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

Abstract

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.

Metadata

Item Type:	Article
Authors/Creators:	Mengel, D. https://orcid.org/0000-0002-4133-7182 Soter, E. Ott, J.M. Wacker, M. Leyva, A. Peters, O. Hellmann-Regen, J. https://orcid.org/0000-0003-0411-9204 Schneider, L.-S. https://orcid.org/0000-0001-5822-1744 Wang, X. Priller, J. Spruth, E. Altenstein, S. Schneider, A. https://orcid.org/0000-0001-9540-8700 Fliessbach, K. Wiltfang, J. https://orcid.org/0000-0003-1492-5330 Hansen, N. https://orcid.org/0000-0001-5785-9594 Rostamzadeh, A. Düzel, E. Glanz, W. Incesoy, E.I. Buerger, K. Janowitz, D. Ewers, M. https://orcid.org/0000-0001-5231-1714 Perneczky, R. https://orcid.org/0000-0003-1981-7435 Rauchmann, B. Teipel, S. Kilimann, I. Laske, C. Sodenkamp, S. Spottke, A. Brustkern, J. Brosseron, F. https://orcid.org/0000-0003-3137-7516 Wagner, M. Stark, M. Kleineidam, L. https://orcid.org/0009-0006-3309-6856 Shao, K. Lüsebrink, F. Yakupov, R. https://orcid.org/0000-0002-3868-284X Schmid, M. Hetzer, S. Dechent, P. Scheffler, K. Berron, D. https://orcid.org/0000-0003-1558-1883 Jessen, F. Synofzik, M. https://orcid.org/0000-0002-2280-7273
Copyright, Publisher and Additional Information:	© The Author(s) 2025. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Keywords:	DELCODE study group; Hippocampus; Humans; Alzheimer Disease; Atrophy; Disease Progression; Neurofilament Proteins; tau Proteins; Longitudinal Studies; Prospective Studies; Cognition; Neuropsychological Tests; Aged; Aged, 80 and over; Middle Aged; United States; Female; Male; Amyloid beta-Peptides; Biomarkers; Cognitive Dysfunction
Dates:	Submitted: 26 July 2024 Accepted: 7 April 2025 Published (online): 18 April 2025 Published: July 2025
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health
Depositing User:	Symplectic Sheffield
Date Deposited:	30 Jun 2025 13:24
Last Modified:	30 Jun 2025 13:24
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41380-025-03021-0
Related URLs:	Author
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:228527

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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

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