Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Reference Assembly: GRCh37/hg19
Transcript: NM_000041; ENSG00000130203
dbSNP ID: NA
Coding/Non-Coding: Both
Genomic Region:

Findings

The APOE region or locus is a segment of DNA with several genes in close apposition, including APOE. Its boundaries are not strictly defined, spanning a stretch between 0.2 and 10 Mb long. In 5’ to 3’ order, it usually includes the mitochondrial membrane translocase gene TOMM40, APOE, and the apolipoprotein genes of the APOC1-C4-C2 gene cluster. Some studies also include genes upstream of TOMM40 (e.g., BCAM, PVRL2 and NECTIN2), and/or genes downstream of the APOC cluster (e.g., CLPTM1 and RELB). Most of these genes form part of biological pathways that have been implicated in AD pathology, including lipid metabolism, the immune system, and mitochondrial function (Blue et al., 2020; Zhou et al., 2021).

Multiple large association studies, including individuals of different ancestries, have found the APOE region associated with late-onset Alzheimer’s disease (AD), with effects on susceptibility, age of onset, and endophenotypes (e.g., Kim et al., 2011; Kamboh et al., 2012; Miyashita et al., 2013; Nho et al., 2017; Yan et al., 2018; Nazarian et al., 2019; Jansen et al., 2019; Blue et al., 2020; Meng et al., 2020; Ali et al., 2023; Wang et al., 2024). Indeed, the APOE region is so strongly associated with AD that studies looking for new AD-relevant variants often exclude it to keep weaker effects from being drowned out (e.g., Bellenguez et al., 2022; Feb 2021 news).

Many variants in the APOE region are in high linkage disequilibrium, that is, they are often inherited together, making it difficult to distinguish between those that cause disease and those simply tagging along as genetic co-travelers (see e.g., Martin et al., 2000). In particular, many variants have proven to be in high linkage disequilibrium with C130R (APOE4), the strongest and most consistent risk factor for AD, at least in cohorts of European ancestry. Indeed, this high degree of linkage fueled a controversy in the field as to whether APOE4 or a nearby polymorphism in the TOMM40 gene underlay elevated AD risk (Roses et al., 2010). Two large studies, including an analysis of 15 genome-wide association study datasets, placed the blame squarely on APOE4 (Jun et al., 2012; Cruchaga et al., 2011), leading to the current consensus that APOE4 is the major causal variant (see, e.g., Andrews et al., 2019; Belloy et al., 2020). Another complication is that, despite the long history of AD research on the common APOE alleles, methodological issues still plague the field. For example, the variability in the reliability of many widely used APOE genotyping methods may result in irreproducible associations (Belloy et al., 2022).

Nevertheless, some studies suggest noncoding variants outside the APOE gene may be associated with AD independently of the common APOE alleles. For example, nine variants in the APOC1 and PVRL2 genes were reported as causally affecting AD risk independently of the APOE4 and APOE2 alleles (Zhou et al., 2019). Strikingly, some of the reported effect sizes were comparable to those of APOE4 and APOE2. Also, Blue and colleagues described an intergenic variant, rs192879175, as associated with AD among APOE3 homozygotes (Blue et al., 2020). In addition, a GWAS of brain biochemical phenotypes found associations between non-coding variants in the APOE region and levels of AD-related proteins, including ApoE and the Aβ42/Aβ40 ratio (Oatman et al., 2023), and a GWAS meta-analysis identified four variants associated with PET amyloid levels (Ali et al., 2023). The effects may vary depending on ancestry—for example, rs5117 has a strong effect on PET amyloid in non-Hispanic whites, a weaker effect in Asians, and no effect in African Americans.

Another way in which variants in the APOE region may contribute to AD risk is by modifying the effects of the common APOE alleles. Roses and colleagues, for example, proposed that one way in which the long poly-thymine repeat variant in TOMM40, also known as ‘523, may increase susceptibility to AD is by modulating expression of APOE4 (Lutz et al., 2016; Linnertz et al., 2014). Subsequent studies have also reported TOMM40 effects on AD risk mediated by APOE genotype (e.g., Blue et al., 2020; Li et al., 2022; Liang et al., 2022). Interestingly, a study of non-demented Blacks found that homozygous carriers of a short ‘523 poly-T repeat experienced a faster decline in global cognition and visuospatial ability with aging if they were also homozygous for the APOE3 allele, but a slower decline if they carried at least one APOE4 allele (Deters et al., 2021). Variants in other genes in the APOE region have also been found to have APOE genotype-specific effects. For example, a variant located upstream of APOC1, rs438811, was associated with increased odds of AD, but only in APOE4 carriers (Zhang et al., 2018; Laws et al., 2003). Short structural variants, including insertions and deletions in transcription factor binding sites, have also been identified ias candidate modifiers of late-onset AD risk n the APOE region (Lutz and Chiba-Falek, 2024).

In addition to single genetic variants, groups of variants that tend to be inherited together as a unit, a.k.a. haplotypes, have also been examined. Zhou and colleagues, for example, defined risk haplotypes that appear to modulate AD endophenotypes including memory performance, hippocampal volume, biomarkers in cerebrospinal fluid and plasma, and transcriptome signatures in the brain and blood (Zhou et al., 2019). Moreover, Kulminski and colleagues have proposed that APOE2 and APOE4 are better understood as components of genetic AD signatures, rather than isolated risk variants (e.g., Kulminski et al., 2018; Kulminski et al., 2020; Kulminski et al., 2020). Indeed, this group reported that an APOE4-bearing haplotype including polymorphisms in TOMM40 and APOC1 confers substantially more AD risk than APOE4 alone (Kulminski et al., 2021, Kulminski et al., 2022). Also of note, a full understanding of genetic risk will likely require analyses of epistatic interactions between variants—i.e., assessing how variants modify each other's effects within a single individual (e.g., Bae et al., 2023).

Studies of the modulation of APOE4’s effects on AD risk in the context of ancestry have yielded particularly interesting findings. It has long been suspected that the association of APOE4 with AD risk is weaker in people of African ancestry compared with Caucasians (Maestre et al., 1995; Tang et al., 1996; Farrer et al., 1997). More recently, a study by Rajabli and colleagues showed that, although measures of global ancestry—average genetic ancestry mapped across the genome—showed no interaction with AD risk, the local genetic ancestry of the APOE region correlated with APOE4-associated risk in both African Americans and Puerto Ricans (Rajabli et al., 2018). When APOE4 alleles were on an African local ancestral background, the risk for AD was lower than when they were on a European background in both the Puerto Rican and African American populations. Similar results were reported in Caribbean Hispanics, with local African-derived ancestry reducing AD risk by 39 percent compared with local European-derived ancestry, after adjusting for APOE genotype, age, and genome-wide ancestry (Blue et al., 2019). Moreover, AD neuropathology associated with APOE4 also appears to be highly influenced by ancestry (Naslavsky et al., 2022).

Causal variants may reside within the local ancestry regions (a.k.a LARs) themselves, or be co-inherited with them. Efforts to identify these key variants are ongoing (e.g., Rajabli et al., 2018; Babenko et al., 2018 [but see a conflicting study by Mezlini et al., 2020], Rajabli et al., 2022), with some studies pinpointing specific variants (Zhang et al., 2018; Choi et al., 2019; Nuytemans et al., 2022; Granot-Hershkovitz et al., 2023). Although the mechanisms underlying the associations remain unclear, modulation of APOE gene expression by nearby sequences has emerged as a likely candidate, with increased expression of APOE4 correlating with increased AD risk (see “Biological Effects” below).

Of note, some studies have failed to find ancestry-associated differences in the effects of APOE4 on AD and AD-related cognitive decline, or have failed to confirm the APOE region as the source of these differences (e.g., Knopman et al., 2009; Sawyer et al., 2009; Mezlini et al., 2020; Curtis, 2021). Differences in cohorts, sample sizes, statistical methodologies, measures of cognition, and racial bias in assessing dementia have been proposed as factors accounting for these discrepancies. Moreover, the small effect sizes of some variants may require large datasets to confirm (e.g., Granot-Hershkovitz et al., 2023).

Also of note, like APOE4’s deleterious effect, the protective effect of R176C (APOE2) may vary between populations of different ancestries. For example, in contrast to what has been reported in Caucasian populations, a meta-analysis of Chinese cohorts indicated a lower incidence of AD associated with APOE3 than with APOE2 (APOE3: OR 0.539, 95% CI [0.504-0.576], P<0.001; APOE2: OR 0.771, 95% CI [0.705-0.843], P<0.001; Chen et al., 2022).

How genetic ancestry modifies the effects of AD susceptibility loci beyond the APOE4 and APOE2 alleles has also been examined. Interestingly, an analysis of whole genome data from the Alzheimer's Disease Sequencing Project (ADSP) suggests genetic variants in the APOE region in particular vary considerably across populations in the magnitude of risk they confer (Lee et al., 2024).

Other Neurological Conditions

Several studies of neurological traits and conditions other than AD have also found associations with non-APOE variants in the APOE region and/or haplotypes in the APOE region, including cognitive ability (e.g., Lyall et al., 2014; Davies et al., 2014; Arpawong et al., 2017; Yu et al., 2017; Deters et al., 2021; Lahti et al., 2022), mild cognitive impairment (e.g., Sofer et al., 2023), dementia with Lewy bodies (e.g., Prokopenko et al., 2019), frontotemporal dementia (e.g., Ferrari et al., 2017), and cerebral amyloid angiopathy (Fujita et al., 2024, March 2024 news). However, as with AD, some of these associations could be due to linkage with the common APOE isoforms, APOE4 or APOE2. Interestingly, in a preprint, the APOE region was described as a potential master regulatory region of neurological relevance, with multiple variants (including 11 index pQTL variants in three linkage dysequilibrium blocks) associated with the levels of more than 300 proteins in cerebrospinal fluid (Cruchaga et al., 2023).

Non-Neurological Conditions

The APOE region has been analyzed for genetic associations with a variety of non-neurological conditions. Associations with cardiovascular health (e.g., Aulchenko et al., 2009; Smith et al., 2010; Middelberg et al., 2011; Allen et al., 2016) and longevity (e.g., Deelen et al., 2019; Timmers et al., 2019; Liu et al., 2021) have been reported, as well as associations with levels of inflammatory markers (e.g., Suchindran et al., 2010; Grallert et al., 2012) and blood lipid species (e.g., Teslovich et al., 2010; Willer et al., 2013; Pirim et al., 2019). As described for the neurological studies, in some cases these associations may be due to the effects of APOE4 or APOE2.

A study focusing on variants found in the APO E-C1-C4-C2 gene cluster identified 11 variants in non-Hispanic Whites and 15 variants in African Blacks associated with at least one blood lipid trait after adjustment for APOE2 and APOE4 (Pirim et al., 2019). The traits examined included plasma levels of low-density lipoprotein cholesterol, total cholesterol, high-density lipoprotein cholesterol, and triglycerides, as well as levels of two correlated apolipoproteins, ApoB and ApoA1. The study included the examination of both common and rare variants. Of note, in addition to ancestry, other factors, such as gender and pregnancy, may help determine variant-lipid trait associations (see, e.g., Ouidir et al., 2022).

Connections between the peripheral and neurological effects of variants in the APOE region have also been examined. For example, a GWAS of European Americans revealed an association of several regional variants with ApoE levels in plasma, a trait that correlated with cognitive function (Aslam et al., 2023). Nine of these variants, including six outside the APOE gene, mediated effects that appeared to be independent from other variants in the region, accounting for approximately 22 percent of the variance in plasma ApoE levels. Some of these variants had been previously associated with AD risk and brain amyloid deposition. Also of note, a large exome-wide association study focusing on AD and 16 cardiovascular traits, reported 13 polymorphisms that modified the risks of AD and one or more cardiovascular phenotypes, nine of which mapped to the APOE region. Interestingly, most of these shared genetic modifiers showed antagonistic pleiotropy: increasing risk of AD, while decreasing risk of harmful cardiovascular traits, or vice versa (Loika et al., 2024).

Biological Effects

The genes in the APOE region are all transcribed in the same direction suggesting their expression may be coregulated by transcriptional regulators on the same chromosome. Interestingly, most of the variants implicated in neurological studies map to noncoding sequences that could affect gene expression, and a few studies have implicated them in transcriptional regulation.

For example, in the temporal and occipital cortices of both controls and AD cases, expression levels of APOE and TOMM40 were higher in homozygotes with very long TOMM40-523 poly-T repeats compared with homozygotes carrying short repeats (Linnertz et al., 2014). In vitro results were consistent with these findings and showed that the magnitude of the effect was greater in neuroblastoma cells than in hepatoma cells.

In addition, genotype-expression association analysis suggested the AD risk variants identified by Zhou and colleagues are likely regulators of transcription, a possibility supported by binding assays and in silico sequence analyses indicating interactions with microRNAs and nuclear proteins. The authors also identified chromatin interactions between the PVRL2, APOE, and APOC1 regions in fetal and adult human brain tissues (Zhou et al., 2019).

Interestingly, a study that profiled gene expression and chromatin accessibility in nuclei from control and AD brains identified several polymorphisms in the APOE region that appear to regulate transcription in a cell type-specific manner (Gamache et al., 2023, see suppl. tables 13-14). In addition, a study that analyzed genetic variants tied to AD risk identified a polymorphism in the APOE region that upregulates APOE expression only in microglia (Fujita et al., 2024; Mar 2024 news). This variant correlated with worse cerebral amyloid angiopathy, but not with AD plaques or tangles. AD risk variants in the APOE region may also alter the expression of alternatively spliced APOE mRNAs. As reported in a preprint, an intronic variant in TOMM40 appears to regulate the expression of an APOE spliced isoform associated with AD neuropathology in the dorsolateral prefrontal cortex (Chen et al., 2023).

Several of the sequences identified as ancestry-specific modifiers of APOE4 have also been implicated in transcriptional control, with variants that increase APOE4 expression correlating with increased AD risk (Vance et al., 2024). For example, a study of single-nuclei RNA in the frontal cortices of APOE4 homozygotes indicated that carriers of European LARs, including 1 Mb on either side of APOE, expressed higher levels of APOE4 in brain than carriers of African LARs (Griswold et al., 2021). In a subsequent study, the researchers identified enhancer sequences in TOMM40 introns 2 and 3, as well as specific variants within the enhancers, that appear to interact with the APOE promoter and upregulate APOE expression in European and Japanese haplotypes compared with African haplotypes (Nuytemans et al., 2022). Interestingly, the interactions were observed in microglia and astrocytes, but not in neurons. Chromatin accessibility at the APOE4 promoter area appears to contribute to these differences in expression, with more accessibility observed in astrocytes with European LARs than those with African LARs (Celis et al., 2023).

Even relatively distant genetic variants may confer protection by reducing APOE4 levels. For example, the A allele of rs10423769, approximately 2 Mb upstream from the APOE gene (Rajabli et al., 2022), appears to protect against APOE4 by decreasing its expression (Vance et al., 2024; J. Vance unpublished data).

Also of note, multiple variants are likely to influence ancestry-associated AD risk. The protective effect of rs10423769, for example, reached statistical significance only in the context of African ancestry where it was substantial—75 percent risk reduction in APOE4 homozygotes—while falling short of statistical significance in non-Hispanic whites (Rajabli et al., 2022). Another consideration in teasing out the genetic underpinnings of ancestry-related effects is that linkage between variants varies between populations (Kulminski et al., 2020).

Research Models

A humanized mouse model has been generated in which the APOE-TOMM40 region in the mouse was replaced with its human counterpart, including upstream and downstream regulatory sequencees (Gottschalk et al., 2023). The 523 poly-T genotype affected gene regulation in multiple organs.

Last Updated: 05 Apr 2024

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

Mutations Citations

Paper Citations

Blue EE, Cheng A, Chen S, Yu CE, Alzheimer’s Disease Genetics Consortium. Association of Uncommon, Noncoding Variants in the APOE Region With Risk of Alzheimer Disease in Adults of European Ancestry. JAMA Netw Open. 2020 Oct 1;3(10):e2017666. PubMed.
Zhou X, Fu AK, Ip NY. APOE signaling in neurodegenerative diseases: an integrative approach targeting APOE coding and noncoding variants for disease intervention. Curr Opin Neurobiol. 2021 Aug;69:58-67. Epub 2021 Feb 26 PubMed.
Kim S, Swaminathan S, Shen L, Risacher SL, Nho K, Foroud T, Shaw LM, Trojanowski JQ, Potkin SG, Huentelman MJ, Craig DW, DeChairo BM, Aisen PS, Petersen RC, Weiner MW, Saykin AJ, Alzheimer's Disease Neuroimaging Initiative. Genome-wide association study of CSF biomarkers Abeta1-42, t-tau, and p-tau181p in the ADNI cohort. Neurology. 2011 Jan 4;76(1):69-79. Epub 2010 Dec 1 PubMed.
Kamboh MI, Barmada MM, Demirci FY, Minster RL, Carrasquillo MM, Pankratz VS, Younkin SG, Saykin AJ, Alzheimer's Disease Neuroimaging Initiative, Sweet RA, Feingold E, DeKosky ST, Lopez OL. Genome-wide association analysis of age-at-onset in Alzheimer's disease. Mol Psychiatry. 2012 Dec;17(12):1340-6. Epub 2011 Oct 18 PubMed.
Miyashita A, Koike A, Jun G, Wang LS, Takahashi S, Matsubara E, Kawarabayashi T, Shoji M, Tomita N, Arai H, Asada T, Harigaya Y, Ikeda M, Amari M, Hanyu H, Higuchi S, Ikeuchi T, Nishizawa M, Suga M, Kawase Y, Akatsu H, Kosaka K, Yamamoto T, Imagawa M, Hamaguchi T, Yamada M, Morihara T, Moriaha T, Takeda M, Takao T, Nakata K, Fujisawa Y, Sasaki K, Watanabe K, Nakashima K, Urakami K, Ooya T, Takahashi M, Yuzuriha T, Serikawa K, Yoshimoto S, Nakagawa R, Kim JW, Ki CS, Won HH, Na DL, Seo SW, Mook-Jung I, Alzheimer Disease Genetics Consortium, St George-Hyslop P, Mayeux R, Haines JL, Pericak-Vance MA, Yoshida M, Nishida N, Tokunaga K, Yamamoto K, Tsuji S, Kanazawa I, Ihara Y, Schellenberg GD, Farrer LA, Kuwano R. SORL1 is genetically associated with late-onset Alzheimer's disease in Japanese, Koreans and Caucasians. PLoS One. 2013;8(4):e58618. Epub 2013 Apr 2 PubMed.
Nho K, Kim S, Horgusluoglu E, Risacher SL, Shen L, Kim D, Lee S, Foroud T, Shaw LM, Trojanowski JQ, Aisen PS, Petersen RC, Jack CR Jr, Weiner MW, Green RC, Toga AW, Saykin AJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI). Association analysis of rare variants near the APOE region with CSF and neuroimaging biomarkers of Alzheimer's disease. BMC Med Genomics. 2017 May 24;10(Suppl 1):29. PubMed.
Yan Q, Nho K, Del-Aguila JL, Wang X, Risacher SL, Fan KH, Snitz BE, Aizenstein HJ, Mathis CA, Lopez OL, Demirci FY, Feingold E, Klunk WE, Saykin AJ, Alzheimer’s Disease Neuroimaging Initiative (ADNI), Cruchaga C, Kamboh MI. Genome-wide association study of brain amyloid deposition as measured by Pittsburgh Compound-B (PiB)-PET imaging. Mol Psychiatry. 2021 Jan;26(1):309-321. Epub 2018 Oct 25 PubMed.
Nazarian A, Yashin AI, Kulminski AM. Genome-wide analysis of genetic predisposition to Alzheimer's disease and related sex disparities. Alzheimers Res Ther. 2019 Jan 12;11(1):5. PubMed.
Jansen IE, Savage JE, Watanabe K, Bryois J, Williams DM, Steinberg S, Sealock J, Karlsson IK, Hägg S, Athanasiu L, Voyle N, Proitsi P, Witoelar A, Stringer S, Aarsland D, Almdahl IS, Andersen F, Bergh S, Bettella F, Bjornsson S, Brækhus A, Bråthen G, de Leeuw C, Desikan RS, Djurovic S, Dumitrescu L, Fladby T, Hohman TJ, Jonsson PV, Kiddle SJ, Rongve A, Saltvedt I, Sando SB, Selbæk G, Shoai M, Skene NG, Snaedal J, Stordal E, Ulstein ID, Wang Y, White LR, Hardy J, Hjerling-Leffler J, Sullivan PF, van der Flier WM, Dobson R, Davis LK, Stefansson H, Stefansson K, Pedersen NL, Ripke S, Andreassen OA, Posthuma D. Genome-wide meta-analysis identifies new loci and functional pathways influencing Alzheimer's disease risk. Nat Genet. 2019 Mar;51(3):404-413. Epub 2019 Jan 7 PubMed.
Meng X, Li J, Zhang Q, Chen F, Bian C, Yao X, Yan J, Xu Z, Risacher SL, Saykin AJ, Liang H, Shen L, Alzheimer’s Disease Neuroimaging Initiative. Multivariate genome wide association and network analysis of subcortical imaging phenotypes in Alzheimer's disease. BMC Genomics. 2020 Dec 29;21(Suppl 11):896. PubMed.
Ali M, Archer DB, Gorijala P, Western D, Timsina J, Fernández MV, Wang TC, Satizabal CL, Yang Q, Beiser AS, Wang R, Chen G, Gordon B, Benzinger TL, Xiong C, Morris JC, Bateman RJ, Karch CM, McDade E, Goate A, Seshadri S, Mayeux RP, Sperling RA, Buckley RF, Johnson KA, Won HH, Jung SH, Kim HR, Seo SW, Kim HJ, Mormino E, Laws SM, Fan KH, Kamboh MI, Vemuri P, Ramanan VK, Yang HS, Wenzel A, Rajula HS, Mishra A, Dufouil C, Debette S, Lopez OL, DeKosky ST, Tao F, Nagle MW, Knight Alzheimer Disease Research Center (Knight ADRC), Dominantly Inherited Alzheimer Network (DIAN), Alzheimer’s Disease Neuroimaging Initiative (ADNI), ADNI-DOD, A4 Study Team, Australian Imaging Biomarkers, Lifestyle (AIBL) Study, Hohman TJ, Sung YJ, Dumitrescu L, Cruchaga C. Large multi-ethnic genetic analyses of amyloid imaging identify new genes for Alzheimer disease. Acta Neuropathol Commun. 2023 Apr 26;11(1):68. PubMed.
Wang L, Nykänen NP, Western D, Gorijala P, Timsina J, Li F, Wang Z, Ali M, Yang C, Liu M, Brock W, Marquié M, Boada M, Alvarez I, Aguilar M, Pastor P, Ruiz A, Puerta R, Orellana A, Rutledge J, Oh H, Greicius MD, Le Guen Y, Perrin RJ, Wyss-Coray T, Jefferson A, Hohman TJ, Graff-Radford N, Mori H, Goate A, Levin J, Sung YJ, Cruchaga C. Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer's disease. Mol Neurodegener. 2024 Jan 3;19(1):1. PubMed.
Bellenguez C, Küçükali F, Jansen IE, Kleineidam L, Moreno-Grau S, Amin N, Naj AC, Campos-Martin R, Grenier-Boley B, Andrade V, Holmans PA, Boland A, Damotte V, van der Lee SJ, Costa MR, Kuulasmaa T, Yang Q, de Rojas I, Bis JC, Yaqub A, Prokic I, Chapuis J, Ahmad S, Giedraitis V, Aarsland D, Garcia-Gonzalez P, Abdelnour C, Alarcón-Martín E, Alcolea D, Alegret M, Alvarez I, Álvarez V, Armstrong NJ, Tsolaki A, Antúnez C, Appollonio I, Arcaro M, Archetti S, Pastor AA, Arosio B, Athanasiu L, Bailly H, Banaj N, Baquero M, Barral S, Beiser A, Pastor AB, Below JE, Benchek P, Benussi L, Berr C, Besse C, Bessi V, Binetti G, Bizarro A, Blesa R, Boada M, Boerwinkle E, Borroni B, Boschi S, Bossù P, Bråthen G, Bressler J, Bresner C, Brodaty H, Brookes KJ, Brusco LI, Buiza-Rueda D, Bûrger K, Burholt V, Bush WS, Calero M, Cantwell LB, Chene G, Chung J, Cuccaro ML, Carracedo Á, Cecchetti R, Cervera-Carles L, Charbonnier C, Chen HH, Chillotti C, Ciccone S, Claassen JA, Clark C, Conti E, Corma-Gómez A, Costantini E, Custodero C, Daian D, Dalmasso MC, Daniele A, Dardiotis E, Dartigues JF, de Deyn PP, de Paiva Lopes K, de Witte LD, Debette S, Deckert J, Del Ser T, Denning N, DeStefano A, Dichgans M, Diehl-Schmid J, Diez-Fairen M, Rossi PD, Djurovic S, Duron E, Düzel E, Dufouil C, Eiriksdottir G, Engelborghs S, Escott-Price V, Espinosa A, Ewers M, Faber KM, Fabrizio T, Nielsen SF, Fardo DW, Farotti L, Fenoglio C, Fernández-Fuertes M, Ferrari R, Ferreira CB, Ferri E, Fin B, Fischer P, Fladby T, Fließbach K, Fongang B, Fornage M, Fortea J, Foroud TM, Fostinelli S, Fox NC, Franco-Macías E, Bullido MJ, Frank-García A, Froelich L, Fulton-Howard B, Galimberti D, García-Alberca JM, García-González P, Garcia-Madrona S, Garcia-Ribas G, Ghidoni R, Giegling I, Giorgio G, Goate AM, Goldhardt O, Gomez-Fonseca D, González-Pérez A, Graff C, Grande G, Green E, Grimmer T, Grünblatt E, Grunin M, Gudnason V, Guetta-Baranes T, Haapasalo A, Hadjigeorgiou G, Haines JL, Hamilton-Nelson KL, Hampel H, Hanon O, Hardy J, Hartmann AM, Hausner L, Harwood J, Heilmann-Heimbach S, Helisalmi S, Heneka MT, Hernández I, Herrmann MJ, Hoffmann P, Holmes C, Holstege H, Vilas RH, Hulsman M, Humphrey J, Biessels GJ, Jian X, Johansson C, Jun GR, Kastumata Y, Kauwe J, Kehoe PG, Kilander L, Ståhlbom AK, Kivipelto M, Koivisto A, Kornhuber J, Kosmidis MH, Kukull WA, Kuksa PP, Kunkle BW, Kuzma AB, Lage C, Laukka EJ, Launer L, Lauria A, Lee CY, Lehtisalo J, Lerch O, Lleó A, Longstreth W Jr, Lopez O, de Munain AL, Love S, Löwemark M, Luckcuck L, Lunetta KL, Ma Y, Macías J, MacLeod CA, Maier W, Mangialasche F, Spallazzi M, Marquié M, Marshall R, Martin ER, Montes AM, Rodríguez CM, Masullo C, Mayeux R, Mead S, Mecocci P, Medina M, Meggy A, Mehrabian S, Mendoza S, Menéndez-González M, Mir P, Moebus S, Mol M, Molina-Porcel L, Montrreal L, Morelli L, Moreno F, Morgan K, Mosley T, Nöthen MM, Muchnik C, Mukherjee S, Nacmias B, Ngandu T, Nicolas G, Nordestgaard BG, Olaso R, Orellana A, Orsini M, Ortega G, Padovani A, Paolo C, Papenberg G, Parnetti L, Pasquier F, Pastor P, Peloso G, Pérez-Cordón A, Pérez-Tur J, Pericard P, Peters O, Pijnenburg YA, Pineda JA, Piñol-Ripoll G, Pisanu C, Polak T, Popp J, Posthuma D, Priller J, Puerta R, Quenez O, Quintela I, Thomassen JQ, Rábano A, Rainero I, Rajabli F, Ramakers I, Real LM, Reinders MJ, Reitz C, Reyes-Dumeyer D, Ridge P, Riedel-Heller S, Riederer P, Roberto N, Rodriguez-Rodriguez E, Rongve A, Allende IR, Rosende-Roca M, Royo JL, Rubino E, Rujescu D, Sáez ME, Sakka P, Saltvedt I, Sanabria Á, Sánchez-Arjona MB, Sanchez-Garcia F, Juan PS, Sánchez-Valle R, Sando SB, Sarnowski C, Satizabal CL, Scamosci M, Scarmeas N, Scarpini E, Scheltens P, Scherbaum N, Scherer M, Schmid M, Schneider A, Schott JM, Selbæk G, Seripa D, Serrano M, Sha J, Shadrin AA, Skrobot O, Slifer S, Snijders GJ, Soininen H, Solfrizzi V, Solomon A, Song Y, Sorbi S, Sotolongo-Grau O, Spalletta G, Spottke A, Squassina A, Stordal E, Tartan JP, Tárraga L, Tesí N, Thalamuthu A, Thomas T, Tosto G, Traykov L, Tremolizzo L, Tybjærg-Hansen A, Uitterlinden A, Ullgren A, Ulstein I, Valero S, Valladares O, Broeckhoven CV, Vance J, Vardarajan BN, van der Lugt A, Dongen JV, van Rooij J, van Swieten J, Vandenberghe R, Verhey F, Vidal JS, Vogelgsang J, Vyhnalek M, Wagner M, Wallon D, Wang LS, Wang R, Weinhold L, Wiltfang J, Windle G, Woods B, Yannakoulia M, Zare H, Zhao Y, Zhang X, Zhu C, Zulaica M, EADB, GR@ACE, DEGESCO, EADI, GERAD, Demgene, FinnGen, ADGC, CHARGE, Farrer LA, Psaty BM, Ghanbari M, Raj T, Sachdev P, Mather K, Jessen F, Ikram MA, de Mendonça A, Hort J, Tsolaki M, Pericak-Vance MA, Amouyel P, Williams J, Frikke-Schmidt R, Clarimon J, Deleuze JF, Rossi G, Seshadri S, Andreassen OA, Ingelsson M, Hiltunen M, Sleegers K, Schellenberg GD, van Duijn CM, Sims R, van der Flier WM, Ruiz A, Ramirez A, Lambert JC. New insights into the genetic etiology of Alzheimer's disease and related dementias. Nat Genet. 2022 Apr;54(4):412-436. Epub 2022 Apr 4 PubMed.
Martin ER, Gilbert JR, Lai EH, Riley J, Rogala AR, Slotterbeck BD, Sipe CA, Grubber JM, Warren LL, Conneally PM, Saunders AM, Schmechel DE, Purvis I, Pericak-Vance MA, Roses AD, Vance JM. Analysis of association at single nucleotide polymorphisms in the APOE region. Genomics. 2000 Jan 1;63(1):7-12. PubMed.
Roses AD, Lutz MW, Amrine-Madsen H, Saunders AM, Crenshaw DG, Sundseth SS, Huentelman MJ, Welsh-Bohmer KA, Reiman EM. A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease. Pharmacogenomics J. 2010 Oct;10(5):375-84. Epub 2009 Dec 22 PubMed.
Jun G, Vardarajan BN, Buros J, Yu CE, Hawk MV, Dombroski BA, Crane PK, Larson EB, Alzheimer's Disease Genetics Consortium, Mayeux R, Haines JL, Lunetta KL, Pericak-Vance MA, Schellenberg GD, Farrer LA. Comprehensive search for Alzheimer disease susceptibility loci in the APOE region. Arch Neurol. 2012 Oct;69(10):1270-9. PubMed.
Cruchaga C, Nowotny P, Kauwe JS, Ridge PG, Mayo K, Bertelsen S, Hinrichs A, Fagan AM, Holtzman DM, Morris JC, Goate AM, Alzheimer's Disease Neuroimaging Initiative. Association and expression analyses with single-nucleotide polymorphisms in TOMM40 in Alzheimer disease. Arch Neurol. 2011 Aug;68(8):1013-9. PubMed.
Andrews SJ, Fulton-Howard B, Goate A. Protective Variants in Alzheimer's Disease. Curr Genet Med Rep. 2019 Mar;7(1):1-12. Epub 2019 Jan 24 PubMed.
Belloy ME, Napolioni V, Greicius MD. A Quarter Century of APOE and Alzheimer's Disease: Progress to Date and the Path Forward. Neuron. 2019 Mar 6;101(5):820-838. PubMed.
Belloy ME, Eger SJ, Le Guen Y, Damotte V, Ahmad S, Ikram MA, Ramirez A, Tsolaki AC, Rossi G, Jansen IE, de Rojas I, Parveen K, Sleegers K, Ingelsson M, Hiltunen M, Amin N, Andreassen O, Sánchez-Juan P, Kehoe P, Amouyel P, Sims R, Frikke-Schmidt R, van der Flier WM, Lambert JC, European Alzheimer & Dementia BioBank (EADB), He Z, Han SS, Napolioni V, Greicius MD. Challenges at the APOE locus: a robust quality control approach for accurate APOE genotyping. Alzheimers Res Ther. 2022 Feb 4;14(1):22. PubMed.
Zhou X, Chen Y, Mok KY, Kwok TC, Mok VC, Guo Q, Ip FC, Chen Y, Mullapudi N, Alzheimer’s Disease Neuroimaging Initiative, Giusti-Rodríguez P, Sullivan PF, Hardy J, Fu AK, Li Y, Ip NY. Non-coding variability at the APOE locus contributes to the Alzheimer's risk. Nat Commun. 2019 Jul 25;10(1):3310. PubMed.
Oatman SR, Reddy JS, Quicksall Z, Carrasquillo MM, Wang X, Liu CC, Yamazaki Y, Nguyen TT, Malphrus K, Heckman M, Biswas K, Nho K, Baker M, Martens YA, Zhao N, Kim JP, Risacher SL, Rademakers R, Saykin AJ, DeTure M, Murray ME, Kanekiyo T, Alzheimer’s Disease Neuroimaging Initiative, Dickson DW, Bu G, Allen M, Ertekin-Taner N. Genome-wide association study of brain biochemical phenotypes reveals distinct genetic architecture of Alzheimer's disease related proteins. Mol Neurodegener. 2023 Jan 7;18(1):2. PubMed.
Lutz MW, Crenshaw D, Welsh-Bohmer KA, Burns DK, Roses AD. New Genetic Approaches to AD: Lessons from APOE-TOMM40 Phylogenetics. Curr Neurol Neurosci Rep. 2016 May;16(5):48. PubMed.
Linnertz C, Anderson L, Gottschalk W, Crenshaw D, Lutz MW, Allen J, Saith S, Mihovilovic M, Burke JR, Welsh-Bohmer KA, Roses AD, Chiba-Falek O. The cis-regulatory effect of an Alzheimer's disease-associated poly-T locus on expression of TOMM40 and apolipoprotein E genes. Alzheimers Dement. 2014 Sep;10(5):541-51. Epub 2014 Jan 15 PubMed.
Li T, Pappas C, Le ST, Wang Q, Klinedinst BS, Larsen BA, Pollpeter A, Lee LY, Lutz MW, Gottschalk WK, Swerdlow RH, Nho K, Willette AA. APOE, TOMM40, and sex interactions on neural network connectivity. Neurobiol Aging. 2022 Jan;109:158-165. Epub 2021 Sep 30 PubMed.
Liang X, Liu C, Liu K, Cong L, Wang Y, Liu R, Fa W, Tian N, Cheng Y, Wang N, Hou T, Du Y, Qiu C. Association and interaction of TOMM40 and PVRL2 with plasma amyloid-β and Alzheimer's disease among Chinese older adults: a population-based study. Neurobiol Aging. 2022 May;113:143-151. Epub 2022 Jan 5 PubMed.
Deters KD, Mormino EC, Yu L, Lutz MW, Bennett DA, Barnes LL. TOMM40-APOE haplotypes are associated with cognitive decline in non-demented Blacks. Alzheimers Dement. 2021 Aug;17(8):1287-1296. Epub 2021 Feb 13 PubMed.
Zhang A, Zhao Q, Xu D, Jiang S. Brain APOE expression quantitative trait loci-based association study identified one susceptibility locus for Alzheimer's disease by interacting with APOE ε4. Sci Rep. 2018 May 23;8(1):8068. PubMed.
Laws SM, Hone E, Gandy S, Martins RN. Expanding the association between the APOE gene and the risk of Alzheimer's disease: possible roles for APOE promoter polymorphisms and alterations in APOE transcription. J Neurochem. 2003 Mar;84(6):1215-36. PubMed.
Lutz MW, Chiba-Falek O. Bioinformatics pipeline to guide post-GWAS studies in Alzheimer's: A new catalogue of disease candidate short structural variants. Alzheimers Dement. 2023 Sep;19(9):4094-4109. Epub 2023 May 30 PubMed.
Kulminski AM, Huang J, Wang J, He L, Loika Y, Culminskaya I. Apolipoprotein E region molecular signatures of Alzheimer's disease. Aging Cell. 2018 Aug;17(4):e12779. Epub 2018 May 23 PubMed.
Kulminski AM, Shu L, Loika Y, He L, Nazarian A, Arbeev K, Ukraintseva S, Yashin A, Culminskaya I. Genetic and regulatory architecture of Alzheimer's disease in the APOE region. Alzheimers Dement (Amst). 2020;12(1):e12008. Epub 2020 Feb 6 PubMed.
Kulminski AM, Philipp I, Loika Y, He L, Culminskaya I. Haplotype architecture of the Alzheimer's risk in the APOE region via co-skewness. Alzheimers Dement (Amst). 2020;12(1):e12129. Epub 2020 Nov 11 PubMed.
Kulminski AM, Philipp I, Shu L, Culminskaya I. Definitive roles of TOMM40-APOE-APOC1 variants in the Alzheimer's risk. Neurobiol Aging. 2022 Feb;110:122-131. Epub 2021 Sep 15 PubMed.
Kulminski AM, Jain-Washburn E, Loiko E, Loika Y, Feng F, Culminskaya I, Alzheimer’s Disease Neuroimaging Initiative. Associations of the APOE ε2 and ε4 alleles and polygenic profiles comprising APOE-TOMM40-APOC1 variants with Alzheimer's disease biomarkers. Aging (Albany NY). 2022 Nov 17;14(24):9782-9804. PubMed.
Bae J, Logan PE, Acri DJ, Bharthur A, Nho K, Saykin AJ, Risacher SL, Nudelman K, Polsinelli AJ, Pentchev V, Kim J, Hammers DB, Apostolova LG, Alzheimer's Disease Neuroimaging Initiative. A simulative deep learning model of SNP interactions on chromosome 19 for predicting Alzheimer's disease risk and rates of disease progression. Alzheimers Dement. 2023 Dec;19(12):5690-5699. Epub 2023 Jul 6 PubMed.
Maestre G, Ottman R, Stern Y, Gurland B, Chun M, Tang MX, Shelanski M, Tycko B, Mayeux R. Apolipoprotein E and Alzheimer's disease: ethnic variation in genotypic risks. Ann Neurol. 1995 Feb;37(2):254-9. PubMed.
Tang MX, Maestre G, Tsai WY, Liu XH, Feng L, Chung WY, Chun M, Schofield P, Stern Y, Tycko B, Mayeux R. Relative risk of Alzheimer disease and age-at-onset distributions, based on APOE genotypes among elderly African Americans, Caucasians, and Hispanics in New York City. Am J Hum Genet. 1996 Mar;58(3):574-84. PubMed.
Farrer LA, Cupples LA, Haines JL, Hyman B, Kukull WA, Mayeux R, Myers RH, Pericak-Vance MA, Risch N, van Duijn CM. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed.
Rajabli F, Feliciano BE, Celis K, Hamilton-Nelson KL, Whitehead PL, Adams LD, Bussies PL, Manrique CP, Rodriguez A, Rodriguez V, Starks T, Byfield GE, Sierra Lopez CB, McCauley JL, Acosta H, Chinea A, Kunkle BW, Reitz C, Farrer LA, Schellenberg GD, Vardarajan BN, Vance JM, Cuccaro ML, Martin ER, Haines JL, Byrd GS, Beecham GW, Pericak-Vance MA. Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations. PLoS Genet. 2018 Dec;14(12):e1007791. Epub 2018 Dec 5 PubMed.
Blue EE, Horimoto AR, Mukherjee S, Wijsman EM, Thornton TA. Local ancestry at APOE modifies Alzheimer's disease risk in Caribbean Hispanics. Alzheimers Dement. 2019 Dec;15(12):1524-1532. Epub 2019 Oct 9 PubMed.
Naslavsky MS, Suemoto CK, Brito LA, Scliar MO, Ferretti-Rebustini RE, Rodriguez RD, Leite RE, Araujo NM, Borda V, Tarazona-Santos E, Jacob-Filho W, Pasqualucci C, Nitrini R, Yaffe K, Zatz M, Grinberg LT. Global and local ancestry modulate APOE association with Alzheimer's neuropathology and cognitive outcomes in an admixed sample. Mol Psychiatry. 2022 Nov;27(11):4800-4808. Epub 2022 Sep 7 PubMed.
Babenko VN, Afonnikov DA, Ignatieva EV, Klimov AV, Gusev FE, Rogaev EI. Haplotype analysis of APOE intragenic SNPs. BMC Neurosci. 2018 Apr 19;19(Suppl 1):16. PubMed.
Mezlini AM, Magdamo C, Merrill E, Chibnik LB, Blacker DL, Hyman BT, Das S. Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans. J Alzheimers Dis. 2020;78(1):467-477. PubMed.
Rajabli F, Beecham GW, Hendrie HC, Baiyewu O, Ogunniyi A, Gao S, Kushch NA, Lipkin-Vasquez M, Hamilton-Nelson KL, Young JI, Dykxhoorn DM, Nuytemans K, Kunkle BW, Wang L, Jin F, Liu X, Feliciano-Astacio BE, Alzheimer’s Disease Sequencing Project, Alzheimer’s Disease Genetic Consortium, Schellenberg GD, Dalgard CL, Griswold AJ, Byrd GS, Reitz C, Cuccaro ML, Haines JL, Pericak-Vance MA, Vance JM. A locus at 19q13.31 significantly reduces the ApoE ε4 risk for Alzheimer's Disease in African Ancestry. PLoS Genet. 2022 Jul;18(7):e1009977. Epub 2022 Jul 5 PubMed.
Choi KY, Lee JJ, Gunasekaran TI, Kang S, Lee W, Jeong J, Lim HJ, Zhang X, Zhu C, Won SY, Choi YY, Seo EH, Lee SC, Gim J, Chung JY, Chong A, Byun MS, Seo S, Ko PW, Han JW, McLean C, Farrell J, Lunetta KL, Miyashita A, Hara N, Won S, Choi SM, Ha JM, Jeong JH, Kuwano R, Song MK, An SS, Lee YM, Park KW, Lee HW, Choi SH, Rhee S, Song WK, Lee JS, Mayeux R, Haines JL, Pericak-Vance MA, Choo IL, Nho K, Kim KW, Lee DY, Kim S, Kim BC, Kim H, Jun GR, Schellenberg GD, Ikeuchi T, Farrer LA, Lee KH, Neuroimaging Initative AD. APOE Promoter Polymorphism-219T/G is an Effect Modifier of the Influence of APOE ε4 on Alzheimer's Disease Risk in a Multiracial Sample. J Clin Med. 2019 Aug 16;8(8) PubMed.
Nuytemans K, Lipkin Vasquez M, Wang L, Van Booven D, Griswold AJ, Rajabli F, Celis K, Oron O, Hofmann N, Rolati S, Garcia-Serje C, Zhang S, Jin F, Argenziano M, Grant SF, Chesi A, Brown CD, Young JI, Dykxhoorn DM, Pericak-Vance MA, Vance JM. Identifying differential regulatory control of APOE ɛ4 on African versus European haplotypes as potential therapeutic targets. Alzheimers Dement. 2022 Jan 3; PubMed.
Granot-Hershkovitz E, Xia R, Yang Y, Spitzer B, Tarraf W, Vásquez PM, Lipton RB, Daviglus M, Argos M, Cai J, Kaplan R, Fornage M, DeCarli C, Gonzalez HM, Sofer T. Interaction analysis of ancestry-enriched variants with APOE-ɛ4 on MCI in the Study of Latinos-Investigation of Neurocognitive Aging. Sci Rep. 2023 Mar 29;13(1):5114. PubMed.
Knopman DS, Mosley TH, Catellier DJ, Coker LH, Atherosclerosis Risk in Communities Study Brain MRI Study. Fourteen-year longitudinal study of vascular risk factors, APOE genotype, and cognition: the ARIC MRI Study. Alzheimers Dement. 2009 May;5(3):207-14. Epub 2009 Apr 11 PubMed.
Sawyer K, Sachs-Ericsson N, Preacher KJ, Blazer DG. Racial differences in the influence of the APOE epsilon 4 allele on cognitive decline in a sample of community-dwelling older adults. Gerontology. 2009;55(1):32-40. Epub 2008 Jun 5 PubMed.
Curtis D, Alzheimer's Disease Neuroimaging Initiative. Analysis of whole genome sequenced cases and controls shows that the association of variants in TOMM40, BCAM, NECTIN2 and APOC1 with late onset Alzheimer's disease is driven by linkage disequilibrium with APOE ε2/ε3/ε4 alleles. J Neurogenet. 2021 Mar-Jun;35(2):59-66. Epub 2021 May 10 PubMed.
Chen Q, Wang T, Kang D, Chen L. Protective effect of apolipoprotein E epsilon 3 on sporadic Alzheimer's disease in the Chinese population: a meta-analysis. Sci Rep. 2022 Aug 10;12(1):13620. PubMed.
Lee S, Hecker J, Hahn G, Mullin K, Alzheimer's Disease Neuroimaging Initiative (ADNI), Lutz SM, Tanzi RE, Lange C, Prokopenko D. On the effect heterogeneity of established disease susceptibility loci for Alzheimer's disease across different genetic ancestries. Alzheimers Dement. 2024 Apr 2; PubMed.
Lyall DM, Harris SE, Bastin ME, Muñoz Maniega S, Murray C, Lutz MW, Saunders AM, Roses AD, Valdés Hernández Md, Royle NA, Starr JM, Porteous DJ, Wardlaw JM, Deary IJ. Are APOE ɛ genotype and TOMM40 poly-T repeat length associations with cognitive ageing mediated by brain white matter tract integrity?. Transl Psychiatry. 2014 Sep 23;4:e449. PubMed.
Davies G, Harris SE, Reynolds CA, Payton A, Knight HM, Liewald DC, Lopez LM, Luciano M, Gow AJ, Corley J, Henderson R, Murray C, Pattie A, Fox HC, Redmond P, Lutz MW, Chiba-Falek O, Linnertz C, Saith S, Haggarty P, McNeill G, Ke X, Ollier W, Horan M, Roses AD, Ponting CP, Porteous DJ, Tenesa A, Pickles A, Starr JM, Whalley LJ, Pedersen NL, Pendleton N, Visscher PM, Deary IJ. A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing. Mol Psychiatry. 2014 Jan;19(1):76-87. Epub 2012 Dec 4 PubMed.
Arpawong TE, Pendleton N, Mekli K, McArdle JJ, Gatz M, Armoskus C, Knowles JA, Prescott CA. Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort. PLoS One. 2017;12(8):e0182448. Epub 2017 Aug 11 PubMed.
Yu L, Lutz MW, Wilson RS, Burns DK, Roses AD, Saunders AM, Gaiteri C, De Jager PL, Barnes LL, Bennett DA. TOMM40'523 variant and cognitive decline in older persons with APOE ε3/3 genotype. Neurology. 2017 Feb 14;88(7):661-668. Epub 2017 Jan 20 PubMed.
Lahti J, Tuominen S, Yang Q, Pergola G, Ahmad S, Amin N, Armstrong NJ, Beiser A, Bey K, Bis JC, Boerwinkle E, Bressler J, Campbell A, Campbell H, Chen Q, Corley J, Cox SR, Davies G, De Jager PL, Derks EM, Faul JD, Fitzpatrick AL, Fohner AE, Ford I, Fornage M, Gerring Z, Grabe HJ, Grodstein F, Gudnason V, Simonsick E, Holliday EG, Joshi PK, Kajantie E, Kaprio J, Karell P, Kleineidam L, Knol MJ, Kochan NA, Kwok JB, Leber M, Lam M, Lee T, Li S, Loukola A, Luck T, Marioni RE, Mather KA, Medland S, Mirza SS, Nalls MA, Nho K, O'Donnell A, Oldmeadow C, Painter J, Pattie A, Reppermund S, Risacher SL, Rose RJ, Sadashivaiah V, Scholz M, Satizabal CL, Schofield PW, Schraut KE, Scott RJ, Simino J, Smith AV, Smith JA, Stott DJ, Surakka I, Teumer A, Thalamuthu A, Trompet S, Turner ST, van der Lee SJ, Villringer A, Völker U, Wilson RS, Wittfeld K, Vuoksimaa E, Xia R, Yaffe K, Yu L, Zare H, Zhao W, Ames D, Attia J, Bennett DA, Brodaty H, Chasman DI, Goldman AL, Hayward C, Ikram MA, Jukema JW, Kardia SL, Lencz T, Loeffler M, Mattay VS, Palotie A, Psaty BM, Ramirez A, Ridker PM, Riedel-Heller SG, Sachdev PS, Saykin AJ, Scherer M, Schofield PR, Sidney S, Starr JM, Trollor J, Ulrich W, Wagner M, Weir DR, Wilson JF, Wright MJ, Weinberger DR, Debette S, Eriksson JG, Mosley TH Jr, Launer LJ, van Duijn CM, Deary IJ, Seshadri S, Räikkönen K. Genome-wide meta-analyses reveal novel loci for verbal short-term memory and learning. Mol Psychiatry. 2022 Nov;27(11):4419-4431. Epub 2022 Aug 16 PubMed.
Sofer T, Kurniansyah N, Granot-Hershkovitz E, Goodman MO, Tarraf W, Broce I, Lipton RB, Daviglus M, Lamar M, Wassertheil-Smoller S, Cai J, DeCarli CS, Gonzalez HM, Fornage M. A polygenic risk score for Alzheimer's disease constructed using APOE-region variants has stronger association than APOE alleles with mild cognitive impairment in Hispanic/Latino adults in the U.S. Alzheimers Res Ther. 2023 Aug 30;15(1):146. PubMed.
Prokopenko I, Miyakawa G, Zheng B, Heikkinen J, Petrova Quayle D, Udeh-Momoh C, Claringbould A, Neumann J, Haytural H, Kaakinen MA, Loizidou E, Meissner E, Bertram L, BIOS consortium, Gveric DO, Gentleman SM, Attems J, Perneczky R, Arzberger T, Muglia P, Lill CM, Parkkinen L, Middleton LT. Alzheimer's disease pathology explains association between dementia with Lewy bodies and APOE-ε4/TOMM40 long poly-T repeat allele variants. Alzheimers Dement (N Y). 2019;5:814-824. Epub 2019 Nov 20 PubMed.
Ferrari R, Wang Y, Vandrovcova J, Guelfi S, Witeolar A, Karch CM, Schork AJ, Fan CC, Brewer JB, International FTD-Genomics Consortium (IFGC),, International Parkinson's Disease Genomics Consortium (IPDGC),, International Genomics of Alzheimer's Project (IGAP),, Momeni P, Schellenberg GD, Dillon WP, Sugrue LP, Hess CP, Yokoyama JS, Bonham LW, Rabinovici GD, Miller BL, Andreassen OA, Dale AM, Hardy J, Desikan RS. Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases. J Neurol Neurosurg Psychiatry. 2017 Feb;88(2):152-164. Epub 2016 Nov 29 PubMed.
Fujita M, Gao Z, Zeng L, McCabe C, White CC, Ng B, Green GS, Rozenblatt-Rosen O, Phillips D, Amir-Zilberstein L, Lee H, Pearse RV 2nd, Khan A, Vardarajan BN, Kiryluk K, Ye CJ, Klein HU, Wang G, Regev A, Habib N, Schneider JA, Wang Y, Young-Pearse T, Mostafavi S, Bennett DA, Menon V, De Jager PL. Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain. Nat Genet. 2024 Apr;56(4):605-614. Epub 2024 Mar 21 PubMed.
Cruchaga C, Western D, Timsina J, Wang L, Wang C, Yang C, Ali M, Beric A, Gorijala P, Kohlfeld P, Budde J, Levey A, Morris J, Perrin R, Ruiz A, Marquié M, Boada M, de Rojas I, Rutledge J, Oh H, Wilson E, Guen YL, Alvarez I, Aguilar M, Greicius M, Pastor P, Pulford D, Ibanez L, Wyss-Coray T, Sung YJ, Phillips B. Proteogenomic analysis of human cerebrospinal fluid identifies neurologically relevant regulation and informs causal proteins for Alzheimer's disease. Res Sq. 2023 Jun 9; PubMed.
Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Döring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L, ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Genet. 2009 Jan;41(1):47-55. Epub 2008 Dec 7 PubMed.
Smith EN, Chen W, Kähönen M, Kettunen J, Lehtimäki T, Peltonen L, Raitakari OT, Salem RM, Schork NJ, Shaw M, Srinivasan SR, Topol EJ, Viikari JS, Berenson GS, Murray SS. Longitudinal genome-wide association of cardiovascular disease risk factors in the Bogalusa heart study. PLoS Genet. 2010 Sep 9;6(9):e1001094. PubMed.
Middelberg RP, Ferreira MA, Henders AK, Heath AC, Madden PA, Montgomery GW, Martin NG, Whitfield JB. Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits. BMC Med Genet. 2011 Sep 24;12:123. PubMed.
Allen NB, Lloyd-Jones D, Hwang SJ, Rasmussen-Torvik L, Fornage M, Morrison AC, Baldridge AS, Boerwinkle E, Levy D, Cupples LA, Fox CS, Thanassoulis G, Dufresne L, Daviglus M, Johnson AD, Reis J, Rotter J, Palmas W, Allison M, Pankow JS, O'Donnell CJ. Genetic loci associated with ideal cardiovascular health: A meta-analysis of genome-wide association studies. Am Heart J. 2016 May;175:112-20. Epub 2016 Jan 23 PubMed.
Liu X, Song Z, Li Y, Yao Y, Fang M, Bai C, An P, Chen H, Chen Z, Tang B, Shen J, Gao X, Zhang M, Chen P, Zhang T, Jia H, Liu X, Hou Y, Yang H, Wang J, Wang F, Xu X, Min J, Nie C, Zeng Y. Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15,651 Chinese individuals. Aging Cell. 2021 Mar;20(3):e13323. Epub 2021 Mar 3 PubMed.
Suchindran S, Rivedal D, Guyton JR, Milledge T, Gao X, Benjamin A, Rowell J, Ginsburg GS, McCarthy JJ. Genome-wide association study of Lp-PLA(2) activity and mass in the Framingham Heart Study. PLoS Genet. 2010 Apr 29;6(4):e1000928. PubMed.
Grallert H, Dupuis J, Bis JC, Dehghan A, Barbalic M, Baumert J, Lu C, Smith NL, Uitterlinden AG, Roberts R, Khuseyinova N, Schnabel RB, Rice KM, Rivadeneira F, Hoogeveen RC, Fontes JD, Meisinger C, Keaney JF Jr, Lemaitre R, Aulchenko YS, Vasan RS, Ellis S, Hazen SL, van Duijn CM, Nelson JJ, März W, Schunkert H, McPherson RM, Stirnadel-Farrant HA, Psaty BM, Gieger C, Siscovick D, Hofman A, Illig T, Cushman M, Yamamoto JF, Rotter JI, Larson MG, Stewart AF, Boerwinkle E, Witteman JC, Tracy RP, Koenig W, Benjamin EJ, Ballantyne CM. Eight genetic loci associated with variation in lipoprotein-associated phospholipase A2 mass and activity and coronary heart disease: meta-analysis of genome-wide association studies from five community-based studies. Eur Heart J. 2012 Jan;33(2):238-51. Epub 2011 Oct 14 PubMed.
Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, Johansen CT, Fouchier SW, Isaacs A, Peloso GM, Barbalic M, Ricketts SL, Bis JC, Aulchenko YS, Thorleifsson G, Feitosa MF, Chambers J, Orho-Melander M, Melander O, Johnson T, Li X, Guo X, Li M, Shin Cho Y, Jin Go M, Jin Kim Y, Lee JY, Park T, Kim K, Sim X, Twee-Hee Ong R, Croteau-Chonka DC, Lange LA, Smith JD, Song K, Hua Zhao J, Yuan X, Luan J, Lamina C, Ziegler A, Zhang W, Zee RY, Wright AF, Witteman JC, Wilson JF, Willemsen G, Wichmann HE, Whitfield JB, Waterworth DM, Wareham NJ, Waeber G, Vollenweider P, Voight BF, Vitart V, Uitterlinden AG, Uda M, Tuomilehto J, Thompson JR, Tanaka T, Surakka I, Stringham HM, Spector TD, Soranzo N, Smit JH, Sinisalo J, Silander K, Sijbrands EJ, Scuteri A, Scott J, Schlessinger D, Sanna S, Salomaa V, Saharinen J, Sabatti C, Ruokonen A, Rudan I, Rose LM, Roberts R, Rieder M, Psaty BM, Pramstaller PP, Pichler I, Perola M, Penninx BW, Pedersen NL, Pattaro C, Parker AN, Pare G, Oostra BA, O'Donnell CJ, Nieminen MS, Nickerson DA, Montgomery GW, Meitinger T, McPherson R, McCarthy MI, McArdle W, Masson D, Martin NG, Marroni F, Mangino M, Magnusson PK, Lucas G, Luben R, Loos RJ, Lokki ML, Lettre G, Langenberg C, Launer LJ, Lakatta EG, Laaksonen R, Kyvik KO, Kronenberg F, König IR, Khaw KT, Kaprio J, Kaplan LM, Johansson A, Jarvelin MR, Janssens AC, Ingelsson E, Igl W, Kees Hovingh G, Hottenga JJ, Hofman A, Hicks AA, Hengstenberg C, Heid IM, Hayward C, Havulinna AS, Hastie ND, Harris TB, Haritunians T, Hall AS, Gyllensten U, Guiducci C, Groop LC, Gonzalez E, Gieger C, Freimer NB, Ferrucci L, Erdmann J, Elliott P, Ejebe KG, Döring A, Dominiczak AF, Demissie S, Deloukas P, de Geus EJ, de Faire U, Crawford G, Collins FS, Chen YD, Caulfield MJ, Campbell H, Burtt NP, Bonnycastle LL, Boomsma DI, Boekholdt SM, Bergman RN, Barroso I, Bandinelli S, Ballantyne CM, Assimes TL, Quertermous T, Altshuler D, Seielstad M, Wong TY, Tai ES, Feranil AB, Kuzawa CW, Adair LS, Taylor HA Jr, Borecki IB, Gabriel SB, Wilson JG, Holm H, Thorsteinsdottir U, Gudnason V, Krauss RM, Mohlke KL, Ordovas JM, Munroe PB, Kooner JS, Tall AR, Hegele RA, Kastelein JJ, Schadt EE, Rotter JI, Boerwinkle E, Strachan DP, Mooser V, Stefansson K, Reilly MP, Samani NJ, Schunkert H, Cupples LA, Sandhu MS, Ridker PM, Rader DJ, van Duijn CM, Peltonen L, Abecasis GR, Boehnke M, Kathiresan S. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010 Aug 5;466(7307):707-13. PubMed.
Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, Ganna A, Chen J, Buchkovich ML, Mora S, Beckmann JS, Bragg-Gresham JL, Chang HY, Demirkan A, Den Hertog HM, Do R, Donnelly LA, Ehret GB, Esko T, Feitosa MF, Ferreira T, Fischer K, Fontanillas P, Fraser RM, Freitag DF, Gurdasani D, Heikkilä K, Hyppönen E, Isaacs A, Jackson AU, Johansson Å, Johnson T, Kaakinen M, Kettunen J, Kleber ME, Li X, Luan J, Lyytikäinen LP, Magnusson PK, Mangino M, Mihailov E, Montasser ME, Müller-Nurasyid M, Nolte IM, O'Connell JR, Palmer CD, Perola M, Petersen AK, Sanna S, Saxena R, Service SK, Shah S, Shungin D, Sidore C, Song C, Strawbridge RJ, Surakka I, Tanaka T, Teslovich TM, Thorleifsson G, Van den Herik EG, Voight BF, Volcik KA, Waite LL, Wong A, Wu Y, Zhang W, Absher D, Asiki G, Barroso I, Been LF, Bolton JL, Bonnycastle LL, Brambilla P, Burnett MS, Cesana G, Dimitriou M, Doney AS, Döring A, Elliott P, Epstein SE, Ingi Eyjolfsson G, Gigante B, Goodarzi MO, Grallert H, Gravito ML, Groves CJ, Hallmans G, Hartikainen AL, Hayward C, Hernandez D, Hicks AA, Holm H, Hung YJ, Illig T, Jones MR, Kaleebu P, Kastelein JJ, Khaw KT, Kim E, Klopp N, Komulainen P, Kumari M, Langenberg C, Lehtimäki T, Lin SY, Lindström J, Loos RJ, Mach F, McArdle WL, Meisinger C, Mitchell BD, Müller G, Nagaraja R, Narisu N, Nieminen TV, Nsubuga RN, Olafsson I, Ong KK, Palotie A, Papamarkou T, Pomilla C, Pouta A, Rader DJ, Reilly MP, Ridker PM, Rivadeneira F, Rudan I, Ruokonen A, Samani N, Scharnagl H, Seeley J, Silander K, Stančáková A, Stirrups K, Swift AJ, Tiret L, Uitterlinden AG, van Pelt LJ, Vedantam S, Wainwright N, Wijmenga C, Wild SH, Willemsen G, Wilsgaard T, Wilson JF, Young EH, Zhao JH, Adair LS, Arveiler D, Assimes TL, Bandinelli S, Bennett F, Bochud M, Boehm BO, Boomsma DI, Borecki IB, Bornstein SR, Bovet P, Burnier M, Campbell H, Chakravarti A, Chambers JC, Chen YI, Collins FS, Cooper RS, Danesh J, Dedoussis G, de Faire U, Feranil AB, Ferrières J, Ferrucci L, Freimer NB, Gieger C, Groop LC, Gudnason V, Gyllensten U, Hamsten A, Harris TB, Hingorani A, Hirschhorn JN, Hofman A, Hovingh GK, Hsiung CA, Humphries SE, Hunt SC, Hveem K, Iribarren C, Järvelin MR, Jula A, Kähönen M, Kaprio J, Kesäniemi A, Kivimaki M, Kooner JS, Koudstaal PJ, Krauss RM, Kuh D, Kuusisto J, Kyvik KO, Laakso M, Lakka TA, Lind L, Lindgren CM, Martin NG, März W, McCarthy MI, McKenzie CA, Meneton P, Metspalu A, Moilanen L, Morris AD, Munroe PB, Njølstad I, Pedersen NL, Power C, Pramstaller PP, Price JF, Psaty BM, Quertermous T, Rauramaa R, Saleheen D, Salomaa V, Sanghera DK, Saramies J, Schwarz PE, Sheu WH, Shuldiner AR, Siegbahn A, Spector TD, Stefansson K, Strachan DP, Tayo BO, Tremoli E, Tuomilehto J, Uusitupa M, van Duijn CM, Vollenweider P, Wallentin L, Wareham NJ, Whitfield JB, Wolffenbuttel BH, Ordovas JM, Boerwinkle E, Palmer CN, Thorsteinsdottir U, Chasman DI, Rotter JI, Franks PW, Ripatti S, Cupples LA, Sandhu MS, Rich SS, Boehnke M, Deloukas P, Kathiresan S, Mohlke KL, Ingelsson E, Abecasis GR, Global Lipids Genetics Consortium. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013 Nov;45(11):1274-1283. Epub 2013 Oct 6 PubMed.
Pirim D, Radwan ZH, Wang X, Niemsiri V, Hokanson JE, Hamman RF, Feingold E, Bunker CH, Demirci FY, Kamboh MI. Apolipoprotein E-C1-C4-C2 gene cluster region and inter-individual variation in plasma lipoprotein levels: a comprehensive genetic association study in two ethnic groups. PLoS One. 2019;14(3):e0214060. Epub 2019 Mar 26 PubMed.
Ouidir M, Chatterjee S, Wu J, Tekola-Ayele F. Genomic study of maternal lipid traits in early pregnancy concurs with four known adult lipid loci. J Clin Lipidol. 2022 Nov 17; PubMed.
Aslam MM, Fan KH, Lawrence E, Bedison MA, Snitz BE, DeKosky ST, Lopez OL, Feingold E, Kamboh MI. Genome-wide analysis identifies novel loci influencing plasma apolipoprotein E concentration and Alzheimer's disease risk. Mol Psychiatry. 2023 Oct;28(10):4451-4462. Epub 2023 Sep 5 PubMed.
Loika Y, Loiko E, Culminskaya I, Kulminski AM. Exome-Wide Association Study Identified Clusters of Pleiotropic Genetic Associations with Alzheimer's Disease and Thirteen Cardiovascular Traits. Genes (Basel). 2023 Sep 22;14(10) PubMed.
Gamache J, Gingerich D, Shwab EK, Barrera J, Garrett ME, Hume C, Crawford GE, Ashley-Koch AE, Chiba-Falek O. Integrative single-nucleus multi-omics analysis prioritizes candidate cis and trans regulatory networks and their target genes in Alzheimer's disease brains. Cell Biosci. 2023 Oct 3;13(1):185. PubMed.
Chen Q, Aguirre L, Zhao H, Borrego F, deRojas I, Su L-Y, Li PP, Zhang B, Kokovay E, Lechleiter J, Goring H, DeJager P, Kleinman J, Hyde T, Ruiz A, Weinberger D, Seshadri S, Ma L. Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease. 2023 Oct 31 10.1101/2023.10.30.23297431 (version 1) medRxiv.
Vance JM, Farrer LA, Huang Y, Cruchaga C, Hyman BT, Pericak-Vance MA, Goate AM, Greicius MD, Griswold AJ, Haines JL, Tcw J, Schellenberg GD, Tsai LH, Herz J, Holtzman DM. Report of the APOE4 National Institute on Aging/Alzheimer Disease Sequencing Project Consortium Working Group: Reducing APOE4 in Carriers is a Therapeutic Goal for Alzheimer's Disease. Ann Neurol. 2024 Apr;95(4):625-634. Epub 2024 Jan 5 PubMed.
Griswold AJ, Celis K, Bussies PL, Rajabli F, Whitehead PL, Hamilton-Nelson KL, Beecham GW, Dykxhoorn DM, Nuytemans K, Wang L, Gardner OK, Dorfsman DA, Bigio EH, Mesulam MM, Weintraub S, Geula C, Gearing M, McGrath-Martinez E, Dalgard CL, Scott WK, Haines JL, Pericak-Vance MA, Young JI, Vance JM. Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds. Alzheimers Dement. 2021 Jul;17(7):1179-1188. Epub 2021 Feb 1 PubMed.
Celis K, Moreno MD, Rajabli F, Whitehead P, Hamilton-Nelson K, Dykxhoorn DM, Nuytemans K, Wang L, Flanagan M, Weintraub S, Geula C, Gearing M, Dalgard CL, Jin F, Bennett DA, Schuck T, Pericak-Vance MA, Griswold AJ, Young JI, Vance JM. Ancestry-related differences in chromatin accessibility and gene expression of APOE ε4 are associated with Alzheimer's disease risk. Alzheimers Dement. 2023 Sep;19(9):3902-3915. Epub 2023 Apr 10 PubMed.
Kulminski AM, Shu L, Loika Y, Nazarian A, Arbeev K, Ukraintseva S, Yashin A, Culminskaya I. APOE region molecular signatures of Alzheimer's disease across races/ethnicities. Neurobiol Aging. 2020 Mar;87:141.e1-141.e8. Epub 2019 Nov 11 PubMed.
Gottschalk WK, Mahon S, Hodgson D, Barrera J, Hill D, Wei A, Kumar M, Dai K, Anderson L, Mihovilovic M, Lutz MW, Chiba-Falek O. The APOE-TOMM40 Humanized Mouse Model: Characterization of Age, Sex, and PolyT Variant Effects on Gene Expression. J Alzheimers Dis. 2023;94(4):1563-1576. PubMed.

Mutations

APOE Region

Quick Links