Naturally occurring autoantibodies as a biomarker for preclinical Alzheimer`s Disease
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
A blood test for Alzheimer`s Disease (AD) is desperately needed, but no such test exists. There are tests today, that can aid diagnosis of AD. These tests are based on the measurement of two central proteins implicated in AD pathology, Aβ and tau. However, such tests either require invasive lumbar puncture to obtain CSF or depend on highly expensive and not widely available imaging techniques. A blood test would be inexpensive, and could easily be done serially for longitudinal monitoring of patients. Here, we focused on the development of ultra-sensitive tests for the measurement of tau in blood. Plasma tau is molecularly complex, and it is not known which forms of tau are elevated in AD. We therefore developed and validated a series of three assays to detect different forms of tau. One assay to detect full-length tau and two distinct assays directed to the N-terminus of tau. Then, we explored whether tau measured with our tests was altered in mild cognitive impairment (AD-MCI), an early stage of AD, and dementia due to AD. One of the assays, that is directed to the N-terminus of tau and which we refer to as NT1, detected higher levels of tau in blood of patients with AD-MCI and AD. In the past years, many blood tests that were reported, did not prove to be reliable. Therefore, we were careful to validate our findings using additional cohorts of patients. We found that plasma levels of NT1 were elevated in AD, and were increased in blood samples taken at a time when a person had AD compared to a timepoint when the same person was cognitively healthy. Recent reports have suggested another neuronal protein, neurofilament light (NfL), as a biomarker for neurodegeneration. Therefore, we also measured NfL in plasma, and found it increased in people who were diagnosed with AD compared to a timepoint when they were healthy. Finally, we analyzed plasma from individuals with Down Syndrome, which are genetically predetermined to develop dementia due to AD. Studying plasma samples from DS individuals at different ages from 3 months up to 68 years showed that both NT1 and NfL are elevated in older people with DS, which is consistent with an increasing occurrence of AD with increasing age in people with DS. Our results suggest that a combination of NT1 and NfL holds promise as a screening test for AD. Further testing of both assays should therefore be vigorously pursued using additional study cohorts.
Publications
- Learnings about the complexity of extracellular tau aid development of a blood-based screen for Alzheimer`s Disease. Alzheimers Dement 2019; 15(3):487-496
Chen, Z., Mengel, D., Keshavan, A., Rissman, R.A., Billinton, A., Perkinton, M., Percival- Alwyn, J., Schultz, A., Properzi, M., Johnson, K., Selkoe, D.J., Sperling, R.A., Patel, P., Zetterberg, H., Galasko, D., Schott, J.M., Walsh, D.
(See online at https://doi.org/10.1016/j.jalz.2018.09.010) - miR-212 and miR-132 are downregulated in neurally-derived plasma exosomes of Alzheimer's patients. Front Neurosci 2019
Cha, D.J., Mengel, D., Mustapic, M., Liu, W., Selkoe, D.J., Kapogiannis, D., Galasko, D., Rissman, R.A., Bennett, D.A., Walsh, D.M.
(See online at https://doi.org/10.3389/fnins.2019.01208)
