Immunogenomics Parameters for Patient Stratification in Alzheimer’s Disease

Article type: Research Article

Authors: Huda, Taha I.^a | Diaz, Michael J.^a | Gozlan, Etienne C.^a | Chobrutskiy, Andrea^b | Chobrutskiy, Boris I.^c | Blanck, George^{a; d; *}

Affiliations: [a] Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA | [b] Department of Pediatrics, Oregon Health and Science University Hospital, Portland, OR, USA | [c] Department of Internal Medicine, Oregon Health and Science University Hospital, Portland, OR, USA | [d] Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

Correspondence: [*] Correspondence to: George Blanck, 12901 Bruce B. Downs Bd. MDC7, Tampa, FL 33612, USA. Tel.: +1 813 974 9585; E-mail: gblanck@usf.edu.

Abstract: Background:Despite the fact that only modest adaptive immune system related approaches to treating Alzheimer’s disease (AD) are available, an immunogenomics approach to the study of AD has not yet substantially advanced. Objective:Thus, we sought to better understand adaptive immune receptor chemical features in the AD setting. Methods:We characterized T-cell receptor alpha (TRA) complementarity determining region-3 (CDR3) physicochemical features and identified TRA CDR3 homology groups, represented by TRA recombination reads extracted from 2,665 AD-related, blood- and brain-derived exome files. Results:We found that a higher isoelectric value for the brain TRA CDR3s was associated with a higher (clinically worse) Braak stage and that a number of TRA CDR3 chemical homology groups, in particular representing bloodborne TRA CDR3s, were associated with higher or lower Braak stages. Lastly, greater chemical complementarity of both blood- and brain-derived TRA CDR3s and tau, based on a recently described CDR3-candidate antigen chemical complementarity scoring process (https://adaptivematch.com), was associated with higher Braak stages. Conclusion:Overall, the data reported here raise the questions of (a) whether progression of AD is facilitated by the adaptive immune response to tau; and (b) whether assessment of such an anti-tau immune response could potentially serve as a basis for adaptive immune receptor related, AD risk stratification?

Keywords: Alzheimer’s Disease Sequencing Project (ADSP), Braak stages, blood and brain sample exomes, CDR3-tau chemical complementarity, T-cell receptor recombination reads

DOI: 10.3233/JAD-220119

Journal: Journal of Alzheimer's Disease, vol. 88, no. 2, pp. 619-629, 2022