, Neurodegeneration and Repair, Yale
States University, New Haven, CT, United States
List of Contributors xv
R.E. Tanzi Genetics and Aging Research Unit, M.S. Wolfe Ann Romney Center for Neurologic
Department of Neurology, Massachusetts Diseases, Brigham and Women’s Hospital and
General Hospital; Department of Neurology, Harvard Medical School, Boston, MA, United
Harvard Medical School, Boston, MA, United States
States T. Yang Department of Neurology and Neuro-
J.Q. Trojanowski Center for Neurodegenera- logical Sciences, Stanford University, Palo Alto,
tive Disease Research, Institute on Aging, Uni- CA, United States
versity of Pennsylvania, PA, United States H. Zetterberg Clinical Neurochemistry Labo-
R. Vassar Department of Cell and Molecular ratory, Department of Psychiatry and Neu-
Biology, Northwestern University, Feinberg rochemistry, Institute of Neuroscience and
School of Medicine, Chicago, IL, United Physiology, Molndal, Västergötland, Sweden
States K. Zhong Cleveland Clinic Lou Ruvo Center
C.M. Wischik School of Medicine and Den- for Brain Health, Las Vegas, NV, United States
tistry, University of Aberdeen, Aberdeen, B.V. Zlokavic Department of Physiology and
United Kingdom; TauRx Therapeutics Ltd., Biophysics and the Zilkha Neurogenetic Insti-
Singapore tute, Keck School of Medicine of the Univer-
D.J. Wischik Computer Science Department, sity of Southern California, Los Angeles, CA,
University College London, UK United States
Foreword
Alzheimer’s disease (AD) arguably is the what currently is the most comprehensive
most important public health issue of the analysis of research into the causes and treat-
21st century. In 2015 in the United States ment of AD.
alone, it is estimated that a new AD case was The 23 chapters in this book would be an
diagnosed every 67 seconds. This frequency is excellent syllabus for a semester course in AD.
expected to rise to every 33 seconds by 2050. The introductory chapters on AD molecular
It has been more than a century since Alois pathology and genetics provide an overall
Alzheimer first presented the case of Auguste perspective on AD and highlight its multifac-
Deter to the South-West German Society of torial nature and its complex genetic under-
Alienists in 1906. Although substantial prog- pinnings. Seven chapters follow that address
ress has been made since then in understand- what can be called the “Aβ problem,” namely
ing the etiology and pathogenesis of AD, how can Aβ production and assembly into
achieving the goal of an FDA-approved dis- neurotoxic structures be prevented and how
ease-modifying therapy, let alone preventives can the body rid itself of such neurotoxins
or cures, has not been achieved. Why is this once formed. In these chapters, the reader
so, and how can these goals be accomplished? will learn about the enzymes responsible for
Answers to these questions, and many oth- Aβ production (β- and γ-secretase) and strat-
ers of importance, are provided in this volume egies to modulate their activities, as well as
compiled and edited by one of the world’s exciting new work on the development of Aβ
foremost authorities on AD, Dr. Michael aggregation inhibitors and immunotherapeu-
S. Wolfe. I have had the honor of calling tic approaches for Aβ elimination. Two areas
Mike a friend and colleague for almost two of research that are gaining prominence rap-
decades, since he first joined the faculty idly, cellular receptors for Aβ and transport of
at Harvard Medical School, at which time Aβ across the blood–brain barrier, conclude
Mike brought a magna cum laude pedigree the Aβ section of the book.
in m edicinal chemistry and fresh, innova- Five chapters address tau, a microtubule-
tive ideas to an AD field in desperate need of stabilizing protein whose structural a lteration
them. Groundbreaking insights by Mike cul- (eg, hyperphosphorylation) and aggregation
minated in the discovery of one of the holy also are tightly linked to disease pathogen-
grails of AD r esearch, an enzyme, γ-secretase, esis. Strategies to stabilize microtubules in the
critical for the production of the amyloid face of impaired tau activity or to inhibit the
β-protein (Aβ), the protein that forms the kinases causing this impaired activity are pre-
amyloid plaques that are characteristic for sented. Preventing tau aggregation or facili-
AD. Mike now has assembled what one could tating tau degradation and removal also are
rightly term a “dream team” of the world’s discussed.
most accomplished and respected AD clini- The strongest risk factor for late-onset AD,
cians and basic science researchers to create besides age itself, is APOE genotype. This fact
xvii
xviii Foreword
has been useful in establishing disease risk in encounter in the future, and of the prom-
epidemiological and genetic studies, but more ises that new insights are likely to bring.
work is needed toward directly targeting this It provides both a realistic and an optimis-
gene and its protein product. Approaches for tic perspective/interpretation of the prior
doing so are discussed in Chapter 10. 22 chapters and serves as an overview of the
Aβ and tau long have been central AD entire book. If one reads but a single chapter
therapeutic targets. However, it is clear that in this fine book, this should be it.
many other factors contribute to, or affect, Who should read this book and how
disease status and should be considered in should it be read? Scientists and clinicians in-
strategies to prevent AD or ameliorate its volved in the study and treatment of AD cer-
symptoms. Four chapters address such fac- tainly will find this book of value as a means
tors, which include neurotrophic and neu- of providing a broad foundation of knowl-
roprotective factors, cognitive enhancers, edge of the most important areas of the field.
oxidative stress and inflammation, and non- Those interested in specific areas will not
pharmacological interventions. be disappointed by their perusal of one or
How does one diagnose AD? How does more chapters of particular interest to them.
one determine if a new therapy is effective? Pharmaceutical scientists will gain an intui-
The answer in both cases is the possession tive sense of areas attractive for therapeutic
of biomarkers that inform the clinician and drug development. Graduate students and
researcher of disease state. Especially useful postdoctoral fellows new to the area of AD
biomarkers have come from brain imaging research should be handed this book the first
and analysis of body fluids (typically blood day they step into a laboratory doing AD re-
and cerebrospinal fluid). Great strides have search, and should not do an experiment un-
been made in recent years in both areas, less and until they have thoroughly read and
strides that have shown that incipient AD thought about its content.
may be discovered as much as 20–30 years In conclusion, in this age of information
prior to symptoms appearing. Two chapters overload, especially in science and medicine,
bring the reader up to date in these impor- it is difficult to keep up with developments
tant areas. in your own specialty, let alone other spe-
If one chapter stands out, it is the final cialties. In the AD field, this is the book that
chapter Mike has written himself (and allows one to do so.
not only because I edited it!). This chapter, David B. Teplow
“Prospects and Challenges for Alzheimer Professor of Neurology and Director,
Therapeutics,” is a superb overview of Biopolymer Laboratory,
where we stand in our efforts to treat AD, of David Geffen School of Medicine at UCLA,
the problems we have encountered and may Los Angeles, California
Preface
The problem of Alzheimer’s disease (AD) The advances in diagnostics and trial design
needs little introduction. With over 5 mil- have further made possible the testing of
lion people in the United States and some both pharmacological and non-pharmaco-
20–30 million worldwide presently affected, logical approaches to disease prevention by
it seems almost everyone knows someone allowing enrollment of presymptomatic in-
who has been devastated by this progressive dividuals likely to develop AD.
neurodegenerative disease that inexorably Notwithstanding these advances, ma-
destroys memory and cognitive function. jor challenges remain. Substantial gaps in
Despite the severity of the problem and in- our knowledge of disease mechanisms add
tense efforts to solve it, there are still no effec- uncertainty to the already risky business of
tive Alzheimer therapeutics. Only a handful drug development. Moreover, as AD targets
of symptomatic treatments of marginal ben- are all human proteins or nucleic acids, the
efit have been FDA-approved, and no new potential for mechanism-based toxicity is
agent of any kind has been approved since ever present. The special problem of deliv-
2003. The purpose of this book is to convey ering therapeutics to the brain presents yet
the substantial progress as well as the major another serious obstacle to Alzheimer drug
challenges in developing Alzheimer thera- developers. Moreover, progress in the area
peutics, topics that are especially significant of biomarkers and diagnostics has led to the
given the dearth of agents that have success- unsettling realization that the disease pro-
fully made it through the drug development cess apparently can begin more than two de-
pipeline. cades before the onset of symptoms, raising
Tremendous progress has been made to- the concern that intervention may need to
ward elucidating the underlying molecular begin much farther in advance.
and cellular basis of the disease, revealing Given the major importance of the prob-
potential therapeutic targets in the process. lem and the tremendous need to solve it be-
Small molecules and biologicals have been fore demographic shifts toward the elderly
developed for many targets, with substantial overwhelm society with Alzheimer patients,
improvements in potency, selectivity, phar- much work has gone on for many years in
macokinetics and other drug-like properties laboratories all over the world to understand
through iterative design and testing. Major the causes of the disease and its progression
advances have also been made toward devel- and to develop effective therapeutics, with
oping useful biomarkers for diagnosis, selec- many different approaches being taken. This
tion of subjects for human trials, and testing book examines these diverse approaches,
target engagement by experimental thera- with internationally recognized investiga-
peutics. The design of clinical trials has also tors serving as authors for each chapter.
dramatically improved, increasing our abil- First and foremost, I thank these leaders
ity to observe disease-modifying effects— in the field for giving their precious time,
slowing or halting of disease progression. carefully putting together their chapters, and
xix
xx Preface
sharing their extensive knowledge and in- I would also like to thank the editorial
sightful perspectives on the field and where staff at Elsevier who helped considerably
it is heading. In working with these leaders in this process, especially Kristine Jones
on the development of this book, I have had and Molly McLaughlin. Finally, I thank all
the privilege of learning more about their ar- those working in the Alzheimer field for
eas of investigation and gaining both a deep- their dedication and perseverance toward
er and broader understanding of the field as elucidating and solving this devastating
a whole. My hope is that the readers of this disease. Because of your efforts, each day
book will likewise be so edified, whether stu- we get closer.
dents, academic researchers, industrial sci-
entists, clinicians, science writers, or venture Michael S. Wolfe
capitalists. Boston, Massachusetts
