失智症的創新生物標記：類澱粉免疫反應

Alzheimer’s disease is a dreadful disease affecting millions of people worldwide. Our lab has been fascinated by identifying peripheral immunological effectors for neuroinflammation. We demonstrated that Aβ-reactive polyfunctional T cell responses can be detected in peripheral blood and are significantly enhanced in individuals with mild cognitive impairment (MCI) compared with cognitively normal older adults. Using samples from both the EMCIT and TPMIC cohorts, we found that amyloid-reactive CD4+ and CD8+ T cells showed increased functional responses to amyloid peptide stimulation, including cytokine production and activation-related markers. In the TPMIC cohort, the total amyloid-reactive T cell response was markedly higher in MCI participants than in controls, and its discriminative performance for identifying MCI was superior to plasma phosphorylated tau181. Importantly, this increase was not explained by generalized T cell hyperreactivity, because responses to unrelated CMV antigen and non-specific stimulation did not show similar discriminatory ability. These findings suggest that peripheral Aβ-reactive T cell polyfunctionality may represent a novel immune-based biomarker for MCI and may provide insight into amyloid-associated immune mechanisms in early neurodegeneration. Our findings have been awarded the National Innovation Award in 2023.

阿茲海默症是一種老人常見的慢性神經退化疾病，它會逐漸損害大腦的功能，包括記憶力、思考能力和日常生活技能。預期全世界目前有五千萬名失智患者，其人數在2050年可能會增加三倍。我們證實周邊血液中可以偵測到對 Aβ 具反應性的多功能性 T 細胞反應，而且此反應在輕度認知障礙（MCI）個案中顯著高於認知功能正常的高齡者。我們利用 EMCIT 與 TPMIC 兩個台灣世代的樣本，發現經 amyloid peptide 刺激後，MCI 個案的 CD4+ 與 CD8+ T 細胞均呈現較高的功能性反應，包括細胞激素產生與活化相關指標。在 TPMIC 世代中，amyloid-reactive T cell 的總反應頻率在 MCI 個案中明顯升高，且其區分 MCI 與正常認知者的能力優於血漿 phosphorylated tau181。重要的是，這種增加並非源自整體 T 細胞過度活化，因為對非相關 CMV 抗原或非特異性刺激的 T 細胞反應並未呈現相同的鑑別能力。這些結果顯示，周邊血液 Aβ-reactive T cell polyfunctionality 可能是一種新的免疫型 MCI 生物標記，並有助於理解早期神經退化過程中與 amyloid 相關的免疫機制。我們的這項研究於2024年獲得國家新創獎。

Chiu Y-L, Yan S-H, Fan Y-T, Chang C-F, Hung R-W, Liu Y-C, Yang TYO, Chuang Y-F. Aβ-reactive T cell polyfunctionality response as a new biomarker for mild cognitive impairment. Alzheimer’s & Dementia: Diagnosis, Assessment & Disease Monitoring. 2025;17:e70042.