APOE c.-494T>C (rs769446)

Other Names: rs769446, -427 T/C, -427C/T


Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Reference Assembly: GRCh37/hg19
Position: Chr19:45408628 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769446
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream


This common polymorphism was identified in a search for regulators of APOE gene expression (Artiga et al., 1998a). Sequencing nucleotides −1017 to +406 in samples of 75 unrelated Spanish individuals, the authors identified three polymorphisms, including c.-494T>C, in the APOE promoter. The minor allele, C, is found at a global frequency of 0.07 (gnomAD v2.1.1, August 2022). 

Studies evaluating the association of this variant with Alzheimer’s disease (AD) risk have yielded mixed results (see table below). The largest genome-wide association studies (GWAS) have revealed statistically significant associations, but the reported effect sizes are weak, and it remains unclear whether the variant itself modifies risk or travels together with a causal variant. Also, the location of the variant relative to the common APOE2/3/4 alleles on individual chromosomes (i.e., whether in cis or trans) is likely to be relevant to this variant's effects, given its location in the APOE promoter.

Artiga and colleagues first reported an association between the c.-494C allele and AD studying small Spanish and American cohorts (Artiga et al., 1998b). A few subsequent studies of small cohorts were consistent with these findings and two meta-analyses identified modest associations with AD risk (Bertram et al., 2007; Xiao et al., 2017). However, the effects reported by these meta-analyses were in opposite directions. The association found by Bertram et al. implicated the T allele and reached significance only after excluding a study to correct for between-study heterogeneity, whereas the association found by Xiao et al. implicated the C allele and was not reflected in analyses of the CC and CT genotypes.

Moreover, a few subsequent studies observed associations of c.-494T>C with AD that did not hold after adjusting for the common APOE alleles R176C (APOE2) and C130R (APOE4) (Yang et al., 2003; Nicodemus et al., 2004; Lynch et al., 2008), and some larger association analyses stratified by APOE2/3/4 genotype have failed to reach thresholds for statistical significance (see table below).

Artiga and colleagues noted an association between the c.-494C allele and APOE2 in a small Spanish population (Artiga et al., 1998). However, larger studies have revealed that linkage is relatively weak between c.-494T>C and the APOE2/E4 alleles. For example, in a study of approximately 75,000 Danish individuals, scores of r2=0.140 and D’=0.436 were obtained for APOE2 and c.-494C, and r2=0.002 and D’=0.308 for APOE4 and c.-494T (Rasmussen et al., 2020). Also of note, a large meta-analysis of AD GWAS listed the c.-494T>C polymorphism in a group of independent significant single nucleotide polymorphisms (p < 5 × 10−8, independent at r2 < 0.6 with APOE2 as the lead SNP at r2 < 0.1; Marioni et al., 2018).

The effect of c.-494T>C on AD risk may also depend on other variants beyond the common APOE isoforms, but results have been inconsistent. Two studies of small cohorts indicated c.-494T>C may boost AD risk together with the c.-558A allele, but one study implicated the C allele of the c.-494T>C variant while the other implicated the T allele (TT genotype) (Artiga et al., 1998b; Parker et al., 2005). Other studies have failed to detect any effect of the c.-494T>C polymorphism as part of different variant sets, or haplotypes (Bizzarro et al., 2009; Nicodemus et al., 2004).  Data on the linkage between this variant and other nearby variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section). Note that even weak linkages can be of importance as they can lead to confounding effects without proper adjustment (e.g., Andrews et al., 2019).

A few studies have reported associations of this variant with other neurological disorders, but they have involved limited numbers of patients. A study of a small cohort of Italian individuals, for example, reported an association with frontotemporal dementia (OR=4.4, 95% CI [1.9-10.2]) (Seripa et al., 2011). Moreover, a study of 350 Chinese infants with cerebral palsy and 242 healthy controls identified this variant as associated with disease (p=0.025 all patients; p=0.005 patients with preterm births; Xu et al., 2014). As a component of a group of five APOE variants, the C allele was associated with a decreased risk for the disease (OR=2.06, 95% CI [1.20-3.53], p=0.035). Isolated studies of dementia in post-stroke patients (Arpa et al., 2003) and subarachnoid hemorrhage (Kaushal et al., 2007) failed to detect an association, as did a meta-analysis of studies examining primary open-angle glaucoma (Guo et al., 2015). 

Interestingly, a GWAS of 2,580 European Americans revealed an association of the C allele with elevated levels of ApoE in plasma (β=0.49, p= 8.33 x 10-18) a trait that correlated with better cognitive function (Aslam et al., 2023). The effect appeared to be independent from other variants in the region based on linkage disequilibrium analysis and a p-value that remained significant (6.91 x 10-3) after adjusting for APOE2, the variant within the APOE region with the highest positive effect on plasma ApoE levels. A previous study, also in individuals of European ancestry, reported higher ApoE plasma levels associated with a lower risk of dementia, and specifically AD (Rasmussen et al., 2020). Some earlier studies have been consistent with Aslam and colleagues’ findings: one found lower ApoE plasma levels in AD patients with the TT genotype (Scacchi et al., 2001), and another recorded increased APOE mRNA levels in human liver samples of carriers of the c.-494C allele (Mannila et al., 2013). However, two other studies failed to detect similar effects (Lambert et al., 2000; Corbo et al., 2001).

Non-Neurological Effects

There are no clear associations between the 494T>C genotype and non-neurological conditions—other than increased ApoE plasma levels—in individuals of European ancestry. One study, for example, found no effect of the c.-494T>C variant on plasma lipid levels or on the risk for myocardial infarction in a small European cohort (Lambert et al., 2000). Another found no relationship between the c.-494T>C genotype and plasma lipoprotein levels in two cohorts of healthy middle-aged Swedes, each including more than 1,000 individuals (Mannila et al., 2013).

However, GWASs of large Japanese populations, including over 50,000 individuals, have detected moderate cardiovascular associations. For example, Matsunaga and colleagues found an association between the T allele and coronary artery disease (OR=1.34, 95% CI [1.22-1.47], p=2.44 X 10-9; Matsunaga et al., 2020). In addition, the C variant was found to be associated with decreased levels of total cholesterol (Matsunaga et al., 2020) and cholesterol in low-density lipoprotein (Kanai et al., 2018). The relationships of these associations with the common APOE2/3/4 polymorphisms have yet to be clarified.

Biological effects

In vitro experiments designed to assess the biological effects of c.-494T>C have yielded mixed results. In transfected human hepatoma cells (Artiga et al., 1998a) and in transfected human neuroblastoma and rat PC12 cells (Maloney et al., 2010), the variant had no detectable effect on APOE promoter activity. However, a subsequent study reported increased transcription mediated by the C allele in human hepatoma cells (Mannila et al., 2013). This study also reported evidence of differences in the binding of nuclear proteins to c.-494C and c.-494T probes, yet no such differences were detected in an earlier study (Artiga et al., 1998a).

Transcriptional effects may vary between populations and depend on other variants beyond c.-494T>C. For example, while Corbo and colleagues found no effect of the variant on ApoE plasma concentrations in patients with coronary heart disease (Corbo et al., 2001), the same group found increased ApoE levels in a cohort of AD patients with the TT genotype (Scacchi et al., 2001). In addition, Artiga et al. reported that in astrocytoma cells, the c.-494C allele boosted transcription together with the A allele of c.-558A>T (Artiga et al., 1998b).

c.-494T is in the APOE promoter region (Paik et al., 1988), within the HuD functional domain which spans nucleotides -651 to -366 (Maloney et al., 2007). HuD was shown to act as a negative regulatory element of transcription in multiple cell types, including neuronal-like rat chromaffin cells (PC12), SK-N-SH neuroblastoma cells, C6 glial cells, and U373 astroctyoma cells. Also of note, c.-494T is close to the liver X receptor-retinoid X receptor (LXR/RXR) response element which regulates lipid synthesis and transport in multiple tissues (Aslam et al., 2023).

This variant's PHRED-scaled CADD score, which integrates diverse information in silico, did not reach 20 (3.024) , a commonly used threshold to predict deleteriousness (CADD v.1.6, Nov 2022).



Association Results Ancestry
GWAS Meta-analysis     388,324 (total) p<5x10-8 UK Biobank and IGAP Marioni et al., 2018
GWAS Meta-analysis T   21,982 | 41,944 p=2.13x10-9 European
(IGAP Rare Variants: Stage 1)
Kunkle et al., 2019a
GWAS T   21,392 | 38,164 p=6.2x10-14 Mixed ancestry
(ADGC Transethnic LOAD: All Samples)
Jun et al., 2017a
T   17,536 | 36,175


(APOE-Stratified Analysis: All Samples)

(IGAP) Jun et al., 2016a
GWAS Meta-analysis C   17,008 | 37,154 p=5.07x10-6 European (IGAP 2013: Stage 1) Lambert et al., 2013
GWAS T   8,654 | 24,314 p=7.5x10-9 Mixed ancestry
(ADGC Transethnic LOAD: APOE4 Non-Carriers)
Jun et al., 2017a
GWAS Meta-analysis T   8,572 | 11,312 p=1.8x10-9 European
(IGAP 2013: ADGC Subset)
Lambert et al., 2013a
GWAS Meta-analysis T   7,184 | 26,968


(APOE-Stratified Analysis)

(IGAP, APOE4 non-carriers) Jun et al., 2016a
Meta-analysis T   2,962 | 2,883 OR=1.04
Mixed ancestry Xin et al., 2010
Meta-analysis TT vs. TG+GG   2,962 | 2,883 OR=1.03
Mixed ancestry Xin et al., 2010
Meta-analysis C   2,819 | 2,567
(10 studies)
Mixed ancestry Xin et al., 2010
Meta-analysis CC vs. TT   2,819 | 2,567
(10 studies)
Mixed ancestry Xin et al., 2010
Meta-analysis CC vs. TC   2,819 | 2,567
(10 studies)
Mixed ancestry Xin et al., 2010
Meta-analysis CC+CT vs TT   2,819 | 2,567
(10 studies)
Mixed ancestry Xin et al., 2010
Meta-analysis CC vs TT+TC   2,819 | 2,567
(10 studies)
Mixed ancestry Xin et al., 2010
Meta-analysis C vs T   2,762 | 2,671 OR=0.85
Mixed ancestry Bertram et al., 2007
Meta-analysis C vs T   2,588 | 2,468 OR=0.80b   [CI=0.67-0.95] Mixed ancestry Bertram et al., 2007
Targeted     1,398
| 1,082
Italian Lescai et al., 2011

aData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage.
bData from one study excluded to correct for between-study heterogeneity.

OR=odds ratio, GWAS=genome-wide association study. Statistically significant associations (as assessed by the authors) are in bold. For data retrieved from NIAGADS, p-values <5x10-8 are in bold.
All GWAS in this table included >=2,000 cases, and all targeted association studies included >=500 cases (subgroups within a study may be smaller).


This table is meant to convey the range of results reported in the literature. As specific analyses, including co-variates, differ among studies, this information is not intended to be used for quantitative comparisons, and readers are encouraged to refer to the original papers. Thresholds for statistical significance were defined by the authors of each study. (Significant results are in bold.) Note that data from some cohorts may have contributed to multiple studies, so each row does not necessarily represent an independent dataset. While every effort was made to be accurate, readers should confirm any values that are critical for their applications.

Last Updated: 13 Sep 2023


No Available Comments

Make a Comment

To make a comment you must login or register.


Mutations Citations

  1. APOE R176C (ApoE2)
  2. APOE C130R (ApoE4)
  3. APOE c.-558A>T (rs449647)

Paper Citations

  1. . Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 1998 Jan 9;421(2):105-8. PubMed.
  2. . Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet. 1998 Nov;7(12):1887-92. PubMed.
  3. . Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007 Jan;39(1):17-23. PubMed.
  4. . Association between polymorphisms in the promoter region of the apolipoprotein E (APOE) gene and Alzheimer's disease: A meta-analysis. EXCLI J. 2017;16:921-938. Epub 2017 Jun 20 PubMed.
  5. . Apolipoprotein E -491 promoter polymorphism is an independent risk factor for Alzheimer's disease in the Chinese population. Neurosci Lett. 2003 Oct 16;350(1):25-8. PubMed.
  6. . Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease. Neurogenetics. 2004 Dec;5(4):201-8. Epub 2004 Sep 29 PubMed.
  7. . Apolipoprotein E promoter polymorphisms (-491A/T and -427T/C) and Alzheimer's disease: no evidence of association in the Irish population. Ir J Med Sci. 2008 Mar;177(1):29-33. Epub 2007 Dec 5 PubMed.
  8. . APOE and dementia - resequencing and genotyping in 105,597 individuals. Alzheimers Dement. 2020 Dec;16(12):1624-1637. Epub 2020 Aug 18 PubMed.
  9. . GWAS on family history of Alzheimer's disease. Transl Psychiatry. 2018 May 18;8(1):99. PubMed.
  10. . Apolipoprotein gene E4 allele promoter polymorphisms as risk factors for Alzheimer's disease. Psychiatr Genet. 2005 Dec;15(4):271-5. PubMed.
  11. . The complex interaction between APOE promoter and AD: an Italian case-control study. Eur J Hum Genet. 2009 Jul;17(7):938-45. Epub 2009 Jan 28 PubMed.
  12. . Protective Variants in Alzheimer's Disease. Curr Genet Med Rep. 2019 Mar;7(1):1-12. Epub 2019 Jan 24 PubMed.
  13. . The APOE gene locus in frontotemporal dementia and primary progressive aphasia. Arch Neurol. 2011 May;68(5):622-8. PubMed.
  14. . The association of apolipoprotein E gene polymorphisms with cerebral palsy in Chinese infants. Mol Genet Genomics. 2014 Jun;289(3):411-6. Epub 2014 Feb 13 PubMed.
  15. . Apolipoprotein E, angiotensin-converting enzyme and alpha-1-antichymotrypsin genotypes are not associated with post-stroke dementia. J Neurol Sci. 2003 Jun 15;210(1-2):77-82. PubMed.
  16. . Subarachnoid hemorrhage: tests of association with apolipoprotein E and elastin genes. BMC Med Genet. 2007 Jul 31;8:49. PubMed.
  17. . Association of MYOC and APOE promoter polymorphisms and primary open-angle glaucoma: a meta-analysis. Int J Clin Exp Med. 2015;8(2):2052-64. Epub 2015 Feb 15 PubMed.
  18. . 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.
  19. . Polymorphisms of the apolipoprotein E gene regulatory region and of the LDL receptor gene in late-onset Alzheimer's disease in relation to the plasma lipidic pattern. Dement Geriatr Cogn Disord. 2001 Mar-Apr;12(2):63-8. PubMed.
  20. . Identification of a functional apolipoprotein E promoter polymorphism regulating plasma apolipoprotein E concentration. Arterioscler Thromb Vasc Biol. 2013 May;33(5):1063-9. Epub 2013 Feb 21 PubMed.
  21. . Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study. Hum Mol Genet. 2000 Jan 1;9(1):57-61. PubMed.
  22. . Polymorphisms in the apolipoprotein E gene regulatory region in relation to coronary heart disease and their effect on plasma apolipoprotein E. Clin Chem Lab Med. 2001 Jan;39(1):2-6. PubMed.
  23. . Transethnic Meta-Analysis of Genome-Wide Association Studies Identifies Three New Loci and Characterizes Population-Specific Differences for Coronary Artery Disease. Circ Genom Precis Med. 2020 Jun;13(3):e002670. Epub 2020 May 29 PubMed.
  24. . Genetic analysis of quantitative traits in the Japanese population links cell types to complex human diseases. Nat Genet. 2018 Mar;50(3):390-400. Epub 2018 Feb 5 PubMed.
  25. . Functional characterization of three single-nucleotide polymorphisms present in the human APOE promoter sequence: Differential effects in neuronal cells and on DNA-protein interactions. Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):185-201. PubMed.
  26. . Identification and characterization of transcriptional regulatory regions associated with expression of the human apolipoprotein E gene. J Biol Chem. 1988 Sep 15;263(26):13340-9. PubMed.
  27. . Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.
  28. . Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019 Mar;51(3):414-430. Epub 2019 Feb 28 PubMed.
  29. . Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement. 2017 Jul;13(7):727-738. Epub 2017 Feb 7 PubMed.
  30. . A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. 2015 Mar 17; PubMed.
  31. . Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 PubMed.
  32. . An APOE haplotype associated with decreased ε4 expression increases the risk of late onset Alzheimer's disease. J Alzheimers Dis. 2011;24(2):235-45. PubMed.

External Citations

  1. GWAS catalog

Further Reading


  1. . Correlation between ESR1 and APOE gene polymorphisms and risk of osteonecrosis of the femoral head: a case-control study. J Orthop Surg Res. 2023 Dec 15;18(1):968. PubMed.

Protein Diagram

Primary Papers

  1. . Allelic polymorphisms in the transcriptional regulatory region of apolipoprotein E gene. FEBS Lett. 1998 Jan 9;421(2):105-8. PubMed.
  2. . Risk for Alzheimer's disease correlates with transcriptional activity of the APOE gene. Hum Mol Genet. 1998 Nov;7(12):1887-92. PubMed.

Disclaimer: Alzforum does not provide medical advice. The Content is for informational, educational, research and reference purposes only and is not intended to substitute for professional medical advice, diagnosis or treatment. Always seek advice from a qualified physician or health care professional about any medical concern, and do not disregard professional medical advice because of anything you may read on Alzforum.