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Background <p>Long-term trajectories of plasma biomarkers relative to clinical symptom onset in Alzheimer’s disease (AD) remain scarce.</p> Methods <p>We analyzed 17-year longitudinal data from 195 initially cognitively unimpaired participants in the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study. Plasma biomarker trajectories were modeled as a function of years from estimated mild cognitive impairment (MCI) symptom onset using generalized additive mixed models.</p> Results <p>In participants who progressed to amyloid-positive MCI, plasma p-tau181/Aβ42 and GFAP diverged from stable controls earliest (about 13 and 12&#xa0;years before symptom onset, respectively), followed by Aβ42/Aβ40, p-tau181, and NfL, all of which became abnormal before symptom onset. Individuals who developed amyloid-negative MCI showed abnormalities only in GFAP (about 11&#xa0;years before onset) and YKL-40 (around the time of symptom onset).</p> Conclusions <p>This study establishes a clinically anchored temporal map of plasma AD biomarkers. Plasma markers detect AD-related pathological changes more than a decade before symptom onset, offering a scalable, non-invasive approach for defining the preclinical phase and identifying at-risk individuals for early intervention.</p>

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Plasma biomarker trajectories across Alzheimer’s clinical onset: a 17-year prospective study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Siqi Xie,
  • Yumei Liang,
  • Yana Pang,
  • Ying Li,
  • Shuman Cao,
  • Yan Li,
  • Qi Wang,
  • Abhay Moghekar,
  • Marilyn Albert,
  • Jianping Jia,
  • Barbara Rodzon,
  • Anja Soldan,
  • Corinne Pettigrew,
  • Leonie Farrington,
  • Maura Grega,
  • Michael Miller,
  • Susumu Mori,
  • Tilak Ratnanather,
  • Anthony Kolasny,
  • Hanzhang Lu,
  • Kenichi Oishi,
  • Laurent Younes,
  • Sara Grace Ho,
  • David Shade,
  • Ann Ervin,
  • Jennifer Jones,
  • Hamadou Coulibaly,
  • Mei-Cheng Wang,
  • Yuxin Zhu,
  • Jiangxia Wang,
  • Juan Troncoso,
  • David Nauen

摘要

Background

Long-term trajectories of plasma biomarkers relative to clinical symptom onset in Alzheimer’s disease (AD) remain scarce.

Methods

We analyzed 17-year longitudinal data from 195 initially cognitively unimpaired participants in the Biomarkers of Cognitive Decline Among Normal Individuals (BIOCARD) study. Plasma biomarker trajectories were modeled as a function of years from estimated mild cognitive impairment (MCI) symptom onset using generalized additive mixed models.

Results

In participants who progressed to amyloid-positive MCI, plasma p-tau181/Aβ42 and GFAP diverged from stable controls earliest (about 13 and 12 years before symptom onset, respectively), followed by Aβ42/Aβ40, p-tau181, and NfL, all of which became abnormal before symptom onset. Individuals who developed amyloid-negative MCI showed abnormalities only in GFAP (about 11 years before onset) and YKL-40 (around the time of symptom onset).

Conclusions

This study establishes a clinically anchored temporal map of plasma AD biomarkers. Plasma markers detect AD-related pathological changes more than a decade before symptom onset, offering a scalable, non-invasive approach for defining the preclinical phase and identifying at-risk individuals for early intervention.