Apolipoprotein E epsilon-4 as a genetic determinant of Alzheimer's disease heterogeneity

Alzheimer's disease (AD) displays a high degree of heterogeneity in terms of its etiology, presentation, prognosis, and treatment response. This can partly be explained by high-penetrance mutations in the amyloid precursor protein, presenilin 1 and presenilin 2 genes causing amyloid beta aggregation, which is a major pathogenic mechanism in the development of early-onset AD in a small subgroup of patients. Late-onset AD is considered a polygenic disorder in which cumulative risk resulting from interaction with modifiable environmental risk factors may be responsible for the majority of cases. The epsilon-4 allele of the apolipoprotein E (APOE) gene has emerged as the most significant genetic risk factor for late-onset AD, influencing nearly every pathogenic domain affected in AD. It is a major risk factor for cerebral amyloid angiopathy, recognized as a common pathological finding in an AD subtype associated with white matter dysfunction. The APOE epsilon-4 allele is also a known risk factor for ischemic stroke, which can result in vascular dementia or contribute to subcortical vascular dysfunction. In this review, we evaluate the clinical relevance of APOE genotyping in relation to cholesterol metabolism and available evidence on risk reduction strategies applicable to AD.