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40 Years of Alzheimer's Research Failure: Now What?

<ѻý class="mpt-content-deck">— Decades-long odyssey with little to show
MedpageToday

The usual topic of my lectures at medical-scientific conferences on Alzheimer's disease (AD) often includes some discussion on prospects of preventing dementia and future challenges in the search for cures. These talks on the current state of therapy development invariably prompt the universal question: when to expect more effective treatment for dementia and AD.

The significance of these probing questions goes beyond mere curiosity. They reflect the growing worries about the lack of lasting treatments for the most disruptive symptoms of AD cognitive impairments. The increasing frustration, voiced by patients, physicians, and policymakers alike, stems from the glaring absence of any breakthroughs for treating AD, the most common form of dementia.

Four decades of intense research and development (R&D) efforts have failed to yield any effective interventions for neurodegenerative diseases. The lack of success in the search for a drug to improve the devastating symptoms of these chronic brain disorders has been one of modern medicine's greatest frustrations with a failure rate of nearly 99.6 % as compared with about 20% success rate for cancer drugs. This situation has already precipitated the strategic decision of some pharmaceutical research companies to terminate their R&D efforts on AD; thus, triggering the worries that others may opt to close down their therapy development operations, as well.

Consumers' annoyance with snail's pace of therapy development for AD is well founded. This impatience boils down to the timely question of "where is the beef"? The field of R&D on treatments for AD is now confronting a "situation," that is, in the words of Theodore Herzl, "critical but not serious."

This mounting urgency for more effective interventions prompts me to shed some light on the nature of the problem. A truly satisfactory answer will require a detailed explanation of how we arrived at the current state of affairs. Here I will highlight some of the critical historical events in the evolution of the present situation, along with the reasons for the current difficulties in this field.

The crucial dilemma of the primary care physician (PCP) in treating the patient with AD stems from the uncertainty of how to tackle such questions like: What are the options for treatments now? What are the appropriate interventions, among those currently available, for particular patients with dementia in my office today? The intent of the narrative here is to describe the detailed circumstances that led to of the current situation; my hope is to improve the understanding of the complete scope of the quandary. Hence the questions: How did we get here? What were the early barriers in the drive to find cures for AD?

The formal campaign against AD began in 1978 at the National Institute on Aging (NIA) within the National Institutes of Health (NIH). From the beginning, the launch of this project faced several overwhelming challenges. Among these, the most difficult initial ordeal was the struggle to gain the acceptance of the medical-scientific community regarding the idea that "systematic studies of AD" is a legitimate topic of research at NIH.

In the late 1970s, the conventional wisdom, associated with best-practices in medicine, regarded AD as a hopeless and untreatable condition. The prevailing theory considered "senility" an ill-defined fuzzy concept as the primary cause of dementia. Thus, the notion that "AD is an inevitable consequence of aging" was the firmly established doctrine, which was widely accepted without any questioning. This pervasive dogma was the basis for the widespread pessimism on the utility of treating the "old," including AD -- i.e., "Why bother to intervene, it is only aging?"

Hence, the lack of knowledge on clear distinctions between the biology "of aging" and the precise molecular underpinnings of the "disease" was a major handicap that impeded the pace of progress. Unfortunately, the needs for more accurate definitions and precise distinctions between "aging" and "disease" (e.g., AD), along with the lingering vestiges of the myths, remain as barriers to surmount. At the present one of the major challenges for therapy development is the ongoing works to explain the exact biological links between the phenomena of aging and AD.

A little-known or often ignored historical fact is that 40 years ago, the national expenditures for research on aging and AD were virtually zero. These topics, as problems to be studied, generated little interest in academic research, except for a handful of investigators. Until the late 1980s, the clinical infrastructures essential for systematic longitudinal or clinical studies of well-characterized AD patients were not available. In the early 1990s, the concepts of "cure" and "prevention" were inconceivable. Crucial clinical tools such as diagnostic criteria, standardized assessment instruments, cadres of specialized professionals, memory disorder clinics, family support groups, or outreach programs did not exist, even though all these tools are taken for granted now.

Although research on brain disorders has a long history, the current profusion of knowledge on the neurobiology of complex chronic brain disorders (e.g., dementia and AD) was only recently acquired. Perhaps up to 90% of current knowledge about the human brain was acquired during the last 40 years. Yet only 30 years ago information on genes and/or biologic pathways involved in the development of the disease was limited at best. Twenty years ago, animal models of the disease did not exist. At that time, persons at high risk for the disease could not be identified, and the idea of clinical trials for prevention or for delaying symptoms was only a pipe dream.

In contrast, today a number of genes along with an array of possible risk factors, including several susceptibility genes involved in the expression of AD, have been identified. The hallmark brain lesions, as well as several biomarkers associated with the disease which could not be directly visualized in patients until 2004, can now be detected with emerging neuroimaging technologies in asymptomatic people in the very early stages of the disease.

In short, nearly a quarter of a century was required for the radical transformation of the myths on dementia. For example, the groundbreaking discoveries, that healthy aging nerve cells are capable of repair-regenerate and that Alzheimer is a "disease" due to degenerating neurons, were essential in the struggle to change the long-established thinking on "aging brain." This type of bit-by-bit construction of a strong scientific foundation, including the "critical-mass" of knowledge and infrastructure, was a vital step necessary for building the national R&D capabilities in the initial phase of the campaign.

The advances, in the early phases of understanding the distinct mechanisms in the biology of aging and the neurodegeneration dementia, during the last three decades propelled this area of research from obscurity to the forefront of modern biomedical science.

During this early period of scientific maturation of the field, we learned how neurochemistry plays a crucial role in neuron-to-neuron communications and how changes in this intricate signaling system of the brain affects the expression of symptoms. We have also uncovered many of facts regarding the genetics, synthesis, degradation, aggregation, toxicity, folding, and clearance of abnormal proteins involved in the pathogenesis. These two broad areas of research; one concerning communication between nerve cells and, the other on protein synthesis degradation; have provided the biological foundation and mechanistic rationale for the drug-discovery/therapy-development paradigms that have been used up to now.

This brief accounting highlights some of the achievements, along with several hurdles, on the road to the development of the first round of treatments by mid-1990s. At the time, in light of the fact that AD was considered an incurable condition, the FDA approval of these medications was a victory, although it proved to be a minor triumph due to a short duration of clinical benefits.

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Now, let us discuss the limitations of current drugs in use, and the difficulties facing the second wave of achievements in order to discover more effective and lasting interventions. Thus, these questions remain: Why current treatments are not satisfactory? Why have the attempts to develop more satisfactory therapies failed? What are the barriers to more positive outcomes? What are the prospects for success?

Until recently the primary therapeutic intent of the first generation of treatments was to achieve symptomatic relief, namely to slow down the cognitive decline functions and ameliorate other problematic signs of the disease. The general scientific rationale for this approach to therapy development was based on the overall notion of enhancing the functions of cell-to-cell communication by replacing a missing chemical -- a neurotransmitter, e.g., acetylcholine. The basic idea of "replacement" therapy has been a widely used strategy in developing treatments for a range of neuropsychiatric disorders. This approach, which began to gain some traction in the late 1980s, initially proved to be promising for treating AD and eventually led to the development of the two classes of drugs that are currently approved drugs.

Unfortunately, it turned out that these first-generation medications are not completely satisfactory particularly due to their relatively brief utility, 6-24 months for symptomatic relief. The primary reason for this short-term duration of benefits of these compounds is not due to shortcomings of the actual drugs, but rather it is the result of the progressive deterioration of the neurons that are intended to profit from this type of intervention. This means if we could find the ways of formulating different compounds that preserve healthy functioning of the neurons (e.g., promoting regeneration-repair of nerve cells), the first-generation treatments in current use will continue to show some benefits. Thus, a distinctly different approach is needed to slow the progression of the disease by a correct separate aspect of neurodegenerative process that goes beyond the loss of communication between neurons.

The distinct therapeutic intent of second-generation of drug discover-development was not only symptomatic relief but also to prevent or slow down neurodegeneration. The generic strategy is to block or to moderate the toxicity of either endogenous or exogenous agent that kills the neuron. This approach, which has been the general underlying logic for most of the recent treatment trials, is aimed at altering or slowing "disease progress" by controlling the synthesis or aggregation of "toxic" or abnormal proteins (e.g., amyloid, tau).

Unfortunately, despite its universal popularity due to a compelling logic for its scientific underpinnings, this line of attack has had a nearly 25-year record of sequential failures in efficacy trials. The rationale of searching for medication that would maintain or promote the normal and healthy functioning of neurons is sound and many scientists are still hopeful that some of the ongoing clinical trials may yet work. However, a growing number of researchers are now beginning to consider alternative approaches to solving the puzzle of AD.

Circling back to the fundamental grounds of this essay, the key questions are:

When will the impressive scientific findings, resulting from 40-years of massive investments in R&D, finally yield lasting treatment?

What are the reasons for the string of successive failures in clinical trials?

Where do we go from here, based on emerging new knowledge on AD?

What is next?

These sobering concerns prodded the ongoing formal re-assessments of all conceivable reasons for the disappointing results of recent clinical trials. An array of plausible explanations has been unveiled for the failure of some particular trials. For example, an efficacy study might be terminated due to drug safety concerns, or un-acceptable tolerance, or the numbers of adverse events. Other reasons for failure might be the wrong "something" such as: a molecule or therapeutic target, trial design, subjects, stage of the disease, dosage, or duration of treatment-trial, etc. The most significant outcome of evaluating these reasons for failures is the growing recognition that long-cherished theories or assumptions about the origins of AD might not be adequate. Therefore, it will be necessary to re-assess all known facts about the disease with the aim of reformulating current theories or creating a novel unifying model that will incorporate all known facts resulting in new knowledge.

In the history of science, the thorniest challenge has always been the task of questioning the conventional wisdom (i.e., prevailing "scientific orthodoxy"); for example, examining the inadequacies of existing ideas in a field of study, e.g., the biology of the disease. This task of modifying "belief-system" or abandoning a "scientific ideology" in favor of new thinking on therapies for AD will be a very tall order for medicine. It will be comparable to a maneuver as difficult as steering a super-tanker in treacherous waters. Yet, the task of unbiased evaluation of different paradigms or radically new approaches in drug R&D is an essential step towards the solution of the problem.

Such impartial stocktaking of all current theories or ideas about AD, which is an ongoing work-in-progress, has begun to single out the vital new challenges the field must tackle. These evolving facts have begun to shed light on some of the limitation of current treatments, as well as a few of the reasons for the failures of recent trials. Thus, the reformulation of any prospective "unifying" theory or novel R&D paradigm for therapy development must incorporate this emerging knowledge about the clinical features of the disease and its biology. The new understanding of the disease will not only have a significant impact on devising alternative approaches to discovery-development of treatments but also influence how PCPs might approach the clinical assessment of patients at the potential risks for the disease.

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The following brief primer highlights some of the evolving knowledge about the distinct feature of the disease that will change future approaches R&D on treatments and also provide some useful new information to the PCP in their interactions with AD patients.

One important new fact about AD is that it is an assorted clinical entity (aka heterogeneous condition), which means there is enormous variation among people with the disease in terms of the types and patterns of clinical [behavioral] and neuropathological features of the disease. Also, there are large differences in the: ages of onset, family history, genetic, risks, lifestyle, and other co-morbid conditions. This characteristic of the disease explains some of the difficulties in clinical studies and provides a possible reason for the failure of some clinical trials; for example, differences in responses to treatment among patients. The significance of this piece of information is to increase PCPs' awareness that "one-size does not fit all" and, thereby emphasizing the need for focusing on more individualized assessment and case management.

Another important new finding about the disease is that the notion of a single etiologic factor triggering the disease is no longer valid. It turns out that the disease has polygenic etiology. This means we are dealing with a complex brain disorder which represents the culmination of intricate connections among multiple pathogenic factors. The complexity of the underlying biology of AD explains not only the failure of some trials in the past but also indicates the need for novel drug development paradigms that take into account the prospects of testing multiple therapeutic targets or agents. Such radical changes in clinical trial design and execution, based on the complexity of the disease, will require better understanding of the relationships among the multiple biological processes. This represents one of the grand challenges for future R&D on therapies.

The third significant feature of AD is that presently the exact starting point of the neurodegenerations is unknown. However, recent finds have shown that an asymptomatic or preclinical stage may actually precede by nearly two decades the next stages known as, mild cognitive disorder [MCI], mild, moderate, and severe phases of the disease. These details on the prolonged intricate mechanisms in progression of neurodegeneration will have profound impact on the design of future clinical trials and also on the day to day operations of a PCP who now must pay more careful attention to the complaints of older or at-risk patients' subjective feelings of memory loss. These new findings now indicate the need to re-engineer therapy development to start the intervention at earlier stages, perhaps in the pre-clinical phase, in order to be effective.

The final area of new information, with important ramification for the design of future clinical studies, as well as PCP practices, is the discovery of a number of risk factors that have shown strong associations with the expression of AD. These predisposing factors include several potential susceptibility genes (e.g., ApoE), lifestyle and some co-morbid conditions such as CVD, diabetes, hypertension, obesity, etc. The underlying biological mechanisms of how these risk factors play a critical role in the expression of the disease is not known yet. However, these preliminary findings have begun to provide some promising potential strategies for reducing the risks AD.

In conclusion, the good news for the PCP is that some novel strategies are being tested in ongoing trials for early interventions. For example, emerging evidence from ongoing studies has shown that nonpharmacological multidomain interventions have some significant beneficial effects such as reducing the decline in cognitive function or delaying the onset of disabling symptoms. These multidomain interventions, as the name implies, require changes in the "behavior habits" of patients in several aspects of their lifestyle, e.g., diets, physical, and mental exercises. These studies also have found that management of comorbid or known risk factors, e.g., vascular disorders, diabetes, hypertension, obesity, etc., have beneficial effects.

Once these preliminary findings are further validated by larger and prospective prevention trials, PCPs will have a number of treatment options based on new applications of safe drugs approved for other diseases such as stroke, CVD, hypertension, etc. Although the physician may still have concerns or questions about the current choices of treatments beyond the two classes of drugs approved for patients in the later stages of the disease (e.g., moderate-severe), hopefully, there will soon be other options for consideration.

The campaign to find a cure for a little-known brain disorder started 40 years ago. It was essentially fueled by optimism even though the battle was considered a hopeless fool's errand.

Now the idea of developing interventions to prevent AD is once again deemed to be an impossible dream. But, I remain as optimistic as I was four decades ago about the prospects of winning this renewed crusade.

Zaven S. Khachaturian, PhD, is former director of the Office of Alzheimer Research at NIH, where he was responsible for coordinating all AD-related activities. Now he serves as editor-in-chief of Alzheimer's & Dementia, one of the most prominent journals in neurology. He also serves as senior advisor to the Alzheimer's Association on medical-scientific affairs.