Variation in APOE ε4 Prevalence and Brain Health Associations by European Descent in White All of Us Participants

Variation in APOE ε4 Prevalence and Brain Health Associations by European Descent in White All of Us Participants | medRxiv /* */ /* */ <!-- <!-- /*! * yepnope1.5.4 * (c) WTFPL, GPLv2 */ (function(a,b,c){function d(a){return"[object Function]"==o.call(a)}function e(a){return"string"==typeof a}function f(){}function g(a){return!a||"loaded"==a||"complete"==a||"uninitialized"==a}function h(){var a=p.shift();q=1,a?a.t?m(function(){("c"==a.t?B.injectCss:B.injectJs)(a.s,0,a.a,a.x,a.e,1)},0):(a(),h()):q=0}function i(a,c,d,e,f,i,j){function k(b){if(!o&&g(l.readyState)&&(u.r=o=1,!q&&h(),l.onload=l.onreadystatechange=null,b)){"img"!=a&&m(function(){t.removeChild(l)},50);for(var d in y[c])y[c].hasOwnProperty(d)&&y[c][d].onload()}}var j=j||B.errorTimeout,l=b.createElement(a),o=0,r=0,u={t:d,s:c,e:f,a:i,x:j};1===y[c]&&(r=1,y[c]=[]),"object"==a?l.data=c:(l.src=c,l.type=a),l.width=l.height="0",l.onerror=l.onload=l.onreadystatechange=function(){k.call(this,r)},p.splice(e,0,u),"img"!=a&&(r||2===y[c]?(t.insertBefore(l,s?null:n),m(k,j)):y[c].push(l))}function j(a,b,c,d,f){return q=0,b=b||"j",e(a)?i("c"==b?v:u,a,b,this.i++,c,d,f):(p.splice(this.i++,0,a),1==p.length&&h()),this}function k(){var a=B;return a.loader={load:j,i:0},a}var l=b.documentElement,m=a.setTimeout,n=b.getElementsByTagName("script")[0],o={}.toString,p=[],q=0,r="MozAppearance"in l.style,s=r&&!!b.createRange().compareNode,t=s?l:n.parentNode,l=a.opera&&"[object Opera]"==o.call(a.opera),l=!!b.attachEvent&&!l,u=r?"object":l?"script":"img",v=l?"script":u,w=Array.isArray||function(a){return"[object Array]"==o.call(a)},x=[],y={},z={timeout:function(a,b){return b.length&&(a.timeout=b[0]),a}},A,B;B=function(a){function b(a){var a=a.split("!"),b=x.length,c=a.pop(),d=a.length,c={url:c,origUrl:c,prefixes:a},e,f,g;for(f=0;f<d;f++)g=a[f].split("="),(e=z[g.shift()])&&(c=e(c,g));for(f=0;f<b;f++)c=x[f](c);return c}function g(a,e,f,g,h){var i=b(a),j=i.autoCallback;i.url.split(".").pop().split("?").shift(),i.bypass||(e&&(e=d(e)?e:e[a]||e[g]||e[a.split("/").pop().split("?")[0]]),i.instead?i.instead(a,e,f,g,h):(y[i.url]?i.noexec=!0:y[i.url]=1,f.load(i.url,i.forceCSS||!i.forceJS&&"css"==i.url.split(".").pop().split("?").shift()?"c":c,i.noexec,i.attrs,i.timeout),(d(e)||d(j))&&f.load(function(){k(),e&&e(i.origUrl,h,g),j&&j(i.origUrl,h,g),y[i.url]=2})))}function h(a,b){function c(a,c){if(a){if(e(a))c||(j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}),g(a,j,b,0,h);else if(Object(a)===a)for(n in m=function(){var b=0,c;for(c in a)a.hasOwnProperty(c)&&b++;return b}(),a)a.hasOwnProperty(n)&&(!c&&!--m&&(d(j)?j=function(){var a=[].slice.call(arguments);k.apply(this,a),l()}:j[n]=function(a){return function(){var b=[].slice.call(arguments);a&&a.apply(this,b),l()}}(k[n])),g(a[n],j,b,n,h))}else!c&&l()}var h=!!a.test,i=a.load||a.both,j=a.callback||f,k=j,l=a.complete||f,m,n;c(h?a.yep:a.nope,!!i),i&&c(i)}var i,j,l=this.yepnope.loader;if(e(a))g(a,0,l,0);else if(w(a))for(i=0;i (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0];var j=d.createElement(s);var dl=l!='dataLayer'?'&l='+l:'';j.src='//www.googletagmanager.com/gtm.js?id='+i+dl;j.type='text/javascript';j.async=true;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-P4HH5NV'); Skip to main content Home About Submit ALERTS / RSS Search for this keyword Advanced Search Variation in APOE ε4 Prevalence and Brain Health Associations by European Descent in White All of Us Participants View ORCID Profile Jaime Perales-Puchalt , View ORCID Profile Clayton O. Mansel , View ORCID Profile Olivia J. Veatch doi: https://doi.org/10.1101/2025.07.16.25331679 Jaime Perales-Puchalt 1 University of Kansas Alzheimer’s Disease Research Center; University of Kansas Medical Center ; Kansas, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Jaime Perales-Puchalt Clayton O. Mansel 2 Department of Cell Biology and Physiology, University of Kansas Medical Center ; Kansas, USA BA Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Clayton O. Mansel Olivia J. Veatch 3 Department of Psychiatry and Behavioral Sciences; University of Kansas Medical Center ; Kansas, USA PhD Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Olivia J. Veatch Abstract Full Text Info/History Metrics Data/Code Preview PDF Abstract Importance The APOE ε4 allele is among the best-established genetic risk factor for Alzheimer’s disease. Different ethnic and racial groups have varying APOE ε4 prevalences. The prevalence of APOE ε4 also varies among European regions, yet White Americans are treated as a monolith, potentially impacting recruitment decisions and risk profile estimations. Objective To test whether White Americans of Southern European descent have a lower prevalence of APOE ε4 than their Northern European descent peers, and secondarily, if APOE ε4-brain health outcomes vary by European descent. Design, setting and participants Cross-sectional analyses of the nationwide All of Us cohort study in the United States. Overall inclusion criteria were reporting only White race, and countries of descent from Northern, Central or Southern Europe without overlap. Enrollment opened in May 2018. Analyses were conducted April-June 2025. Exposures Regions of European descent (Northern, Central and Southern) from the Basics Survey. Main Outcomes and Measures APOE ε4 using variants rs429358 and rs7412, coded as zero, one or two copies. Results Among those aged ≥18 (n=77,676), the percentage of European descent was 7.7% Southern and 64.7% Northern. Age and female sex at birth were 55.5 years and 55.8% among Americans of Southern and 56.3 years and 57.4% among those of Northern European descent. APOE ε4 allele frequency was 17.4% for one and 0.1% for two copies among Americans of Southern, and 24.9% and 2.0% for Northern European descent. Logistic regression models confirmed these differences: compared to Americans of Southern European descent, those of Northern European descent had an Odds Ratio of having one APOE ε4 allele of 1.60 (1.49-1.71), and 2.21 (1.71-2.88) of having two APOE ε4 alleles. European descent moderated associations between APOE ε4 allele frequency and two brain health outcomes (interaction p≤0.10). Conclusions and Relevance The frequency of APOE ε4 among Americans of Southern European descent was lower than that of Northern European descent and associations with some brain health outcomes varied. Future studies need to use probabilistic samples to confirm these findings. The concept of White race might be too broad when making racial comparisons of APOE ε4 frequency and its effects. Question Is the prevalence of APOE ε4 reduced when comparing Southern European to Northern European descent American adults who identify as only White race? Findings In this cross-sectional analysis of a cohort study (n=77,676 American adults), those of Northern European descent had 60% higher odds of having one, and 120% of having two copies of APOE ε4 compared to those of Southern European descent. Meaning Among White American adults, the prevalence of APOE ε4 differs by region of European descent; future studies need to confirm these findings using genetically inferred ancestry and probabilistic samples with stronger external validity. Introduction Apolipoprotein ε4 ( APOE ε4) is the strongest allelic risk factor for late-onset Alzheimer’s disease (AD). 1 US-based studies suggest that the prevalence and effects of APOE ε4 vary by race/ethnicity. 2 These ethnoracial differences matter because APOE ε4 is often related to adverse events and outcomes, 3 , 4 and self-identified ethnoracial data provide an inexpensive approach to make recruitment decisions, estimating risk profiles, and tailoring interventions. However, ethnoracial classifications ignore within-group variability. White Americans are largely of European descent, 5 and are the largest group in the US population and dementia trials. 6 Previous studies in Europe show that APOE ε4 prevalence is lower among Southern, than among Northen Europeans with AD. 7 , 8 Europeans and European Americans from these regions can be differentiated consistently in a genome-wide single nucleotide polymorphism panel. 9 In this manuscript, we tested whether the prevalence of APOE ε4 and its association with brain health outcomes differ between Americans of Northern (AmEuro-N) and Southern European descent (AmEuro-S). In line with previous research, 7 , 8 we hypothesize that White AmEuro-S will have a lower prevalence of APOE ε4 than AmEuro-N. Methods Sample This was a cross-sectional secondary analysis of the All of Us cohort study. 10 This study opened for enrollment in May 2018 and consists of a convenience sample of participants ≥18 years old who were recruited via multiple approaches at more than 340 recruitment sites across the US. The study collects health questionnaires, electronic health records (EHRs), and biospecimens. Informed consent is conducted in person or through eConsent. The protocol was reviewed by the Institutional Review Board (IRB) of the All of Us Research Program. We selected three subsamples of participants: Subsample 1 (APOE ε4 prevalence): Age at consent ≥18; available APOE ε4 genotypes; White race only; descend from Northern, Central or Southern European countries without overlap. Subsample 2a and 2b (health survey APOE ε4-brain health association): Same as ‘Subsample 1’ plus age ≥60; no missing data on sex at birth and health survey outcomes. Subsample 3 (EHRs APOE ε4-brain health association): Same as ‘Subsample 2’ but no missing EHR-derived outcome data instead of health survey outcomes. Race, Ethnicity, Country of Descent Definitions, and APOE Genotyping Self-reported Race, Ethnicity and country/es of descent were drawn from the Basics survey. We categorized European descent into Northern, Central, and Southern based on previous studies. 7 , 8 APOE ε4 genotypes (primary outcome) were ascertained from single-nucleotide variants from the All of Us Allele Count/Allele Frequency unphased callset (rs429358 and rs7412), which encompasses variants exceeding a population-specific minor allele frequency threshold of >1% or allele count depth >100. 11 Genotype extraction was performed using PLINK 1.9.12 and imputed with R as previously described. 11 Secondary Brain Health Outcomes The first outcome, from the Behavioral Health and Personality survey, was self-reported frequency of memory problems based on the question, “How often do you have problems remembering appointments or obligations?” Responses (five-point Likert scale) were dichotomized into never vs sometimes to very often. The second outcome, from the Personal and Family Health survey, was self-reported history of dementia or cognitive impairment (yes/no), based on whether participants endorsed themselves in response to either of two questions about family history of dementia or memory loss. The third outcome was dementia diagnosis (yes/no), ascertained from EHRs and defined using a validated computable phenotype with excellent predictive value. 13 Participants were labelled as a dementia case if they had five or more visits with matching ICD-9/ICD-10 codes or one matching drug prescription. Statistical Analysis We conducted analyses between April and June 2025. We used descriptive statistics to characterize the subsamples. The association between APOE genotype and European country descent group was analyzed using a multinomial logistic regression with Southern European set as the reference group using the nnet package in R. In Subsample 1, models were analyzed raw and controlling for ethnicity, as suggested by literature. 2 The results are presented as odds ratios (95% confidence interval) and p values were calculated using Wald tests. For subsamples 2a, 2b, and 3, the associations between APOE genotype (0 vs 1 APOE ε4 copy and 0 vs 2 copies) and the outcome were analyzed using multivariable logistic regression models stratified by European descent country group. Models were adjusted for ethnicity, sex assigned at birth, and age, as suggested by literature. 2 We used Likelihood Ratio tests comparing the additive to the multiplicative model to test for interactions between APOE genotype and European country descent group. The threshold for statistical significance for all non-interactive analyses was set at α=0.05, as we only proposed one hypothesis and all other tests were exploratory. For the interaction tests, the threshold was set at α=0.10. All analyses were conducted using R version 4.4.0 and RStudio version 2024.04.0 within the All of Us Researcher Workbench. Results Out of a total of 133,074 participants who reported only White race, 77,676 participants were included in subsample 1, 10,112 in subsample 2a, 24,274 in subsample 2b, and 39,197 in subsample 3 ( Table 1 ). In Subsample 1, the most frequent countries were England (67.7%) and Ireland (37.0%; AmEuro-N), Germany (70.8%) and Poland (33.3%; Central: AmEuro-C), and Italy (86.6%) and Spain (16.1%; AmEuro-S). APOE ε4 allele prevalence was 17.4% for one and 0.1% for two copies among AmEuro-S, 22.5% and 1.7% for AmEuro-C and 24.9% and 2.0% for AmEuro-N. Logistic regressions showed that AmEuro-C and AmEuro-N had a significantly higher APOE ε4 prevalence thano AmEuro-S ( Table 2 ). Odds ratios increased slightly when including only those ≥60 years old and barely changed when controlling for Latino ethnicity. View this table: View inline View popup Table 1. Characteristics of the subsamples View this table: View inline View popup Download powerpoint Table 2. Associations between descent groups and APOE ε4 status in subsample 1 Associations between APOE ε4 frequency and self-reported memory loss and dementia diagnosis were modified by descent (interaction p≤0.10; Table 3 ). Trends generally showed stronger associations between APOE ε4 and outcomes among AmEuro-N than AmEuro-S, and were statistically significant among AmEuro-N but not AmEuro-S. An outlier was the association between two vs zero copies of APOE ε4 on dementia diagnosis, which was stronger among AmEuro-S than AmEuro-N (p<0.05). View this table: View inline View popup Table 3. Associations between APOE ε4 status and brain health outcomes by descent group Discussion To our knowledge, this is the first study to explore the variation in APOE ε4 prevalence and brain health associations by European descent in White US individuals. In line with our hypothesis, we showed that the prevalence of APOE ε4 among AmEuro-S was lower than that of AmEuro-N. Like previous research, 7 , 8 prevalence among AmEuro-C resembled that of AmEuro-N. European descent moderated associations between APOE ε4 frequency and some brain health outcomes. Study limitations included 1) a non-population-based sample, with questionable generalizability, despite prevalence estimates that resemble European population-based samples (e.g., 14.4% in Spain and 27.0% in the UK); 7 , 8 2) lower sample sizes among AmEuro-S; 3) the use of EHR billing codes instead of clinical protocols to identify dementia cases, and 4) not accounting for intra-country descent variability. Future studies should 1) use probabilistic samples to confirm these findings, 2) assess AD and cognitive impairment using standard criteria, and explore 3) operationalizations to represent Americans of mixed European descent, 4) effect mechanisms, and 5) the role of genetic ancestry. We conclude that the concept of White race might be too broad when comparing APOE ε4 prevalence and risk among races and ethnicities. Researchers need to consider intra-group European descent differences among White Americans for power-sampling, recruitment, developing risk profiles and plan for adverse effects. Data Sharing Statement Data Data Available No Additional Information Data from the All of Us Research Program are publicly available at www.allofus.nih.gov . We used release version 8, which includes participant data with a cutoff date of October 1, 2023. All data access and analyses were conducted within a secure informatic workspace provided by the National Institutes of Health. Data Availability statement All data used in this study can be accessed by qualified researchers at allofus.nih.gov . Source code for these analyses is published as a Community Workspace within the All of Us Researcher Workbench and is available at ( https://workbench.researchallofus.org/workspaces/aou-rw-662ce24a/europeandescentofwhiteamericansandapolipoprotein4/data ) Acknowledgements We acknowledge All of Us participants for their contributions, without whom this research would not have been possible. We also thank the National Institutes of Health’s All of Us Research Program for making available the participant and genetic data examined in this study. The All of Us Research Program is supported by the National Institutes of Health, Office of the Director: Regional Medical Centers: 1 OT2 OD026549; 1 OT2 OD026554; 1 OT2 OD026557; 1 OT2 OD026556; 1 OT2 OD026550; 1 OT2 OD 026552; 1 OT2 OD026553; 1 OT2 OD026548; 1OT2 OD026551; 1 OT2 OD026555; IAA #: AOD 16037; Federally Qualified Health Centers: HHSN 263201600085U; Data and Research Center: 5 U2C OD023196; Biobank: 1 U24 OD023121; The Participant Center: U24 OD023176; Participant Technology Systems Center: 1 U24 OD023163; Communications and Engagement: 3 OT2 OD023205; 3 OT2 OD023206; and Community Partners: 1 OT2 OD025277; 3 OT2 OD025315; 1 OT2 OD025337; 1 OT2 OD025276. In addition, the All of Us Research Program would not be possible without the partnership of its participants. References 1. ↵ Long JM , Holtzman DM . Alzheimer Disease: An Update on Pathobiology and Treatment Strategies . 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