Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease
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.
Authors
- Emrah Düzel (ORCID: https://orcid.org/0000-0002-0139-5388)
- Madeleine Wacker
- Jens Wiltfang (ORCID: https://orcid.org/0000-0003-1492-5330)
- Ayda Rostamzadeh (ORCID: https://orcid.org/0000-0001-5189-134X)
- Robert Perneczky (ORCID: https://orcid.org/0000-0003-1981-7435)
- Annika Spottke (ORCID: https://orcid.org/0000-0001-9854-2972)
- Oliver Peters (ORCID: https://orcid.org/0000-0003-0568-2998)
- Stefan Johannes Teipel (ORCID: https://orcid.org/0000-0002-3586-3194)
- David Berron (ORCID: https://orcid.org/0000-0003-1558-1883)
- Niels Hansen (ORCID: https://orcid.org/0000-0001-5785-9594)
- Frederic Brosseron (ORCID: https://orcid.org/0000-0003-3137-7516)
- Johanna Brustkern (ORCID: https://orcid.org/0000-0001-5204-1013)
- Matthias Schmid (ORCID: https://orcid.org/0000-0002-0788-0317)
- Matthis Synofzik (ORCID: https://orcid.org/0000-0002-2280-7273)
- Boris‐Stephan Rauchmann (ORCID: https://orcid.org/0000-0003-4547-6240)
- Klaus Scheffler (ORCID: https://orcid.org/0000-0001-6316-8773)
- Renat Yakupov (ORCID: https://orcid.org/0000-0002-3868-284X)
- Luca Kleineidam (ORCID: https://orcid.org/0009-0006-3309-6856)
- Michael Ewers (ORCID: https://orcid.org/0000-0001-5231-1714)
- David Mengel (ORCID: https://orcid.org/0000-0002-4133-7182)
- Michael Wagner (ORCID: https://orcid.org/0000-0003-2589-6440)
- Katharina Büerger (ORCID: https://orcid.org/0000-0002-5898-9953)
- Klaus Fließbach (ORCID: https://orcid.org/0000-0002-0183-7510)
- Enise I. Incesoy (ORCID: https://orcid.org/0000-0003-2014-4098)
- Josef Priller (ORCID: https://orcid.org/0000-0001-7596-0979)
- Ester Soter
- Stefan Hetzer (ORCID: https://orcid.org/0000-0002-1773-1518)
- Daniel Janowitz (ORCID: https://orcid.org/0009-0003-4090-547X)
- Ingo Kilimann (ORCID: https://orcid.org/0000-0002-3269-4452)
- Julian Hellmann‐Regen (ORCID: https://orcid.org/0000-0003-0411-9204)
- Anja Schneider (ORCID: https://orcid.org/0000-0001-9540-8700)
- Kai Shao (ORCID: https://orcid.org/0000-0002-1355-8463)
- Slawek Altenstein (ORCID: https://orcid.org/0000-0003-2753-5999)
- Luisa‐Sophie Schneider (ORCID: https://orcid.org/0000-0001-5822-1744)
- Wenzel Glanz (ORCID: https://orcid.org/0000-0002-5865-4176)
- Melina Stark (ORCID: https://orcid.org/0009-0005-3812-023X)
- Xiao Wang (ORCID: https://orcid.org/0000-0001-8824-6280)
- Sebastian Sodenkamp
- Falk Lüsebrink
- Peter Dechent (ORCID: https://orcid.org/0009-0006-4005-3352)
- Julia Maren Ott
- Eike Jakob Spruth
- Christoph Laske
- Alejandra Leyva
- Frank Jessen
Institutions
- University of Bonn (DE)
- Capital Medical University (CN)
- Lund University (SE)
- University Hospital Bonn (DE)
- German Center for Neurodegenerative Diseases (DE)
- TUM Klinikum (DE)
- Stroke Association (GB)
- LMU Klinikum (DE)
- Humboldt-Universität zu Berlin (DE)
- Munich Cluster for Systems Neurology (DE)
- Universitätsmedizin Göttingen (DE)
- UK Dementia Research Institute (GB)
- German Centre for Cardiovascular Research (DE)
- Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (DE)
- University Hospital Magdeburg (DE)
- Hertie Institute for Clinical Brain Research (DE)
- University Hospital Cologne (DE)
- University of Rostock (DE)
- Imperial College London (GB)
- University of Aveiro (PT)
- Technical University of Munich (DE)
- University of Göttingen (DE)
- Charité - Universitätsmedizin Berlin (DE)
- University of Tübingen (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Sheffield (GB)
- Otto-von-Guericke-Universität Magdeburg (DE)
Publication Details
- Journal
- Molecular Psychiatry
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1038/s41380-025-03021-0
- Citations
- 8
- Primary Topic
- Dementia and Cognitive Impairment Research
- Type
- article
- Field-Weighted Citation Impact
- 11.77
Funders
- Else Kröner-Fresenius-Stiftung
- Deutsches Zentrum für Neurodegenerative Erkrankungen