A multi-hit hypothesis for an APOE4-dependent pathophysiological state.

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• The Apolipoprotein E (APOE) gene is a major genetic risk factor for late-onset Alzheimer's disease (AD).
• The APOE4 genotype elevates AD risk compared to APOE3 and APOE2, and is linked to neurological deficits independent of amyloid or tau pathology.

Approach:

• This review synthesizes preclinical data comparing APOE3 and APOE4 effects on the central nervous system.
• A multi-hit hypothesis is proposed to elucidate how APOE4 induces a shift from cerebral physiology to pathophysiology.

Key Points:

• APOE4 is associated with neurodegeneration, neurovascular dysfunction, neuroinflammation, oxidative stress, and impaired cellular processes.
• These interconnected "hits" create a vulnerable APOE4 brain state, exacerbating degeneration and cognitive deficits.
• This vulnerability can occur with or without concurrent Alzheimer's disease-specific pathologies.

Conclusions:

• The APOE4 multi-hit hypothesis provides a framework for understanding APOE4-associated brain dysfunction.
• Further research is needed to clarify the complex interplay of these mechanisms and their downstream effects.