Multimodal biomarker characterization of amnestic objective subtle cognitive decline in aging and preclinical Alzheimer’s disease - 09/06/26

Doi : 10.1016/j.tjpad.2026.100612

David López-Martos ^a,^b,^⁎ , Raffaele Cacciaglia ^a,^b,^c, Marc Suárez-Calvet ^a,^b,^c,^d, Gemma Salvadó ^a,^e, Mahnaz Shekari ^a,^b, Armand González-Escalante ^a,^b, Marta Milà-Alomà ^a,^f,^g, Anna Brugulat-Serrat ^a,^b,^c,^h, Carolina Minguillon ^a,^b,^c, Matteo Tonietto ⁱ, Edilio Borroni ⁱ, Gregory Klein ⁱ, Clara Quijano-Rubio ^j, Gwendlyn Kollmorgen ^k, Henrik Zetterberg ^l,^m,^n,^o,^p,^q,^r, Kaj Blennow ^l,^m, Juan Domingo Gispert ^a,^b,^c,^s, Oriol Grau-Rivera ^a,^b,^c,^d,^⁎ , Gonzalo Sánchez-Benavides ^a,^b,^c,^⁎
for the
ALFA study ^¹
The complete list of collaborators of the ALFA study can be found in the acknowledgments section.

^a Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation, Barcelona, Spain

^b Hospital del Mar Research Institute, Barcelona, Spain

^c Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable, Instituto de Salud Carlos III, Madrid, Spain

^d Servei de Neurologia, Hospital del Mar, Barcelona, Spain

^e Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden

^f Department of Veterans Affairs Medical Center, Northern California Institute for Research and Education (NCIRE), San Francisco, CA, USA

^g Department of Radiology, University of California, San Francisco, San Francisco, CA, USA

^h Global Brain Health Institute, San Francisco, CA, USA

ⁱ Pharma Research and Early Development, F Hoffmann-La Roche Ltd., Basel, Switzerland

^j Roche Diagnostics International Ltd, Rotkreuz, Switzerland

^k Roche Diagnostics GmbH, Penzberg, Germany

^l Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, University of Gothenburg, Mölndal, Sweden

^m Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden

ⁿ Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK

^o UK Dementia Research Institute at UCL, London, UK

^p Hong Kong Center for Neurodegenerative Diseases, Clear Water Bay, Hong Kong, China

^q Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA

^r Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

^s Centro de Investigación Biomédica en Red Bioingeniería, Biomateriales y Nanomedicina, Instituto de Salud Carlos III, Madrid, Spain

^⁎ Corresponding authors at: Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation. Wellington 30, 08005, Barcelona, Spain. Barcelonaβeta Brain Research Center (BBRC), Pasqual Maragall Foundation Wellington 30 Barcelona 08005 Spain

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Abstract

Background

The objective of this study was to provide a multimodal biomarker characterization of amnestic objective subtle cognitive decline (obj-SCD) in aging and preclinical Alzheimer’s disease (AD).

Methods

Prospective observational study; data from the Alzheimer’s and Families+ (ALFAs+) cohort, including cognitively unimpaired (CU) individuals with available baseline CSF biomarkers (normal or AD continuum profiles) and longitudinal neuropsychological assessment (2 time points, 3-year follow-up). Amnestic obj-SCD was defined using robust longitudinal neuropsychological references with multivariate base rate thresholds of significant decline (Free and Cued Selective Reminding Test, Memory Binding Test, Wechsler Memory Scale IV: Logical Memory). Study outcomes included plasma p-tau217, NfL, and GFAP; CSF p-tau181/Aβ42, NfL, and GFAP; Aβ and tau PET; and MRI Grey Matter volume (GMv). The associations of amnestic obj-SCD with fluid (plasma and CSF) and neuroimaging biomarkers (PET and GMv) were evaluated using mixed-effects and voxel-wise linear regression models, respectively.

Results

350 CU individuals were included (mean age 61 years; 60% female; mean education 14 years; 35% CSF Aβ-positive). Amnestic obj-SCD was identified in 10% of the sample, associated with greater AD pathology (higher plasma p-tau217, CSF p-tau181/Aβ42, global Aβ PET, medial temporal tau PET), neurodegeneration (higher plasma and CSF NfL, reduced GMv in cingulate cortex, longitudinal GMv reductions in hippocampus) and inflammation (higher plasma and CSF GFAP, longitudinal GMv increases in neocortical brain regions).

Discussion

These findings highlight the need for standardized clinical staging criteria to enhance early detection and risk stratification in aging and preclinical AD.

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Keywords : Alzheimer’s disease, Amnestic objective subtle cognitive decline (obj-SCD), Episodic memory, Multimodal biomarkers

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Vol 13 - N° 7

Article 100612- août 2026 Retour au numéro

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Multimodal biomarker characterization of amnestic objective subtle cognitive decline in aging and preclinical Alzheimer’s disease - 09/06/26

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