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<p>Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer’s disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.</p>

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Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月18日

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  • David Mengel,
  • Ester Soter,
  • Julia Maren Ott,
  • Madeleine Wacker,
  • Alejandra Leyva,
  • Oliver Peters,
  • Julian Hellmann-Regen,
  • Luisa-Sophie Schneider,
  • Xiao Wang,
  • Josef Priller,
  • Eike Spruth,
  • Slawek Altenstein,
  • Anja Schneider,
  • Klaus Fliessbach,
  • Jens Wiltfang,
  • Niels Hansen,
  • Ayda Rostamzadeh,
  • Emra Düzel,
  • Wenzel Glanz,
  • Enise I. Incesoy,
  • Katharina Buerger,
  • Daniel Janowitz,
  • Michael Ewers,
  • Robert Perneczky,
  • Boris Rauchmann,
  • Stefan Teipel,
  • Ingo Kilimann,
  • Christoph Laske,
  • Sebastian Sodenkamp,
  • Annika Spottke,
  • Johanna Brustkern,
  • Frederic Brosseron,
  • Michael Wagner,
  • Melina Stark,
  • Luca Kleineidam,
  • Kai Shao,
  • Falk Lüsebrink,
  • Renat Yakupov,
  • Matthias Schmid,
  • Stefan Hetzer,
  • Peter Dechent,
  • Klaus Scheffler,
  • David Berron,
  • Frank Jessen,
  • Matthis Synofzik

摘要

Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer’s disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum.