Blood transcriptomic signatures link β-amyloid deposition to molecular pathways across SCD, MCI, and dementia

Brain β-amyloid (Aβ) accumulation is a hallmark of Alzheimer's disease, but noninvasive detection remains challenging. Blood transcriptomics may provide accessible biomarkers associated with Aβ pathology.

We integrated peripheral blood transcriptomic profiling and MRI-derived structural metrics from 48 individuals across the cognitive continuum, including subjective cognitive decline (SCD), mild cognitive impairment (MCI), and dementia, stratified by Aβ-PET status. Predictive models were constructed using leave-one-out cross-validation (LOOCV), and selected genes were validated by qRT-PCR.

Cross-stage analysis identified RUNX1T1 and COL14A1 as consistently downregulated in Aβ-positive individuals regardless of clinical stage. A predictive model incorporating these two genes demonstrated moderate discrimination of Aβ-PET status in internal leave-one-out cross-validation (LOOCV) evaluation (AUC = 0.81). In addition, COL14A1 expression was associated with cortical thickness and hippocampal volume, whereas RUNX1T1 was primarily associated with hippocampal structure. Among individuals with MCI or dementia, HCN1 and NRG3 were upregulated, whereas KCNMB2 was downregulated in Aβ-positive subjects. A three-gene model based on these markers achieved an LOOCV AUC of 0.79.

These findings indicate that peripheral blood transcriptomic alterations are associated with Aβ pathology across clinical groups. RUNX1T1 and COL14A1 represent candidate peripheral biomarkers associated with Aβ pathology, while the observed molecular signatures and their associations with brain structural measures provide a basis for further validation in larger, longitudinal cohorts and mechanistic studies.