Cardiovascular and lipid profile in APOEε3 Christchurch (R136S) variant carriers within the Colombian PSEN1-E280A kindred

Introduction: APOE variants modulate Alzheimer’s disease (AD) risk and influence lipid and cardiovascular profiles. The APOE3 Christchurch (APOE3Ch; R136S) variant has been associated with resistance to autosomal dominant Alzheimer’s disease, yet its systemic and cardiovascular effects remain poorly characterized. This is critical to inform the safety and translational potential of emerging APOE3Ch-targeted therapeutic strategies

Objective: To characterize the lipid and cardiovascular profiles of APOE3Ch carriers to explore its broader systemic implications

Methods: We studied 37 individuals from the Colombian PSEN1-E280A kindred stratified by APOE3Ch genotype (1 homozygote, 29 heterozygotes, 7 non-carriers), aged 19–77 years. Participants underwent standardized clinical assessments, fasting lipid profiles, and comprehensive cardiovascular phenotyping. Data were summarized using descriptive statistics and nonparametric tests, when appropriate.

Results: Sociodemographic, cardiovascular and lipid profile data are presented in Tables 1 and 2. No notable differences were observed in arterial stiffness, ankle–brachial index, carotid Doppler, or Holter measures. Sympathovagal indices are presented in Figure 1. APOE3Ch carriers showed less favorable age-stratified lipid/risk indices than non-carriers. Exploratory analyses of six PSEN1-E280A carriers found no distinct or deleterious cardiovascular profile.

Conclusions: Our findings provide a description of cardiovascular profiles in APOE3Ch carriers. Variations remained within or only slightly above established physiological ranges in heterozygous and were not accompanied by increased disease burden. A possible gene-dose effect suggests that APOE3Ch may exert a cumulative influence on systemic metabolism. These results offer a preliminary framework to inform cardiovascular biomarkers for future APOE3Ch-based therapies in AD.

Acknowledgments: The authors thank the participants of the Resist Alzheimer’s Project for making this work possible and honor Dr. Francisco Lopera’s lifelong dedication to advancing Alzheimer’s disease and related dementia research. A gift from Coefficient Giving and Remondi Family Foundation made this work possible.