Exploring brain‐derived exosomal miRNA as a novel blood‐based biomarker for Alzheimer’s disease

Abstract Background Biomarkers of Alzheimer’s disease (AD) currently rely on invasive and time‐consuming methods such as cerebrospinal fluid analysis and neuroimaging. Non‐invasive blood‐based biomarkers are needed for early diagnosis and risk prediction. Brain‐derived exosomes are promising candidates for blood biomarkers, as they can cross the blood‐brain barrier and enter the bloodstream, and exosomal miRNAs could serve as potential biomarkers for identifying patients with AD and screening individuals at high risk. Here, we conducted a hospital‐based case‐control study to investigate exosomal miRNAs as biomarkers for AD. Method Exosomes were isolated from plasma samples of AD patients (n = 18) and healthy controls (HC; n = 18), and exosomal miRNAs were analyzed using high‐throughput sequencing. AD‐differentially expressed miRNAs were identified and their associations with Mini‐Mental State Examination (MMSE) and amyloid positron emission tomography with standardized uptake value ratio (PET‐SUVR) were evaluated by Spearman’s correlation analyses. Logistic regression was used to select miRNA biomarkers and construct a classifier to discriminate AD from HC. Result We identified 65 miRNAs (47 downregulated and 18 upregulated) that were differentially expressed in AD, and 20 of which were significantly associated with both MMSE and PET‐SUVR (all false discovery rate adjusted P <0.05) (Figure 1). We selected hsa‐miR‐33a‐5p and hsa‐miR‐342‐3p as potential biomarkers to identify AD from HC, with an area under the curve (AUC) reaching 100% in the internal validation, whereas a model consisting of gender, age, and apolipoprotein E ε4 only had an AUC of 0.63. Both miRNAs were significantly correlated with MMSE and PET‐SUVR after adjusting age and sex. The miRNA target analysis revealed that the target genes of hsa‐miR‐33a‐5p and hsa‐miR‐342‐3p were involved in multiple processes related to the nervous system, including axon guidance, neurotransmitter receptors and postsynaptic signal transmission, and dopaminergic synapse, among others (Figure 2). Conclusion Our results suggest that differentially expressed miRNAs are significantly correlated with the pathological process of AD and cognitive function, and that blood exosomal miRNAs have the potential to detect AD with high sensitivity and specificity. These findings may provide a basis for the development of non‐invasive blood‐based biomarkers for AD diagnosis and risk prediction.