Endogenous Human Antibodies Associated with Alzheimer’s Disease

2024

Naturally occurring antibodies (Nabs) in human blood are the front line of defense against a broad range of infectious agents, and antibodies are increasingly useful and important therapeutic agents against human disease. Three antibodies against amyloid beta (Aducanumab, Lecanemab, and Donanemab) are the first disease-modifying drugs for Alzheimer’s disease (AD) that have recently been approved by the FDA and provide proof that targeting amyloid beta is therapeutically beneficial. One of these antibodies, Aducanumab, is a naturally occurring antibody isolated from the blood of an elderly, cognitively normal person. Our goal is to characterize the specificity and binding targets of Nabs associated with human AD. We do this by giving human antibody samples 100 trillion random amino acid sequences and determining what they bind to. We found that the average blood sample contains approximately 4,000 different antibodies, and the spectrum of Nabs is highly individualized and stable over several years. When we compared Nabs in the AD and age-matched cognitively normal populations, we found that approximately 55 antibodies are elevated in the AD population while 900 are elevated in cognitively normal individuals, indicating that the diversity of AD-associated antibodies is dramatically lower in AD. Some of the antibodies target amyloid beta, but the specific binding site is different in the antibodies that are elevated in NC than in AD. Some of the antibodies appear to target normal human proteins, including proteins that have been previously implicated in AD pathogenesis. The overall goal is to test whether these antibodies are useful diagnostic or prognostic tools and to identify novel protective and therapeutic antibodies for AD that may be more effective than the antibodies that are currently approved for human use.

2023

Naturally occurring antibodies in human blood are the front line of defense against a broad range of infectious agents, and antibodies are increasingly useful and important therapeutic agents against human disease. Two antibodies against amyloid beta (aducanumab and lecanemab) are the first disease-modifying drugs for Alzheimer’s disease (AD) that have recently been approved by the U.S. Food and Drug Administration—and they provide proof that targeting amyloid beta is therapeutically beneficial. One of these antibodies, aducanumab, is a naturally occurring antibody isolated from the blood of an elderly cognitively normal person. Although human blood contains hundreds of different antibodies and is 10% by weight antibodies, surprisingly there is very little known about what these antibodies bind to and what the targets of the antibodies are. We have developed a novel and powerful approach to characterize the binding specificity of hundreds, if not thousands, of antibodies in individual human blood samples by using the antibodies to select random peptide sequences from a library containing 3 billion peptides that are 12 amino acids long. Using this information about antibody binding specificity, we determine which antibodies are elevated in the AD and cognitively normal population. Using this approach, we have identified a total of approximately 700 antibodies in the human population that are associated with AD. We also have developed a computer program that predicts the protein targets of the antibodies that bind these specific amino acid sequences. Using this prediction program, we found that the No. 2 ranked protein target in terms of statistical significance is the human amyloid precursor protein, which is the protein from which amyloid beta that is associated with AD is derived. Surprisingly, some of the antibodies appear to target normal human proteins, including proteins that previously have been implicated in AD pathogenesis. The overall goal is to test whether these antibodies are useful diagnostic or prognostic tools, and to identify novel protective and therapeutic antibodies for AD that may be more effective than the antibodies currently approved for human use.