I recently returned from the 6th Annual Clinical Trials in Alzheimer's Disease (CTAD) conference in San Diego. At the meeting, I had a chance to catch up on some of the latest scientific advances for the detection and treatment of AD. A recurring theme for improving the diagnosis and prognosis of AD is the increased use of biomarker data. Imaging biomarkers enable earlier detection of the disease state, more accurate patient classification and can provide a better understanding of the mechanisms which contribute to AD.
Early Detection of AD
Clinicians rely on a small handful of biomarkers, including beta amyloid and the cerebrospinal fluid (CSF) markers Ab42 and Tau to define AD risk. A popular model for AD biomarker progression is that amyloid biomarkers precede pathology, occurring while the subject is CN at baseline (determined by neuropsychological and clinical criteria). Incident amyloid positivity has already been shown to be associated with higher rates of brain atrophy in cognitively normal (CN) subjects. Subsequently, patients progress from the presence of amyloid to neurodegeneration (as measured by FDG-PET and structural MRI) and lastly to clinical symptoms of AD.
A primary objective for scientists and clinicians in the fight against AD is to gain the ability to identify Alzheimer's Disease (AD) prior to clinical detection of memory loss and dementia. This would allow the opportunity to detect, diagnose, and even treat AD at a very early stage, improving the likelihood for more successful outcomes.
PET scans using targeted, high-affinity radioactive tracers (e.g. Florbetapir) enable the non-invasive visualization of amyloid in the brain and are being used to identify the first signs of amyloid positivity. This imaging biomarker is becoming an extremely valuable tool for diagnosing preclinical AD and for facilitating enrollment in AD clinical trials. Additionally, there is a resurgence in the use of FDG-PET for assessing regional and global brain glucose metabolism as a marker of neuronal injury.
Multiple Mechanisms to Preclinical AD
To gain clinical insight into early amyloid detection, a recent study compared the cognitive and imaging findings associated with incident amyloid positivity in a large cohort of elderly CN subjects. The study, published last month in journal Neurology, reports two different mechanisms involved in the progression of dementia:
- 'Amyloid-first', in which subjects first manifest amyloid positivity followed by brain atrophy.
- 'Neurodegeneration-first', in which subjects first show signs of brain atrophy (amyloid negative until later in the course of disease). The mechanism for this pathway may involve deregulation of the microtubule stabilizing protein Tau (taopathy).
Evidence for multiple mechanisms in the progression of AD suggests that amyloid positivity by itself is not enough to predict preclinical AD in all patients. To obtain a more complete picture of the disease state, clinicians will likely have to screen and subsequently monitor subjects for more than one biomarker, each of which is tied to a different pathophysiological mechanism.
As we continue to learn more about the mechanisms of AD progression and develop the tools and biomarkers to probe for the earliest signs of AD, we inch closer to the goal of improved diagnosis and treatment for this debilitating disease.
Clifford JR et al. Amyloid-first and neurodegeneration-first profiles characterize incident amyloid PET positivity. Neurology. 2013 Nov 12;81(20):1732-40