A new study published in Circulation Research demonstrates the increased risk of Alzheimer’s disease (AD) posed by the APOE4 variant is also associated with the risk of subclinical atherosclerosis in middle age. Further, the APOE2 variant protects against the development of subclinical atherosclerosis, similar to its protection against the development of AD.
The research, conducted at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, sheds new light on the role of APOE in cardiovascular diseases and suggests the need for treatment and prevention measures, especially in the first half of adult life.
“The results indicate that knowledge of which APOE isoform an individual has could improve the stratification of cardiovascular risk, especially during the initial phases of the development of cardiovascular disease,” noted co-first author Catarina Tristão Pereira a PhD candidate in neuroimaging at CNIC who is studying the connection between AD and atherosclerosis.
The APOE gene encodes apolipoprotein E, one of the functions of which is to help transport lipids in the blood. The main APOE alleles give rise to three apolipoproteins isoforms called APOE2, APOE3, and APOE4.
“Inheriting one or other of these alleles confers a different risk of developing distinct diseases, among them cardiovascular disease and Alzheimer disease,” said Cortés Canteli, PhD, a neuroscientist at the CNIC. Notably, people with APOE4 have high levels of circulating cholesterol which conveys a higher risk of developing atherosclerosis, while those with APOE2 have lower cholesterol and a lower risk of atherosclerosis.
The findings were part of the PESA-CNIC-Santander study, led by CNIC general director Valentin Fuster, MD, PhD, a prospective study of more than 4000 asymptomatic middle-aged participants who have been periodically examined with advanced imaging technologies since 2010 to screen for the presence and development of subclinical atherosclerosis.
While the exact mechanisms of APOE associations remain unclear, the CNIC team showed that APOE4 carriers between the ages of 40 to 50 years have higher levels of low-density lipoprotein (LDL) cholesterol—the so-called “bad” cholesterol—which confers an elevated risk of subclinical atherosclerosis development.
Meanwhile, the team noted that the study cohort who were carriers of APOE2 were largely protected from subclinical atherosclerosis in their femoral, carotid, and coronary arteries due to them having normal triglyceride levels and, in the case of the women and those in the age range of 40 to 44 years, low levels of circulating LDL. But among older men, aged 45 to 54 years, the protective effects of APOE2 required another factor, in this population this population was found to have enriched molecular pathways associated with anti-inflammatory processes, as wells as a reduced activity of genes that help drive blood coagulation and complement-cascade activation.
“These findings suggest that modulation of the immune system contributes to the protection against the early development of atherosclerosis in APOE2 carriers,” noted co-first author Raquel Toribio Fernández, PhD, a postdoc at CNIC.