Why Alzheimer’s Disease needs to be Identified at the “Pre-Clinical” Stage

“It’s unlikely that any therapy will be effective after the clinical presentation of Alzheimer’s disease. The best chance we have to alter its course is to intervene at earlier stages.” Dr. A. Claudio Cuello

2016 Claudio Cuello Picture

Dr. A. Claudio Cuello holds the Charles E. Frosst Merck Chair in the McGill Department of Pharmacology and Therapeutics. An Associate Member of the Departments of Anatomy and Cell Biology, and Neurology and Neurosurgery at McGill University; adjunct Professor of the Scripps Institute (LaJolla); and Visiting Professor at Oxford University, Dr. Cuello leads CCNA’s Team 2: Inflammation and Nerve Growth Factors.


Alzheimer’s disease develops decades before it can be clinically detected. And by the time it is detected, it’s already too late to change the disease’s course. By then, the brain will have undergone extensive and irreversible damage, Dr. A. Claudio Cuello explains.


Efforts must therefore be directed at getting ahead of the clinical presentation of the disease.  


Attempting to do just that, CCNA’s Team 2, led by Cuello, is using molecules related to inflammation and neuron function to detect and target Alzheimer’s disease before the physical symptoms begin to appear. Theirs is a research area known as “pre-clinical Alzheimer’s disease.”


Encouraging preliminary findings led the team to focus on the role that inflammation plays in advancing pre-clinical Alzheimer’s disease to clinical Alzheimer’s disease. Specifically, they identified a type of inflammation that emerges just before plaque begins to form in the brain. That is significant because this “very early pre-inflammatory process” marks a time when many toxic molecules are released – making neurons sick – and impairing cell-to-cell signaling in the brain. At later brain stages the amyloid plaques give rise to an overt inflammatory and immunity reaction.


In their mouse and rat models, the team has found that “if you apply anti-inflammatories at the pre-inflammatory stage, you delay the progression of Alzheimer’s disease,” Cuello explains.


One advantage of using these animal models is that they allow dementia researchers to test potential candidates for diagnosis and treatment at the earliest stages of Alzheimer’s disease (AD), as they reveal the progression of the disease course in a predictable way. Because the team uses “transgenic models,” the brain genes have been modified so that they will replicate key essential components of the amyloid pathology just like in humans with AD.


Of course, the value of anti-inflammatory molecules must ultimately be measured in human trials. In fact, this is being taken up by Cuello’s colleague, Dr. John Breitner. The lab is comparing the early, inflammation-related, changes observed in the animal models with those in post-mortem human brains, to reconstruct the early, “disease-aggravating” inflammation in the continuum of the AD pathology.  Dovetailing, Dr. Rosa Neto’s lab aims to identify this early inflammatory process in vivo with imaging rat transgenic models and in the human.


The Cuello lab has also made progress in identifying biomarkers in the blood samples of people with Down’s syndrome who eventually develop AD. Working with researchers based in Italy, the team has shown that, in the transition between Down’s syndrome and Down’s syndrome plus AD pathology, there are key inflammatory and nerve growth factor (NGF) metabolism markers in one’s plasma that anticipate cognitive deterioration leading to clinical AD. Likewise, Cuello’s colleague, Dr. Fahnestock has revealed that the Alzheimer’s pathology is accompanied by a compromise in the synthesis of another trophic factor: BDNF (brain-derived neurotrophic factor).


To date, the team has supported the CCNA in:

  • Gathering evidence that inflammation is a marker for the early detection of AD, using non-invasive imaging techniques;


  • Validating the presence of an inflammatory process in “pre-clinical AD” using genetically altered animal models; and


  • Identifying new early biomarkers related to inflammation.


Building on this progress, Team 2 will apply the early biomarkers they’ve identified to attempt to detect early signs of AD in human body fluids. For this, they will draw on data from CCNA’s clinical cohorts to monitor inflammatory markers in the cerebrospinal fluid (CSF) and plasma of early-stage AD adults (who are still scoring well on cognitive tests), and adults who have clinical AD. These individuals have been targeted, because – by working with them – the team will learn how effective their plasma, CSF and imaging markers are at predicting AD in humans in its earliest stages.


At the same time, the team will continue to monitor inflammation in their animal models throughout the course of AD’s progression.


Taken together, Team 2’s project paves the way for future preventative strategies to monitor the progression of AD; monitor the effectiveness of the therapies that are developed to target AD in its early days; and, perhaps one day, even prevent pre-clinical AD from advancing to clinical AD. This approach is based on the hard-won assumption that in order to develop effective treatment methods for AD, one must first fully understand what’s going on in the brain at the pre-clinical level.


In Dr. Cuello’s words, “nothing in the clinic will move unless we create the conditions for it through basic science, and that’s what we’re trying to do.”


To learn more about Dr. A. Claudio Cuello’s team and his research lab, click here.