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Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults

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Abstract

We investigated combining a core AD neuropathology measure (plasma amyloid-beta [Aβ] 42/40) with five plasma markers of inflammation, cellular stress, and neurodegeneration to predict cognitive decline. Among 401 participants free of dementia (median [IQR] age, 76 [73–80] years) from the Multidomain Alzheimer Preventive Trial (MAPT), 28 (7.0%) participants developed dementia, and 137 (34.2%) had worsening of clinical dementia rating (CDR) scale over 4 years. In the models utilizing plasma Aβ alone, a tenfold increased risk of incident dementia (nonsignificant) and a fivefold increased risk of worsening CDR were observed as each nature log unit increased in plasma Aβ levels. Models incorporating Aβ plus multiple plasma biomarkers performed similarly to models included Aβ alone in predicting dementia and CDR progression. However, improving Aβ model performance for composite cognitive score (CCS) decline, a proxy of dementia, was observed after including plasma monocyte chemoattractant protein 1 (MCP1) and growth differentiation factor 15 (GDF15) as covariates. Participants with abnormal Aβ, GDF15, and MCP1 presented higher CCS decline (worsening cognitive function) compared to their normal-biomarker counterparts (adjusted β [95% CI], − 0.21 [− 0.35 to − 0.06], p = 0.005). In conclusion, our study found limited added values of multi-biomarkers beyond the basic Aβ models for predicting clinically meaningful cognitive decline among non-demented older adults. However, a combined assessment of inflammatory and cellular stress status with Aβ pathology through measuring plasma biomarkers may improve the evaluation of cognitive performance.

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Acknowledgements

We acknowledge Christelle Cantet at CERPOP, UMR1295, Inserm Université Toulouse III, for her thoughtful suggestions and confirmation of our statistical modeling approach and interpretation.

Members of the MAPT/DSA group include:

MAPT/DSA group

MAPT Study group: principal investigator, Bruno Vellas (Toulouse); coordination, Sophie Guyonnet; project leader, Isabelle Carrié; CRA, Lauréane Brigitte; investigators, Catherine Faisant, Françoise Lala, Julien Delrieu, Hélène Villars; psychologists, Emeline Combrouze, Carole Badufle, Audrey Zueras; methodology, statistical analysis, and data management, Sandrine Andrieu, Christelle Cantet, Christophe Morin; multidomain group, Gabor Abellan Van Kan, Charlotte Dupuy, Yves Rolland (physical and nutritional components), Céline Caillaud, Pierre-Jean Ousset (cognitive component), Françoise Lala (preventive consultation) (Toulouse). The cognitive component was designed in collaboration with Sherry Willis from the University of Seattle and Sylvie Belleville, Brigitte Gilbert, and Francine Fontaine from the University of Montreal.

Co-investigators in associated centers, Jean-François Dartigues, Isabelle Marcet, Fleur Delva, Alexandra Foubert, Sandrine Cerda (Bordeaux); Marie-Noëlle-Cuffi, Corinne Costes (Castres); Olivier Rouaud, Patrick Manckoundia, Valérie Quipourt, Sophie Marilier, Evelyne Franon (Dijon); Lawrence Bories, Marie-Laure Pader, Marie-France Basset, Bruno Lapoujade, Valérie Faure, Michael Li Yung Tong, Christine Malick-Loiseau, Evelyne Cazaban-Campistron (Foix); Françoise Desclaux, Colette Blatge (Lavaur); Thierry Dantoine, Cécile Laubarie-Mouret, Isabelle Saulnier, Jean-Pierre Clément, Marie-Agnès Picat, Laurence Bernard-Bourzeix, Stéphanie Willebois, Iléana Désormais, Noëlle Cardinaud (Limoges); Marc Bonnefoy, Pierre Livet, Pascale Rebaudet, Claire Gédéon, Catherine Burdet, Flavien Terracol (Lyon), Alain Pesce, Stéphanie Roth, Sylvie Chaillou, Sandrine Louchart (Monaco); Kristel Sudres, Nicolas Lebrun, Nadège Barro-Belaygues (Montauban); Jacques Touchon, Karim Bennys, Audrey Gabelle, Aurélia Romano, Lynda Touati, Cécilia Marelli, Cécile Pays (Montpellier); Philippe Robert, Franck Le Duff, Claire Gervais, Sébastien Gonfrier (Nice); Yannick Gasnier and Serge Bordes, Danièle Begorre, Christian Carpuat, Khaled Khales, Jean-François Lefebvre, Samira Misbah El Idrissi, Pierre Skolil, Jean-Pierre Salles (Tarbes).

MRI group: Carole Dufouil (Bordeaux), Stéphane Lehéricy, Marie Chupin, Jean-François Mangin, Ali Bouhayia (Paris); Michèle Allard (Bordeaux); Frédéric Ricolfi (Dijon); Dominique Dubois (Foix); Marie Paule Bonceour Martel (Limoges); François Cotton (Lyon); Alain Bonafé (Montpellier); Stéphane Chanalet (Nice); Françoise Hugon (Tarbes); Fabrice Bonneville, Christophe Cognard, François Chollet (Toulouse).

PET scan group: Pierre Payoux, Thierry Voisin, Julien Delrieu, Sophie Peiffer, Anne Hitzel, (Toulouse); Michèle Allard (Bordeaux); Michel Zanca (Montpellier); Jacques Monteil (Limoges); Jacques Darcourt (Nice).

Medico-economics group: Laurent Molinier, Hélène Derumeaux, Nadège Costa (Toulouse).

Biological sample collection: Bertrand Perret, Claire Vinel, Sylvie Caspar-Bauguil (Toulouse).

Safety management: Pascale Olivier-Abbal.

DSA Group: Sandrine Andrieu, Christelle Cantet, Nicola Coley.

Funding

The present work was performed in the context of the Inspire Program, a research platform supported by grants from the Region Occitanie/Pyrénées-Méditerranée (Reference number: 1901175) and the European Regional Development Fund (ERDF) (Project number: MP0022856). This study received funds from Alzheimer Prevention in Occitania and Catalonia (APOC Chair of Excellence – Inspire Program). This study has been partially supported through the grant EUR CARe N°ANR-18-EURE-0003 in the framework of the Programme des Investissements d'Avenir. The plasma measures of this study were supported by institutional gift funds (RJ Bateman, PI), institutional startup funds (AD Nguyen, PI), and National Institute on Aging grants NIH R56AG061900 and RF1AG061900 (RJ Bateman, PI). The MAPT study was supported by grants from the Gérontopôle of Toulouse, the French Ministry of Health (PHRC 2008, 2009), Pierre Fabre Research Institute (manufacturer of the omega-3 supplement), ExonHit Therapeutics SA, and Avid Radiopharmaceuticals Inc. The promotion of this study was supported by the University Hospital Center of Toulouse. The data sharing activity was supported by the Association Monegasque pour la Recherche sur la maladie d’Alzheimer (AMPA) and the INSERM-University of Toulouse III UMR 1295 Unit.

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Conceptualization, W-HL and PSB; methodology, W-HL and PSB; formal analysis, W-HL; investigation, JEM, AP, GA, ADN, YL, and RJB; data curation, W-HL; writing—original draft preparation, W-HL; writing—review and editing, KVG, JEM, SG, AP, GA, ADN, YL, RJB, BV, and PSB; supervision, BV and PSB; funding acquisition, ADN, RJB, and BV.

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The MAPT Study was approved by the French Ethical Committee located in Toulouse (CPP SOOM II) and authorized by the French Health Authority. All participants signed informed consent.

Conflict of interest

Washington University and Randall Bateman have equity ownership interest in C2N Diagnostics and receive income based on technology (blood plasma assay) licensed by Washington University to C2N Diagnostics. RJB receives income from C2N Diagnostics for serving on the scientific advisory board. Washington University, with RJB as co-inventor, has submitted the US nonprovisional patent application “Plasma Based Methods for Determining A-Beta Amyloidosis.” RJB has received honoraria as a speaker/consultant/advisory board member from Amgen, AC Immune, Eisai, and Hoffman-LaRoche, and reimbursement of travel expenses from AC Immune.

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Lu, WH., Giudici, K.V., Morley, J.E. et al. Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults. GeroScience 44, 1489–1503 (2022). https://doi.org/10.1007/s11357-022-00554-y

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