Apolipoprotein E genotype: the innocent bystander or active bridge between metabolic syndrome and cognitive impairment?

Apolipoprotein E [ApoE, APOE (gene)] is a multifunctional protein of the lipid and lipoprotein transport system mainly involved in metabolism of dietary lipids. Its polymorphic variants are considered a genetic risk factor of cognitive impairment in several neurodegenerative disorders such as Lewy body dementia, Huntington's disease, and Alzheimer's disease, as well as in vascular dementia and cerebrovascular disease. The precise mechanism by which APOE affects neurodegeneration is still unclear. Epidemiological and experimental studies demonstrated an influence of APOE on metabolic parameters but, to the best of our knowledge, no data are available about the exact role in humans of the effect of APOE on metabolic-cognitive syndrome (MCS). The latter is a model of cognitive impairment linked to metabolic syndrome identifying a grey zone between metabolic disorders and neuropathological process driving late-life cognitive decline. Although it may be a daring project that does not reach a final conclusion because of disease complexity, I hope to elucidate whether APOE may have a prominent role in MCS, going beyond the simple addition of separate mechanisms already known.