SMALL FRAGMENTS OF AB FOR THE DIAGNOSIS OF ALZHEIMER´S DISEASE AND PREDICTION OF ARIA IN IMMUNOTHERAPY

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tau tangles. As populations age, AD represents a growing global health challenge, with prevalence rising with aging and an expected three-fold increase in affected individuals by 2050. This escalating burden highlights the urgent need for improved tools for early diagnosis and disease monitoring.
Plasma-based biomarkers have gained increasing attention due to their non-invasive and broad clinical accessibility nature. Among these, plasma pTau217 has emerged as one of the most promising markers of AD pathology. However, additional biomarkers are required to improve diagnostic accuracy, prognostic value, and mechanistic understanding of disease progression.
Proteolytic and immune-mediated clearance pathways are consistently reported to be disrupted in AD and play a critical role in cerebral Aβ homeostasis. Impairments in these pathways contribute to reduced Aβ clearance leading to Aβ accumulation within the brain. Proteolytic processing of Aβ generates mid-domain fragments, which reflect downstream degradation by Aβ-clearing pathways. Dysregulation of these clearance-related processes may therefore provide complementary information on disease stage and progression and may be detectable in peripheral blood.
Here, we demonstrate that small Aβ fragments are detectable in blood and can reflect the stage of AD pathology. In addition, we show a novel assay to assess Aβ-clearance efficiency in monocytes, a functional measure strongly associated with AD and cerebral amyloid angiopathy. Together, these findings support the potential of clearance-related biomarkers as valuable additions to current plasma-based diagnostic strategies for AD.