APOE c.43+78G>A (rs769449)

Other Names: rs769449


Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Reference Assembly: GRCh37/hg19
Position: Chr19:45410002 G>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs769449
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: Intron 2


This common intronic variant is associated with increased risk for Alzheimer’s disease (AD). At least in Europeans and Asians, the minor allele A has been found to be tightly linked to the major risk factor for AD, C130R (APOE4) (e.g., Deming et al., 2017; Nazarian et al., 2019).

Whether c.43+78G>A has an effect on AD risk in addition to that of APOE4 remains uncertain. One large genome-wide association study (GWAS) hints at this possibility, revealing that in cohorts of mixed ancestry an elevated risk of AD was associated with c.43+78A even in subgroups of individuals who were either all carriers or all non-carriers of the APOE4 allele (Jun et al., 2017; Table 1). However, while the p-value for the APOE4 carrier association was robust, the p-value for the non-carrier group exceeded the default cut-off value of 5x10-8 used by the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS).

Interestingly, one study focusing on five common APOE variants, including c.43+78G>A, suggested the G allele may confer protection against APOE4 (Babenko et al., 2018). The researchers examined how different combinations of the five variants in cis—or different haplotypes—in small cohorts of different ancestries related to risk for AD and mild cognitive impairment. They observed that a haplotype commonly found in people of African descent, including APOE4 and c.43+78G, was associated with reduced risk compared with a haplotype common in people of European descent, including APOE4 and c.43+78A.

A subsequent, larger study, however, found no difference in the risk or age of onset of AD between these two haplotypes, neither in African American nor European populations (Mezlini et al., 2020, Table 1). Furthermore, while APOE4 itself was associated with a faster rate of cognitive decline, no differences were found in rate of decline nor in clinical or neuropathological features between the two APOE4-linked haplotypes. To explain the discrepancy, Mezlini and colleagues suggested differences in the studies’ sample sizes, statistical methodologies, and/or cohorts, particularly since African populations are heterogenous (for more information on the relationship between ancestry and APOE4-associated AD risk, see APOE4).

Several studies have also reported associations with AD endophenotypes but many have not taken into account the variant’s linkage with APOE4 (e.g., Liu et al., 2018; Seo et al., 2020; Meng et al., 2020; Lee et al., 2022 [GWAS Catalog]). In those that have, the effects have often disappeared after adjustment. For example, a meta-analysis of amyloid burden in Americans of European ancestry, as assessed by brain imaging using PiB-PET, found an association with c.43+78G>A, but the effect did not survive conditioning for APOE4 (Yan et al., 2018).

However, c.43+78G>A may have an independent, albeit small, effect on tau pathology, at least in individuals of European ancestry. In a GWAS that indicated APOE influences tau pathology independently of Aβ or AD  status, the variant emerged as the most significant single nucleotide polymorphism (SNP) associated with levels of total tau and tau phosphorylated at threonine 181 (p-tau181) in CSF (Cruchaga et al., 2013). The effect prevailed after stratification for clinical status, CSF Aβ levels, and even after the APOE genotype of the common isoforms APOE2/3/4 was included as a covariate, although the effect size was substantially reduced, and the p-values were above the 5 × 10-8 threshold for genome-wide significance. The authors concluded that APOE4 is the dominant variant driving the associations, but c.43+78G>A, or other SNPs linked to it, may contribute to the effect. A subsequent study with a larger number of participants, reproduced the findings and yielded statistically significant results after adjustment for CSF Aβ and APOE2/3/4 (total tau: β=0.045, p=1.04x10-8; p-tau181 β=0.042, p=1.65x10-8, Deming et al., 2017). Of note, c.43+78G>A also emerged as the most significant SNP associated with p- tau181 levels in plasma, although the p-value was slightly greater than the threshold for GWAS statistical significance (p = 6.26 x 10-8; Huang et al., 2022).

As noted above, the linkage between c.43+78G>A and APOE4 varies across populations and so does its frequency. While in Europeans the frequency of the A allele is 0.11, it is 0.087 in East Asians, and only 0.019 in Africans/African Americans (gnomAD v2.1.1, July 2022). No carriers of South Asian ancestry were reported. Linkage data between c.43+78G>A and other neighboring variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section).

Other Neurological Associations

As expected, c.43+78G>A has been found associated with neurological impairments that have also been tied to APOE4. For example, studies have reported associations with Lewy body dementia (Chia et al., 2021), age-related cognitive decline (Zhang and Pierce 2013), performance on cognitive tests (Arpawong et al., 2017, Kang et al., 2023 suppl table 3), serum levels of C1M, a protease that correlates with tau degradation markers (Tang et al., 2020), age-related macular degeneration (Sharma et al., 2020), and brain microbleeds (Knol et al., 2020). In addition, GWAS data suggest associations with age-dependent changes in brain ventricular volume (Brouwer et al., 2022) and low-density lipoprotein (LDL) cholesterol levels in cohorts stratified by sleep duration (Noordam et al., 2019). Also, a large exome-wide study reported that an interaction between c.43+78G>A and a SNP from the low-density lipoprotein receptor-related protein1 (LRP1) gene was associated with visual attention (Chakraborty and Kahali, 2023). 

Non-Neurological Associations

The c.43+78G>A SNP correlates with blood levels of lipid particles, as does APOE4. Genome-wide studies including thousands of individuals have shown increased levels of total cholesterol, LDL cholesterol, and triglycerides associated with the A allele, as well as decreased levels of high-density lipoprotein (HDL) cholesterol (Chasman et al., 2008; Wu et al., 2013; Tang et al. 2015; Hoffman et al., 2018; Wojcik et al., 2019; Gallois et al., 2019; Sinnott-Armstrong et al., 2021). Several of these studies included participants of diverse ancestries (Wu et al., 2013; Hoffman et al., 2018; Wojcik et al., 2019; Hu et al., 2020). Associations of c.43+78G>A with other blood markers of lipid metabolism, as well as with markers of glucose metabolism, and liver and kidney function have also been examined by GWAS (Sinnott-Armstrong et al., 2021; Li-Gao et al., 2021). Also, the c.43+78 A allele was associated with low plasma ApoE levels in European Americans, a trait that correlated with reduced cognitive function (Aslam et al., 2023). The effect size was very similar to that of APOE4.

Several studies have also reported an association with C-reactive protein (Ridker et al., 2008; Curocichin et al., 2011; Kocamik et al., 2018; Wojcik et al., 2019; Sinnott-Armstrong et al., 2021, see GWAS Catalog), an inflammation marker in blood whose elevation in mid-life, appears to correlate with later cognitive decline (Feb 2019 news; Walker et al., 2019). Of note, the c.43+78 A allele is associated with decreased, rather than increased, C-reactive protein levels, as is APOE4 (Judson et al., 2004).  

In addition, ties between c.43+78G>A and longevity have been reported. One GWAS that included tens of thousands of individuals of European ancestry found decreased lifespan associated with carriers of the A allele (Wright et al., 2019) and another large GWAS reported an association of the G allele with parental longevity (Pilling et al., 2016). Moreover, the A allele has been found to be depleted in Europeans over age 95 (Soerensen et al., 2013; Ryu et al., 2016). Adjusting for APOE4 in one of the studies voided the effect (Soerensen et al., 2013).

More detailed data on associations revealed by GWAS can be found in the GWAS Catalog.

Biological Effect

As noted, the association of this variant with multiple neurological and lipid-metabolism phenotypes can be attributed most often to its genetic linkage to APOE4. However, a few studies indicate it may have biological effects of its own. Some intronic sequences are capable of modulating gene expression, and the c.43+78G>A variant, located 78 base pairs into intron 2 in an area containing several transcription factor binding sites, might fall in this category (Babenko et al., 2018). Moreover, substitution of the major allele G with the minor allele A results in the loss of a putative methylation site in the inverse strand, and the methylation status of this region is inversely proportional to APOE expression (Babenko et al., 2018; Ma et al., 2015).

This variant's PHRED-scaled CADD score (7.59), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Nov 2022).


Study Type

Risk Allele(s) Allele Freq.
Cases | CTRL
Association Results Ancestry
GWAS Meta-analysis   0.123 71,8880a | 383,378 z-score = 51.62
Jansen et al., 2019
GWAS     21,392 | 38,164 p=5.3x10-435 Mixed ancestry
(ADGC Transethnic LOAD: All Samples)
Jun et al., 2017b
GWAS Meta-analysis A   25,580 | 48,466 OR=3.52
p= 9.86×10−523
European Lambert et al., 2013
GWAS Meta-analysis A   17,536 | 36,175


(APOE-Stratified Analysis: SNP - APOE4 Status Interaction)

(IGAP) Jun et al., 2016b
GWAS A   12,738 | 13,850 p=4.6x10-30 Mixed ancestry
(ADGC Transethnic LOAD:APOE4 carriers)
Jun et al., 2017b
GWAS Meta-analysis A   10,352 | 9,207


(APOE-Stratified Analysis: APOE4 Carriers)

(IGAP) Jun et al., 2016b
GWAS A   8,654 | 24,314 p=1.29x10-7 Mixed ancestry
(ADGC Transethnic LOAD: APOE4 Non-Carriers)
Jun et al., 2017b
GWAS     2,741 | 14,739 OR=3.87
European Nazarian et al., 2019c
Targeted G
(in cis with APOE4)
0.078 | 0.034 3,106 | 3,797 OR=3.61
(NACC, African/Ancestral E4 haplotype)
Mezlini et al., 2020
Targeted A
(in cis with APOE4)
0.285 | 0.122 3,106 | 3,797 OR=3.48
(European E4 haplotype)
Mezlini et al., 2020
Targeted G
(in cis with APOE4)
  380 | 714 OR=3.85
African American
(NACC, African/Ancestral E4 haplotype)
Mezlini et al., 2020
Targeted A
(in cis with APOE4)
  380 | 714 OR=4.23
African American
(NACC, European E4 haplotype)
Mezlini et al., 2020
GWAS     1,968 | 3,928 p=4.9x10-11 African American
(ADGC: African Americans 2013)
Reitz et al., 2013b
GWAS A 0.037 1,137 | 1,707 pd=1.49x10-11 African American (ADSP) Lee et al., 2023

a24,087 LOAD cases; 47,793 offspring of parents with AD
bData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) rs769449, June 2022
cData from GWAS Catalog rs769448, July 2022
dAssociation not found after APOE4 adjustment (p cut-off=5x10-8)

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 data retrieved from the GWAS catalog (p-values <1x10-5) are in bold.
All genome-wide association studies 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: 17 Nov 2023


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Mutations Citations

  1. APOE C130R (ApoE4)

News Citations

  1. Midlife Peripheral Inflammation May Drive Later Cognitive Decline

Paper Citations

  1. . Genome-wide association study identifies four novel loci associated with Alzheimer's endophenotypes and disease modifiers. Acta Neuropathol. 2017 May;133(5):839-856. Epub 2017 Feb 28 PubMed.
  2. . Genome-wide analysis of genetic predisposition to Alzheimer's disease and related sex disparities. Alzheimers Res Ther. 2019 Jan 12;11(1):5. PubMed.
  3. . Transethnic genome-wide scan identifies novel Alzheimer's disease loci. Alzheimers Dement. 2017 Jul;13(7):727-738. Epub 2017 Feb 7 PubMed.
  4. . Haplotype analysis of APOE intragenic SNPs. BMC Neurosci. 2018 Apr 19;19(Suppl 1):16. PubMed.
  5. . Characterizing Clinical and Neuropathological Traits of APOE Haplotypes in African Americans and Europeans. J Alzheimers Dis. 2020;78(1):467-477. PubMed.
  6. . Genome-Wide Association and Mechanistic Studies Indicate That Immune Response Contributes to Alzheimer's Disease Development. Front Genet. 2018;9:410. Epub 2018 Sep 24 PubMed.
  7. . Genetic associations of in vivo pathology influence Alzheimer's disease susceptibility. Alzheimers Res Ther. 2020 Nov 19;12(1):156. PubMed.
  8. . 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.
  9. . Genome-Wide association study of quantitative biomarkers identifies a novel locus for alzheimer's disease at 12p12.1. BMC Genomics. 2022 Jan 28;23(1):85. PubMed.
  10. . 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.
  11. . GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer's disease. Neuron. 2013 Apr 24;78(2):256-68. Epub 2013 Apr 4 PubMed.
  12. . Genome-wide association study identifies APOE locus influencing plasma p-tau181 levels. J Hum Genet. 2022 Aug;67(8):459-463. Epub 2022 Mar 7 PubMed.
  13. . Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture. Nat Genet. 2021 Mar;53(3):294-303. Epub 2021 Feb 15 PubMed.
  14. . Genetic susceptibility to accelerated cognitive decline in the US Health and Retirement Study. Neurobiol Aging. 2014 Jun;35(6):1512.e11-8. Epub 2013 Dec 26 PubMed.
  15. . 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.
  16. . A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores. Mol Neurodegener. 2023 Jun 22;18(1):40. PubMed.
  17. . Matrix metalloproteinase-degraded type I collagen is associated with APOE/TOMM40 variants and preclinical dementia. Neurol Genet. 2020 Oct;6(5):e508. Epub 2020 Sep 10 PubMed.
  18. . Gene networks determine predisposition to AMD. Genomics. 2021 Jan;113(1 Pt 2):514-522. Epub 2020 Sep 24 PubMed.
  19. . Association of common genetic variants with brain microbleeds: A genome-wide association study. Neurology. 2020 Dec 15;95(24):e3331-e3343. Epub 2020 Sep 10 PubMed.
  20. . Genetic variants associated with longitudinal changes in brain structure across the lifespan. Nat Neurosci. 2022 Apr;25(4):421-432. Epub 2022 Apr 5 PubMed.
  21. . Exome-wide analysis reveals role of LRP1 and additional novel loci in cognition. HGG Adv. 2023 Jul 13;4(3):100208. Epub 2023 May 20 PubMed.
  22. . Genetic loci associated with plasma concentration of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, apolipoprotein A1, and Apolipoprotein B among 6382 white women in genome-wide analysis with replication. Circ Cardiovasc Genet. 2008 Oct;1(1):21-30. PubMed.
  23. . Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. PLoS Genet. 2013 Mar;9(3):e1003379. Epub 2013 Mar 21 PubMed.
  24. . Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nat Commun. 2015 Dec 22;6:10206. PubMed.
  25. . A large electronic-health-record-based genome-wide study of serum lipids. Nat Genet. 2018 Mar;50(3):401-413. Epub 2018 Mar 5 PubMed.
  26. . Genetic analyses of diverse populations improves discovery for complex traits. Nature. 2019 Jun;570(7762):514-518. Epub 2019 Jun 19 PubMed.
  27. . A comprehensive study of metabolite genetics reveals strong pleiotropy and heterogeneity across time and context. Nat Commun. 2019 Oct 21;10(1):4788. PubMed.
  28. . Genetics of 35 blood and urine biomarkers in the UK Biobank. Nat Genet. 2021 Feb;53(2):185-194. Epub 2021 Jan 18 PubMed.
  29. . Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genet. 2020 Mar;16(3):e1008684. Epub 2020 Mar 30 PubMed.
  30. . Genetic Studies of Metabolomics Change After a Liquid Meal Illuminate Novel Pathways for Glucose and Lipid Metabolism. Diabetes. 2021 Dec;70(12):2932-2946. Epub 2021 Oct 5 PubMed.
  31. . 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.
  32. . Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am J Hum Genet. 2008 May;82(5):1185-92. Epub 2008 Apr 24 PubMed.
  33. . Single-nucleotide polymorphisms at five loci are associated with C-reactive protein levels in a cohort of Filipino young adults. J Hum Genet. 2011 Dec;56(12):823-7. Epub 2011 Sep 22 PubMed.
  34. . Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study. Hum Mol Genet. 2018 Aug 15;27(16):2940-2953. PubMed.
  35. . Systemic inflammation during midlife and cognitive change over 20 years: The ARIC Study. Neurology. 2019 Feb 13; PubMed.
  36. . New and confirmatory evidence of an association between APOE genotype and baseline C-reactive protein in dyslipidemic individuals. Atherosclerosis. 2004 Dec;177(2):345-51. PubMed.
  37. . A Prospective Analysis of Genetic Variants Associated with Human Lifespan. G3 (Bethesda). 2019 Sep 4;9(9):2863-2878. PubMed.
  38. . Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging (Albany NY). 2016 Mar;8(3):547-60. PubMed.
  39. . Evidence from case-control and longitudinal studies supports associations of genetic variation in APOE, CETP, and IL6 with human longevity. Age (Dordr). 2013 Apr;35(2):487-500. Epub 2012 Jan 12 PubMed.
  40. . Genetic landscape of APOE in human longevity revealed by high-throughput sequencing. Mech Ageing Dev. 2016 Apr;155:7-9. Epub 2016 Feb 27 PubMed.
  41. . Genetic variants modify the effect of age on APOE methylation in the Genetics of Lipid Lowering Drugs and Diet Network study. Aging Cell. 2015 Feb;14(1):49-59. Epub 2014 Dec 4 PubMed.
  42. . 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.
  43. . 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.
  44. . A novel Alzheimer disease locus located near the gene encoding tau protein. Mol Psychiatry. 2015 Mar 17; PubMed.
  45. . Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E ϵ4,and the risk of late-onset Alzheimer disease in African Americans. JAMA. 2013 Apr 10;309(14):1483-92. PubMed.
  46. . Association of Common and Rare Variants with Alzheimer's Disease in over 13,000 Diverse Individuals with Whole-Genome Sequencing from the Alzheimer's Disease Sequencing Project. 2023 Sep 02 10.1101/2023.09.01.23294953 (version 1) medRxiv.

External Citations

  1. GWAS Catalog
  2. GWAS catalog

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study. Am J Hum Genet. 2008 May;82(5):1185-92. Epub 2008 Apr 24 PubMed.

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