Inflammation-related miR-155-5p as an APOE ε4-modulated biomarker for amyloid pathology in mild cognitive impairment

Background Alzheimer's disease (AD), the most common neurodegenerative cause of dementia, is defined by amyloid-β (Aβ) plaques and neurofibrillary tangles of hyperphosphorylated tau, while inflammatory processes are increasingly recognized as contributors to its pathogenesis. However, the clinical relevance of inflammation-related microRNAs (miRNAs) in AD remains unclear. Objective To evaluate whether inflammation-related miRNAs in plasma and cerebrospinal fluid (CSF) are associated with AD pathology and apolipoprotein E ( APOE ) ε4 status in individuals with mild cognitive impairment (MCI). Methods We investigated the expression of inflammation-related miR-125b, miR-146a, and miR-155-5p in plasma and CSF of individuals with MCI (N = 103), stratified by APOE ε4 status. Associations with established CSF biomarkers of AD pathology were assessed. In a subset receiving the anti-Aβ antibody lecanemab (N = 18), longitudinal changes in plasma inflammation-related microRNA levels were evaluated. Results Plasma miR-155-5p levels in APOE ε4 non-carriers were associated with the CSF Aβ 42/40 ratio, whereas in ε4 carriers, CSF miR-155-5p levels correlated with phosphorylated tau 181 and total tau. miR-155-5p was the only inflammation-related miRNA showing consistent APOE ε4-dependent differential expression in both plasma and CSF. In the lecanemab-treated subset, plasma miR-155-5p increased significantly after 6 months and remained elevated at 12 months. Conclusions miR-155-5p, an inflammation-related miRNA modulated by APOE ε4, is associated with AD-relevant pathological features and may provide complementary information at the MCI stage, with potential utility in monitoring biological responses to anti-Aβ therapy.