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ImportanceA few case studies have reported the APOE Christchurch (APOECh) variant to confer protective effects for Alzheimer’s disease (AD) and a higher risk of premature cardiovascular disease (CVD). However, these studies primarily focused on a single individual or siblings from the same family.ObjectiveWe sought to characterize the clinical characteristics of individuals with APOECh variation in 455,306 participants of the UK Biobank (UKB) to determine whether it is associated with AD protection or cardiovascular risk.Design, Setting, and ParticipantsA total of 37 individuals were identified as heterozygous carriers of APOECh in UKB sequencing data as of March 2022, resulting in allele frequency consistent with gnomAD (4.06×10−5). We limited our study to 36 European carriers and generated a noncarrier cohort matched on age, sex, and ancestry. Case-control analyses were performed to evaluate the frequency of 11 binary traits and differences in distributions of 80 quantitative traits and 10 polygenic risk scores (PRS) for lipid traits, CVD, and neurodegenerative diseases.Main Outcomes and MeasuresWe compared the frequencies of binary traits (binomial distribution probability) and distributions of quantitative traits and PRS (Kolmogorov-Smirnov test).ResultsAll 37 carriers are free of AD and only 4 have a parental history of AD. There are 22 out of 37 carriers with>1 cardiovascular (CV) condition in clinical and/or self-reported data, two of whom passed away due to heart disease. However, frequency of CVD, dyslipidemia, and hypertension is not enriched in carriers compared with matched non-carriers. Additionally, apolipoprotein B (apoB) is significantly lower in APOECh carriers before (p=0.004) and after statin adjustment (p=0.04). Comparisons of PRS show that carriers and non-carriers have a similar genetic burden of developing dyslipidemia and CVD, but carriers have lower PRS-based AD risk (p=0.02).Conclusions and RelevanceThis study demonstrates that APOECh carriers may have lower levels of apoB and a lower risk of AD. Cohorts with enriched cases are needed to further investigate whether the protective effect is linked to APOE genotypes or other factors.Key PointsQuestionHow does APOE Christchurch (APOECh) variant influence risk of Alzheimer’s disease (AD), cardiovascular disease, and dyslipidemia?FindingsAPOECh carriers do not have an elevated risk of dyslipidemia. However, carriers have lower levels of apolipoprotein B (apoB). Comparing polygenic risk scores of carriers vs. noncarriers of APOECh shows carriers are at a lower risk of developing AD before but not after adjusting for multiple comparisons.MeaningCarriers of APOECh may have a lower risk of developing AD due to lower apoB; however, further epidemiological and model organism studies are needed to validate these observations from the current study.