Alzheimer’s disease (AD) accounts for 60–80% of all dementia cases, with women at higher risk due to both longevity and biological factors. Familial AD, caused by mutations in APP, PSEN1, and PSEN2, represents less than 5% of cases, whereas sporadic AD (>90%) is mainly associated with polymorphisms in APOE and TREM2, which influence amyloid beta (Aβ) clearance. The APOE4 allele remains the strongest genetic risk factor for sporadic AD, yet the precise role of Apolipoprotein E (ApoE) in disease pathogenesis is still not fully understood.

ApoE is a key regulator of lipid homeostasis in the central nervous system (CNS) and is predominantly expressed in astrocytes, with lower levels in microglia. Experimental models, including ApoE knockout and humanized APOE4 knock-in mice, as well as studies in human APOE4 carriers, reveal disruptions in lipid metabolism, cognitive function, and neuronal maintenance. Within the CNS, astrocytes and microglia play essential roles in immune regulation and tissue repair, but when ApoE function is compromised, these cells can become dysfunctional, driving chronic inflammation and neurodegeneration.

MicroRNAs (miRNAs) are small, non-coding RNA molecules that regulate the expression of most human genes. Their high stability in extracellular environments makes them promising candidates for diagnostic and prognostic biomarkers. Altered miRNA expression has been documented in biofluids and postmortem tissues from individuals with mild cognitive impairment (MCI) and AD, as well as in transgenic AD mouse models. However, the influence of ApoE dysfunction on miRNA regulation and its contribution to AD pathogenesis remain largely unexplored.

This Research Topic aims to bring together studies that connect miRNA dysregulation and ApoE biology to the molecular mechanisms underlying sporadic AD. We particularly encourage investigations addressing sex-specific effects, neuroinflammatory pathways, and the diagnostic potential of extracellular miRNAs.

- We welcome original research, reviews, and perspectives on, but not limited to:

- miRNAs and Apolipoprotein E deficiency in neurodegenerative diseases

- miRNAs and Apolipoprotein E polymorphisms in neurodegenerative diseases

- miRNAs as biomarkers in biofluids in relation to Apolipoprotein E polymorphisms

- Tissue-level miRNA dysregulation and its association with ApoE variants

- Sex-specific differences in miRNA regulation and ApoE-related pathology

- Interactions between miRNAs, ApoE, and neuroinflammation

Are you interested in contributing a manuscript to this Research Topic?

MicroRNA dysregulation and Apolipoprotein E in sporadic Alzheimer’s disease: molecular mechanisms, biomarkers, and sex-specific effects