A six-year risk assessment for dementia and Alzheimer's disease in the general population through immunoprecipitation-mass spectrometry plasma amyloid quantification - 16/04/25

Doi : 10.1016/j.tjpad.2025.100186

Germain U. BUSTO ^1,^2,^{⁎
Germain U. Busto and Christophe Hirtz contributed equally as co–first authors}, Christophe HIRTZ ^1,^3,^{⁎
Germain U. Busto and Christophe Hirtz contributed equally as co–first authors}, Isabelle CARRIERE ¹, Karim BENNYS ^1,², Laure-Anne GUTIERREZ ¹, Jana KINDERMANS ³, Catherine HELMER ⁴, Audrey GABELLE ^1,^2,^{^{†
Sylvain Lehmann, Claudine Berr and Audrey Gabelle contributed equally to this work as co–senior authors}}, Sylvain LEHMANN ^1,^3,^{^{†
Sylvain Lehmann, Claudine Berr and Audrey Gabelle contributed equally to this work as co–senior authors},}^⁎ , Claudine BERR ^1,^{^{†
Sylvain Lehmann, Claudine Berr and Audrey Gabelle contributed equally to this work as co–senior authors}}
¹ INM, University of Montpellier, INSERM, 80 Av. Augustin Fliche, 34000, Montpellier, France
² Memory Resource and Research Center, Department of Neurology, University of Montpellier Hospital, 80 avenue Augustin Fliche, 34295, Montpellier, France
³ University of Montpellier, IRMB, CHU Montpellier, 80 avenue Augustin Fliche, 34295, Montpellier, France
⁴ University of Bordeaux, INSERM UMR U1219, Bordeaux Population Health (BPH) Research Centre, 146 rue Léo-Saignat. 33076, Bordeaux, France

^‡Corresponding author. Pr Sylvain Lehmann, CHU and University of Montpellier, 80 av Fliche, 34295 Montpellier, France, Tel: +33 (0)4 67 33 71CHU and University of Montpellier80 av FlicheMontpellier34295France

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Abstract

BACKGROUND

Identifying individuals at risk for dementia and Alzheimer’s disease (AD) in the general population (GP) is increasingly essential due to new diagnostic criteria and opportunities for effective interventions. Plasma-based biomarkers (pBB) offer a promising approach for detecting positive amyloid profile. However, their effectiveness in predicting clinical dementia and AD risk at the GP level remains largely unexplored.

OBJECTIVES

To assess the risk of clinical dementia and AD using pBB amyloid biomarkers in GP using the most up-to-date proteomic techniques.

DESIGN

Case-cohort study randomly selected from a prospective cohort.

SETTING

The three-city community-living study.

PARTICIPANTS

Over 65 years recruited from the electoral rolls of three French cities.

MEASUREMENTS

pBB amyloid levels (Aβ42, Aβ40 and APP669–711) were measured in the plasma using the mass spectrometry-based (IPMS)-Shimadzu modified technology. Patients were monitored for up to 6 years for incident dementia and AD according to DSM-IV and NINCDS/ADRDA criteria. Cox proportional hazard models adjusted for multiple covariables, including age and renal function, were used to estimate hazard ratios.

RESULTS

Plasma samples from 327 participants were analyzed with a mean age 83 years (80-87), 64.8% females and a median follow-up time of 2.7 years (0.8-4.8) and including 121 incident dementia cases. Our findings indicate that the Aβ42/Aβ40 ratio, along with a composite score that encompasses APP669–711 and Aβ40/Aβ42 ratios, serves as significant predictors of clinical dementia [HR(95%CI) = 3.52 (1.69-7.32), p-value<0.001 and 4.34 (2.06-9.17), p-value<0.001, respectively] and AD risk over a six-year period, while also accounting for age and sex interactions. Furthermore, elevated Aβ40 levels correlate with an increased risk of developing dementia (HR=2.56, 95% CI 1.22-5.35, p=0.01) and AD (HR=2.60, 95%CI 1.06-6.36, p=0.04), and our study confirms that Aβ42 concentrations are significantly influenced by renal function.

CONCLUSIONS

This research advances the potential application of plasma amyloid biomarkers for assessing the risk of clinical dementia and AD in the general population within short period of time, positioning it as a valuable tool alongside existing plasma PT217 biomarkers or using ratio of both of them.

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Keywords : Population-based, Alzheimer’s disease, dementia, plasma, amyloid