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Biomarkers for Alzheimer s Disease Drug Development Methods in Molecular Biology 2785 Perneczky
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Preface
The prevalence of Alzheimer’s disease and its healthcare and socioeconomic impact are exploding worldwide, and drug development success rates need to be improved urgently; the traditional linear model of pharmaceutical R&D has become outdated and virtually all new drugs have failed since the cholinesterase inhibitors were introduced to the markets two decades ago. Drug development has been more successful in other fields of medicine such as infectious diseases and cancer, in which translational models are applied, linking population-based cohorts and genetic data with potential drug targets and study endpoints. This powerful translational approach is fuelled by technology platforms such as neuroimaging, -omics, and fluid biomarkers. The Alzheimer’s disease field requires a significant cultural change to discover and develop effective disease-modifying treatment options (until 2025, as postulated at the 2013 G8 Dementia Summit).
The main objective of this book is to bridge and converge population, -omics, and imaging sciences (typically owned by academia) with R&D approaches for new technologies and novel, effective drugs (the traditional remit of industry). The book will help building a new generation of experts with a broader understanding of key topics to initiate the disr uptive innovation required to make real progress. Given the high complexity and multifactorial disease nature related to dementias, a precision/personalized medicine approach in designing the next generation R&D strategies is now urgently required.
This publication comprises nine parts: In Part I (Chapters 1–3) we explain why Alzheimer’s disease is one of the major challenges for the global societies and healthcare systems, and how population-based and systems biology approaches can be leveraged to develop more effective treatments. In Part II (Chapters 4–6) we present innovative approaches to the discovery of novel biomarkers in cerebrospinal fluid, whereas in Part III (Chapters 7–9) innovation in blood-based biomarkers is discussed. Part IV (Chapters 10–12) and Part V (Chapters 13–16) provide a comprehensive over view of magnetic resonance imaging and molecular imaging approaches and their value for developing drugs for Alzheimer’s disease, respectively. In Part VI (Chapters 17 and 18) cutting-edge developments in neuropathology and their relevance for Alzheimer’s disease trials are presented. Part VII (Chapters 19–21) covers novel genomic strategies for biomarker development. Part VIII (Chapters 22 and 23) highlights the contribution of preclinical research to the development of novel biomarkers and drugs. Finally, in Part IX (Chapters 24 and 25), we consider relevant related topics including neuropsychological testing and advanced analytical methods.
The book is targeted at individuals with an interest in the use of advanced biomarker strategies to accelerate the development of effective, disease-modifying drugs for Alzheimer’s disease. This includes researchers, clinicians, and those interested in regulatory and medical affairs, both from academia and industry. We wish to present biomarker development approaches as a strategy for the study of Alzheimer’s disease with the hope and expectation that the results will translate into more effective treatments. We expect this book to complement other excellent volumes and monographs on Alzheimer’s disease that cover basic science or clinical aspects of the disease.
Munich, Germany
Rober t Perneczky
Preface v Contributors
Part I the Need for alzheImer’s dIsease BIomarkers
1 Epidemiology of Dementia: The Burden on Society, the Challenges for Research 3
Frank J. Wolters and M. Arfan Ikram
2 Population-Based Approaches to Alzheimer’s Disease Prevention 15
Robert Perneczky
3 Systems Biology Methods for Alzheimer’s Disease Research Toward Molecular Signatures, Subtypes, and Stages and Precision Medicine: Application in Cohort Studies and Trials 31
Juan I. Castrillo, Simone Lista, Harald Hampel, and Craig W. Ritchie
Part II INNovatIve aPProaches to cereBrosPINal fluId BIomarker dIscovery
4 CSF Lipidomics Analysis: High-Resolution Mass Spectrometry Analytical Platform 69 Paul L. Wood and Randall L. Woltjer
5 CSF N-Glycomics Using MALDI MS Techniques in Alzheimer’s Disease
Angelo Palmigiano, Angela Messina, Rosaria Ornella Bua, Rita Barone, Luisa Sturiale, Mario Zappia, and Domenico Garozzo
6 MicroRNA Profiling of Alzheimer’s Disease Cerebrospinal Fluid
Johannes Denk and Holger Jahn
7 Validation of a Chemiluminescence Immunoassay for Measuring Amyloid-β in Human Blood Plasma 111
Jonathan Vogelgsang, Jens Wiltfang, and Hans W. Klafki
8 Mass Spectrometry-Based Metabolomic Multiplatform for Alzheimer’s Disease Research
Raúl González-Domínguez, Álvaro González-Domínguez, Ana Sayago, and Ángeles Fernández-Recamales
9 Blood-Based Biomarker Screening with Agnostic Biological Definitions for an Accurate Diagnosis Within the Dimensional Spectrum of Neurodegenerative Diseases 139 Filippo Baldacci, Simone Lista, Sid E. O’Bryant, Roberto Ceravolo, Nicola Toschi, Harald Hampel, and for the Alzheimer Precision Medicine Initiative (APMI)
Part Iv magNetIc resoNaNce ImagINg methods
10 Functional Magnetic Resonance Imaging in Alzheimer’ Disease Drug Development 159
Stefan Holiga, Ahmed Abdulkadir, Stefan Klöppel, and Juergen Dukart
11 Neuroimaging Methods for MRI Analysis in CSF Biomarkers Studies . .
Carles Falcon, Grégory Operto, José Luis Molinuevo, and Juan Domingo Gispert
165
12 Hybrid PET-MRI in Alzheimer’s Disease Research 185
Ismini C. Mainta, Maria I. Vargas, Sara Trombella, Giovanni B. Frisoni, Paul G. Unschuld, and Valentina Garibotto
Part v molecular ImagINg aPProaches
13 Amyloid PET Imaging: Standardization and Integration with Other Alzheimer’s Disease Biomarkers . .
Silvia Morbelli and Matteo Bauckneht
14 The Use of 18F-FDG PET in the Diagnostic Workup of Alzheimer’s Dementia .
Marion M. Ortner
15 Quantification of Tau Load in Alzheimer’s Disease Clinical Trials Using Positron Emission Tomography
Tessa Timmers, Bart N.M. van Berckel, Adriaan A. Lammertsma, and Rik Ossenkoppele
16 Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach 231
Elena Rodriguez-Vieitez and Agneta Nordberg
Part vI NeuroPathology
17 Unbiased Lipidomics and Metabolomics of Human Brain Samples
Giuseppe Astarita, Matteo Stocchero, and Giuseppe Paglia
18 Neuropathological Assessment as an Endpoint in Clinical Trial Design
Steve Gentleman and Alan King Lun Liu
Part vII geNomIc methods
19 Analysis of Micro-RNA Expression by qPCR on a Microfluidics Platform for Alzheimer’s Disease Biomarker Discovery
Petros Takousis
20 Telomere Length Shortening in Alzheimer’s Disease: Procedures for a Causal Investigation Using Single Nucleotide Polymorphisms in a Mendelian Randomization Study
Yiqiang Zhan and Sara Hägg
21 Quantifying miRNA Deregulation in Alzheimer’s Disease
Ana L. Cardoso and Joana R. Guedes
22 Imaging of Microglial Activation in Alzheimer’s Disease by [11C]PBR28 PET
Cornelius K. Donat, Nazanin Mirzaei, Sac-Pharm Tang, Paul Edison, and Magdalena Sastre
23 In Vivo Two-Photon Calcium Imaging of Hippocampal Neurons in Alzheimer Mouse Models
Marc Aurel Busche
Part IX related coNcePts: cogNItIve testINg aNd advaNced aNalytIcs
25 Data Mining and Machine Lear ning Methods for Dementia Research
Rui Li
Contributors
ahmed aBdulkadIr · University Hospital of Old Age Psychiatry and Psychotherapy Bern, Bern, Switzerland
m. arfaN Ikram · Departments of Epidemiology, Radiology, Neurology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands
gIusePPe astarIta · Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, USA
fIlIPPo BaldaccI · AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Boulevard de l’hôpital, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l’hôpital, Paris, France; Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Boulevard de l’hôpital, Paris, France; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
rIta BaroNe · CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania, Catania, Italy; Pediatric Neurology Unit, Department of Pediatrics, University of Catania, Catania, Italy
matteo BauckNeht · Nuclear Medicine Unit, Polyclinic San Martino Hospital, Genova, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
Bart N.m. vaN Berckel · Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
rosarIa orNella Bua · CNR, Istituto per i Polimeri, Compositi e i Biomateriali
Catania, Catania, Italy
marc aurel Busche · Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Charlestown, MA, USA; Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany
aNa l. cardoso · Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
JuaN I. castrIllo · Genetadi Biotech S L Parque Tecnológico de Bizkaia, Derio, Bizkaia, Spain
roBerto ceravolo · Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
JohaNNes deNk · Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
corNelIus k. doNat · Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
JuergeN dukart · F . Hoffmann-La Roche, Pharma Research Early Development, Roche Innovation Centre Basel, Basel, Switzerland; Roche Pharmaceutical Research and Early Development, Neuroscience, Ophthalmology and Rare Diseases, Discovery and Translational Area, Roche Innovation Center Basel, Basel, Switzerland
Paul edIsoN · Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
carles falcoN · Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
ÁNgeles ferNÁNdez-recamales · Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence
CeiA3, University of Huelva, Huelva, Spain
gIovaNNI B. frIsoNI · Faculty of Medicine, Nuclear Medicine Department, Geneva University Medical Center, University of Geneva, Geneva, Switzerland; Department of Internal Medicine, Geneva University Hospitals, Geneva, Switzerland
valeNtINa garIBotto · Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland; Faculty of Medicine, Nuclear Medicine Department, Geneva University Medical Center, University of Geneva, Geneva, Switzerland
domeNIco garozzo · CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania, Catania, Italy
steve geNtlemaN · Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
JuaN domINgo gIsPert · Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), Madrid, Spain
raúl goNzÁlez-domíNguez · Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence
CeiA3, University of Huelva, Huelva, Spain
Álvaro goNzÁlez-domíNguez · Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence
CeiA3, University of Huelva, Huelva, Spain
JoaNa r. guedes · Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
sara hägg · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
harald hamPel · AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la Pitié-Salpêtrière, Boulevard de l’hôpital, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l’hôpital, Paris, France; Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Boulevard de l’hôpital, Paris, France
stefaN holIga · F . Hoffmann-La Roche, pharma Research Early Development, Roche Innovation Centre Basel, Basel, Switzerland
holger JahN · Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
haNs W. klafkI · Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany
Contributors
stefaN klöPPel · University Hospital of Old Age Psychiatry and Psychotherapy Bern, Bern, Switzerland
adrIaaN a. lammertsma · Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
ruI lI · Alibaba, Hangzhou, Zhejiang, China
sImoNe lIsta · AXA Research Fund & UPMC Chair, Paris, France; Sorbonne Université, AP-HP, GRC n° 21, Alzheimer Precision Medicine (APM), Hôpital de la PitiéSalpêtrière, Boulevard de l’hôpital, Paris, France; Institut du Cerveau et de la Moelle Épinière (ICM), INSERM U 1127, CNRS UMR 7225, Boulevard de l’hôpital, Paris, France; Institut de la Mémoire et de la Maladie d’Alzheimer (IM2A), Département de Neurologie, Hôpital de la Pitié-Salpêtrière, AP-HP, Boulevard de l’hôpital, Paris, France
alaN kINg luN lIu · Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK
IsmINI c. maINta · Division of Nuclear Medicine and Molecular Imaging, Geneva University Hospitals, Geneva, Switzerland; Faculty of Medicine, Nuclear Medicine Department, Geneva University Medical Center, University of Geneva, Geneva, Switzerland
aNgela messINa · CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania, Catania, Italy
NazaNIN mIrzaeI · Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
José luIs molINuevo · Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain; CIBER Fragilidad y Envejecimiento Saludable (CIBERFES), Madrid, Spain
sIlvIa morBellI · Nuclear Medicine Unit, Polyclinic San Martino Hospital, Genova, Italy; Department of Health Sciences, University of Genoa, Genoa, Italy
agNeta NordBerg · Division of Translational Alzheimer Neurobiology, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden; Department of Geriatric Medicine, Karolinska University Hospital Huddinge, Stockholm, Sweden
sId e. o’BryaNt · Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, TX, USA
grégory oPerto · Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain
marIoN m. ortNer · Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
rIk osseNkoPPele · Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
gIusePPe PaglIa · EURAC Institute for Biomedicine, Institute for Biomedicine, European Academy of Bolzano/Bozen, Bolzano, Italy
aNgelo PalmIgIaNo · CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania, Catania, Italy
roBert PerNeczky · Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-Universität München, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE) Munich, Munich, Germany; Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science, Technology and Medicine, London, UK; West London Mental Health NHS Trust, London, UK
geraINt PrIce · Faculty of Medicine, Neuroepidemiology and Ageing Research Unit, School of Public Health, The Imperial College of Science Technology and Medicine, London, UK
craIg W. rItchIe · Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
eleNa rodrIguez-vIeItez Division of Translational Alzheimer Neurobiology, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
magdaleNa sastre · Division of Brain Sciences, Imperial College London, Hammersmith Hospital, London, UK
aNa sayago Department of Chemistry, Faculty of Experimental Sciences, University of Huelva, Huelva, Spain; International Campus of Excellence CeiA3, University of Huelva, Huelva, Spain
matteo stocchero Department of Women’s and Children’s Health, University of Padova, Padova, Italy
luIsa sturIale CNR, Istituto per i Polimeri, Compositi e i Biomateriali Catania, Catania, Italy
Petros takousIs · Neuroepidemiology and Ageing Research Unit, School of Public Health, Imperial College, London, UK
sac-Pharm taNg Imanova Limited, London, UK
tessa tImmers Department of Neurology and Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands; Department of Radiology and Nuclear Medicine, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands
NIcola toschI · Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy; Department of Radiology “Athinoula A Martinos”, Center for Biomedical Imaging, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
sara tromBella Faculty of Medicine, Nuclear Medicine Department, Geneva University Medical Center, University of Geneva, Geneva, Switzerland
Paul g uNschuld · Institute for Regenerative Medicine and Hospital for Psychogeriatric Medicine, University of Zurich, Zurich, Switzerland
marIa I. vargas Faculty of Medicine, Nuclear Medicine Department, Geneva University Medical Center, University of Geneva, Geneva, Switzerland; Division of Neuroradiology, Geneva University Hospitals, Geneva, Switzerland
JoNathaN vogelgsaNg · Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany
JeNs WIltfaNg Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, Georg-August-University, Goettingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany; Medical Sciences Department, iBiMED, University of Aveiro, Aveiro, Portugal
Contributors
fraNk J. Wolters Department of Epidemiology, Erasmus Medical Centre, Rotterdam, The Netherlands
raNdall l. WoltJer Department of Neurology, Oregon Health Science University and Portland VA Medical Center, Portland, OR, USA
Paul l Wood · Metabolomics Unit, College of Veterinary Medicine, Lincoln Memorial University, Harrogate, TN, USA
marIo zaPPIa Section of Neurosciences, Department of GF Ingrassia, University of Catania, Catania, Italy
yIqIaNg zhaN · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
Part I
The Need for Alzheimer’s Disease Biomarkers
Epidemiology of Dementia: The Burden on Society, the Challenges for Research
Frank J. Wolters and M. Arfan Ikram
Abstract
Dementia is among the leading causes of death and disability. Due to the ageing population, its prevalence is expected to nearly triple worldwide by 2050, urging the development of preventive and curative interventions. Various modifiable risk factors have been identified in community-based cohort studies, but insight into the underlying pathophysiological mechanisms is lacking. Clinical trials have thus far failed in the development of disease-modifying therapy in patients with dementia, thereby triggering a shift of focus toward the presymptomatic phase of disease. The extensive preclinical disease course of Alzheimer’s disease warrants reliable, easily obtainable biomarkers to aid in timely application of preventive strategies, selecting participants for neuroprotective trials, and disease monitoring in trials and clinical practice. Biomarker and drug discovery may yield the fruits from technology-driven developments in the field of genomics, epigenetics, metabolomics, and brain imaging. In that context, bridging the gap between translational and population research may well prove a giant leap toward development of successful preventive and curative interventions against dementia.
At present, 48 million people worldwide are suffering from dementia, and this number is projected to increase to 131 million by 2050 [1]. The enormous burden this poses on patients, their caregivers, and society as a whole is only in part reflected by the estimated $818 billion per annum needed for dementia care worldwide. Costs for dementia already exceed those for any other disease [2, 3], and as the number of patients with dementia grows the annual health expenditure is projected to reach one trillion dollars as soon as 2018 [1]. Every year, nearly ten million people develop dementia, with a median age at diagnosis of around 80 years (Fig. 1). Similar to other disorders with steeply increasing prevalence at higher ages, the burden of dementia arises predominantly from disability rather than mortality. In industrialized countries, 80% of those in care homes
have dementia or significant cognitive problems, and despite good care less than half experience a good quality of life [4]. Prior to institutionalization, caregivers alleviate much of the burden of disease, but often at the cost of their own well-being [5].
Meanwhile, health expenditure continues to fall short in anticipating long-term care costs. A 2012 study in the UK found that every £10 of health and social care costs attributable to dementia are counterbalanced by only £0.08 for dementia research [6]. This is particularly striking, as investments in long-term prevention are projected to result in cost-effective gains in quality-adjusted life years in the population [7]. Driven by the projections of the burden on public health, governments have only recently designated dementia as a major public health threat, and started to prioritize research in their federal budgets accordingly. This will undoubtedly spark advances in research and clinical care, but time is not on our side. Subclinical alterations in brain health are thought to occur decades before diagnosis of dementia [8], and the social and economic burden of dementia will thus increase enormously, unless curative and preventive measures can be rapidly established.
As the burden of dementia grows across the globe, the largest increase will occur in low- and middle-income countries, such that by 2050 roughly two-thirds of people with dementia will live in these regions (Fig. 2). Yet, only a minority of patients receive (extensive) investigation or a formal diagnosis, particularly in settings poor in resources [9, 10]. Together with differences in patient care, the low rate of diagnoses accounts for a stark contrast in global healthcare expenditure, where over 90% of current dementia care costs are incurred in high-income countries [11]. It shows above all that wide availability and accessibility of diagnostics, preventive measures, and feature disease-modifying agents will be vital to control the global dementia epidemic.
Fig. 1 Age-specific incidence of dementia per geographic area. Data source: World Alzheimer Report, 2015
Fig. 2 The numbers of people living with dementia in millions (black box) per geographic area in 2015 (light grey), with projections for 2030 (dark blue) and 2050 (dark grey). Corresponding percentage increase compared to 2015 is depicted in red labels. Data source: World Alzheimer Report, 2015
In this chapter, we shall provide a brief overview of the current state of affairs in preventive and curative medicine, and highlight the main challenges and opportunities encountered in etiological research and drug development.
2 Preventive and Curative Efforts: Small Successes in the Light of Failure
The urgency for new drugs is reflected in a steep increase in the number of trials registered for drugs against Alzheimer’s disease. Over the past 20 years, hundreds of registered trials set out to determine the efficacy of potential drugs for dementia, but this has resulted in only four drugs offering limited symptom relief (Table 1), while thus far no disease-modifying therapies are available. The cost of these trials culminates to billions of euros. Of 244 compounds that were assessed in 413 trials in the past decade, none have made it to the market since the approval of memantine for symptom relief in 2003 [12]. Of every 100 compounds entering phase 1 trials for Alzheimer’s disease, 28% make it to phase 2, in which 8% succeed [12]. For comparison, success rates of phase 1 and phase 2 trials for infectious disease are 70% and 43%, respectively, while for cardiovascular disease these percentages are 59% and 24% [13]. As of 2016, another large phase 3 Alzheimer trial, assessing the efficacy of amyloid antibody solanezumab, has joined the long list of unsuccessful intervention for (mild) Alzheimer’s disease, along with the 5-HT6 antagonist idalopirdine that was aimed
Frank J. Wolters and M. Arfan Ikram
Table 1
Overview of currently approved drugs for Alzheimer’s disease
Generic drug (brand name)Approval for disease stageYear of approvalIndication
Donepezil (Aricept) All stages 1996 Symptom relief
at symptom relief. Nevertheless, over 20 phase 3 trials are currently ongoing, of which the majority is directed against amyloid, either by antibodies, vaccines, or inhibiting beta-secretase 1 (BACE).
With regard to prevention, various modifiable risk factors have been identified in community-based cohort studies over the past 20–30 years. Midlife hypertension, obesity, smoking, diabetes mellitus, low educational attainment, and physical activity are consistently associated with an increased risk of disease, and account for about 25% of all cases of dementia [14, 15]. As these risk factors are largely shared with other (cardiovascular) diseases, improvements in cardiovascular risk management may have had positive effects on dementia risk over the past decades also. In fact, multiple reports now suggest a decline in the incidence of dementia in industrialized countries by about 20% per decade since the 1970s [16–18]. However, the precise causes of this trend have not been accounted for, data from low- and middle-income countries are not available, and even if the current trend continues it will not suffice to offset the effects of a rapidly ageing population on the number of patients with dementia. In addition, trials assessing the efficacy of specific preventive interventions for lowering the risk of dementia have thus far been largely unsuccessful [19]. Following the failures of these dementia prevention trials in the late 1990s and early 2000s, subsequent trials have determined the effect of interventions on cognition as a more sensitive outcome measure than dementia, with more positive results in particular for trials assessing the efficacy of physical activity and multi-domain interventions [19]. For example, the Scandinavian FINGER trial (a multi-domain intervention involving diet, exercise, vascular risk monitoring, and cognitive training) has shown benefit on cognitive function [20], and participants continue to be surveyed for the incidence of dementia. Despite generally modest effect sizes at the individual level, these preventive efforts could greatly reduce the burden of disease at the population level. If preventive efforts succeed in delaying the onset of dementia by merely 5 years, this could reduce the incidence of dementia by as much as 50% over the next decades [3]. Yet again, in an unselected population of elderly Dutch people (the preDIVA trial), multi-
domain vascular care intervention did not significantly lower dementia incidence, and the French Multi-domain Alzheimer Prevention Trial (MAPT—testing similar interventions plus omega-3 supplements) found no significant benefit on cognitive decline over a 3-year period [21, 22]. These inconsistencies across trials employing closely aligned interventions emphasize that much work remains to be done to understand the specific pathways underlying successes and failures of these preventive trials.
Summarizing the small successes and many disappointing past attempts to halt dementia at any stage of disease, the question rises why so many efforts have thus far failed. What are the difficulties medical research faces in developing treatments against dementia and specifically Alzheimer’s disease, while successful battles have been fought against many other similarly common and age-related diseases? The next section will therefore focus on the challenges and opportunities in striving to improve the process and outcomes of drug discovery.
3 Challenges in Clinical Trials
Part of the lagging behind of dementia treatments, compared to improvements in treatment of cardiovascular disease and cancer, could be linked to lack of research funding [6]. Every £10 of health and social care costs attributable to dementia are counterbalanced by £0.08 for dementia research in the UK, compared with £1.08 for cancer and £0.65 for heart disease [6]. This 8–14-fold difference in research investment may reflect the differences in disease perception and heterogeneous nature of cancer as a disease entity, as well as less direct effects of preventive measures for dementia, compared to acute vascular events. Today’s intervention might prevent tomorrow’s myocardial infarction, whereas the long preclinical phase of dementia precludes return of investment within several years from initiation of preventive measures. Nevertheless, a Swedish-Finnish study that modeled cost and utilities of such investments suggests that long-term prevention can in fact result in a cost-effective gain in quality-adjusted life years in the population [7], emphasizing the necessity of prioritizing dementia research funding.
Other challenges in dementia research pertain to the disease course and impairment of dementia itself, which make it different from other diseases that medicine has successfully engaged. These include high attrition rates in trials, insensitive or inaccurate outcome assessments [23], and—perhaps foremost—a long and variable presymptomatic disease phase that has repeatedly been put forward as an explanation for why so many clinical trials have failed. By the time of diagnosis, the brain of patients with dementia shows high degrees of degeneration that vary greatly across patients and are unlikely to be ameliorated by treatment. Moreover, markers for
Frank J. Wolters and M. Arfan Ikram
risk of neurodegeneration may arise years before diagnosis of dementia [8], and intervention at the time of disease may consequently be too late. Trials have therefore moved from including patients in any stage of disease to those with mild dementia only, and, driven by yet again disappointing results, ongoing trials now focus on presymptomatic individuals. As such, the Alzheimer Prevention Initiative’s A4 trial currently enrols cognitively healthy individuals in the USA, Canada, and Australia for 39 months of treatment with intravenous solanezumab or placebo (ClinicalTrials. gov Identifier NCT02008357). However, when targeting earlier, presymptomatic stages of the disease, enrichment of people at highest risk of developing the disease is vital for the trial to be sufficiently powered. Strategies for enrichment include targeting individuals who are at increased genetic risk, and several studies now focus exclusively on genetically high-risk individuals, such as crenezumab for preclinical PSEN1 mutation carriers of Colombian kindred (ClinicalTrials.gov Identifier NCT01998841), and the Generation Study for individuals aged 60–75 years who carry two copies of the apolipoprotein E epsilon 4 allele (ClinicalTrials.gov Identifier NCT02565511). Although this might in part circumvent the problem of eleventh-hour interventions, it could render results less applicable to the large population at risk due to the strong selection on relatively rare genetic variants. In addition, time to event in these preventive trials remains prolonged, making them costly and unable to provide rapid answers to urgent questions. The feasibility of future trials will therefore depend on the ability to either recruit (representative) individuals at risk of developing disease during the trial period or develop reliable biomarkers that can serve as surrogate endpoints for preventive trials.
4 Biomarkers and Treatment Targets: The Search Continues
Risk stratification of individuals for a certain disease generally starts with easily obtainable demographics and details about personal history. This approach has been highly effective in predicting for instance longterm risk of cardiovascular disease in the community [24], short-term risk of stroke in patients with transient ischemic attack [25], or odds of having pulmonary embolism [26]. However, for dementia, such simple models using demographics and personal history have thus far proven of limited predictive value in the general population [27]. Of potential predictors, educational attainment, a positive family history, and subjective memory complaints appear most informative, but their incremental value over merely age and gender is limited. In the setting of memory clinics, additional, more advanced tools are generally available for diagnosis. Biomarker levels of (phosphorylated) tau and β-amyloid in cerebrospinal fluid are consistently associated with a diagnosis of dementia or mild cognitive impairment due to AD [28], but
this does not automatically translate into improved diagnostic accuracy above and beyond clinical observations [29]. Similarly, prediction of conversion from mild cognitive impairment to dementia might be improved by advanced (PET) imaging, but currently available data are deemed insufficient to recommend these expensive investigations for routine use in clinical setting [30]. Regardless, the stage at which patients present at memory clinics may be too late in the disease process to initiate a prevention trial, because those patients are symptomatic per definition. Standardization of any marker will be vital to prevent the large inter-site variability in measurements that currently hampers definition of prediction rules across clinical sites [31]. Moreover, diagnostic value cannot simply be inferred from association studies, and diagnostic accuracy strongly depends on the screening strategy and setting [32]. For example a biomarker with high sensitivity and low specificity can be very useful as a first screening phase in primary care, while it will likely not be very helpful in clinical setting. Similarly, a biomarker that is more reflective of late-state disease can be very useful in the monitoring disease course, whereas it will be of limited value in risk stratification in asymptomatic individuals. Screening strategy and setting will also largely affect cost-effectiveness, which should be taken into account in the development of any biomarker. While investigations in memory clinics generally include state-of-the-art brain imaging and cerebrospinal fluid samples, screening strategies in the general population, by contrast, should rely on more readily attainable measures from for instance blood, urine, or saliva. In any case, high intraindividual reliability is essential for disease monitoring, and for these tests to be applied in clinical trials. Given the multifactorial nature of dementia, incremental value of biomarkers for the prediction of dementia, or even Alzheimer’s disease, is likely to be found only by the combination of multiple entities, rather than individual markers. Lastly, any candidate (set of) biomarker(s) will require validation in independent samples to confirm and establish their predictive value. Similar to biomarker development, identification and validation of potential treatment targets is an important combined task for population, clinical, and translational medicine. As highlighted above, many modifiable risk factors for dementia have been identified, but lack of understanding of their biological underpinning has long hampered drug development. Amyloid has been the major target for drug interventions, but the string of negative trial results has led to fierce criticism in the field that amyloid might be a downstream result of changes leading to Alzheimer’s disease [33]. The challenge for alternative theories is to explain why amyloid accumulates in the brain if it is not causing neurodegeneration while proposing reasonable alternative mechanisms for neurodegeneration in Alzheimer’s disease. Alternatives that have been put forward include (but are not limited to) mechanisms related to microvascular function and neurovascular coupling, inflammation, angiogenesis, and lipid or iron metabolism. While these ideas frequently originate from
Frank J. Wolters and M. Arfan Ikram
observations in clinical or population studies, identification of the biological underpinning of these mechanisms relies on translational medicine. Yet, also at the preclinical stage, models in the past decades have been mostly aimed at overexpression of amyloid or tau, thereby overlooking a range of important determinants of dementia in population studies. Animal models are generally built on rare familial types of Alzheimer’s disease, and may therefore not reflect the pathology of the common late onset, in which for example vascular disease and diabetes are prominent features. Although therapeutic targets may produce desired effects in transgenic mouse models, current animal studies have not been able to aid discovery of Alzheimer therapy, and have consequently faced criticism about questionable validity to reflect human disease [34]. At the same time, limitations to in vivo imaging of amyloid and tau have long precluded etiological research of amyloid and tau in humans, and still the required tracers at a price of around €1500 per acquired brain scan are generally beyond the scope of (large) population studies. Aside efforts to incorporate these types of research on a population level, the matching of findings from preclinical models to observations in clinical and population studies is vital to unravel pathophysiological mechanisms. It is this translation of group differences to the individual variation that is the biological underpinning of the disease. Understanding the interindividual differences in pathology and clinical presentation is the step forward to developing and electing proper treatments for very individual (future) patient.
5 Big Data and Precision Medicine
“Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type –that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature?” With these words US President Barack Obama kicked of the Precision Medicine Initiative in early 2015. Aside short-term goals for personalizing cancer care, the long-term ambitions of the program focus on all areas of health, including neurological disease. And given the multifactorial and complex pathophysiological nature of dementia, a personalized approach in the development of interventions may benefit dementia as much as cancer therapy.
Over the past decades, the quest for unraveling the etiology of common diseases has led to instigation of multiple large studies in the general population. These studies’ sizes range from 10,000 to 15,000 participants for community-based cohorts like the Framingham Heart Study and the Rotterdam Study [35, 36] to an intended 500,000 subjects examined for the UK Biobank and
1,000,000 for the US Precision Medicine Initiative. Already, these types of studies have shown to be valuable in identifying genetic risk alleles and imaging markers predisposing for dementia. Since the first genome-wide association studies in the early 2000s, increasingly large quantities of genetic data have revolutionized the way aforementioned research questions can be addressed. Together with epigenetics and proteomics, genomics and neuroimaging have yielded previously unimagined opportunities to obtain rich information about the influence of an individual’s biological sketch and the environment on virtually any phenotype. But big data does not just allude to large quantity. More than sheer numbers, it is the opportunities presented by the combination of aforementioned modalities that allows hypothesis-free research of the -omics data. Also, the linkage of these cohort data to potential drug targets holds promise for drug development, as is increasingly acknowledged among researchers, funding agencies (e.g., the U.S. National Institutes of Health BD2K project), pharmaceutical industry, and consultant companies alike. By no means does such an approach substitute detailed study about disease pathways and singular treatment targets. On the contrary, sometimes this may lead directly to development of new drugs, such as for PCSK9 inhibitors [37–39], while arguably more often (genetic) data could be applied to increase success rate of drug development by selecting genetically supported drug targets from potential candidates [40, 41]. Also for Alzheimer’s disease, genomics approaches have recently shown interest in identifying disease-relevant tissues, variants, and regulators [42].
At the same time, the diverse and often complex methods pose new challenges of their own. Data harmonization, storage, access and sharing, and analysis are some of the main hurdles to largescale analyses and collaborations that can be taken only by international standardization, improvements in infrastructure for collaboration, and advanced technology for data acquisition, storage, and analyses. In addition, unlike genetic studies, application of proteomics and epigenetics is vulnerable to selection bias, confounding, and other biases that traditionally hamper research [43]. For example, while the UK Biobank achieves its intended 10% response rate [44], this is far lower than the response rates of about 60–80% in population-based cohort studies. Sufficient response rates are important to avoid selection bias and guarantee generalizability of findings to a larger population. Similarly, other fundamentals of epidemiology need to be upheld, such as avoidance of attrition, accuracy of outcome assessment, and accounting for potential biases. These methodological challenges cannot be counterbalanced by quantity, and warrant careful study design and choice of appropriate methods for data analysis. If, and only if, these hurdles can be overcome, the combination of powerful computational methods and large-scale -omics data with biological information about the disease from translational models has the Epidemiology of
Frank J. Wolters and M. Arfan Ikram
potential to boost drug discovery and biomarker development. It may well be the bridge between observations in large-scale population data and (molecular) biology of a disease that can transform the -omics era into that of precision medicine, with Alzheimer’s disease as one of its primary targets.
6 Concluding Remarks
The increasingly heavy burden of dementia on society poses one of the greatest challenges for modern medicine. Despite our best efforts, to date no disease-modifying treatments have evolved from identification of various risk factors in (clinical) populations. It is therefore not simply an option, but a necessity to combine insights and approaches in laboratory, clinics, and population setting toward the development of biomarkers and treatments for dementia. Science presents us with an increasing number of research tools to this aim. In the coming years, we are to use these tools inventively and in compliance with fundamental epidemiological principles, if we are to fulfil the potential for the development of preventive and curative interventions that these approaches hold.
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Chapter 2
Population-Based Approaches to Alzheimer’s Disease Prevention
Robert Perneczky
Abstract
Progress in prevention and treatment of Alzheimer’s disease (AD) and dementia is hampered by the restricted understanding of the biological and environmental causes underlying pathophysiology. It is widely accepted that certain genetic factors are associated with AD and a number of lifestyle and other environmental characteristics have also been linked to dementia risk. However, interactions between genes and the environment are not yet well understood, and coordinated global action is required to utilize existing cohorts and other resources effectively and efficiently to identify new avenues for dementia prevention. This chapter provides a brief summary of current research on risk and protective factors and opportunities and challenges in relation to population-based approaches are discussed.
Key words Alzheimer’s disease, Dementia, Drug development, Population-based, Cohort studies, Lifestyle, Environment, Genetics
1 Introduction
The traditional linear model of pharmaceutical research and development has become outdated and attrition rates have almost been 100% over the last two decades in the field of Alzheimer’s disease (AD). At the same time the prevalence of AD and its healthcare and socioeconomic impact are exploding worldwide and drug development success rates need to be improved urgently. Successful drug discovery and development in other fields of medicine, such as cancer and infectious diseases, have shown that translational models linking epidemiological cohort and genetic data to potential drug targets and study end points can lead to success [1]. Technology platforms such as neuroimaging, -omics, and biomarkers have been shown to be powerful tools in this translational process. A significant cultural change has to be initiated to discover and develop novel disease-modifying treatments in the dementia field until 2025, as postulated at the 2013 G8 Dementia Summit [2].
Increased life expectancy is a major achievement of modern society, which however comes at the price of a growing prevalence of age-associated disorders with severe consequences for the global healthcare systems. Within the next 30–40 years, the number of people affected by late-onset neurodegenerative disorders such as AD and Parkinson’s disease will globally be three to four times higher than today [3]. The individual risk for these disorders is highly variable and the development of effective preventive and therapeutic strategies is hindered by the still incomplete knowledge about factors influencing the vulnerability to neurodegeneration. There is emerging academic consensus that an individual’s susceptibility to AD is determined by both biological and environmental factors, which has important implications for the development of effective treatment options [4]. Even though AD has a significant heritability, monogenic familial forms caused by clearly pathogenic mutations in certain genes are extremely rare; the vast majority of AD cases are likely to be caused by an interplay between common genetic variants and other factors. The biological mechanisms by which genes influence the individual vulnerability to AD are still largely unknown, but recently identified risk genes point to the involvement of certain biological pathways such as immune response and lipid processing [5].
As with most complex diseases, an individual’s vulnerability to AD is not exclusively defined by genetic factors, but also by nongenetic determinants such as the environment and epigenetic mechanisms. Genetic susceptibility is innate but risk associated with certain environmental factors may be modifiable and changes in lifestyle may offer a chance to prevent or treat AD. Many of the known environmental risk factors are related to obesity, diabetes mellitus, and vascular disease, all of which can potentially be modified; the impact of protective environmental factors such as Mediterranean diet and cognitive and physical activity can also be actively strengthened. An individual’s personality and inherent beliefs affect their behavior and therefore have an important impact on their lifestyle choices and the associated dementia risk [6]. Furthermore, factors outside an individual’s control also influence their chronic disease risk, such as the current healthcare system, air pollution, and wider economy (Fig. 1).
2 Epidemiological Approaches to Alzheimer’s Disease Research
While the link between AD risk and certain environmental and lifestyle factors seems well established, the biological mechanisms underlying these associations are not yet well understood. The application of high-throughput “omics” technologies to prospective cohort studies with stored biospecimens offers a unique opportunity to phenotype individuals at the molecular level. Cutting-edge
1.1 A Multicausal Model of Alzheimer’s Disease
technologies such as epigenomics and metabolomics can be applied to pre-diagnostic biosamples for the detection of early disease markers. Etiological research combining epidemiologic and molecular data, with a focus on gene-environment interactions, can pave the way to the identification of etiopathogenetic pathways via systems biology approaches.
Worldwide, several large-scale prospective cohort studies on ageing and neurodegenerative disease have been established in the past decades (for a comprehensive listing of European cohorts see [7]); the studies have collected detailed dietary, lifestyle, and clinical information, and in some cases biological samples and neuroimaging data, from very large numbers of participants at various points in life. The continued follow-up of these existing infrastructure and a collection of repeated and additional detailed information from these ageing populations is a highly efficient strategy to address the existing knowledge gaps. However, data analysis has so far mostly been restricted to individual cohorts due to differences in assessment procedures and applied methods between countries. Concerted action is therefore urgently required to facilitate the comprehensive analysis of large datasets and to increase knowledge transfer between experts in different countries. It is crucial to achieve standardized data analysis across global ageing and neurodegeneration cohorts and effective networking activities between researchers in the field. The main aims of such networking activities
2.1 The Value of Established Global Infrastructures
Fig. 1 A multicausal model of Alzheimer’s disease
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explication of them.” Give me leave therefore, Rev Sir, if you are pleased to favour me with another letter, to let me know how you explain these important points, or what you can find inconsistent with scripture, or the articles of the church of England, in those discourses which I have published, and in which I have endeavoured to treat on these points in an explicit manner.
I would observe to you, that I wish every non-resident minister in England, could give as good an account of their non-residence, as I can of my absence from Savannah. To satisfy you, Rev. Sir, I will acquaint you with the whole. When I first went abroad, I was appointed to be minister of Frederica. But upon my arrival in Georgia, finding there was no minister at Savannah, and no place of worship at Frederica, by the advice of magistrates and people, I continued at Savannah, teaching publicly, and from house to house, and catechising the children day by day, during the whole time of my first continuance in Georgia; except about a fortnight in which I went to Frederica to visit the people, and to see about building a church, for which I had given fifty pounds out of some money I had collected, and of which I have given a public account. About four months after, I came over to England to receive priest’s orders, and collect money for building an Orphan-house. At the request of many, the honourable trustees presented me to the living of Savannah. I accepted it, but refused the stipend of fifty pounds per annum, which they generously offered me. Neither did I put them to any expence during my stay in England, where I thought it my duty to abide, till I had collected a sufficient sum wherewith I might begin the Orphanhouse, though I should have left England sooner, had I not been prevented by the embargo. However, I was more easy because the honourable trustees, I knew had sent over another minister, who arrived soon after I left the colony. Upon my second arrival at Georgia, finding the care of the Orphan-house, and the care of the parish, too great a task for me, I immediately wrote over to the honourable trustees to provide another minister. In the mean while, as most of my parishioners were in debt, or ready to leave the colony for want of being employed, and as I believed, that erecting an Orphan-house would be the best thing I could do for them and their
posterity, I thought it my duty, from time to time, to answer the invitations that were sent me to preach C J in several parts of America, and to make more collections towards carrying on the Orphan-house. The L stirred up many to be ready to distribute and willing to communicate on this occasion. I always came home furnished with provisions and money, most of which was expended among the people, and by this means the northern part of the colony almost entirely subsisted for a considerable time. This was asserted, not very long ago, before the house of commons. And now, Sir, judge you whether my non-residence, was any thing like the non-residents of most of the English clergy. When I was absent from my parishioners, I was not loitering or living at ease, but preaching and begging for them and theirs: and when I returned, it was not to fleece my flock, and then go and spend it upon my lusts, or lay it up for a fortune for myself and relations. No: freely as I had received, freely I gave: and “therefore when the ear heard me, then it blessed me; and when the eye saw me, it gave witness to me: because I delivered the poor that cried, and the fatherless, and him that had none to help him. The blessing of him that was ready to perish came upon me; and I caused the widow’s heart to sing for joy.” I am become a fool in glorying. But you have compelled me. The G and Father of our L J C knoweth that I lie not. I fought not theirs, but them. And however you may judge me, (page 20th) as though I chose this itinerant way of preaching for the sake of Profit; yet I assure you the last day will prove that you and all like-minded are quite mistaken. I choose a voluntary poverty. The love of G and the good of souls is my only aim. The manner of my call to my present way of acting, if the L gives me freedom, shall be the subject of a future tract. I send you this short letter, to convince you that I am really willing to give an answer of the hope that is in me, with ♦meekness and fear. I shall only add, if you do not like the example of Gallio (page 27th) I would humbly recommend to you the advice of Gamaliel “Refrain from these men, and let them alone: for if this council, or this work be of men, it will come to nought: but if it be of G , ye cannot overthrow it, lest haply ye be found even to fight against G .” I am, Rev. Sir,
Your affectionate brother and servant,
G W .
♦ “meakness” replaced with “meekness”
A N S W E R
TO
The F P of an A P , entitled, “Observations upon the Conduct and Behaviour of a certain Sect usually distinguished by the Name of M .”
IN A
L E T T E R
TO
The R R the BISHOP of LONDON, and the other R R the BISHOPS concerned in the Publication thereof.
False Witnesses did rise up: they laid to my Charge Things that I knew not, Psalms xxxv. 11.
L E T T E R
To the Right Reverend
The Bishop of L , &c.
London, March 1744.
My Lords,
THE Apostle Peter exhorts us, “to be ready to give an answer to every one that asketh us a reason of the hope that is in us, with meekness and fear.” And if this is to be our conduct towards every one, much more are we bound to behave thus to those who are overseers of the church of G , and consequently are invested with an authority to require an answer at our hands.
A desire of complying with this apostolical injunction, induced me, my Lords, about five weeks ago, to publish an Advertisement¹ , wherein I desired an open publication of several anonymous papers, entitled, Observations upon the conduct and behaviour of a certain sect, usually distinguished by the name of Methodists. Papers, which, upon enquiry, I found had been printed some considerable time, had been read in the societies of London and Westminster, and handed about in a private manner to particular friends, with strict orders to part with them to no one. What could be the meaning of such a procedure, I know not. But this I know, however such a clandestine way of acting, may savour of the wisdom of the serpent, it does not bespeak that ♦ harmlessness of the dove, which our Saviour in an especial manner recommends to his ministers.
¹ Whereas some anonymous papers against the people called Methodists in general, and myself and friends in particular, have been for some weeks printed in a large edition, and handed about and read in the religious societies of the cities of London and Westminster, and given into the hands of many private persons, with strict injunctions to lend them to no one, nor let them go out of their hands to any; and whereas, after having accidentally had the hasty perusal of them, I find many queries of great importance concerning me, and my conduct, contained therein; and as it appears that one paper has little or no connexion with another, and a copy, when applied for, was refused me, and I know not how soon I may embark for Georgia; I am therefore obliged hereby to desire a speedy open publication of the aforesaid papers, in order that a candid, impartial answer may be made thereto by me, George Whitefield.
London, January 26, 1744
♦ “harmlesness” replaced with “harmlessness”
Who the real author of these papers may be, I am not yet able for a certainty to find out. But I had reason to believe, that my Lord of London was concerned in composing or revising them. That I might not be mistaken, after the publication of the advertisement, I wrote his Lordship a letter¹ , wherein I desired to know, whether his Lordship was the author of this paper or not, and also desired a copy. His Lordship was pleased to send word by my friend, who carried the letter, that “I should hear from him.” Hitherto his Lordship has not favoured me with an answer. Only some time ago, one Mr. Owen, a printer, in Amen-Corner, Pater-noster Row, who is printer to my Lord of London, left a letter² for me, wherein he informed me, that he had orders from S B to print the Observations on the conduct and behaviour of the Methodists ( A ) for their use; and when the impression was finished, I should have a copy. Why my Lord of London, or the several other Bishops concerned, should conceal their names, or why a copy should be denied me, so long after the papers had been
printed, I leave the world to judge. I cannot think such a way of proceeding can gain your Lordships any credit from the public, or any thanks from the other Bishops who have not interested themselves in this affair, and who, I believe, are more , than to countenance the publication of any such performance.
¹ My Lord,
London, February 1, 1744
Simplicity becomes the followers of Jesus Christ, and therefore I think it my duty to trouble your Lordship with these few lines. I suppose your Lordship has seen the advertisement published by me, about four days ago, concerning some anonymous papers, which have been handed about in the societies for some considerable time. As I think it my duty to answer them, I should be glad to be informed whether the report be true, that your Lordship composed them, that I may the better know to whom I may direct my answer. A sight also of one of the copies, if in your Lordship’s keeping, would much oblige, my Lord, Your Lordship’s most obliged, dutiful son and servant, George Whitefield.
P. S. The bearer will bring your Lordship’s answer; or if your Lordship please to favour me with a line, be pleased to direct for me, to be left with Mr. J. Syms, &c.
² Sir,
February 3. 1744.
My name is Owen I am a printer in Amen-Corner; and I waited upon you to let you know, that I have had orders from several of the Bishops, to print for their use, such numbers of the Observations upon the conduct and behaviour of the Methodists, (with some few additions) as they have respectively bespoken And I will not fail to wait upon you with one copy, as soon as the impression is finished. I am, Sir,
Your most obedient, &c
It is a weighty thing with me, my Lords, to have insinuations made, or queries put to me, in respect to my practice and doctrine, in such a public manner, by persons that are placed at the head of the church. It is true, your Lordships have not put queries to me in your own names; but as the author has concealed his, and these papers are printed by your Lordships orders, you have thereby adopted them for your own; consequently, I am put under a necessity of directing this letter as I have done. And I can assure your Lordships, that with great deference to the dignity of your office, after earnest prayer, with I trust some degree of humility, and unfeigned simplicity of heart, I now sit down to perform my promise, to give a candid and impartial answer to the fore-mentioned papers, which were sent me last week, (collected into a pamphlet) by Mr. Owen; and I suppose, by your Lordships order.
I never yet was, and hope never shall be so far left to lean to my own understanding, as to fancy myself infallible. Young as I am, I know too much of the devices of Satan, and of the desperate wickedness and deceitfulness of my own heart; not to be sensible, that I am a man of like passions with others, and consequently may have sometimes mistaken nature for grace, imagination for revelation, and the fire of my own temper, for the pure and sacred flame of holy zeal, which cometh from G ’s altar.—If therefore, upon perusing the pamphlet, I find that I have been blameable in any respect (as in all probability I may) I will not only confess it, but return hearty thanks both to the compiler and your Lordships, though unknown.
Indeed, it is but of little consequence to the merits of the cause to know who the author is. Only thus much may be said, your Lordships yourselves being judges, it is not quite fair to give stabs in the dark; and it is some satisfaction to the person attacked, to know who and what his antagonists are, that he may know the better how to deal with them. But since that cannot be granted, it may be more to the purpose, to consider the matters contained in the pamphlet, and to answer for myself, so far as I am concerned.
It is entitled, Observations upon the conduct and behavior (i. e. upon the conduct and conduct) of a certain sect, usually distinguished by the name of Methodists. I think the title ought rather to run thus,—Misrepresentations of the conduct and , of many orthodox, well-meaning ministers, and members of the church of England, and loyal subjects to his Majesty King George, S , and usually distinguished, , by the name of M . This title, my Lords, would just answer the contents. For the principles as well as conduct of the Methodists are struck at, and greatly misrepresented in this pamphlet And the Methodists are no sect, no separatists from the established church, neither do they call people from her communion. Besides, the author ought to have added, A new edition, with several alterations, additions and corrections; for otherwise the world is made to believe, that this is the self-same composition which was handed about some months ago, and of which I had a hasty reading. Whereas there are several things omitted, some things added, and divers alterations made in this new edition; so that the title-page is not only injudicious, but false and scandalous.
And if the title-page is so bad, I fear the design and scope of the pamphlet itself is much worse. For is it not to represent the proceedings of the Methodists as dangerous to the church and state, in order to procure an act of parliament against them, or oblige them to secure themselves by turning dissenters?
But is not such a motion, at such a season as this, both uncharitable and unseasonable? Is not the administration engaged enough already in other affairs, without troubling themselves with the Methodists? Or who would now advise them to bring farther guilt upon the nation, by persecuting some of the present government’s most hearty friends? I say, my Lords, the present government’s most hearty friends. For though the Methodists (as the world calls them) disagree in some particulars, yet I dare venture to affirm, that to a man they all agree in this, to love and honour the king. For my own part, I profess myself a zealous friend to his present Majesty King George, and the present administration. ♦Wherever I go, I think it my
duty to pray for, and to preach up obedience to him, and all that are set in authority under him, in the most explicit manner. And I believe, should it ever come to the trial, the poor despised Methodists, who love his Majesty out of principle, would cleave close to him in the most imminent danger, when others that adhere to him, only for preferments, perhaps might not appear altogether so hearty. My Lords, I have now been a preacher above seven years, and for these six years past, have been called to act in a very public way. Your Lordships must have heard of the very great numbers that have attended me: sometimes several of the nobility, and now and then, even some of the clergy have been present. Did they ever hear me speak a disloyal word? Are there not thousands can testify, how fervently and frequently I pray for his Majesty King George, his royal offspring, and the present government? Yes, my Lords, they can. And I trust, through the divine assistance, I should be enabled to do so, though surrounded with popish enemies, and in danger of dying for it as soon as my prayer was ended. This, my Lords, as far as I am acquainted with them, is the present temper of my friends, as well as myself. And may I not then appeal to your Lordships, whether it be not the interest of the administration to encourage such persons, or at least to let them alone? Gallio, on a like occasion, thought it his wisdom to act thus. “For when the Jews made insurrection with one accord against Paul, and brought him to the judgment-seat, saying, this fellow persuadeth men to worship G contrary to the law; he said unto the Jews, if it were a matter of wrong or wicked lewdness, O ye Jews, reason would that I should bear with you. But if it be a question of words and names, and of your law, look ye to it, for I will be no judge of such matters.” Nay, he was so far from approving of their motion, that he drove them from the judgment-seat.
♦ “Whereever” replaced with “Wherever”
My Lords, I know of no law of the state that we have broken, and therefore we have not incurred the displeasure of the civil power. If your Lordships apprehend that we are liable to ecclesiastical
censures, we are ready to make a proper defence whenever called to it by our ecclesiastical superiors. As for myself, your Lordships very well know that I am a Batchelor of Arts, have taken the oaths, subscribed to the articles, and have been twice regularly ordained. In this character I have acted both at home and abroad, and know of no law of our government which prohibits my preaching in any field, barn, street, or out-house whatsoever.
It is true, one or two of my friends, who preach as I do, were bred dissenters, and had been licensed, and preached in licensed places before my acquaintance with them; and one or two of the houses where the Methodists meet, have, without my knowledge, been licensed since; and therefore the author of the pamphlet is quite mistaken in his first paragraph (as well as the title page and design of his pamphlet) wherein he declares, that “it does not appear that any of the preachers among the Methodists have qualified themselves and the places (it would have been better English if he had said, qualified themselves, and licensed the places) of their assembling, according to the act of toleration; which act warrants separate assemblies for the worship of G , that before were unlawful.” I wish the author had taken a little more care to inform himself before he published the pamphlet. He would not then have been guilty of so many egregious mistakes, or without cause have condemned the innocent, as he hath done. However, in the general, he is right,—for, as yet, we see no sufficient reason to leave the church of England, and turn dissenters; neither will we do it till we are thrust out. When a ship is leaky, prudent sailors, that value the cargo, will not leave it to sink, but rather continue in it so long as they can, to help pump out the water I leave the author, my Lords, to make the application.
But whether the Methodists are church-men or dissenters, the acts of King Charles II. referred to, page 3. paragraph 1. and page 4, paragraph 2. make nothing against them, neither do they prove the Methodists to be violaters of the statute law, by their being fieldpreachers. And what the author so peremptorily affirms, page 4. paragraph 3. (and which, by the way, is one of the few additions
made in this, which was not in the last edition) is directly false. For he says, that “it has not been known, that a Dissenting teacher of any denomination whatever, has thought himself warranted under the act of toleration, to preach in fields or streets.” It may not, indeed, be known to the author; but I know, my Lords, two of the most eminent among the Dissenting ministers, who have thought themselves warranted, if not by the act of toleration, yet by the laws of the land, to preach out of doors; and accordingly, when the house would not contain the people, they have preached in a field or orchard, and near the common high-way My Lords, I have been perusing all the acts of King Charles II. wherein the word field is mentioned, and find they are intended “to suppress seditious conventicles, for promoting further, and more proper, speedy remedies against the growing and dangerous practices of seditious sectaries, and other disloyal persons, who, under pretence of tender consciences, have, or may, at their meetings contrive insurrections (as late experience hath shewn)”. These, my Lords, are the preambles of the acts. These are the only field-meetings I can find that are prohibited. And how, my Lords, can such acts be applied to the Methodists? Does not such an application imply a charge against the Methodists, as though they were seditious sectaries, disloyal persons, who, under pretence of tender ♦consciences, have, or may contrive insurrections? Has any late experience shewn this? No, my Lords, and I hope no future experience ever will. How then can your Lordships, with a safe conscience, encourage such a pamphlet, or bespeak any number of Mr. Owen, in order, as may be supposed, that they should be dispersed among your Lordships’ clergy? Well might the author conceal his name. A more notorious libel has not been published. I am apt to believe, that Mr. Owen the printer is of my mind also; for he has taken care in the title-page, not to let the world know where, or by whom, this pamphlet was printed. It comes into public like a child dropt, that no body cares to own. And, indeed, who can be blamed for disowning such a libel? For how, my Lords, does it appear by these acts, what the author so confidently asserts, page 4, paragraph 2, “that this new sect of Methodists have broken through all these provisions and restraints, neither regarding the penalties of the laws, which stand in full force against them, nor
embracing the protection which the act of toleration might give them, in case they complied with the conditions of it?” How can he immediately add, “and if this be not an open defiance to government, it is hard to say what is?” May I not more justly say, if this be not an open defamation, and open defiance of all rules of charity, it is hard to say what is? Might he not as well tax the Methodists with high treason? Father, forgive him! L J , lay not this sin to his charge!
♦ “consciencies” replaced with “consciences”
Though the reign, my Lords, of King Charles II. wherein the acts before referred to were made, was not the most mild and moderate in religious matters, yet your Lordships very well know the famous trial of Mede and Penn; and, after the jury had been confined a long time, they brought them in, guilty only of speaking in Gracechurchstreet. And if Quakers met with so much lenity under the reign of King Charles, what liberty of preaching in fields, and elsewhere, may not the loyal ministers and members of the church of England, nay, protestant Dissenting teachers also, expect under the more gentle and moderate reign of his present Majesty King George, who, as I have been informed, has declared, “there shall be no persecution in his days.” May the crown long flourish on his royal head, and a popish Pretender never be permitted to sit upon the English throne! To this, I believe, all the Methodists will heartily say, Amen, and Amen.
That the Methodists, in general, are members of the Established Church, the author of the pamphlet himself confesses. For, page 4, paragraph 4. after he has, without proof, charged them with making open inroads upon the national constitution; he adds, that “these teachers and their followers affect to be thought members of the national church.” And his following words prove that they not only affect it, but are members of the Established Church in reality: for, says he, “and do accordingly join in communion with it.” And it appears, paragraph 6. that some of the Methodists communicate
every Lord’s-day What better proof can they give of their being members of the Church of England? It would be well if all her members gave a like proof. But then, says our author, page 4, paragraph 4, they do it in a manner that is “very irregular, and contrary to the directions laid down in the rubrick before the communion, which is established by the act of uniformity.” (Here is another correction in this new edition.) In the copy that I read, it was “contrary to the directions laid down in our great rule, the act of uniformity.” I am glad the author found out his mistake, in putting the act of uniformity, for the rubrick. I hope the next edition will come out more correct still. This rubrick, says he, directs as follows: page 4, paragraph 4: “So many as intend to be partakers of the holy communion, shall signify their names to the curate, at least, some time the day before.” And, for not doing this, the new sect of Methodists, paragraph 5. page 6. is charged not only with breaking through, but “notoriously despising these wholsome rules.” But how unjust is such a charge? When I read it, it put me in mind of what the poor persecuted officers of the children of Israel said to Pharaoh, Exodus v. 15, 16. “Wherefore dealest thou thus with thy servants? There is no straw given unto thy servants. They say unto us, Make brick, and behold thy servants are beaten, but the fault is in thy own people.” For, my Lords, is it not the business of the clergy to see this rubrick put in execution? And is it not the duty of the churchwardens, according to the 28th canon, quoted by our author, page 5, paragraph 4, “to mark whether any strangers come often, and commonly from other parishes to their churches, and to shew the ministers of them.” But, my Lords, where is this rubrick or canon observed, or insisted on by the ministers or church-wardens through England, Ireland, Wales, or his Majesty’s town of Berwick upon Tweed, except now and then, when they entertain a grudge against some particular Methodists? These, my Lords, would rejoice to see, that ministers and church-wardens would do their duty in this particular For many of them have been so offended by the clergy’s promiscuously and carelesly admitting all sorts of people to the communion, that if it had not been for me, they would have left the church only upon this account. We would therefore humbly recommend it to your Lordships, that you, and the rest of the Right
Reverend the Bishops, would insist upon curates and churchwardens putting this, and all other such wholesome laws and rubricks into execution. That which is holy would not then be given unto dogs, nor so many open and notorious evil-livers take the sacred symbols of our L ’s most blessed body and blood into their unhallowed hands and mouths. The Methodists wish your Lordships prosperity in this much wished-for, though long neglected part of reformation, in the name of the L .
At the same time, my Lords, I would not say any thing that might any way encourage disorders; neither would I persuade the Methodists to leave their own parish-churches when the sacrament is administered there. On the contrary, I would have them take the author’s advice, page 6, paragraph 6, “If particular persons are disposed to receive weekly, when the sacrament is not administered at their own parish-church, to repair privately to the church nearest their own, where the sacrament is administered every Lord’s-day, having first signified their names to the minister, as the rubrick directs.” This, I believe, they will readily comply with. For I cannot think with this author (in the same paragraph), that the reason of their coming in such numbers is, that they may have the “vain pleasure of appearing together in a body, and as a distinct sect.” We would rather, according to the rules of that charity which hopeth all things for the best, believe that they come together in such companies to animate and encourage one another. Dr. Horneck, I remember, in his account of the primitive christians, remarks, that “where you saw one christian, you might generally see more.” And is it not delightful, my Lords, to behold a communion table crouded? Do not such as complain of it, discover something of the spirit of those Pharisees, who were angry when so many people brought their sick to be healed by our L J on the sabbath-day? For I cannot think, that the ministers complain of this, only on account of their being hereby “put under the difficulty (paragraph 5, page 6.) either of rejecting great numbers as unknown to them, or administering the sacrament to great numbers, of whom they have no knowledge,” because it is too notorious that hundreds receive the blessed sacrament, both in London and other places, where there are no
Methodists, whom the minister knows little or nothing at all about, and takes no pains to enquire after. O that the Author’s mentioning this, may be a means of stirring up the clergy to approve themselves good shepherds, by seeking, as much as in them lies, to know the state of all that come to the holy communion! Glad am I, my Lords, to find that the author, in this edition, hath left out the complaint which was in the copy I first read, of such crowds coming to receive the sacrament, “because the ministers who are afternoon-lecturers, were thereby put under the hardship of not having time for necessary rest and refreshment, between morning and evening duties. For might not our L say unto them, “You slothful servants, cannot you labour for me one day in a week? Cannot you lose one meal to feed my lambs, without complaining of it as an hardship?” Surely none can make such a complaint, but such “whose god is their belly, whose glory is their shame, who mind earthly things.” But I need not mention this, because the Author himself seems ashamed of it.
And indeed this, as well as the other objections against the Methodists, are so trivial, and the acts referred to as discountenancing their field-preaching, so impertinent, that the Author, without the least degree of a prophetic spirit, might easily foresee, paragraph 8, page 8, “that this, and every other such complaint against the Methodists, would be censured not only by them, (but by every impartial person) as a discouragement to piety and devotion, and particularly a religious observation of the Lord’sday.” Nay, my Lords, he might have foreseen that it would be censured as a wicked, false, and ill-designing libel. For is it not wicked, to represent innocent and loyal persons as open defiers of government, page 4, paragraph 2, and making open inroads upon the national constitution, (paragraph 4.) without bringing any real proofs of either?
I am not, my Lords, of the Author’s opinion, paragraph 8, page 8, “that this slander (of his being a libeller) is effectually confuted, by looking back to the state of the several religious societies in London and Westminster for many years past.” This will only serve to increase every unprejudiced person’s censure of this performance,
and more effectually, without the least degree of slander, prove it a notorious libel. For wherein do the Methodist societies transgress the laws of church or state, any more than the societies in London and Westminster? “Do the particular members of each society (paragraph 8. page 8.) attend the public duties of the day, together with their neighbours, as the laws of church and state direct?” Do not the members of the Methodist societies the same? “Have the members of the religious societies in London and Westminster (as the Author mentions in the same paragraph) also (by private agreements among themselves) their evening meetings, to employ the remainder of the day in serious conversation, and in reading good books, &c.” Have not the members of the Methodist societies liberty to enter into a like private agreement among themselves? “Have the members of the London societies behaved with modesty and decency, without any violation of public order and regularity?” So have ours, my Lords, as all must confess who have been present when our societies met.
And therefore, my Lords, if these London societies, as our Author says, paragraph 8, page 8. have received no discouragements, but, on the contrary, have been countenanced and encouraged by the bishops and clergy; why do not the Methodists meet with the same treatment? Are they not as loyal subjects? If the one read a prayer, may not the other pray extempore? Does any law of G or man forbid it? If the one meet in a vestry, or private house, may not the other meet in a Foundery or Tabernacle? Are not your Lordships, therefore, reduced to this dilemma, either to encourage both or neither? or at least give the world better reasons than the Author of this pamphlet has, why your Lordships should countenance and encourage the one, and so strenuously discountenance and discourage the other.
For my own part, my Lords, I know of no reason why they are discountenanced, except this, “The Methodist societies (as they are called) are more for the power of godliness than those other societies of London and Westminster.” I assure your Lordships, I have not been altogether a stranger to these societies. I used to
meet with some of them frequently, and have more than once preached their quarterly sermon at Bow-church. Some, who before had only the form of godliness, our Saviour was since pleased to call effectually by his grace. But when they began to talk feelingly and experimentally of the new-birth, free justification, and the indwelling of the Spirit of G in believers hearts, they were soon looked upon as righteous over-much, and accordingly were cast out by their selfrighteous brethren. These were the late extravagances, my Lords, into which the Author (just at the conclusion of his first part) says, that some have been unhappily misled; and this, my Lords, was the first rise of the societies which the Methodists now frequent. O that he and all who oppose them, had been misled into the like extravagances! I mean a real experience of the new-birth, and the righteousness of J C imputed and applied to their souls by faith, through the operation of the eternal Spirit! For without this they cannot enter into the kingdom of heaven. These things, my Lords, the first members of the religious societies in London and Westminster were no strangers to. Nay, their being misled into what the Author calls the Methodists late extravagancies, was the rise of their societies, as well as ours; and they met for the very same ends, and I believe in the very same spirit as the Methodists now do. For a proof of this, I would refer the Author to Dr. Woodward’s account of the rise and progress of the religious societies in the city of London, &c. My Lords, I have been reading over this second chapter, and in reading it, could scarce refrain weeping, when I considered how blind the author of this pamphlet must be, not to discern, that the first religious societies answered, as to their spirit, experience, and ends of meeting, to the Methodist societies, as face answers to face in the water. Let him not, therefore, mention the predecessors of the present London societies (the last words of the first part) as though that would strengthen his cause. Indeed, my Lords, it weakens it much. For, was it possible for these predecessors to rise from the dead, and examine our principles and practices, and those of the present religious societies of London and Westminster, I believe they would utterly disown them, and turn Methodists too.
And why, my Lords, should the Author be so averse to fieldpreaching? Has not our Saviour given a sanction to this way of preaching? Was not the best sermon that was ever preached, delivered on a mount? Did not our glorious Emmanuel (after he was thrust out of the synagogues) preach from a ship, in a wilderness, &c.? Did not the Apostles, after his ascension, preach in schools, public markets, and such like places of resort and concourse? And can we copy after better examples? If it be said, “that the world was then heathen,” I answer, and am persuaded your Lordships will agree with me in this, that there are thousands and ten thousands in his Majesty’s dominions, as ignorant of true and undefiled religion, as ever the heathens were? And are not persons who dare venture out, and shew such poor souls the way to heaven, real friends both to church and state? And why then, my Lords, should the civil power be applied to in order to quell and suppress them? Or a pamphlet encouraged by several of the Right Reverend the Bishops, which is manifestly calculated for that purpose? I would humbly ask your Lordships, whether it would not be more becoming your Lordships characters, to put your clergy on preaching against revelling, cockfighting, and such like, than to move the government against those, who out of love to G and precious souls, put their lives in their hand, and preach unto such revellers, repentance towards G , and faith towards our L J ? What if the Methodists, “by public advertisements do invite the rabble?” (as our Author is pleased to write, page 4, paragraph 2.) Is not the same done by other clergy, and even by your Lordships, when you preach charity sermons? But, my Lords, what does the Author mean by the rabble? I suppose, the common people. If so, these are they who always heard the blessed J gladly. It was chiefly the poor, my Lords, the οχλος, the turba, the mob, the multitude, these people, who, the scribes and pharisees said, knew not the law, and were accursed; these were they that were evangelized, had the gospel preached unto them, and received the Spirit of G ’s dear Son. Not many mighty, not many noble are called, says the Apostle. Indocti rapiunt cœlum, dum nos cum doctrina descendimus in Gehennam, says one of the fathers. And therefore, my Lords, supposing we do advertise the rabble, and none but such make up our auditories, (which is quite false) if this be the
