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Purpose <p>Cortisol dysregulation has been implicated in Alzheimer’s disease (AD), but its associations with amyloid and tau-related outcomes remain unclear. This study examined whether baseline CSF cortisol was associated with cross-sectional and baseline-adjusted 24-month multimodal AD biomarkers and cognitive outcomes.</p> Methods <p>A total of 764 participants were included, comprising cognitively normal (CN; <i>n</i> = 284), individuals with mild cognitive impairment (MCI; <i>n</i> = 356), and patients with AD dementia (<i>n</i> = 124). Associations between baseline CSF cortisol, multimodal AD biomarkers, and cognitive outcomes were assessed with FDR correction.</p> Results <p>CSF cortisol increased modestly from CN to MCI and AD dementia, with a small but statistically significant overall group difference after FDR correction. Cross-sectionally, in the MCI group, higher CSF cortisol was associated with higher CSF total tau and p-tau181 and a lower Aβ42/total tau ratio. In baseline-adjusted 24-month analyses, in MCI groups, higher CSF was associated with higher CSF total tau and p-tau181, greater temporal tau-PET burden, lower hippocampal volume, greater ventricular volume, and poorer cognitive outcomes. In the full cohort and MCI group, CSF-defined amyloid positivity strengthened associations of higher baseline CSF cortisol with adverse 24-month tau-related outcomes. Exploratory analyses suggested that 24-month CSF total tau and hippocampal volume partly accounted for the association between higher baseline CSF cortisol and poorer 24-month cognition in MCI; however, these findings do not establish causal mediation.</p> Conclusion <p>Higher CSF cortisol may be linked to tau-related pathology and poorer cognition, supporting further evaluation of its prognostic value across the AD continuum.</p>

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Higher baseline CSF cortisol is associated with adverse 24-month tau-related, neuroimaging, and cognitive outcomes across the Alzheimer’s disease continuum

  • 期刊论文

  • 发表日期：

    2026年7月28日

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  • Nahlah Fahad Alreshidi,
  • Abdulaziz Abdullah Alghamdi,
  • Kholoud S. Almasoudi,
  • Iman M. Mirza,
  • Sahar Abduljawad,
  • Soha S. Zakaria,
  • Saud S Alharbi

摘要

Purpose

Cortisol dysregulation has been implicated in Alzheimer’s disease (AD), but its associations with amyloid and tau-related outcomes remain unclear. This study examined whether baseline CSF cortisol was associated with cross-sectional and baseline-adjusted 24-month multimodal AD biomarkers and cognitive outcomes.

Methods

A total of 764 participants were included, comprising cognitively normal (CN; n = 284), individuals with mild cognitive impairment (MCI; n = 356), and patients with AD dementia (n = 124). Associations between baseline CSF cortisol, multimodal AD biomarkers, and cognitive outcomes were assessed with FDR correction.

Results

CSF cortisol increased modestly from CN to MCI and AD dementia, with a small but statistically significant overall group difference after FDR correction. Cross-sectionally, in the MCI group, higher CSF cortisol was associated with higher CSF total tau and p-tau181 and a lower Aβ42/total tau ratio. In baseline-adjusted 24-month analyses, in MCI groups, higher CSF was associated with higher CSF total tau and p-tau181, greater temporal tau-PET burden, lower hippocampal volume, greater ventricular volume, and poorer cognitive outcomes. In the full cohort and MCI group, CSF-defined amyloid positivity strengthened associations of higher baseline CSF cortisol with adverse 24-month tau-related outcomes. Exploratory analyses suggested that 24-month CSF total tau and hippocampal volume partly accounted for the association between higher baseline CSF cortisol and poorer 24-month cognition in MCI; however, these findings do not establish causal mediation.

Conclusion

Higher CSF cortisol may be linked to tau-related pathology and poorer cognition, supporting further evaluation of its prognostic value across the AD continuum.