Cholesterol: A Possible Mediator of APOE Risk for Alzheimer's Disease

Abstract

Despite the well-established link between the ε4 allele of the apolipoprotein E (APOE) gene and AD, the underlying mechanisms that mediate the risk of developing AD remain elusive. Literature on the role of APOE in cholesterol metabolism suggests that blood cholesterol may be a key factor in the development of AD pathology. Current study aims to investigate whether total cholesterol differs by APOE status and whether this relationship is predictive of AD diagnosis and its biomarkers. Baseline total cholesterol, APOE status, AD diagnosis, global cognitive function, brain Aβ, plasma Aβ40 and Aβ42, and cerebrospinal fluid (CSF) Aβ, tau, and phosphorylated tau were collected between 2004 and 2019 from a sample of 3,099 older adults in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Higher total cholesterol was associated with AD incidence, higher Aβ in the brain, lower CSF Aβ, lower plasma Aβ40 and Aβ42, poorer cognitive function, and the APOE ε4 allele. Survival analysis showed that ε4 carriers had highest hazard rates of AD, but that cholesterol did not alter time to AD diagnosis. The findings suggest that total cholesterol in later life is predictive of AD and related biomarkers, but further research is needed to elucidate how blood cholesterol may relate to APOE risk for AD.