TY - JOUR
T1 - Disease staging of Alzheimer’s disease using a CSF-based biomarker model
AU - Salvadó, Gemma
AU - Horie, Kanta
AU - Barthélemy, Nicolas R.
AU - Vogel, Jacob W.
AU - Pichet Binette, Alexa
AU - Chen, Charles D.
AU - Aschenbrenner, Andrew J.
AU - Gordon, Brian A.
AU - Benzinger, Tammie L.S.
AU - Holtzman, David M.
AU - Morris, John C.
AU - Palmqvist, Sebastian
AU - Stomrud, Erik
AU - Janelidze, Shorena
AU - Ossenkoppele, Rik
AU - Schindler, Suzanne E.
AU - Bateman, Randall J.
AU - Hansson, Oskar
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/5
Y1 - 2024/5
N2 - Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0–5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aβ-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.
AB - Biological staging of individuals with Alzheimer’s disease (AD) may improve diagnostic and prognostic workup of dementia in clinical practice and the design of clinical trials. In this study, we used the Subtype and Stage Inference (SuStaIn) algorithm to establish a robust biological staging model for AD using cerebrospinal fluid (CSF) biomarkers. Our analysis involved 426 participants from BioFINDER-2 and was validated in 222 participants from the Knight Alzheimer Disease Research Center cohort. SuStaIn identified a singular biomarker sequence and revealed that five CSF biomarkers effectively constituted a reliable staging model (ordered: Aβ42/40, pT217/T217, pT205/T205, MTBR-tau243 and non-phosphorylated mid-region tau). The CSF stages (0–5) demonstrated a correlation with increased abnormalities in other AD-related biomarkers, such as Aβ-PET and tau-PET, and aligned with longitudinal biomarker changes reflective of AD progression. Higher CSF stages at baseline were associated with an elevated hazard ratio of clinical decline. This study highlights a common molecular pathway underlying AD pathophysiology across all patients, suggesting that a single CSF collection can accurately indicate the presence of AD pathologies and characterize the stage of disease progression. The proposed staging model has implications for enhancing diagnostic and prognostic assessments in both clinical practice and the design of clinical trials.
UR - http://www.scopus.com/inward/record.url?scp=85188240159&partnerID=8YFLogxK
U2 - 10.1038/s43587-024-00599-y
DO - 10.1038/s43587-024-00599-y
M3 - Article
C2 - 38514824
AN - SCOPUS:85188240159
SN - 2662-8465
VL - 4
SP - 694
EP - 708
JO - Nature Aging
JF - Nature Aging
IS - 5
ER -