Alzheimer Disease Pathogenesis: The Role of Autoimmunity

Abstract

Background In addition to deposits of amyloid β (Aβ) plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. The recent failures of clinical trials based on the amyloid hypothesis and the presence of Aβ plaques in cognitively healthy elderly persons without AD point toward a need to explore novel pathobiological mechanisms of AD. Content In the search for alternative AD mechanisms, numerous genome-wide association studies and mechanistic discoveries suggest a potential immunologic component of the disease. However, new experimental tools are needed to uncover these immunogenic components. The current methods, such as ELISAs or protein microarrays, have limitations of low throughput and/or sensitivity and specificity. In this article, we briefly discuss evidence of potential autoimmune contributions to AD pathobiology, describe the current methods for identifying autoantibodies in patient fluids, and outline our own efforts to develop new techniques for novel autoantibody biomarker discovery. Summary Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy. Impact Statement In addition to deposits of amyloid β plaques and neurofibrillary tangles, growing evidence demonstrates that complex and multifaceted biological processes can arise during Alzheimer disease (AD) pathogenesis. Numerous research directions, including genome-wide association, clinical correlation, and mechanistic studies, have pointed to a potential autoimmunologic contribution to AD pathology. We present research suggesting the association between autoimmunity and AD and demonstrate the need for new laboratory techniques to further characterize potential brain antigen-specific autoantibodies. Uncovering the putative autoimmune components of AD may be crucial in paving the way to new concepts for pathogenesis, diagnosis, and therapy.

A combination of multiple autoantibodies is associated with the risk of Alzheimer’s disease and cognitive impairment

“…Therefore, it is speculated that ATCAY-like brain specific proteins may be newly exposed to the blood immune system due to BBB breakdown, generating autoantibodies in the AD pathogenesis 44 . There are a growing number of literatures indicating that natural autoantibodies play a protective or pathogenic role in the pathogenesis of neurodegenerative diseases including AD 47 , 48 . Our results suggest that autoantibody repertoires are changing in the AD pathogenesis, supporting that AD is a autoantibody-related autoimmune disorder.…”

Multiomics Profiling of Alzheimer’s Disease Serum for the Identification of Autoantibody Biomarkers

“…This could be due to differences between the operating procedures followed for each array and the IP experiment, and between the screened samples (serum pools vs individual sera), suggesting that different methodologies should be simultaneously tried to detect for autoantibody targets. In addition, due to the absence of the overlap of the identified antigens targeted by AD autoantibodies between the methodologies and with previously identified AD autoantibodies in other reports, 19,23,25,60 it cannot be discarded that a fraction of the autoantibodies not further validated by ELISA or Halotag-based bead immunoassay might be rare or personalized autoantibodies with limited diagnostic ability of the disease. Although the validation of the screening phase results using PrEST suspension bead arrays showed that the multiomics approach using planar arrays and MS-based methods increased the number of identified reactive antigens, alternative experiments using native antigens were also performed for a more comprehensive of the targets identified by the IP-MS/ MS approach.…”

“…This could be due to differences between the operating procedures followed for each array and the IP experiment, and between the screened samples (serum pools vs individual sera), suggesting that different methodologies should be simultaneously tried to detect for autoantibody targets. In addition, due to the absence of the overlap of the identified antigens targeted by AD autoantibodies between the methodologies and with previously identified AD autoantibodies in other reports, ,,, it cannot be discarded that a fraction of the autoantibodies not further validated by ELISA or Halotag-based bead immunoassay might be rare or personalized autoantibodies with limited diagnostic ability of the disease.…”

“…Remarkably, plasma and serum autoantibodies have been successfully used as blood-based biomarkers for the detection of a range of diseases before the development of clinical symptoms, including different cancer types, , osteoarthritis, or neurodegenerative diseases as Parkinson’s disease or AD, due to tissue degeneration and the subsequent activation of the immune system. − As autoantibodies are stable circulating proteins that can be easily detected and measured in serum and plasma, either autoantibodies or their target proteins (autoantigens) are good candidates as AD biomarkers. , …”

Multi-Modal Neuroimaging Neural Network-Based Feature Detection for Diagnosis of Alzheimer’s Disease

“…Alzheimer’s disease (AD) is a neurodegenerative brain disease that leads to the damage and death of brain nerve cells in disease progression. It destroys people’s memory, learning, language, cognition, life, and other abilities, and seriously affects the quality of life of patients and families ( Zhang and Wang, 2015 ; Lam et al, 2021 ; Lim et al, 2021 ). AD risk is also greater later in life for people with cardiovascular disease, high blood pressure, and diabetes.…”