Antibody Signature of Alzheimer’s Disease: Promise of an Early Diagnostic Test

A physician can’t cure what he can’t diagnose. The diagnosis of Alzheimer’s disease is based on the exclusion of several neurological syndromes, rather than directly testing for the disease of interest. This can be an inaccurate exercise in up to 20% of the cases. Promising biomarkers are being developed, such as the cerebrospinal fluid profile of beta amyloid and tau proteins, as well as amyloid imaging with positron-emission tomography. However, these tests are not universally available and have some disadvantages, including the need for a spinal tap or the injection of radioactive material. A plasma biomarker capable of identifying asymptomatic individuals developing Alzheimer’s-type pathology is needed, as they are ideal targets for intervention (i.e., amyloid-binding therapies) to prevent dementia or delay its onset. PSEN-1 mutations cause a predictable onset of mild cognitive dysfunction by age 40, followed by frank dementia a few years later. If characteristic biomarkers accompany different disease stages, these patterns could guide clinicians in the future to decide when to pursue more elaborate tests such a spinal tap and PET scans.  Immunosignaturing, a technology that employs antibody binding to a random-peptide microarray, is capable of generating profiles that distinguish transgenic mice engineered with familial Alzheimer’s disease mutations (APPswe and PSEN1-dE9) from non-transgenic littermates. The signature is distinguishable in transgenic mice as early as 2 months of age and intensifies as animals grow older. Immunosignatures can also distinguish individuals with non-genetic Alzheimer’s disease from non-demented elderly controls. In this project, we will evaluate whether late-stage Alzheimer’s disease patients with presenilin-1 (PSEN-1) mutations have a different signature as compared to young non-demented PSEN-1 carriers. In addition, we will assess the differences between the signature of demented patients with PSEN-1 mutations and elderly Alzheimer’s disease patients without PSEN-1 mutations. We will also investigate whether age-matched individuals without the mutation can be distinguished from asymptomatic carriers. Finally, we will determine if patients with different PSEN-1mutations born and raised in different continents (North America and South America) have similar signatures. This will be a collaborative project between 4 institutions: Arizona State University (Tempe, AZ), Banner Alzheimer’s Institute (Phoenix, AZ), Universidad de Antioquia (Medellin, Columbia) and UCLA Medical Center.