Naturally occurring autoantibodies as a biomarker for preclinical Alzheimer`s Disease

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A blood test to identify cognitively unimpaired individuals in a preclinical stage of Alzheimer`s Disease (AD) is desperately needed, but no such test exists. Here we propose experiments to address this unmet need. Specifically, we will measure levels of proteins implicated in the etiology of AD (amyloid-beta and tau), and naturally occurring autoantibodies (nabs) against these proteins. A number of prior studies have investigated the diagnostic utility of nabs against amyloid-beta and tau but these were methodologically compromised and produced variable results. Experimental confounders included problems with patient and control selection criteria and/or the assays used to detect nabs. Importantly, all studies on nabs against amyloid-beta and tau evaluated their levels at only one time-point and there have been no longitudinal studies. Considering the long duration of both the pre-clinical and clinical phases of AD and how distinct forms of nabs may change during these protracted periods it is not surprising that cross-sectional studies have thus far yielded variable and inconclusive results. Mindful of these pitfalls we propose the following interrelated aims to enable measurement of amyloid-beta, tau, and nabs against both proteins in plasma samples from carefully characterized study subjects. We will establish and validate assays to detect both free nabs and such that are bound to their antigen (amyloid-beta and tau). Great care will be taken to include control antibodies and internal standards so as to monitor the sensitivity and reproducibility of our assays. In addition to nabs, free and nabs-bound amyloid-beta and tau proteins in plasma will also be measured. Since plasma levels of amyloid-beta and tau are too low to be reliably detected using standard immunoassays we will use state-of-the-art in-house developed ultra-sensitive assays (single molecule assays). To gain insight on how amyloid-beta, tau, and nabs against both proteins change throughout disease we will apply our well characterized assays to plasma samples from 3 distinct study cohorts. These will include 315 samples that have been collected prospectively every 12 months for at least 4 years from elderly individuals along with a detailed set of clinical and brain imaging data, and 100 samples from 6-65 years old Down Syndrome (DS) subjects. DS is the most common genetic cause of early-onset AD and the great majority of DS adults becomes demented by the end of their 7th decade of life, thus studying samples from different aged DS subjects provides a window on different stages of AD. Dynamic changes of amyloid-beta, tau, and nabs levels in different trajectories (study subjects with no cognitive impairment over time, and patients that develop AD) and different aged DS subjects will be investigated to evaluate their usefulness as a biomarker for preclinical AD.