CSF-Derived CD4+ T-Cell Diversity Is Reduced in Patients With Alzheimer Clinical Syndrome

Abstract

Background and objectives: Patients with Alzheimer dementia display evidence of amyloid-related neurodegeneration. Our focus was to determine whether such patients also display evidence of a disease-targeting adaptive immune response mediated by CD4⁺ T cells. To test this hypothesis, we evaluated the CSF immune profiles of patients with Alzheimer clinical syndrome (ACS), who display clinically defined dementia.

Methods: Innate and adaptive immune profiles of patients with ACS were measured using multicolor flow cytometry. CSF-derived CD4⁺ and CD8⁺ T-cell receptor repertoire genetics were measured using next-generation sequencing. Brain-specific autoantibody signatures of CSF-derived antibody pools were measured using array technology or ELISA. CSF from similar-age healthy controls (HCs) was used as a comparator cohort.

Results: Innate cells were expanded in the CSF of patients with ACS in comparison to HCs, and innate cell expansion increased with age in the patients with ACS, but not HCs. Despite innate cell expansion in the CSF, the frequency of total CD4⁺ T cells reduced with age in the patients with ACS. T-cell receptor repertoire genetics indicated that T-cell clonal expansion is enhanced, and diversity is reduced in the patients with ACS compared with similar-age HCs.

Discussion: Examination of CSF indicates that CD4⁺ T cell-mediated adaptive immune responses are altered in patients with ACS. Understanding the underlying mechanisms affecting adaptive immunity will help move us toward the goal of slowing cognitive decline.

Figure 1. Innate Cells in the CSF Are Expanded and Positively Correlate With Age in Patients With ACS

(A) The frequency (%) of innate cells in the CSF of 21 patients with ACS was compared with 12 similar-age healthy controls (HCs). (B) Correlation of CSF-derived innate cell frequency with age in the ACS cohort. (C) The relative frequencies of innate cell subtypes in the CSF of an ACS subcohort. CD45⁺ leukocytes that did not express any other lineage markers in the panel were categorized as other leukocytes. The mean ± SEM of each group is provided in panels A and C. Circles indicate HC donors, solid black squares represent CLIA-tested patients with ACS, and solid gray squares represent non–CLIA-tested patients with ACS. ACS = Alzheimer clinical syndrome. *p < 0.05.

Figure 2. CD4+ T Cells in the CSF Negatively Correlate With Age and Display Reduced Diversity Index in Patients With ACS

(A) The frequency of CD4⁺ T cells in the CSF of 21 patients with ACS was compared with 12 similar-age healthy controls (HCs). (B) Correlation of CSF-derived CD4⁺ T-cell frequency with age of the ACS cohort. (C) TCRB diversity indices for CD4⁺ T cells in the ACS population as compared to HCs. (D) TCRB diversity differences for CD8⁺ T cells in the ACS population as compared to HCs. The mean ± SEM of each group is provided below each column of panels A, C, and D. Circles indicate HC donors, solid black squares represent CLIA-tested patients with ACS, and solid gray squares represent non–CLIA-tested patients with ACS. ACS = Alzheimer clinical syndrome; TCRB = T-cell receptor beta.

Figure 3. B-Cell Subset Frequencies in the CSF Are Unaltered in Patients With ACS

The frequencies of (A) CD19⁺ B cells and subsets including (B) naive cells, (C) memory cells, and (D) antibody-producing B cells were comparable. The mean ± SEM of each group and number of samples (n) included are given below each column. Circles indicate HC donors, solid black squares represent CLIA-tested patients with ACS, and solid gray squares represent non–CLIA-tested patients with ACS. ACS = Alzheimer clinical syndrome; HC = healthy control.