Biomarkers in Alzheimer's Disease

254 Pages·2016·6.59 MB·English

by  Tapan Khan

To
Blanchette Rockefeller
and
those who suffer from Alzheimer’s disease
Biomarkers in
Alzheimer’s Disease
T.K. Khan, PhD
Blanchette Rockefeller Neurosciences
Institute, Morgantown, WV, United States
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Foreword
While monographs on Alzheimer’s disease (AD) are the norm for family sup-
port books, it is a rare treasure to have a single voice, Tapan Khan, to skillfully
vii
lead us through the full spectrum of biomarkers. His authority puts imaging,
genetics, cells, CSF, peripheral, and other markers into the immediate and long-
term goals of supporting AD clinical therapeutics. If and when a disease-modify-
ing drug is developed, it will be critical to intervene prior to major pathological
changes. In the past decades, biomarkers have revealed diagnoses as specific as
those confirmed by autopsy, by revealing that AD is a concurrent clinical and
biological diagnosis. Biomarkers have revealed AD-like changes are seen in most
middle-aged, apparently normal, individuals. Further study is required to deter-
mine if these AD-like changes are the beginning of AD or instead a novel feature
of aging. Biomarkers are essential to sorting out these questions.
It is no surprise that biomarkers are one of the hottest areas of AD research and
continue to be refined. This effort by Tapan Khan is a landmark in advancing the
area by authoritatively reviewing, with a single objective voice, where we are and
where we are going. The clarity of the book sets a path to single authored books
as the new standard.
G. Perry
San Antonio, Texas
Preface
Research in the field of Alzheimer’s disease (AD), and particularly in the area of
AD biomarkers, continues its extraordinary growth with support from federal
ix
and nongovernmental funding sources, alongside stunning technological ad-
vances in imaging and diagnostics. Waves of neurobiological discovery in AD
research have influenced new thinking on how to detect the disease earlier so it
can be treated earlier to improve the lives of patients. In the last three decades,
a rich array of new ideas, new discoveries, and new technologies have acceler-
ated AD biomarker research. Even in the last few years, we have witnessed an
explosive increase in the discovery, validation, and application of AD biomark-
ers for diagnosis, assessment of prognosis, longitudinal tracking, evaluation of
therapeutic efficacy, and clinical trials. Despite this increase in our understand-
ing about AD neurobiology and disease biomarkers, an integrated and cohesive
summary of the field has been sorely lacking.
This book was written in an attempt to consolidate the history of AD biomarkers
and new discoveries into a comprehensive collection, covering every testing mo-
dality and biomarker and their applications, and including a critical evaluation
of each and the need for ongoing biomarker research. This book presents what
we have learned about AD biomarkers from various disciplinary perspectives,
including imaging, genetics, biochemistry, physiology, and neurology. In writ-
ing this book, I attempted to provide an unbiased and comprehensive discus-
sion of all AD biomarkers, including neuroimaging biomarkers, cerebrospinal
fluid (CSF) biomarkers (biochemical assays of Aβ , total tau [t-tau], and phos-
1-42
phorylated tau-181 [p-tau]), genetic biomarkers, and biomarkers in peripheral
fluids and cells. The book contains 7 chapters, beginning with a brief introduc-
tion of AD in Chapter 1. Chapter 2 presents the different neuropsychological
tests and their accuracies for clinical diagnosis of AD, the prodromal stages of
Alzheimer’s disease (preclinical, mild cognitive impairment, and dementia due
to Alzheimer’s disease), and the clinical overlap of AD with non-AD dementias
[eg, vascular dementia (VaD), Lewy body dementia (LBD), frontotemporal de-
mentia (FTD), Creutzfeldt–Jacob disease (CJD)]. The neuroimaging modalities
and their use in the detection of specific AD imaging biomarkers are covered in
Chapter 3. In Chapter 4, I discuss methodological approaches to identifying ge-
netic AD biomarkers and provide a summary of AD genetic biomarker research.
Chapter 5 includes a critical evaluation of the performance of AD biomarkers in
the CSF in autopsy-validated cohorts, and discusses their crosscorrelation with
other AD biomarkers and their clinical utility for early and preclinical diagnosis
of AD, longitudinal assessment, differential diagnosis of AD and non-AD de-
mentias, and assessment of drug efficacy in AD clinical trials. Because CSF can
x Preface
only be collected by lumbar puncture, the invasiveness of the procedure limits
the clinical utility of the most widely researched CSF biomarkers in diagnostic
screening of elderly patients. Detection of neuroimaging biomarkers is expen-
sive and requires specialized training, which also limits their more widespread
use in the clinical setting. For this reason, researchers have actively pursued less
invasive, simple, and inexpensive biomarkers of AD, in particular, biomarkers
in peripheral tissues. Chapter 6 summarizes recent findings of cross-sectional
and longitudinal studies of AD markers in blood plasma, crosscorrelation of
plasma AD biomarkers with other biomarkers, and the possible application
of plasma AD biomarkers in clinical trials. Other peripheral sample sources of
AD biomarkers, such as urine and saliva, have been explored and are also dis-
cussed in Chapter 6. Cell-based AD biomarkers are reviewed in the last chapter
(Chapter 7).
The scope of this book is not limited to only a few well-studied AD biomarkers,
but covers all modalities and biomarkers, from neuroimaging to cell-based bio-
assays. This book is intended to not only provide a comprehensive summary of
the literature on all AD biomarkers, but also illustrate their current and potential
applications and their utility in the detection of AD (preferably at the earliest,
preclinical stages), prognosis, and guiding therapeutic intervention in the ev-
eryday care of patients. Each chapter presents the background and rationale for
development of each type of AD biomarker, starting from a basic understanding
of the biology to the advanced concepts applied in each field. I hope this book
serves as a valuable resource for trainees, researchers, and clinicians in the fields
of neurology and neurobiology, as well as investigators and supporters of clini-
cal trials in AD, as they continue to push the field of AD research and medicine
forward and make cutting-edge discoveries that will impact the lives of those
affected by this devastating disease.
T.K. Khan, PhD
Associate Professor
Blanchette Rockefeller Neurosciences Institute,
Morgantown, WV, United States
Acknowledgments
I am grateful to all Alzheimer’s disease researchers and the important work they
have done and continue to do to understand and find treatments for this dev-
xi
astating disease. My sincere thanks go to those whose painstaking and brilliant
work have contributed to the growth of research, discovery, and validation of
potential Alzheimer’s disease biomarkers. The main inspiration to write this
book was to finally bring their unsung efforts into the light. I also wish to thank
those researchers whose work has indirectly helped move the field forward but
might not have been acknowledged in each chapter.
I would like to thank the manuscript proposal reviewers who provided thought-
ful comments and suggestions on the organization of specific chapters. I have
included many figures previously published in the literature and also want to
express my gratitude to all the authors and journal staff members for their per-
mission to use these images in the book. I am also incredibly grateful to my col-
leagues and collaborators for their contributions toward my own education and
accomplishments in the field of Alzheimer’s disease research.
I must also thank my mother and late father for their unconditional love and
support throughout my life. Without moral support of my wife, Manabika K.
Khan, I cannot imagine how this project would have been completed. I first
started this work when our son, Soujatya K. Khan, came into our lives, and the
manuscript grew along with him. My wife took care of raising our young son
while I took care of the manuscript, and for this I am forever grateful to her. My
elder brother and sister, and all my relatives (uncles, aunts, in-laws, cousins,
nephews and nieces), also deserve my whole hearted thanks as well, supporting
my efforts to their conclusion.
I am indebted to Dr. Stacey Tobin for assisting in the preparation of this manu-
script. Ms. Kathy Padilla, the Editorial Project Manager and Ms. Melanie Tucker,
the Senior Acquisitions Editor, Neuroscience of the Academic Press/Elsevier, have
helped from the beginning. Last but not least, I would like to express my grati-
tude to the Academic press/Elsevier publishing group for their tireless support.
T.K. Khan, PhD
Associate Professor
Blanchette Rockefeller Neurosciences Institute,
Morgantown, WV, United States
CHAPTER 1
Introduction to Alzheimer’s
Disease Biomarkers
3
Chapter Outline
1.1 Historical Background 3 1.7.2 B. Definition of Common
1.2 Important Events in Alzheimer’s Statistical Parameters to
Disease (AD) Research 4 Quantify the Performance
1.3 Some Facts About Alzheimer’s of Biomarkers 14
Disease 7 1.8 Biomarkers of Alzheimer’s
1.4 Common Features of Alzheimer’s Disease 15
Disease 9 1.9 Future Focus: Detecting
1.5 Classification of Alzheimer’s Preclinical Stages of
Disease 10 Alzheimer’s Disease 17
1.6 Risk Factors for Alzheimer’s 1.10 Economic Impact of Alzheimer’s
Disease 11 Disease Biomarkers 18
1.7 Definition of a Biomarker 12 1.11 Conclusions 20
1.7.1 A. Categorization of Bibliography 20
Biomarkers According to
Their Role 14
1.1 HISTORICAL BACKGROUND
Alzheimer disease (AD) was discovered in 1906 by Dr. Alois Alzheimer based on
his observations and treatment of a 51-year-old patient, Miss Augusta “D” (Mau-
rer et al., 1997; Strassnig and Ganguli, 2005), at the Frankfurt Psychiatric Hospi-
tal starting in Nov 1901. At the time, Dr. Alzheimer was a senior assistant at the
institution. When Miss Augusta “D” died on Apr. 8, 1906, Dr. Alzheimer con-
ducted the autopsy of her brain and described the morphological and histological
changes in the brain that continue to stand as hallmarks of modern day AD neu-
ropathology (Hippius and Neundörfer, 2003). Dr. Alzheimer presented his first
report of Alzheimer’s disease at a congress in Tübingen, Germany, in 1906. He de-
scribed two neuropathological phenomena: amyloid plaques, which he referred
to as “miliary bodies,” and neurofibrillary tangles, which he described as “dense
bundles of fibrils.” In 1910, Dr. Emil Kraepelin (Dr. Alzheimer’s supervisor) intro-
duced the term “Alzheimer’s disease” to recognize Dr. Alzheimer’s contribution to
Biomarkers in Alzheimer's Disease. http://dx.doi.org/10.1016/B978-0-12-804832-0.00001-8
Copyright © 2016 Elsevier Inc. All rights reserved.
4 Biomarkers in Alzheimer's Disease
the discovery of this disorder. Dr. Alzheimer died in 1915 without knowing the
outstanding contribution he made to the history of medical science.
1.2 IMPORTANT EVENTS IN ALZHEIMER’S DISEASE
(AD) RESEARCH
Breakthroughs in AD research are presented chronologically in Table 1.1, along
with historical perspectives. The first test used to quantify the cognitive and
functional decline in individuals with dementia, including AD, was the Blessed
Dementia Rating Scale (Blessed et al., 1968). In 1976, Dr. Robert Katzman was
the first to identify AD as the most common cause of dementia among the el-
derly population, and predicted that AD would become one of the major pub-
lic health problems in modern day society (Katzman, 1976). The purification,
characterization, and amino acid sequence analysis of the amyloid protein seen
in the post-mortem AD brain provided the first biochemical evidence of disease
pathology and laid the foundation of the amyloid cascade hypothesis of AD
(Glenner and Wong, 1984). The first clinical guidelines focused on the clinical
diagnosis of AD were formulated in 1984 by the National Institute of Neuro-
logical and Communicative Disorders and Stroke and the Alzheimer’s Disease
and Related Disorders Association (NINCDS-ADRDA, McKhann et al., 1984).
Based on available clinical diagnostic tools, the NINCSD-ADRDA guidelines cat-
egorized AD as either probable AD or possible AD and concluded that definitive
diagnosis of AD was only possible through histological confirmation at autopsy.
This NINCDS-ADRDA diagnostic guidelines successfully served AD clinicians
and researchers worldwide for 27 long years until they were finally modified in
2011 (National Institute on Aging and Alzheimer's Association, 2011; McKhann
et al., 2011), though there was an earlier attempt by the International Working
Group 1 to revise them in 2007 (Dubois et al., 2007).
The “gold standard” of AD diagnosis is the presence of amyloid plaques and
neurofibrillary tangles in the brain at autopsy. Amyloid plaques form as a result
of the deposition of different truncated forms of amyloid beta peptides (Aβ)
originating from the cleavage of amyloid precursor protein (APP). Grundke-
Iqbal et al. discovered that hyper-phosphorylated tau protein is the main con-
stituent of the neurofibrillary tangles in the AD brain in 1986 (Grundke-Iqbal
et al., 1986). In the same year, a clinical trial of the cholinesterase inhibitor
tetrahydroaminoacridine (tacrine [Cognex]) reported a temporary effect on
improving clinical measures of cognitive function in AD patients (Summers
et al., 1986). Tacrine was the first FDA-approved drug for the treatment of the
memory impairment due to AD. In 1987, the first genetic evidence of an in-
herited form of familial AD (FAD) was reported, specifically mutations in the
APP gene located on chromosome 21 (Robakis et al., 1987; Tanzi et al., 1987).
This discovery further supported the amyloid cascade hypothesis of AD patho-
genesis. Later in 1993, APOE4 was implicated as a genetic risk factor for late-
onset AD (Saunders et al., 1993; Strittmatter et al., 1993). In 1995, a second
AD gene, presenilin1 (PSEN1), was discovered (Sherrington et al., 1995). Most
FAD patients carry a mutation in the PSEN1 gene (total of 185 mutations found
Table 1.1 Important Events and Their Impact in Alzheimer’s Disease (AD)
Event Impact to Alzheimer’s Disease References
The 37th Meeting of South-West German Discovery of Alzheimer’s disease: Dr. Emil Kraepelin first
Psychiatrists First presentation about Alzheimer’s disease by names “Alzheimer’s
(37 Versammlung Südwestdeutscher Irrenärzte) Dr. Alzheimer. Disease” in the eighth I
n
was held in Tübingen on Nov. 3, 1906. edition of his book t
r
Psychiatrie, 1910. o
d
Blessed Dementia Rating Scale First cognitive test to quantify cognitive and Blessed et al. (1968) u
c
functional decline in adults. t
i
o
First evidence of public health problem First to identify AD as the most common cause Katzman (1976) n

of dementia among elderly population and t
o
predict that it will be a major public health
A
problem in the modern day. l
z
h
Isolation of amyloid protein; foundation of Amyloid protein was isolated from fibrils in Glenner and Wong (1984) e
i
amyloid hypothesis cerebrovascular amyloidosis associated with m
AD. e
r
First guideline of clinical diagnosis of Clinical diagnosis of AD can be categorized as McKhann et al. (1984) ’s

D
Alzheimer’s disease by The National Institute of probable AD or possible AD.
i
Neurological and Communicative Disorders and Definitive diagnosis of AD is possible by s
e
Stroke and the Alzheimer’s Disease and Related histopathological confirmation at autopsy. a
s
Disorders Association (NINCDS-ADRDA, 1984). e

B
Discovery of phosphorylated tau related to AD Tau is a major component of Alzheimer paired Grundke-Iqbal et al. (1986)
i
helical filaments, a hallmark of AD brain o
m
pathology.
a
r
First clinical trial for AD: Clinical trial of tacrine for targeting symptoms Summers et al. (1986) k
e
Warner-Lambert Pharmaceutical Co. with the of AD. r
s
association of NIA and Alzheimer’s Association. Tacrine (Cognex) was the first FDA-approved
drug for the treatment of memory problems due C
to AD. H
A
Genetic mutation in APP (amyloid precursor Foundation of amyloid β hypothesis. Robakis et al. (1987), Tanzi P
T
protein) gene at chromosome et al. (1987)
E
21q21.3 R

(Continued) 1
5