Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44906745 G>A
Position: (GRCh37/hg19):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

Findings

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).

Table

^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).

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References

Mutations Citations

1. APOE C130R (ApoE4)

News Citations

1. Midlife Peripheral Inflammation May Drive Later Cognitive Decline 20 Feb 2019

Paper Citations

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External Citations

1. GWAS Catalog
2. GWAS catalog

Further Reading

No Available Further Reading