Apolipoprotein E in Neurodegenerative Disorders

Apolipoprotein E (apoE) is a 34 kDa glycoprotein central to lipid transport in the brain and periphery. In humans three major isoforms—apoE2, apoE3 and apoE4—differ by single amino-acid substitutions yet exert profoundly different effects on neuronal health and disease. The ε4 allele of APOE is the strongest genetic risk factor for late-onset Alzheimer’s disease and is implicated in other neurodegenerative disorders through mechanisms that include altered lipid metabolism, promotion of amyloid-β aggregation, tau pathology and dysregulation of neuroinflammatory responses. In the central nervous system apoE is produced mainly by astrocytes and microglia, where it mediates cholesterol redistribution essential for synaptic remodelling and repair. Structural differences in apoE4 favour domain interaction and proteolytic cleavage, generating neurotoxic fragments that impair mitochondrial function and provoke cytoskeletal destabilisation. Beyond Alzheimer’s pathology, apoE variants modulate glial phagocytosis, blood–brain barrier integrity and cytokine release, thereby influencing the onset and progression of multiple disorders characterised by protein misfolding and chronic inflammation. Understanding isoform-specific effects on lipid homeostasis, protein aggregation and immune signalling is central to both biomarker development and targeted therapeutic strategies.

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Apolipoprotein E in Neurodegenerative Disorders publication trend

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Technical terms

Isoform: A variant of a protein differing in amino-acid sequence but arising from the same gene.

Amyloid-β: A peptide prone to aggregate into plaques, a hallmark of Alzheimer’s disease.

Microglia: Resident immune cells of the brain that clear debris and mediate inflammatory responses.

Glycosylation: The enzymatic attachment of sugar moieties to proteins, affecting stability and interactions.

Domain interaction: Intramolecular contacts between protein regions that influence overall conformation and function.

References

1. Apolipoprotein E aggregation in microglia initiates Alzheimer’s disease pathology by seeding β-amyloidosis. Immunity (2024).
2. Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate. Molecular Neurodegeneration (2023).
3. An association of CSF apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele. Alzheimer's Research & Therapy (2023).
4. Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders. Journal of Molecular Medicine (2016).