Identification of potential blood biomarkers for early diagnosis of Alzheimer’s disease through immune landscape analysis

Abstract

Mild cognitive impairment (MCI) is a clinical precursor of Alzheimer’s disease (AD). Recent genetic studies have reported on associations between AD risk genes and immunity. Here, we obtained samples and data from 317 AD, 432 MCI, and 107 cognitively normal (CN) subjects and investigated immune-cell type composition and immune clonal diversity of T-cell receptor (TRA, TRB, TRG, and TRD) and B-cell receptor (IGH, IGK, and IGL) repertoires through bulk RNA sequencing. We found the proportions of plasma cells, γδ T cells, neutrophils, and B cells were significantly different and the diversities of IGH, IGK, and TRA were significantly small with AD progression. We then identified a differentially expressed gene, WDR37, in terms of risk of MCI-to-AD conversion. Our prognosis prediction model using the potential blood-based biomarkers for early AD diagnosis, which combined two immune repertoires (IGK and TRA), WDR37, and clinical information, successfully classified MCI patients into two groups, low and high, in terms of risk of MCI-to-AD conversion (log-rank test P = 2.57e-3). It achieved a concordance index of 0.694 in a discovery cohort and of 0.643 in an independent validation cohort. We believe that further investigation, using larger sample sizes, will lead to practical clinical use in the near future.

The HLA-DRB1*09:01-DQB1*03:03 haplotype is associated with the risk for late-onset Alzheimer’s disease in APOE $${{\varepsilon }}$$4–negative Japanese adults

“…Xu et al previously reported that the diversity of TCR repertoires was significantly lower in samples from AD patients than in samples from CN individuals, as analyzed with single-cell RNA-seq 34 . Our previous study also reported that the diversity of B-cell receptor repertoires (IGH and IGK) and TRA were significantly smaller in people with LOAD progression, using a large number of RNA-seq datasets (> 850 Japanese samples) 35 . These results suggest that the DRB1*09:01-DQB1*03:03 haplotype and the diversity of TCR repertoires could potentially be associated with the onset of LOAD through different mechanisms.…”

Stereotypic persistent B cell receptor clonotypes in Alzheimer’s Disease

“…Briefly, 2 μg of the Aβ42 peptide was coated to the surface of the immunotube with a high binding surface (SPL Life Sciences, 43015) for 16 hours at 4°C, and blocked with 5 ml of 3% bovine serum albumin (BSA) in PBS (w/v). Then the scFv phage library (about 10 13 phages) was incubated for 2 hours at room temperature. During the first round of panning, the tube was washed once with 5 ml of 0.05% (v/v) Tween 20 (Sigma-Aldrich, P1379) in phosphate-buffered saline (PBST).…”

“…B cells play a fundamental role in the adaptive immune system particularly in humoral immunity, by recognizing antigens via membrane-expressed B cell receptors (BCR) and producing antigen-specific immunoglobulin (Ig) in response 12 . Accordingly, recent studies have investigated the differences in immune cell type compositions and the clonal diversity of BCR repertoires among AD patients through single-cell RNA sequencing data or single-cell BCR libraries of peripheral blood mononuclear cells (PBMCs) 5,13 . The results showed that the proportion of B cells and the clonal diversity of both the heavy and kappa () light chains of BCR repertoires all significantly decreased with the progression of AD.…”