Abstract
INTRODUCTION: Alzheimer's disease (AD) involves neuroinflammation and amyloid plaque deposition, yet the role of amyloid-reactive immune response in neurodegeneration remains unclear. We investigate amyloid-reactive T cell levels in the Epidemiology of Mild Cognitive Impairment Study in Taiwan (EMCIT) and Taiwan Precision Medicine Initiative of Cognitive Impairment and Dementia (TPMIC) cohorts. METHOD: Using diverse amyloid peptide formulations, we established a polyfunctionality assay for five T cell functions and compared mild cognitive impairment (MCI) patients to control subjects in both cohorts. RESULTS: In both cohorts, MCI individuals exhibit higher amyloid-reactive T cell responses than controls. In the TPMIC cohort, CD4+ and CD8+ total response frequencies are notably elevated in MCI (CD4: 1.3%, CD8: 1.91%) versus controls (CD4: 0.15%, CD8: 0.28%; both p < 0.001). Amyloid-reactive T cell response outperforms plasma phosphorylated tau 181 (p-tau181) in discriminating MCI (area under the receiver operating characteristic curve CD4+: 0.97; CD8+: 0.96; p-tau181: 0.72; both p < 0.001). DISCUSSION: Amyloid-reactive T cell polyfunctional response distinguishes MCI from normal aging and could serve as a novel MCI biomarker. HIGHLIGHTS: Amyloid-reactive polyfunctional T cell responses can be detected in the peripheral circulation.Amyloid-reactive T cell response is significantly enhanced in individuals with mild cognitive impairment compared to age-matched, cognitively unimpaired individuals.The unique discriminative accuracy of amyloid-reactive T cell response is significantly higher than phosphorylated tau181 and is not a result of overall T cell hyperreactivity.Future studies are needed to determine the predictive role of amyloid-reactive T cell responses in disease progression and if the amyloid-reactive immune response could be a therapeutic target for the treatment of neurodegeneration.