Early Β-Amyloid Accumulation in the Brain Is Associated With Blood T and B Cell Alterations

Abstract

Fast and minimally invasive approaches for early, preclinical diagnosis of neurodegenerative Alzheimer’s disease (AD) are highly anticipated. Evidence of adaptive immune cells responding to cerebral β-amyloidosis, one of the pathological hallmarks of AD, has raised the question of whether immune markers could be used as proxies for β-amyloid accumulation in the brain. Here, we deploy multidimensional mass cytometry combined with unbiased machine learning techniques to immunophenotype peripheral blood mononuclear cells from study participants in cross-sectional and longitudinal cohorts. We show that increases in antigen-experienced T and B cell subpopulations in blood are associated with early accumulation of β-amyloid in still cognitively healthy human brains. Our results suggest that preclinical AD pathology stages are associated with systemic alterations of the adaptive immune system. These β-amyloid-induced immunophenotype changes may be exploited in the future to identify and develop novel diagnostic tools for early AD detection and prediction of clinical outcomes.

Funding Information: This work was supported by grants from the Synapsis Foundation – Alzheimer Research Switzerland ARS (No. 2019-PI06 to R.M.N., C.G., and A.G.), the Swiss National Science Foundation (SNF 33CM30-124111, SNF 320030-125387/1 to C.H.), the Mäxi Foundation (to C.H.) and the Velux Foundation (to L.K.).

Declaration of Interests: T.K. is currently an employee of Biogen, Switzerland; L.K. and V.Tosevski are employees of Roche, Switzerland; C.H. and R.M.N. are members of the board of directors and shareholders of Neurimmune AG, Switzerland; M.T.F. is co-founder and CSO of the Women’s Brain Project.

Ethics Approval Statement: All participants gave written informed consent. The studies were conducted in concordance with the guidelines of the local ethics committee (Kantonale Ethikkommission Zürich) and the Declaration of Helsinki (World Medical Association, 2013). The current analyses were conducted with permission of the ethics committee for further use of data and samples.

Keywords: Alzheimer’s disease, β-amyloid, β-amyloidosis, Mass cytometry, CyTOF, Immunophenotyping, T cells, B cells, TEMRA cells