Current forecasts indicate that a looming tidal wave of Alzheimer's disease (AD) is inevitable. If the ongoing trend in the escalating numbers of people touched by this disease continues unabated, this global public-health problem is destined to be the major contributor of the future insolvency of healthcare financing systems, e.g., Medicare. Therefore, this blog will describe the 40-year struggle to grapple with the dilemma and the important milestones achieved in the efforts to address it.
The aspiration "to create a world without AD" is frequently articulated by advocacy groups as the grand vision for solving the medical, scientific, social, and economic challenges of AD. Now, in light of the 40-year failure in therapy development, the question is whether this hope is a realistic goal?
If the menace of AD is stoppable, what will be required to attain this strategic goal?
Conversely, if this is an impossible goal, what are the alternative strategies to address this looming problem?
My earlier blog, narrating the 40-year search for treatments ended with the declaration of a forward-looking sentiment that reflected my optimism "about the prospects of winning this renewed crusade." This segment of the "story" will describe the struggles to promulgate national policies and programs to foster 'prevention', as a strategic public health objective. Despite the well-publicized failures of some clinical trials, it will clarify the reasons for optimism about future prospects of more effective interventions being developed.
In 1978, at the start of the NIA/NIH drive to create a national program of research and development (R&D), the primary focus of the initiative was to build the biological underpinning for treatment of dementia-AD and infrastructure for clinical trials. The idea of "interventions," as a broad concept that included various forms of "treatment," was neither part of the thinking nor in the lexicon of that time. The thought of "prevention," meaning the need for a much broader range of "treatments" beyond traditional medications, began to gain some foothold slowly during the next few decades. The following is the story of what happened.
The idea for a "national initiative to prevent Alzheimer's disease" began to take shape in the mid-1980s. During this period, the NIA's point of view on future needs [via new initiatives] on "treatment" began to shift towards the idea of a wider range of "interventions" that would include different modes of treatments or a variety of therapeutic strategies. This transformation of ideas about "treatment," beyond the prevailing conventional wisdom was largely due to the emergence of two distinct lines of new knowledge, which gradually broadened NIA's perspective on future directions of program development in this area.
The first crucial line of new knowledge that was instrumental in expanding ideas on interventions surfaced from a series of longitudinal epidemiological studies on the prevalence of the disease. These studies revealed an age-associated nearly exponential increase in the prevalence of dementia, including AD, after the age of 65. This dramatic rise in frequency, in the form of a J-shaped curve, appeared to almost double the rate of the disease every 10 years of aging (e.g., 10% at age 65; 20% at age 75; and 40% at age 80). The most profound aspect of these epidemiological findings was the consistency in the discovery of an age-associated exponential increase in prevalence (i.e., the J-shaped curve), despite some variations in the actual prevalence rates reported by different studies or those found in different populations/regions/countries.
The second decisive line of new knowledge that helped to expand the notions of interventions, was derived from health services research. Systematic research on both formal and informal care, including studies on the role of psychosocial factors and research on nursing and patient management, began to reveal an array of pragmatic facts about best practices in nursing care and patient management. This emerging knowledge on care-management of patients' disabilities began to show the potency of behavioral (i.e., non-pharmacological) interventions in easing the burdens of caretaking, as well as, reducing "excess disability" of patients with the disease.
Thus, the combination of these two new findings (i.e., variability in the age of onset of symptoms, and the fact that behavioral/social interventions could modify or ameliorate symptom management) were instrumental in broadening the philosophy of interventions and shepherding new thinking. This reassessment of program directions or priorities led NIA to formulate new strategic goals for future programs on therapy development. These renewed aims placed a sharper focus on the concept of 'prevention'; meaning the discovery-development of strategies or interventions to delay the onset of disabling symptoms.
The details of this concept were outlined in an editorial entitled the "Five-five and ten-ten plan to defeat Alzheimer's disease" in 1992, which was the first articulation of a formal proposal for a national 'prevention' plan. This perspective paper, in the form of a "call to arms," declared the need for massive mobilization of national resources to discover and develop interventions to delay the onset of symptoms successively by five and then ten years within a decade. The rationale for this new emphasis was based on the prospect that postponing the onset of disabling symptoms would reduce the number of people with the disease. For example, given the J-shaped pattern in the prevalence of the disease, the NIA calculations showed that a modest delay of 5 years in the incidence of the disease will cut the prevalence by 50%.
The two reasons for recounting the chronicle of therapy development at NIA are:
- The first aim is to explain how the concept of "prevention" emerged namely as an array of interventions with the focus on delaying disabling symptoms. Nowadays, the term "prevention" is widely used without much knowledge about the critical milepost in the evolution of 'new thinking' or the history of protracted struggles to gain acceptance of the idea by the medical-research community.
- The second objective is to tell the reader about the whys and wherefores of the prolonged struggle to change directions or adopt "new thinking" in the worlds of science R&D and public policies for funding research. For example, it required nearly two decades for policymakers to adopt "prevention" as a goal for the national plan for AD.
Such delays for "new ideas" to gain acceptance by the "established order" is not a novel phenomenon in the history of science or medicine. Likewise, the field of therapy development for AD is not exempt from the after-effects of this enduring dilemma in science. Thus, a critical hindrance to the pace of progress is injected into the discovery of interventions. To further document this predicament, some notable benchmarks will be described briefly during the two-decade-long endeavor toward the formulation and adoption of a national plan to prevent Alzheimer's disease.
Evolution of National Policy
Following the 1992 initial call for a national prevention initiative, the second attempt to redirect national public policy was prompted by the groundbreaking discovery by Richard Caselli, Eric Reiman, and others that brain metabolic changes (measured by PET imaging) associated with AD can be detected in people who are asymptomatic (but at genetic risk) during the early stages of the disease process. This pioneering research, combining brain imaging with genomics, set the stage for the possibility for unusually early detection and tracking of brain changes in AD, thus, helping to launch the prospects for a new era in Alzheimer's prevention research. The Caselli-Reiman findings provided the strong scientific rationale for a second attempt to promote a national initiative in 1997 in the form of a congressional testimony on prospects for preventing Alzheimer's disease, which called for "mobilizing our nation's resources within this decade to prevent Alzheimer's disease or to delay its onset by 5 to 10 years. It is essential to slow the rate of deterioration in AD patients and discover treatments that will allow patients to continue to function independently. The ultimate goal is to reduce the duration of illness; reduce the numbers of persons affected by AD; and, ultimately, reduce the cost of long-term care."
In the intervening period during 1997-2007, the idea and prospective scientific feasibility of "prevention" slowly gained some traction, which culminated in widespread support.
Finally, the proposal for a national plan to prevent AD gained a partial victory with the formal recognition of the idea by the Alzheimer Study Group (ASG). In 2007, under the auspices of the Congressional Task Force on Alzheimer's Disease, the ASG was established with the specific charge to create a "National Alzheimer's Strategic Plan to Overcome America's Mounting Alzheimer's Crisis" with former Speaker of the House Newt Gingrich and former U.S. Sen. Bob Kerrey as co-chairs, and included 11 distinguished ASG members who were national leaders with careers in government, law, business, medicine, and academia.
The ASG's final report was delivered to the 111th Congress on March 25, 2009, which thoroughly assessed the burden of AD, including the anticipated trajectory of the disease, and recommended the development of a rigorous research plan to be fully funded by Congress. The ASG staff worked with several experts to address specific scientific challenges and formulate recommendations for an action plan.
As part of this effort, the specific goal to "Prevent Alzheimer's Disease by 2020," was proposed to the ASG by the Campaign to Prevent Alzheimer's Disease by 2020 (PAD2020). This recommendation reflected the culmination of a series of think-tank style research planning meetings (known as the Leon Thal Symposia) convened specifically to probe the thinking of the scientific community on unanswered questions and special resources required to solve the problem of AD. The plan of action suggested by PAD2020 to ASG indicated that "the mission to prevent AD by 2020 requires not only radical changes in the current paradigms of organizing research and development therapies for prevention, but also an unwavering national commitment to allocate appropriate levels of funding in the next decade. The success of this venture will require a sustained investment of $1 billion per year in new funds over current expenditures for the next 10 years. An investment of $10 billion dollars to solve the most urgent looming public-health problem is not too high a cost...." This proposal presented to ASG reflected the collective thinking and endorsement of nearly 100 of the most prominent scientists and opinion leaders around the world engaged in AD and aging research regarding high priority outcomes in research and new initiative programs.
Finally, a measure of success was achieved in the prolonged ordeal toward the adoption of a national plan of action for "prevention." In 2010 Congress acted on the ASG's recommendations by passing the National Alzheimer's Project Act. This landmark legislation required the Department of Health and Human Services to formulate the framework for the National Plan to Address Alzheimer's Disease, which was released in January 2012. The National Institutes of Health (NIH) then followed in 2013 with a specific research agenda to achieve the national plan's goal to "prevent and effectively treat Alzheimer's disease by 2025." To enable the implementation of the provisions of this plan, Congress tripled NIH's annual budget for AD over three years to $1.9 billion. The expected growth spurt will continue through FY'19 with proposed spending bills for NIH that would bring the total to $2.3 billion -- nearly 5% of NIH's overall budget.
Now that a historic milestone was reached in the prolonged struggle to broaden R&D on therapies with a greater emphasis on prevention, where do we go from here?
- How do we respond to the misgivings of luminaries in science-medicine (e.g., Harold Varmus, former NIH director; Richard Hodes, current NIA Director) questioning whether the aspiration "to create a world without AD" is a realistic goal?
- If the strategic goal of "prevention" is pragmatic, what will be required to attain it?
- If this objective is an impossible dream, what are the alternatives strategies to address this looming problem?
- When are the reasons for optimism on the prospects of more effective interventions becoming available, despite the history of 40-year failure in therapy development?
What the Critics Don't Get
The campaign for a national initiative on prevention of AD, which began a quarter of a century ago in the late 1980s, did not lack resistance and controversy. The polemics in the scientific community, which expressed misgivings about attaching a specific date to the goal and cast doubts whether the strategic goal is attainable, has some justification. The primary concerns of these skeptics, on the ultimate success of the national plan, is based on past experience at NIH with other similar plans. The doubters point at the mixed successes of earlier "plans" or "declarations of war on cancer or AIDS. For example, the war on cancer led to some treatments that improved survival, but the disease remains a major cause of death. The increased funding of AIDS research yielded drugs that allow people with HIV to lead nearly normal lives but, the War on AIDS has not led to a cure.
The agnostics, questioning whether the strategic goals of the National Plan for AD is realistic, unfortunately have failed to appreciate the distinct difference beyond some superficial similarities between the present initiative on AD and the earlier Wars on Cancer or AIDS.
First and foremost, the primary strategic aim of the AD prevention initiative was to broaden the options for interventions, i.e., secondary or tertiary prevention, beyond the traditional notions of treatments and primary prevention, aiming for eradication of the disease. The immediate objective from the inception of the prevention campaign was and still is to reduce or delay disability but not necessarily achieve a cure.
Second, the doubters do not seem to grasp the distinction between a "strategic goal" and a "promise" to deliver an end result. Clearly, a "promise" must be realistic and authentic, however, a "goal" is an aspiration and need not be realistic. For example, the goal of placing a man on the moon was not realistic in 1960. It was a vision designed to capture imagination and mobilize the application of resources towards a specific target. The philosophy of this approach was best articulated by W. Clement Stone: "Always aim for the moon; even if you miss, you'll land among the stars."
Third, unlike the wars on cancer and AIDS, where the essential aims were to reduce mortality caused by these conditions, the vital public health issue for AD is the prolonged duration of progressive disability (i.e., disease burden years) rather than being a cause of death. Thus, the aim is to delay the onset of disability and/or reduce the period of labor-intensive personalized care by promoting interventions that would enhance independent functioning. Ironically this objective has been touted as one of the successes of the War on AIDS.
What if the pessimists are correct in asserting that the "strategic goal of prevention" is unrealistic and very unlikely to succeed by 2025? What are the alternative strategies to address this looming crisis?
A Strategy Is Essential
The "problem" of AD is the prototype for the looming global public health crisis. Thus, a potential solution will serve as an alternative for addressing a number of other chronic brain disabilities and disorders that are conditions requiring prolonged healthcare and consume costly resources. Such chronic conditions represent a unique class of disabilities not only due to their profound economic impact but also their psychosocial ramifications. The most common clinical features of these unremitting brain conditions, such as, progressive functional impairments of cognition, motor skills, and emotional impact, eventually lead to total dependence on labor-intense care to sustain life. Due to increasing lifespan, the average period of disability for these chronic conditions is gradually being prolonged. At-risk individuals destined to survive beyond the 9th or 10th decade of life now face the prospects of 30–40 years of disability associated with total dependence for personal care, increasing economic burden, and deteriorating quality of life.
Regarding the question of alternative strategies to solve this predicament, the public policy options are limited to two choices:
- Gamble on the success of the strategy to invest massive funds to expand research on prevention
- Or start to develop plans and/or policies to ration healthcare for an aging population, assuming policy makers will have the political resolve and moral fortitude
Arguably, the enormous scale of the pending health-economics crisis justifies a 10-year wager on the bold vision outlined by the National Plan, along with a compelling scientific agenda formulated by NIH, to address this far-reaching dilemma. The unique feature of the National Alzheimer's Plan is to "Prevent and Effectively Treat Alzheimer's Disease by 2025" and calls for a three-prong attack on the problem, designed to reduce the number of people with disability or at risk (i.e., primary prevention], shorten the duration of disability with more effective interventions, and lower the cost of care with new, innovative models of care.
The question is, what will be required to attain these objectives of the national plan for AD?
The strategic goal to prevent AD within a decade is universally acknowledged to be a very complex and challenging enterprise. However, this undertaking is no more difficult, ambitious, or premature than the Apollo space program was 60-years ago. The long-range aspiration for a prevention strategy by 2025 and the specific scientific agenda for implementing that vision is an attainable objective, well within the grasp of science according to a large number of experts.
All the vital requirements to secure the ultimate success of this challenging mission are already in place. These prerequisites are:
- Consensus on clearly defined scientific and technical objectives. Several new program initiatives have already been announced by NIA/NIH and the Alzheimer's Association.
- Establishment of an efficient organizational system for a single-centralized management approach, a center to coordinate the implementation of the plan and provide oversight on the progress of the mission. This aspect for a successful execution of a complex project has been accomplished by NAPA Advisory Council and a clear mandate to NIA/NIH to coordinate this endeavor.
Due to multiple components, the complexity of the mission will require a systems approach for the execution-implementation of the national plan, including a system for efficient integration of new knowledge emerging from multiple sources and rapid exchange of scientific- technical information.
Commitment Needed
An unwavering national commitment will be necessary from all stakeholders, including the scientific community, various advocacy groups, policy makers, pharma-biotech companies, government agencies, and Congress, in order to support the strategic vision and the implementation plans toward the goal of the National Plan. This vital requirement for the success of this project began to materialize in 2017 with the establishment of ASG and subsequent enactment of NAPA, when the balkanization of conflicting agendas of various stakeholders was ended by merging specific interests of these groups towards a common objective, identified as the National Plan.
To assure success over a 10-year period, a sustained investment of adequate funds will be crucial for the support of this mission. This requirement is now in the process of being fulfilled. During the last three years, funds have started flowing into AD research. In September 2018, the U.S. government allocated $2.34 billion for FY 2019, injecting an extra $425 million into its AD budget as compared to last year. In addition to this type of increase in funding, private donations by philanthropists have begun flowing into universities (e.g., the donation of $5 million to the University of Texas at San Antonio for the Oskar Fischer Project), as well as charitable organizations such as the Alzheimer's Association.
When are the reasons for optimism on the prospects of more effective interventions becoming available, despite the history of a 40-year failure in therapy development?
Making It Work
Although, it is factually correct to assert that a 40-year investment in research has not yielded any effective treatments for AD, this outlay of funds has not been a futile exercise. During these four-decades remarkable progress has been made to understand the neurobiology of an unknown chronic brain disorder that has now become a central contributor to a global crisis for healthcare systems. The new knowledge generated from potential origins of neurodegenerative disorders/dementia/AD now are poised to be utilized for adaptation into the development and testing of novel therapeutic targets and strategies for treatments. The rich array of ideas for interventions that are ready for evaluation are fresh and there are numerous approaches based on longstanding but untested theories on neurodegeneration. For example, some of these approaches include calcium hypothesis, neuroinflammation, metabolic or mitochondrial dysfunction, brain microvessel disease, and lifestyle and risk factors.
The therapeutic paradigm in AD has already begun to shift towards secondary prevention, namely aiming for intervention to delay the onset of symptoms in pre-symptomatic individuals at risk of developing dementia. The key feature of this approach for interventions is the need to develop the tools/technologies/resources for accurate prediction of the risk or people with the disease before the onset of symptoms, and an array of safe interventions to be used for years or even decades before the onset of cognitive-behavioral or functional decline.
Currently, there is growing evidence strongly supporting the proposition that vascular problems in midlife can take their toll on the brain decades down the line. A recent study proposes findings that implies stroke might be a strong and potentially modifiable risk factor for all-cause dementia. Another report found that even mild cardiovascular problems in middle age could have drastic consequences on cognition a quarter-century later. Other corroborating studies have found that diabetes, hypertension, and smoking all increased dementia risk, along with a preliminary report indicating that intensive BP lowering (<120 vs <140 mm Hg) with antihypertensive drug therapy resulted in a significant decrease in mild cognitive impairment. In short, mounting epidemiological evidence for strong associations between cognitive changes and various forms of cardiovascular/cerebrovascular changes provide compelling justification for a major prevention trial with re-purposing previously approved safe and effective drugs for stroke or other vascular disorders.
Another promising array of new ideas to focus on "prevention" stems from the general consensus among researchers in aging is that engagement in various forms of activities to stimulate the brain, (e.g., exercise, diet, nutrition, and cognitive and social activities), are major factors in preserving cognitive health and well-being in the elderly. For example, earlier studies had shown a positive association between healthier dietary patterns (e.g., Mediterranean diet) with less cognitive decline or lower risk for Alzheimer's disease. Now, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) has demonstrated beneficial effect of a 2-year multi-domain intervention for cognitive performance in a heterogeneous population of older adults. The nutritional component of the FINGER intervention also proved successful in promoting healthy dietary changes. These results have shown that adherence to dietary guidelines predicts subsequent improvement in global cognitive performance and favorable changes in decision-making functions over 2 years among older adults.
In a study where people participated in physical activity/exercise for at least 150 minutes per week were found that this increase in physical activity was associated with improved measures of cognition, lower cerebrospinal fluid markers, and delayed onset of mild cognitive impairment in patients with the rare form of autosomal dominant Alzheimer's disease. The symptoms of early-onset autosomal dominant Alzheimer's disease appeared to come on later in life for those with relatively greater physical activity. The subjects were selected from individual volunteers from the Dominantly Inherited Alzheimer Network (DIAN) project, which focuses on people who carry mutations associated with a rare, genetically driven form of early-onset Alzheimer's disease.
Although the recent wave of encouraging results, showing the promise for developing more effective interventions to delay the onset of disability (e.g., reduce the rate of cognitive decline), provide some justification for an optimistic future, the real cause for celebration of victory will come by discovering the means for primary intervention. The prospects for such a breakthrough is in the unknown future. Clearly, no one can predict whether or when a radical new insight or discovery will be made in science. However, the chance for such an event has substantially improved. Paradoxically, one of the unintended consequences of the 40-year history of failures in the search for the "magic elixir" has been the loosening of dogmatic thinking in the field of therapy development. There is a growing recognition that the biology of AD is substantially more complex than hitherto theories have attempted to explain. Ironically, the recent failure of clinical trials based on prevailing scientific orthodoxy has been a blessing in disguise, by opening the door for new thinking and alternative conceptual models that may provide more options for solutions. The future looks bright.
Zaven S. Khachaturian, PhD, is editor-in-chief of Alzheimer's & Dementia and serves as a senior advisor on medical-scientific affairs to the Alzheimer's Association. He is also president of the Campaign to Prevent Alzheimer's Disease by 2020. He formerly directed the Office of Alzheimer Research at NIH. His longstanding research interest is in the neurophysiology of memory and learning.
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