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The aging of populations globally has precipitated a demographic “sea change” that is having a profound impact on societies worldwide and is the most powerful driver of the increase in age-related disorders, including Alzheimer's disease (AD) and related neurodegenerative disorders. Addressing these changes is among the most important challenges facing scientists, health care providers, policy makers, the business community, and governments worldwide [1–3].
To address the pending public health crisis due to AD and related neurodegenerative disorders, the Marian S. Ware Alzheimer Program at the University of Pennsylvania organized a meeting entitled “State of the Science Conference on the Advancement of Alzheimer’s Diagnosis, Treatment and Care”, on 21–22 June. 2012. The meeting comprised four workgroups focusing on Biomarkers, Clinical Care and Health Services Research, Drug Development, and Health Economics, Policy and Ethics, all of which must be addressed simultaneously. The intent of the Ware meeting was to develop both cross-cutting and domain specific recommendations for a range of stakeholders, including the scientific community, policy makers, legislators, advocacy groups, and clinicians. To this end, each workgroup met via conference call over several months to develop a preliminary set of recommendations (Appendix 1). At the conference, these recommendations were shared, discussed, and compiled into an integrated set of priorities, recommendations, and action plans, which are presented here.
While the four workgroups each developed focused recommendations reflecting their individual perspectives (Appendix 2), they reached remarkable consensus on the core principles and priorities that must be addressed both short and long-term. Attention to these issues would enable us to provide good quality care for affected patients and families, advance our understanding of the pathophysiology and natural history of AD and other dementias, develop effective treatments to slow or prevent these diseases, and translate scientific advances successfully into policy and practice. The overarching goals identified at the Ware Invitational Summit (Table 1) mirror those reflected in the United States National Plan to address Alzheimer's Disease (USNPAAD, or the “National Plan”) , released May 15, 2012 by the United States Department of Health and Human Services (HSS) as part of the National Alzheimer’s Project Act (NAPA). The National Plan outlines a comprehensive approach of prevention and treatment for AD by 2025.
Recognizing the urgency of the challenges faced by the Alzheimer's field as well as the population at large, the recommendations outlined in this paper call for a number of immediate policy changes as well as introduction of legislative initiatives that would produce effective and sustainable long-term changes in efforts to address the oncoming public health challenges. These recommendations should provide a catalyst to drive research planning, develop alternative care delivery models, and allocate resources to achieve these goals.
Underlying these recommendations are several core principles intended to advance the clinical delivery of care and scientific understanding of AD and related disorders. Efforts to link science with care and engaging the participation of patients, families, scientists, pharmaceutical companies, regulatory agencies, and advocacy organizations were seen by conference participants as path-breaking and instrumental for developing better outcomes for people with AD as has been demonstrated for cardiovascular disease, diabetes, and cancer. The Alzheimer's field should learn from and expand on this model, keeping in mind the need to:
The complete list of recommendations made by the four individual workgroups is available in Appendix 2. These have been reorganized and integrated to address the goals outlined in Table 1. Recommendations across all workgroups and goals are compiled in Table 2, with the highest priority recommendations noted. In making these recommendations, conference participants considered both the urgency of the public health challenges facing the nation and world as well as the reality of shrinking federal budgets. Yet despite the challenging funding environment, there is an undeniable need for increased investment for Alzheimer's research, including basic, translational, clinical, and health-services research, and attention to caregivers.
The effort to develop disease modifying therapies for AD has reached a crisis  and finding a path forward to overcome this impasse will require the collaborative efforts of the research, clinical, pharmaceutical, and regulatory communities, as well as policy makers, to identify barriers and solutions at each stage of drug development. Moreover, there has been a shift in thinking about the treatment of AD, away from the possibility that a single drug could ameliorate the disease. Today, there is increasing recognition of the complexity of the disease, the likelihood that multiple treatments will be needed at different phases of the disease, and that treatment will require more than drugs. To this end, one of the highest priorities is to better understand the pathophysiology of AD and related disorders by broadening the research focus to encompass cardiovascular, metabolic, and inflammatory diseases, all of which play important roles in the development of dementia.
Biomarkers have become essential tools in drug development, both for enriching study populations with subjects likely to respond to the drug and for monitoring response to treatment. Objectively monitoring changes in AD is extremely valuable, but may not be sufficient for monitoring progression of disease pathology or neurodegeneration per se. Biomarkers that separate AD and AD dementia from other aging related dementias would also be valuable.
In contrast to early-onset familial AD, the far more common and sporadic late-onset AD (LOAD) is a multi-factorial disease intermixed with universal senescent processes. Frequently, other common pathological conditions such as vascular disease or other proteinopathies due to α-synuclein or TDP-43, which are characteristic of Parkinson’s disease (PD) and frontotemporal degeneration (FTD) respectively, co-exist with AD in the same patient. At present, we do not have biomarkers to differentiate these conditions, quantify the relative contributions of different disease processes, or measure how active any one might be relative to another. In addition, new biomarkers that assess other aspects of the disease such as synaptic function and inflammation are needed to improve prediction beyond what is available now, to determine contributions from other diseases, and to better assess disease progression and treatment efficacy. Biomarkers that indicate the degree of disease or neurodegeneration at any given point after diagnosis could help guide treatment and assess treatment effectiveness in clinical trials.
The current situation for the pharmaceutical industry to bring a new medical entity (NME) to market is both expensive and extremely long, with the average time now estimated to be 10–12 years and the cost about $1.8 billion and rising rapidly . But more importantly, a series of patent expirations on blockbuster drugs and a dwindling drug pipeline has resulted in a dramatically weakened industry, which could also adversely affect public health efforts to control AD. Drug discovery may need to transition to a new model where discovery and early development of well-defined therapeutic products emanates from academic or non-profit institutions, or small biotechnology companies . In this framework, federal money will help leverage and launch new public-private partnerships, similar to the AD Neuroimaging Initiative (ADNI) , and could also play important roles in filling the pre-competitive space .
Recent disappointing clinical trials of AD pharmacological treatments have slowed new investment into AD drug development. Regardless of whether drug trials currently underway demonstrate efficacy, there is a growing consensus within the AD clinical research community that clinical trials must be redesigned for greater efficiency and that the data gathered in these trials must be carefully analyzed to provide lessons for future drug development. It is essential to improve research and development (R&D) productivity by increasing the efficiency of work in process and the probability of success, and by decreasing Phase II and III attrition , or by changing the current regulatory paradigm. For example, neurodegenerative disease biomarkers provide new opportunities to shorten the length of clinical trials so that they do not consume the period of exclusivity on a new drug. Concerns regarding the length of clinical trials have been compounded by patent law changes that will take effect in March, 2013 , which may shorten effective patent life after the lengthy product approval process.
Public-private partnerships such as ADNI have proven to be effective models for collecting and sharing data in pre-competitive space. ADNI and its international partners (Worldwide ADNI), as well as the Alzheimer’s Biomarker Standardization Initiative (ABSI)  and the Alzheimer's Association’s Global QC program for AD CSF biomarkers  have also led the way in standardization and validation of biomarkers, and this process should be completed. International standardization of AD biomarkers could impact the field in much the same way that standardization of cholesterol or hemoglobin A1c measurement led to widespread use of these tests in clinical trials and the discovery and development of effective treatments for cardiovascular disease and diabetes.
Because cognition is currently thought to be the most clinically relevant characteristic of the disease, it is also imperative that more sensitive and specific cognitive and functional markers be identified, standardized, validated, and correlated with other biomarkers across the continuum of the disease process; and that these cognitive markers are also incorporated into all clinical trials. Moreover, data collected in these trials can prove extremely valuable in planning future drug discovery efforts, and should be made available to other researchers, with appropriate compensation for sponsors (e.g., prompt release of clinical data from placebo treatment groups).
There is a growing consensus in the AD clinical research community of the need to identify individuals at risk for AD or those in whom the neurodegenerative process has already begun [8–11]. New diagnostic criteria proposed by three workgroups convened by the National Institute on Aging in partnership with the Alzheimer's Association (NIA-AA) [12–15] as well as by an International Working Group (IWG) , recognized the value of incorporating biomarkers of AD and neurodegeneration in research studies but concluded that they have not been sufficiently standardized or validated for use in clinical care. The field is rapidly moving forward, with the goal of using biomarkers to ascertain AD as a diagnosis of inclusion with a level of certainty, rather than a diagnosis to be made after excluding other disorders. However, the consensus at this time is that the science does not support the widespread clinical application of a biomarker-based diagnosis.
The NIA-AA committees distinguished three stages of disease: 1) a preclinical phase, where the pathophysiological processes of AD have begun before any evident signs of cognitive impairment, 2) a prodromal or MCI due to AD phase, where there is evident decline in memory or other cognitive functions, and 3) AD dementia, where cognitive and functional deterioration have reached a threshold at which an individual needs help with activities of daily living.
While substantial data indicate that leading CSF and neuroimaging biomarkers provide clinically useful information for patients with evident cognitive impairment (i.e., MCI and dementia), current longitudinal data are not sufficient to warrant the use of AD biomarkers in a-symptomatic individuals . About one third of older adults with normal cognition exhibit abnormal CSF Aβ levels or Aβ PET scans; however, it is not yet known whether abnormal AD biomarkers in asymptomatic people indicate a disease process that will manifest in MCI and AD at some future point, and if so, when. While ADNI has been extraordinarily successful in identifying, standardizing, and validating biomarkers, the population studied does not necessarily reflect the general population. Thus, in order to establish appropriate biomarker cutoffs for both clinical trials and clinical usage, it is imperative to conduct longitudinal, population-based studies using standardized protocols and multiple biomarkers and cognitive markers. Establishing an international population-based registry of older adults, including geographically and culturally different populations and individuals with co-morbid conditions, is thus a high priority recommendation from this conference . This registry could take advantage of existing clinical databases such as those managed by the Department of Veteran’s Affairs and the Center for Medicare and Medicaid Services, and could be modeled after other large longitudinal studies such as the Framingham study, the Cardiovascular Health Study, the Health and Retirement Study, and other population based studies of aging (summarized in ).
Using biomarkers to define risk, however, presents several concerns, particularly since a therapy that impacts an AD biomarker is not certain to translate into clinically meaningful endpoints . The experience of other biomarker-based processes demonstrates the need for caution in disseminating a biomarker into clinical practice without clarifying its value . Clinicians do not yet have a good way to predict the future of AD, including the speed of progression and to what extent function will be affected.
If an effective disease modifying therapy is reported, research needs to address how it will change AD. In particular, as ongoing and planned research enhances our understanding of the preclinical stages of AD, both how we think about the disease and its treatment will change. What was once a disease defined by clinical signs and symptoms, with treatments designed to reduce these clinical features, will become a disease defined by the risk of developing these signs and symptoms, and, once they occur, the risk of their worsening. The concept of successful treatment (including non-pharmacologic treatment) will then be transformed to mean reducing risk and improving quality of life, and it will be imperative that the prevention of signs and symptoms is shown to be both clinically meaningful and cost effective.
As the value of biomarkers and other risk factors emerge and become clinically useful, patients and society will be better served if we think of biomarkers not as labels of a category such as “preclinical AD,” but instead as one, but not the only, measure of risk for disability as a result of progressive cognitive decline. To make the best use of established and emerging biomarkers and other risk factors for AD, an important goal of the AD research community should be to develop and validate a risk-stratification model for the development of endpoints such as MCI or dementia, in order to guide clinical and care management decisions by patients, families, and health care providers; policymaking; and research to test new interventions. Such a risk-prediction model, which incorporates drugs, clinical trials, and biomarkers , holds substantial promise for improving public health. Moreover, it is possible that certain biomarkers will ultimately identify individuals who will ultimately progress to AD and hence prove critically important for identifying early treatment and intervention strategies as these emerge akin to how a Pap smear is currently used to identify women at risk of uterine cancer. The Economics, Ethics and Health Policy Workgroup drew upon their collective expertise in both neurodegenerative diseases and other diseases of aging, such as cardiovascular disease, osteoporosis, and cancer, to propose how the promise of this risk-based model can be realized.
The risk stratification model should be developed using data from representative population-based samples so as to accurately represent the clinical complexity of typical older adults, and the resulting competing health risks (e.g., heart disease, diabetes, cancer) that may have an important impact on life expectancy and quality of life, and, therefore, the efficacy and value of drug and other interventions to prevent or treat AD. Further, the risk-stratification models should be in the public domain, and should be evaluated and updated by a public body (e.g. HHS) using established standards for the reliable and valid measurement of AD risk factors, including the standardization of AD biomarkers. The ongoing evaluation of risk-stratification models should include assessments of the costs (e.g., unnecessary treatment and treatment side-effects) that result from mis-classification when using the models.
AD and other dementias represent the most urgent problem facing the aging population, but these health challenges exist within the larger context of aging, multiple morbidity and resulting disabilities, and social risks. Providing good quality and cost effective care to persons with dementia and their families means providing care across the continuum of the illness, beginning at the “something is wrong” stage. This will require accelerating advances in knowledge and policy that would foster care delivery systems more closely aligned with people’s needs throughout their health and illness trajectories, a better understanding of current best practices, and developing and implementing new strategies to build and expand the workforce capacity to create and support a high-value care system for people with AD and their family caregivers.
Cognitive impairment in combination with other acute and chronic illnesses complicates the care of patients, although the precise effect of co-existing chronic conditions on health care utilization and delivery is not well understood . A truly responsive health care system needs to address the needs of family members and other caregivers along an individualized and changing illness trajectory and in the multiple contexts. As people move along this continuum, their needs become more complex often because many chronic problems are progressive in nature. Additionally, limited social support, health literacy and equity, language and cultural barriers, financial limitations, and other factors may exacerbate the nature and intensity of these needs.
Bringing care to persons with dementia and their families can best be realized by integrating in one place healthcare and social services as well as research and training programs. Numerous models for such community-based health care delivery exist internationally, including, in the United States, the Program of All-Inclusive Care for the Elderly (PACE), and various palliative care programs. The best of these programs join proactively with community partners to enable preservation of cognitive and physical health through primary prevention strategies such as public health awareness programs and fitness training .
In order to identify the model that best fits the needs of patients with dementia and their families, health services research is needed to explore diverse delivery models and their applicability at different stages of illness and with different levels of family need and capability. These care models then need to be tested with regard to their effects on key clinical and utilization metrics within the overall population and among different subgroups. Further, there is a need to better understand the goals identified as most meaningful by the people served--an enhanced care experience, improved health and quality of life, and/or survival –while choosing wisely with finite resources .
Following the identification of best practices, there will be a need to integrate these priorities into the HHS/NAPA National Plan and articulate the value proposition to key stakeholders including governmental organizations, legislators, advocacy groups, and the public at large. Technical assistance skill sets designed to meet the needs of patients, families, and clinicians can be developed to speed implementation of best practices into the community.
Optimal care of patients and families also requires protection of their rights and interests, attention to issues such as stigma, and protection against possible misuse of clinical information, including results from biomarker tests and risk assessment. Thus, we recommend review and possible revision of existing laws that pertain to institutions and social structures (such as insurance and employment) to ensure protection of patients and their families.
The goal of the Ware Conference on the Advancement of Alzheimer’s Diagnosis, Treatment and Care was to formulate a set of recommendations that will inform efforts underway around the world to address the escalating AD public health crisis. This paper represents the work of a multidisciplinary group of researchers, advocates, and clinicians from academia, industry, and advocates. These experts first addressed concerns specific to four different domains: drug development, biomarkers, clinical care and health services research, and economics, ethics and policy. This group subsequently came together to incorporate their recommendations into a fully integrated and comprehensive strategy, which is presented here to the field at large as well as to individual stakeholder groups, including the leadership of HHS/NAPA, the NIH, policy makers, researchers, clinicians, and advocacy and patient groups.
Implementing many of these recommendations, including increased research funding, will require creative thinking, repurposing of existing funds, vigilance in reducing waste, and a constant focus on cost effectiveness. The enormity and complexity of AD demands no less.
We wish to thank the Marian S. Ware 2006 CWG Charitable Lead Annuity Trust for sponsoring this program. The authors also thank Lisa J. Bain for editorial assistance.