Alzheimer’s disease is a debilitating neurological condition characterized by a progressive loss of near-term memory, and has proven surprisingly resistant to treatments. Histologically the disease is characterized by the presence in the brain, of misfolded protein deposits, including amyloid plaques and tau tangles. A definitive diagnosis of the disease can only be made post-mortem. Today, guidelines proposed by the National Institutes of Aging and the Alzheimer’s Association, favor the A/T/N criteria. To be considered on the Alzheimer’s Continuum, a patient must have both A+ and T+, i.e. evidence must exist for both pathological amyloid deposits and pathological deposits. In addition, N+, i.e. neuropsychological or cognitive measures may also be present, but it is recognized that the deposition of pathological amyloid and tau precede the onset of neuropsychological symptoms by many years. An early diagnosis of the disease in the pre-symptomatic, or prodromal stage, is therefore critical for the development of early interventions.
Amyloid and tau measurements in the brain can be done by direct imaging methods, using PET ligands, or by indirect means by measuring CSF or serum biomarkers. While imaging methods provide a higher level of confidence in the diagnosis, they are extremely expensive ($12-24,000 per patient) and are not reimbursed. Additionally, the poor availability and distributability of PET ligands makes the technique only available in large academic medical centers.
Over the last 8 years,to address these challenges we have developed ADx a novel MRI imaging platform for molecular imaging, initially focusing on amyloid plaque imaging. By virtue of being an MRI agent, ADx is an order of magnitude cheaper PET, and is easy to distribute worldwide. We have demonstrated in mouse models of the disease that these particles, injected i.v., transport from the blood to the brain, and successfully label 95+% of amyloid plaques, and enable visualization by MRI with practically 100% accuracy. Toxicological testing in several species demonstrates safety of the material and method. This technology has been licensed, and will be in clinical trials in 2020.
More recently, we have investigated the application of this technology to tau imaging. The formation of pathological tau tangles is an intracellular process, unlike amyloid deposition which is an extracellular process. Therefore, we have investigated an extracellular surrogate for intracellular tau, using a black-box aptamer screen against neuronal cells in a hyperphosphorylative state: a precursor of tau pathology. Binding the hits to cell membrane proteins and analyzing the proteomic profile has led to the identification of these surrogate markers. MRI visible nanoparticles targeted using the aptamer hits, injected i.v. in mouse models of tau pathology, are able to bind pathological neurons and identify future tau pathology with high accuracy. This technology has also been licensed, and is in development for clinical trials in the near future.
A summary of the last 8 years of work and the current state of the art will be presented.
Funding: This work was funded by a grant from the National Institute of Aging: R44AG051292, and research contracts with Alzeca Inc. SRA-1, SRA-2 and SRA-3. The speaker is also funded by NIH grants R01HD094347 and U01DE028233.
Declaration of Conflicts of Interest: The speaker is a founder, shareholder, board member and scientific advisory board member of Alzeca Inc., a sponsor of this research.