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TOPLINE:

A fully automated plasma biomarker panel detected amyloid-beta (Aβ) positivity and monitored early amyloid accumulation in middle-aged cognitively unimpaired (CU) adults at risk for Alzheimer's disease.

METHODOLOGY:

• This study involved 400 middle-aged CU individuals at risk for the disease from the Alzheimer's and Families study longitudinal cohort, of whom 135 (median age, 63 years) were Aβ-positive (A+) and 265 (median age, 60.5 years) were Aβ-negative (A−); 54 of 342 participants with PET imaging were PET A+, and assessments were performed every 3 years.
• Plasma biomarkers — Aβ42/40, p-tau181, glial fibrillary acidic protein, neurofilament light, p-tau217, ApoE4, and p-tau181/Aβ42 and p-tau217/Aβ42 ratios — were quantified via fully automated immunoassays; cerebrospinal fluid (CSF) biomarkers included Aβ42/40, p-tau181, and total tau; MRI assessed cortical thickness, and amyloid PET quantified Aβ deposition.
• Aβ status was defined using CSF Aβ42/40 ratio (< 0.071) or amyloid PET Centiloid (A+; > 12). Cognitive function was assessed using the modified Preclinical Alzheimer's Cognitive Composite.
• The primary outcome was the performance of plasma biomarkers in detecting Aβ pathology; secondary outcomes included longitudinal associations between biomarkers and changes in Aβ, tau, neurodegeneration, and cognitive pathology.

TAKEAWAY:

• Plasma p-tau217/Aβ42 showed the highest accuracy in detecting PET Aβ positivity (area under the curve, 0.94), significantly outperforming all other biomarkers.
• All plasma biomarkers were significantly different between A+ and A− individuals, with plasma p-tau217/Aβ42 and p-tau217 showing the largest effect sizes (η², 0.28 and 0.23, respectively).
• Plasma Aβ42/40 was highly sensitive to random variability, affecting its reliability in detecting Aβ pathology, particularly when the coefficient of variation exceeded 9% for PET or 16% for CSF classification.
• Longitudinal increases in plasma p-tau217 and p-tau217/Aβ42 best predicted future Aβ accumulation (CSF Aβ42/40 reduction: β, −0.44; P < .0001; PET Centiloid increase: β, 0.33; P < .0001).

IN PRACTICE:

"Fully automated immunoassay-based blood biomarkers offer significant diagnostic, prognostic, and monitoring capabilities for CU individuals at risk of AD [Alzheimer's disease] even in a relatively short time span," the authors of the study wrote.

SOURCE:

This study was led by Armand González-Escalante, Barcelonaβeta Brain Research Center, Pasqual Maragall Foundation, Barcelona, Spain. It was published online on May 24, 2025, in eBioMedicine.

LIMITATIONS:

This study was limited by unmeasured factors such as lifestyle factors, occupational exposures, or genetic variants, which may still influence plasma biomarker levels and Aβ accumulation. Results from a middle-aged, at-risk cohort with low progression to mild cognitive impairment limited the generalisability to older populations. As a single-centre study, the results need to be replicated in larger, independent cohorts.

DISCLOSURES:

This study was funded by the European Research Council, ERA PerMed-ERA NET, and the Generalitat de Catalunya. Some authors reported receiving consultancy/speaker fees from several pharmaceutical organisations.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.