A new era for Alzheimer's research
By: Olga Uspenskaya-Cadoz, MD, PhD | December 17, 2015
Alzheimer’s Disease (AD) continues to have a devastating toll around the world. Worldwide, approximately 44 million people have dementia, AD being its most frequent cause. Yet only one-in-four people with the disease have been correctly diagnosed. This is large part due to the fact that until relatively recently, the diagnosis of probable AD could be established only at dementia stage, whereas the definite diagnosis could be certified only by post-mortem brain examination. This lack of diagnosis meant patients with AD couldn’t begin to be treated until after they show noticeable signs of dementia, and even then a “probable diagnosis” of AD could only be concluded after all other potential causes of dementia were eliminated. This created a significant barrier to research, as drugs couldn’t be developed to treat patients in the prodromal phase,prior to the appearance of full-blown dementia.
Even for the drugs being developed, patients couldn’t be recruited to trials until their symptoms were fully apparent and by then the damage is already done. Once a patient exhibits symptoms of AD, resulting from the buildup of amyloid beta peptide in the brain and downstream neurodegeneration, those symptoms cannot be fully reversed.
Biomarkers chart new AD research path
This all lead to the recognition that we must find ways to identify AD patients very early in the course of the disease, at prodromal and even pre-symptomatic stage, which is becoming possible. There is growing evidence that biologic processes of AD begin decades before symptoms appear or a clinical diagnosis can occur, and recent discoveries are enabling researchers to identify the biomarkers that indicate AD far earlier in the disease progression. In 2007, an International Working Group (IWG) on AD provided a new conceptual framework on how AD advances, and that it can be recognized through the presence of a specific clinical phenotype with a supportive evidence of biomarkers. It was the first time the presence of biomarkers would be used in the diagnosis of AD, which was a huge step forward for the AD research community. In 2014 the IWG further refined the concept of AD as clinic-biological entity and revised the diagnostic algorithm of typical and atypical AD, and also pre-clinical stage of AD.
The biomarkers of AD can be divided into two groups: the pathophysiological markers, which are mainly identified in positive results of PET amyloid scan or cerebral spinal fluid (CSF) biomarkers of AD (decreased Aβtogether with increased total and phosphorylated Tau protein concentration); and topographical markers helping to identify downstream changes (noted in hippocampal atrophy on volumetric MRI, decreased FDG uptake on FDG PET, etc). Both types of biomarkers support the diagnosis of AD prior to the onset of dementia and integrate biomarkers of Alzheimer’s pathology into the diagnostic framework.
Now that we can measure these biomarkers early in a patient’s disease progression, we can change the way AD research and clinical trials are conducted. This discovery enables researchers to identify and recruit at-risk patients prior to the appearance of dementia, and to pursue development of treatments for secondary and even primary prevention.
New obstacles to address
It is exciting and important step forward for AD research, though it also creates an entirely new set of challenges. Trial designs for drugs to treat prodromal or asymptomatic-at-risk of AD patients will be completely different from those for moderate to severe stage AD sufferers requiring different criteria for patient recruitment, safety surveillance, efficacy and outreach. It is more complicated to identify and recruit patients to these trials as they are showing very early or even no signs of the disease and are thus not working with a physician, connecting with patient advocacy groups, or joining registries – all key tools in a traditional recruitment process. The exclusion rates will also be high as many interested patients will falsely attribute normal forgetfulness to early AD warning signs, and the drop rate will be a challenge as these studies will need to follow patients for multiple years.
It is also important to note that the data around AD diagnosis are still emerging, and verification of the presence of biomarkers, and the reliability, reproducibility and validity of these tests still needs to be concluded for the research to move forward. Even now, the additive value of multiple biomarkers and the challenges of biomarker inconsistency need additional investigation. And though we may be able to identify at-risk high-functioning patients, to date there are no drugs in the market to slow or prevent the onset of the disease.
However projects are under way to move this research forward. The most well-known is the European Prevention of Alzheimer's Disease Consortium (EPAD), which plans to draw thousands of patients from across the EU who have a family history of AD, and funnel them into an adaptive trial where multiple biopharma companies can test and compare drugs in order to streamline the discovery process. Study leaders set the goal to engage 24,000 study candidates who demonstrate biomarkers or other neurocognitive traits for Phase II trials. In addition, several other trials are underway to test therapeutic intervention before the onset of clinical symptoms of AD: the A4 study, the DIAN study, the TOMMORROW study and the EARLY trial.
Even though we still do not have approved drugs curing or preventing AD, the accomplishments in the understanding of the processes underlying AD and AD drug development are significant. We are moving forward in our efforts to diagnose and treat this disease. The cohort studies in asymptomatic and early AD are currently being conducted and will hopefully help to establish links between risk factors and health outcomes in order to develop the correct drugs to efficiently treat AD in well-defined patient populations. Hopefully progress will continue to be made, so that we can help future generations avoid this devastating disease.