Evidence for Reduced Somatic T‐Cell Receptor Sequence Diversity Profiles Among Midwestern Amish in an Aging Cohort Study

BACKGROUND: The causes of late onset Alzheimer disease (LOAD) are not known but several recent lines of evidence implicate the adaptive immune system. OBJECTIVE: To characterize the adaptive immune system among Midwestern Amish participating in longitudinal studies of aging. METHODS: We immunosequenced the T-cell receptor (TCR) beta chain from genomic DNA of 72 participants, including those with clinically diagnosed LOAD (n = 6), mild cognitive impairment (MCI; n = 16), cognitive impairment but not AD (n = 3), and 35 cognitively unaffected. For a subset of participants, LOAD pathogenesis plasma biomarkers were available. RESULTS: TCR sequence diversity measured as Simpson's clonality was lower among LOAD+MCI compared with non-LOAD, but these differences were not independent of age. Relatively few clonotypes (exact nucleotide sequences) were shared across participants; of those few shared include the Epstein Barr virus associated clonotype. HLA-A*03:01 and several HLA-DRB1 alleles were under-represented among LOAD+MCI participants compared with cognitively unaffected participants, but these associations were no longer significant in adjusted analyses. Among LOAD+MCI participants, increased p-tau181 was nominally associated with decreased TCR sequence diversity, and the nominal association was independent of age; however, this association did not remain statistically significant after strict correction for multiple testing and the limited sample size precluded formal tests of heterogeneity. RESULTS: In this limited Midwestern Amish sample, the preliminary TCR diversity trends are consistent with the involvement of the adaptive immune system in LOAD.