Today, the urgency to successfully develop effective interventions for neurodegenerative disorders/dementia/Alzheimer's disease (AD) is greater than ever. However, this compelling global public health dilemma faces three critical challenges that need to be surmounted in order to accelerate the discovery and testing of disease-modifying treatments.
The three major impediments to the national strategic goal of delaying or preventing the progression of neurodegeneration include:
- Untangling the "complexity" of neurodegenerative disorders, and understanding the intricate relationships among multiple causative factors and risk factors to account for their respective roles
- Developing new knowledge/criteria/algorithms/technologies for early detection of those at risk for the disease, before the onset of symptoms
- Improving the efficiency (e.g., reducing the cost and duration of clinical trials) and facilitating the recruitment of volunteers for clinical studies
A Heterogeneous Disease
As progress is being made in understanding Alzheimer's disease, there is growing recognition that we are dealing with a very complex neurological disorder.
The "disease" -- which some consider a "syndrome" -- has multifaceted clinical and biological characteristics due to the involvement of a large number of genes and multiple potential risk factors. The intricate details of the interactions among variables such as genes, risk factors, and lifestyle that play a role in the genesis of the disease is yet to be sorted out.
Now it appears that Alzheimer's may not be a single disease, but rather a "heterogeneous" condition with differing patterns of expression. This means the disorder (or syndrome) has different forms, where individuals may differ in their age of onset, behavioral-clinical profile, neuropathology, family history, genetics, risk factors, lifestyle, and other comorbid conditions.
Although the age for the onset of symptoms varies in the different disease forms, these all share a common feature -- a lengthy neurodegenerative process that includes a prolonged phase of several years without any signs or symptoms.
This "stage" of the disease is known as the "prodromal" or pre-clinical phase. We do not yet know exactly when and how the prodromal aspects of the disease start. Nevertheless, this discovery that the disease has a long, clinically silent stage has begun to define the new frontier for the discovery of cures.
Until recently, the primary focus of therapy development efforts was the alleviation of symptoms in later stages of the disease, after the onset of symptoms. But now these efforts are being s, before any signs of brain deterioration are noticed.
But before a full-scale effort to attack the disease in earlier stages can be launched, one major challenge has to be addressed -- namely, the development of tools for early identification of people at elevated risk.
Untangling Complexity
The recent string of disappointments in treatment studies are giving further credence to the growing recognition that there are major gaps in understanding the biology of Alzheimer's disease.
Until recently, the key strategies for customary paradigms of treatment have focused on modulating a presumed pathobiology mechanism. These approaches to therapy development, essentially derived from current ideas on models of etiology, unfortunately have not yet yielded any effective treatments.
One example is the failure of existing knowledge on pathogenesis to provide a complete account for the "cause-effect" relationships between the clinical features and biological phenotypes of the "disease." Therefore, it is very likely that the present notions on the pathogenesis of Alzheimer's dementia, which provide the mechanistic rationale for typical models of drug discovery-development, may not be sufficient.
This breakdown in treatment strategies, based on current ideas, indicates the need to examine the problem from a different perspective. The challenge of bringing about a quantum shift in current approaches to therapy development will require the adoption of radically different concepts on pathogenesis.
To address this problem, we at the journal Alzheimer's & Dementia have . The ultimate goal of the journal is to establish a platform for systematically considering the relative merits of different conceptual models of dementia.
The expectation is that such a formal process for critical analysis of major pathogenic concepts in our field that currently drive therapeutic development will help to broaden the spectrum of therapeutic targets and introduce new paradigms for drug development. A series of Workgroups have been assembled to re-assess all major ideas and theories on the condition.
In the research arena there are two related developments that are critical to addressing the problem of disease complexity.
First, there is a growing interest in the field to import concepts and ideas from "Complexity Science" and the application of "Systems Theory" or "Systems Biology" into the discovery and development of new therapeutic targets.
Then there is the use of the epigenome to understand the complex interactions among causative genes and putative risk factors. In recent years, through epidemiological and biomarker studies, a large number of potential risk factors have been identified. Results from major studies now explain in greater detail the relationship among neurobiological mechanisms that underlie various risk factors associated with dementia.
These landmark studies show the utility of epigenomic analysis for not only explaining the complexity of dementia, but they may also provide the necessary tools for early detection of people at risk by more detailed analysis of risk factors.
Early Detection
The importance of detecting cognitively asymptomatic stages of AD pathology is a key preliminary step for any prevention trial. Current endeavors for the detection of incipient AD pathology and, even more importantly, the accurate prediction of whether it will lead to cognitive decline, have had mixed success.
Now there is a striving toward the establishment of a clinically meaningful and scientifically sound framework for defining and characterizing the initial stages of Alzheimer's from the first speck of amyloid deposition to the onset of consequential cognitive impairment.
The discussion above regarding epigenetics has important implications for identifying and validating potential new biomarkers of the disease in early stages.
Improving Trial Efficiency
There are two ongoing initiatives to address this problem. One initiative is designed to address the crisis in patient recruitment. You can read more about this effort in this .
A second initiative is the formation of a centralized institutional review board (IRB) for clinical trials, known as the National Biomedical Research Ethics Council (NBREC). In response to the National Alzheimer's Project Act and an NIH mandate, NBREC and the highly reputable Schulman IRB have forged an innovative alliance for Alzheimer's clinical research that aims to improve research volunteer participation in Alzheimer's disease trials by enhancing research participant safety, increasing efficiencies in the conduct of large-scale, multi-site trials, and serving as an international model for trans-national interventional studies of Alzheimer's, dementia, and other neurodegenerative diseases.
Specifically, this alliance provides a significant innovation for centralized IRB requirements by enhancing the regulatory ethics review requirement with the addition of an expert scientific review committee (SRC). The addition of the SRC will provide early identification of potential areas of improvement in study design that will minimize study delays and the need for costly protocol amendments.
Ara Khachaturian, PhD, is the Executive Editor and Zaven Khachaturian, PhD, is the Editor-in-Chief of Alzheimer's & Dementia, the journal of the Alzheimer's Association.