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MADRID — The apolipoprotein E4 (APOE4) genetic variant is associated with a higher risk for developing subclinical atherosclerosis in middle age, while the ε2 allele of the same gene confers vascular protection, conditioned by good control of low-density lipoprotein (LDL) cholesterol and triglycerides.

Researchers from the National Center for Cardiovascular Research (CNIC) in Spain have determined that one of the genes considered the most potent risk factor for developing late-onset Alzheimer's disease, the APOE4 gene, is also associated with a higher risk for developing subclinical atherosclerosis in middle age. The research also shows the positive side for carriers of the APOE2 variant, who are protected against early atherosclerotic cardiovascular disease, initially in the inflammatory context. The variant is also considered to be protective against Alzheimer's disease.

A study published in Circulation Research reflects research coordinated by Marta Cortés Canteli, PhD, neuroscientist at the CNIC and Miguel Servet researcher at the Jiménez Díaz Foundation Health Research Institute, and Valentín Fuster, MD, PhD, general director of CNIC. Its results may have important preventive and therapeutic implications for cardiovascular health, especially for young adults.

Conditioned Genetic Advantage

Cortés told the Medscape Spanish edition, "All carriers of the ε2 allele have the enormous genetic advantage of having a lower risk for developing atherosclerosis. However, we have identified that this protection depends on LDL-C levels in women and in the younger individuals in our study [between 40 and 44 years old]." Likewise, "we have observed that those ε2 patients who have triglyceride levels above 150 mg/dL also lose that protection." That is, maintaining a healthy lifestyle is important, "but this study reveals to us that controlling LDL-C and triglycerides, in the case of women and younger patients, allows the maintenance of the genetic advantage conferred by the ε2 allele."

The PESA-CNIC-Santander Study (Progression of Early Subclinical Atherosclerosis), led by Fuster, is a prospective study that includes more than 4000 asymptomatic middle-aged participants who have been exhaustively evaluated for the presence and development of subclinical atherosclerosis since 2010. This substudy included 3887 participants aged 45.8 ± 4.3 years, and 62% of participants were men. The included subjects were genotyped for APOE, and omic data were also evaluated.

APOE encodes apolipoprotein E, which, among other functions, helps transport lipids in the blood. The gene has three main alleles that give rise to different isoforms of this lipoprotein: APOE2, APOE3, and APOE4. "Having inherited one or the other of these alleles gives the individual a different risk of developing various diseases, including Alzheimer's and cardiovascular disease," Cortés pointed out.

In this study, the frequencies of the APOE ε2, ε3, and ε4 alleles were 0.060, 0.844, and 0.096, respectively.

Strict Control for ε4 Carriers

Genotype is a nonmodifiable risk factor for cardiovascular and neurodegenerative disease, but "it has been shown that the development of these diseases can be delayed in carriers of the ε4 allele with more years of education, more leisure activities, by following a healthy lifestyle, maintaining a balanced diet, exercising, and controlling cardiovascular risk factors," said Cortés. 

"All of this underscores, once again, the importance of maintaining a healthy lifestyle," said Fuster.

As expected, the study indicated that APOE4 carriers had the highest risk for cardiovascular disease and significantly higher odds of having subclinical atherosclerosis, compared with ε3/ε3 carriers. 

"The higher cardiovascular risk in individuals carrying the ε4 allele is largely due to their high levels of LDL-C. However, we cannot rule out that other cardiovascular risk factors may contribute, such as high-density lipoprotein cholesterol (HDL-C), triglycerides, hypertension, diabetes, and smoking, among others," said Cortés.

Other Risk Factors

Conversely, APOE2 carriers had the lowest risk for cardiovascular disease and significantly lower odds of having subclinical atherosclerosis in various vascular territories (carotids: 0.62, P = .00043; femorals: 0.60, P = 9.96 × 10⁻⁵; coronaries: 0.53, P = .00013).

This atheroprotective effect of APOE2 was largely independent of the associated lower levels of LDL-C and other cardiovascular risk factors. The protection conferred by the ε2 allele was greater with age (50 to 54 years: 0.49, P = .00045) and with normal (< 150 mg/dL) triglyceride levels (0.54, P = 4.70 × 10⁻⁹ versus 0.90, P = .67 if ≥ 150 mg/dL).

Furthermore, omic analysis of the study revealed an enrichment of several canonical pathways associated with anti-inflammatory mechanisms together with modulation of erythrocyte homeostasis, coagulation, and complement activation in ε2 carriers that could play a role in the atheroprotective effect of this allele.

This finding suggests, as coauthor Raquel Toribio Fernández, PhD, noted in a press release, that "the modulation of the immune system present in APOE2 individuals could be contributing to protection against atherosclerosis in the earlier stages."

Inflammation and Coagulation 

The atheroprotective mechanisms of the ε2 allele are not fully understood. "Our omics analysis allowed us to find molecular pathways involved in inflammatory and coagulation processes, among others, that are expressed differently in ε2 allele carriers, but with these analyses, causality cannot be demonstrated," said Cortés. That is, it is not certain that these pathways are responsible for the protective effect of ε2. However, an individual carries ε2 from birth, "so it is reasonable to think that, for example, the immunomodulation observed in ε2 individuals sustained over time may have a beneficial impact on the development of atherosclerosis, especially when it is known that inflammation is one of the most important factors in the development of the [disease]," said Cortés.

These results suggest that knowing which APOE isoform is present in each patient could improve the stratification of cardiovascular risk, "especially during the early stages of cardiovascular disease development," emphasized coauthor Catarina Tristão, a PhD student at CNIC.

APOE and Subclinical Atherosclerosis

Cardiovascular risk measured by typical scales is based on the presence of risk factors and implemented in clinics to identify individuals who should follow prevention or medication strategies. But the PESA study has shown that almost 60% of patients considered to be at low cardiovascular risk have subclinical atherosclerosis in at least one vascular territory. "This tells us that there is a portion of the population that develops atherosclerosis but is not subjected to those intervention strategies because they are not identified as being at high cardiovascular risk," said Cortés.

"Performing genetic testing for APOE would improve that prediction, and more aggressive strategies for controlling LDL-C and triglycerides could be implemented, for example, in APOE4 individuals (to decrease their risk), and in APOE2 individuals (so they do not lose their protection)." However, "any genetic test carries important ethical implications that the scientific community would have to carefully consider," Cortés added.

The study was funded by the European Regional Development Fund (FEDER — A Way to Build Europe) and the European Social Fund (ESF — Investing in Your Future). The authors declared no relevant financial conflicts of interest. 

This story was translated from the Medscape Spanish edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.