Plasma Aβ42/Aβ40 determined by mass spectrometry is associated with longitudinal changes in amyloid accumulation, brain atrophy, and conversion to mild cognitive impairment due to Alzheimer’s disease in individuals with subjective cognitive decline: 5-year follow-up of the FACEHBI cohort - 09/01/26

Doi : 10.1016/j.tjpad.2025.100465

Noelia Fandos ^a,^⁎ , María Pascual-Lucas ^a , Leticia Sarasa ^a , Jose Terencio ^a,^b , Mª Eugenia Sáez ^c , Juan Pablo Tartari ^d , Ángela Sanabria ^d,^e , Oscar Sotolongo-Grau ^d , Amanda Cano ^d,^e , Lluís Tárraga ^d,^e , Miren Jone Gurruchaga ^d , Agustín Ruíz ^d,^e,^f,^g , Xavier Montalban ^d,^e,^h , Mercè Boada ^d,^e , Montserrat Alegret ^d,^e , Marta Marquié ^d,^e,^{^{1
Marta Marquié and José Antonio Allué contributed equally to this work as co–senior authors.}} , José Antonio Allué ^a,^{^{1
Marta Marquié and José Antonio Allué contributed equally to this work as co–senior authors.}}
on behalf of the FACEHBI study group
N. Aguilera ¹, E. Alarcón-Martín ¹, M. Alegret ^1,², J.A. Alllué ³, P. Bayón-Bujan ¹, M. Berthier ⁴, J. Blázquez-Folch ¹, M. Boada ^1,², M. Buendia ¹, S. Bullich ⁵, F. Campos ⁶, B. Calm-Salvans ¹, A. Cano ^1,², F. Casales ¹, P. Cañabate ^1,², L. Cañada ¹, C. Cuevas ¹, I. de Rojas ¹, S. Diego ¹, G. Domingues-Kolinger ⁵, J.M. Escudero ⁷, A. Espinosa ^1,², N. Fandos ³, M.V. Fernández ¹, A. Gailhajenet ¹, P. García-González ^1,², J. Giménez ⁷, M. Gómez-Chiari ⁷, M. Guitart ¹, M.J. Gurruchaga ¹, P.C. Gutiérrez ¹, I. Hernández ^1,², M. Ibarria ¹, A. Lafuente ¹, F. Lomeña ⁶, M. Marquié ^1,², E. Martín ¹, C. Martínez ¹, M. Martinez ¹, A. Miguel ¹, M. Moreno ¹, A. Morera ¹, L. Montrreal ¹, N. Muñoz ¹, A. Muñoz-Morales ¹, A. Niñerola ⁶, A.B. Nogales ¹, L. Núñez ⁸, C. Olivé ¹, A. Orellana ^1,², G. Ortega ^1,², A. Páez ⁸, A. Pancho ¹, E. Pelejà ¹, E. Pérez-Martínez ⁵, A. Pérez-Cordon ¹, V. Pérez-Grijalba ³, M. Pascual-Lucas ³, A. Perissinotti ⁶, S. Preckler ¹, R. Puerta ¹, M.I. Ramis ¹, J.N. Rodríguez ¹, N. Roé-Vellvé ⁵, J. Romero ³, M. Rosende-Roca ¹, A. Ruiz ^1,², A. Sanabria ^1,², P. Sanz-Cartagena ¹, L. Sarasa ³, S. Seguer ¹, A. Solivar ¹, O. Sotolongo-Grau ¹, A. Stephens ⁵, J.P. Tartari ¹, L. Tárraga ^1,², M.A. Tejero ⁷, J. Terencio ³, M. Torres ⁸, A. Valenzuela ¹, S. Valero ^1,², L. Vargas ¹, A. Vivas ⁷
¹ Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya (UIC). Barcelona, Spain.
² CIBERNED, Center for Networked Biomedical Research on Neurodegenerative Diseases, National Institute of Health Carlos III, Ministry of Economy and Competitiveness. Madrid, Spain.
³ Araclon Biotech-Grifols. Zaragoza, Spain.
⁴ Cognitive Neurology and Aphasia Unit (UNCA). University of Malaga. Málaga, Spain.
⁵ Life Molecular Imaging GmbH. Berlin, Germany.
⁶ Servei de Medicina Nuclear, Hospital Clínic i Provincial. Barcelona, Spain.
⁷ Departament de Diagnòstic per la Imatge. Clínica Corachan, Barcelona, Spain.
⁸ Grifols®. Barcelona, Spain.

on behalf of the AMYPAD consortium^²
Data used in the preparation of this article were obtained from the AMYPAD project. As such, the investigators within AMYPAD contributed to the design and implementation of AMYPAD and/or provided data but did not participate in the analysis or writing of this report. A complete listing of AMYPAD contributors can be found at: partners/
^a Araclon Biotech-Grifols. Vía Hispanidad 21, 50009 Zaragoza, Spain
^b Scientific Innovation Office, Grifols. Parque Empresarial Can Sant Joan, Avinguda de la Generalitat, 152-158, 08174 Sant Cugat del Vallès, Barcelona, Spain
^c CAEBi Bioinformática S.L. Pasaje Antonio Villegas 16, 41704 Dos Hermanas, Sevilla, Spain
^d Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya. C/ Gran Via de Carles III, 85 bis, 08028 Barcelona, Spain
^e Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III. C/ Melchor Fernández Almagro, 3, Fuencarral-El Pardo, 28029 Madrid, Spain
^f Glenn Biggs Institute for Alzheimer's & Neurodegenerative Diseases, University of Texas Health Science Center. 8300 Floyd Curl Drive, San Antonio, TX 78229, USA
^g Department of Microbiology, Immunology and Molecular Genetics, Long School of Medicine. University of Texas Health Science Center. 7703 Floyd Curl Drive, San Antonio, TX 78229 MC 7758, USA
^h Department of Neurology and Multiple Sclerosis Center of Catalonia (Cemcat), Vall d’Hebron University Hospital, Universitat Autònoma de Barcelona (UAB). Pg. de la Vall d'Hebron, 119-129, 08035 Barcelona, Spain

^⁎Corresponding author at: Araclon Biotech, 21, Vía Hispanidad, 50009 Zaragoza (Spain).Araclon Biotech21, Vía HispanidadZaragoza50009Spain

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Abstract

Background

The accurate identification of individuals at risk of Alzheimer’s disease (AD) through blood-based biomarkers remains challenging.

Objectives

To evaluate the association between plasma amyloid-beta (Aβ)42/Aβ40 ratio and longitudinal amyloid deposition, clinical progression, brain atrophy and cognitive decline.

Design, setting and participants

This study extends the Fundació ACE Healthy Brain Initiative (FACEHBI) study (Barcelona, Spain), comprising 200 individuals with subjective cognitive decline (SCD) followed over five years.

Measurements

Aβ42/Aβ40 ratio was quantified using ABtest-MS, an antibody-free mass-spectrometry (MS) method. Survival analyses compared conversion risks to amyloid-PET positivity and mild cognitive impairment (MCI), in participants classified as low or high Aβ42/Aβ40, based on a cutoff of ≤ 0.241. Linear mixed-effect models evaluated associations of this biomarker with longitudinal changes in amyloid deposition, brain volume, and cognition.

Results

Low baseline Aβ42/Aβ40 was significantly associated with increased amyloid accumulation (β = 0.257, 95% confidence interval (CI) 0.177–0.336, P < 0.001), and with higher risk of conversion to Aβ-PET positivity (Hazard ratio (HR) = 2.84, 95% CI 1.14–7.04, P = 0.025) and to MCI due to AD (HR = 3.25, 95% CI 1.17–9.01, P = 0.024). It was also linked to decreased hippocampal (β = -1.183, 95% CI -2.154 to -0.211, P = 0.017) and cortical (β = -75.921, 95% CI -151.728 to -0.113, P = 0.050) volumes, and increased ventricular volume (β = 35.175, 95% CI 18.559–51.790, P < 0.001). Moreover, lower baseline levels of Aβ42/Aβ40 were weakly associated with greater worsening in Mini-Mental State Examination and complex associative memory.

Conclusions

Our findings suggest that the plasma Aβ42/Aβ40 ratio is associated with future amyloid accumulation, brain atrophy, and conversion to prodromal AD in individuals with SCD. This biomarker may help characterize individuals with a higher likelihood of progression and could support earlier and more personalized strategies.

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Keywords : Alzheimer’s disease, Aβ42/Aβ40, Blood biomarkers, Mass spectrometry, Subjective cognitive decline

Abbreviations : Aβ, AD, APOE, AUC, CH, CI, CL, CSF, FACEHBI, FBB, GFAP, HR, IP-MS, IQR, LMEMs, MCI, MMSE, MRI, MS, NBACE, NfL, p-Tau, PET, ROC, SCD, S-FNAME, SUVR