Annals of human genetics · 2026
Evidence for Reduced Somatic T-Cell Receptor Sequence Diversity Profiles Among Midwestern Amish in an Aging Cohort Study.
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Cruz Lauren A, Liu Shiying, Miskimen Kristy L, Cooke Bailey Jessica N, Kinzy Tyler, Song Yeunjoo E, Laux Renee A, Miron Penelope, Ogrocki Paula K, Lerner Alan J, Lynn Audrey, Fuzzell Sarada L, Hochstetler Sherri D, Konidari Ioanna, McCauley Jacob L, Scott William K, Pericak-Vance Margaret A, Haines Jonathan L, Crawford Dana C
Аннотация
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.
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.