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<p>Peripheral immunosenescence has been increasingly implicated in dementia pathogenesis. However, the contributions of specific lymphocyte subsets to cognitive outcomes remain poorly defined, and evidence from large-scale longitudinal studies is scarce. We leveraged data from the US Health and Retirement Study (<i>n</i> = 7444; mean age: 67.7 ± 9.7 years). Our primary analysis calculated three ratio metrics to quantify T-cell immunosenescence: the CD4:CD8 ratio, CD4 + EMRA: Naïve and CD8 + EMRA: Naïve ratios. Their longitudinal associations with 6-year cognitive decline were evaluated by linear mixed model adjusted for multiple covariates. We found that a higher CD8 + EMRA: Naïve ratio was significantly associated with accelerated cognitive decline (-0.050 point/year per SD; 95% CI: −0.066 to −0.033, <i>P</i> &lt; 0.001). A nonlinear association was observed for the CD4:CD8 ratio (<i>P</i> for nonlinearity = 0.033), with only an intermediate level (the third quartile) associated with a slower cognitive decline. No significant association was found for the CD4 + EMRA: Naïve ratio. This study reveals a compartmentalized pattern in the associations of immunosenescent metrics with cognitive aging. The findings indicate a specific detrimental pathway characterized by an elevated CD8 + EMRA:Naïve ratio, whereas balanced CD4:CD8 homeostasis may play a beneficial role.</p>

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Peripheral immunosenescence biomarkers and longitudinal cognitive decline: a large population-based study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月2日

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  • Rong Hua,
  • Aimin Yang,
  • Chun Sing Lam,
  • Yuanyuan Wang,
  • Chenglong Li

摘要

Peripheral immunosenescence has been increasingly implicated in dementia pathogenesis. However, the contributions of specific lymphocyte subsets to cognitive outcomes remain poorly defined, and evidence from large-scale longitudinal studies is scarce. We leveraged data from the US Health and Retirement Study (n = 7444; mean age: 67.7 ± 9.7 years). Our primary analysis calculated three ratio metrics to quantify T-cell immunosenescence: the CD4:CD8 ratio, CD4 + EMRA: Naïve and CD8 + EMRA: Naïve ratios. Their longitudinal associations with 6-year cognitive decline were evaluated by linear mixed model adjusted for multiple covariates. We found that a higher CD8 + EMRA: Naïve ratio was significantly associated with accelerated cognitive decline (-0.050 point/year per SD; 95% CI: −0.066 to −0.033, P < 0.001). A nonlinear association was observed for the CD4:CD8 ratio (P for nonlinearity = 0.033), with only an intermediate level (the third quartile) associated with a slower cognitive decline. No significant association was found for the CD4 + EMRA: Naïve ratio. This study reveals a compartmentalized pattern in the associations of immunosenescent metrics with cognitive aging. The findings indicate a specific detrimental pathway characterized by an elevated CD8 + EMRA:Naïve ratio, whereas balanced CD4:CD8 homeostasis may play a beneficial role.