Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants

Importance A 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. Objective We 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 Participants A 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 Measures We compared the frequencies of binary traits (binomial distribution probability) and distributions of quantitative traits and PRS (Kolmogorov-Smirnov test). Results All 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 Relevance This 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. Question How does APOE Christchurch (APOECh) variant influence risk of Alzheimer’s disease (AD), cardiovascular disease, and dyslipidemia? Findings APOECh 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. Meaning Carriers 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. ### Competing Interest Statement All authors are employees at the Janssen Pharmaceutical Companies of Johnson & Johnson at the time this work was performed. Simon Lovestone is a founding director of Akrivia Health Ltd (UK). Mary Helen Black is currently an employee at Foresite Labs. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The UK Biobank study was conducted under generic approval from the NHS National Research Ethics Service (approval letter dated 17th June 2011, Ref 11/NW/0382). All participants gave full informed written consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript and/or supplement. Data used in the preparation of this article were obtained from the UK Biobank (https://www.ukbiobank.ac.uk/researchers/). All bona fide researchers from academic, commercial, and charitable organizations can apply access to the UK Biobank resource to conduct health-related research that is in the public interest.