Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44905579 T>G
Position: (GRCh37/hg19):Chr19:45408836 T>G
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs405509
Coding/Non-Coding: Non-Coding
DNA Change: Substitution
Reference Isoform: APOE Isoform 1
Genomic Region: 2kb upstream

Findings

Summary
This common single nucleotide polymorphism (SNP) in the APOE promoter is associated with Alzheimer’s disease (AD). Although many studies have examined this association, it is still unclear whether the variant has an independent effect on AD risk, potentiates the effect of the risk allele C130R (APOE4), or is simply inherited together with a damaging variant. One intriguing possibility is that the variant contributes to differences in APOE4 vulnerability in populations of different ancestries, but so far, only one study has provided supporting evidence.

Understanding this variant’s relationship to AD has been challenging because its effect on AD is likely moderate, whether and how linkage with other genetic variants was accounted for has varied between studies, and the location of the variant relative to the APOE2/3/4 alleles on individual chromosomes (i.e., whether they are in cis or trans) has rarely been examined. Moreover, the influence of other factors, such as age and hormonal status, appear to be important, but have yet to be examined in depth.

In addition to AD risk, the variant has been associated with many other conditions, most notably several related to lipid metabolism and cardiovascular health.

As expected from its location in the APOE promoter, this variant modulates APOE transcription. Compared with the G allele, the T allele appears to reduce expression and this reduction seems to correlate with increased methylation of the APOE gene. Also, transcription factors that bind to other positions in the APOE promoter, as well as regulatory molecules that vary between cell types and species, appear to affect c.-286T>G function.

Association with AD | Association with AD endophenotypes | Other neurological effects | Non-neurological effects | Biological effects |

Association with AD

The c.-286T>G SNP was first described 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 new polymorphisms, including c.-286T>G, in the APOE promoter. Shortly after, c.-286T>G was identified in a search for variants that modify the risk of AD associated with APOE4 (Lambert et al., 1998a; Lambert et al., 1998b). The authors sequenced 375 bp of the APOE promoter and identified the -219 site, corresponding to c.-286T>G, as being polymorphic in two French elderly cohorts. The site was named Th1/E47cs, short for Th1/E47 consensus sequence, because it mapped to a potential binding site for the Th1/E47 transcription factor. Examining the polymorphism’s association with APOE4 and AD, the authors reported the c.-286T allele was linked to APOE4 and increased AD risk beyond that associated with APOE4. Consistent with these early findings, most subsequent association studies and meta-analyses, including thousands of individuals, have identified statistically significant associations between c.-286T and AD (Table 1).

However, whether the polymorphism potentiates the effect of APOE4 as suggested by the early studies, or has an independent effect on AD risk, or is simply inherited together with APOE4 or another damaging variant, remains unclear (Table 2). Multiple studies in the late ‘90s and early 2000s, including small cohorts of different ancestries, reported associations between c.-286T and AD that failed to hold after adjustment for APOE4.

Linkage between c.-286T and APOE4 does not appear to be the sole explanation for c.-286T’s association with elevated AD risk, however. Although early studies reported that the c.-286T allele and APOE4 are very often inherited together, as are the c.-286G and APOE2 alleles (e.g., Lambert et al., 1998b, Rebeck et al., 1999, Zurutuza et al., 2000, Belbin et al., 2007), more recent, larger studies show weak linkage. For example, a study of over 17,000 Caucasians reported linkage disequilibrium values that failed to reach statistical significance ([T allele with E4] D’=0.650, r²=0.087; Nazarian et al., 2019). Similar values were reported in a study of 74,940 Danish individuals (Rasmussen et al., 2020). Additional data on the linkage between c.-286T>G and other nearby variants, across several populations, can be found in the GWAS catalog (click on “Linkage Disequilibrium” tab in the “Available data” section).

A few studies support the possibility of c.-286T>G acting as a modulator of APOE4-associated risk, as originally suggested by Lambert and colleagues (Lambert et al., 1998a; Lambert et al., 1998b). This group pointed out that c.-286T>G was likely to have effects in cis, given its location in a promoter. Thus, APOE3/E4 heterozygotes, for example, are expected to experience different physiological consequences depending on whether they carry a c.-286T allele on their APOE3- or their APOE4-bearing chromosome. Lescai and colleagues reported that, in individuals over 75, when c.-286T and APOE4 were predicted to be in phase, i.e., on the same chromosome, only then did the variant boost the risk for late-onset AD (see Table 2, Lescai et al., 2011).

Interestingly, evidence for c.-286T>G modulating APOE4 risk surfaced again in a search for genetic factors that modify this risk in populations of different ancestries (Choi et al., 2019, see Table 2). After screening the promoter and 3’ untranslated region of APOE in approximately 20,000 East Asians, 16,000 individuals of European ancestry, and 5,000 African Americans, c.-286T>G emerged as the SNP with the largest difference in allele frequency between ancestries, particularly among APOE4 homozygotes, with the T allele being frequent in East Asians (0.74), less frequent in European Americans (0.53), and least frequent in African Americans (0.28), mirroring the populations’ APOE4-associated risk. Moreover, among APOE4 homozygotes of European ancestry, AD risk increased in a dose-dependent manner with the number of c.-286T alleles, and T homozygotes had a younger age of disease onset and more severe cortical atrophy than those carrying a G allele. Similarly, in the East Asian group, the odds of AD associated with APOE4 homozygosity were substantially higher for TT individuals compared with GT individuals. African Americans were excluded from these analyses due to small sample size. Of note, c.-286T>G is just one of several candidates that may contribute to population differences in APOE4 risk; see APOE4 and APOE region.

How other factors, such as estrogen (Lambert et al., 2004) and age (Lambert et al., 2002, Beyer 2002b, Beyer et al., 2005, Nicodemus et al., 2004), may affect c.-286T>G’s relationship with AD have also been studied. One meta-analysis, for example, indicated that age accentuated the risk associated with the TT genotype, and in the oldest carriers, increased risk was seen in both APOE4 carriers and non-carriers (see table 2, Lambert et al., 2002).

Association with AD endophenotypes

In addition to being studied in the context of AD risk, c.-286T>G has been examined for its associations with AD endophenotypes. For example, Choi et al.’s study found that APOE4 homozygotes, from both East Asian and Caucasian ancestry, suffered from greater atrophy in the medial temporal cortex, precuneus, and hippocampus than APOE3 homozygotes when carrying two T alleles (p<0.01), but not two G alleles (p>0.05, Choi et al., 2019). Moreover, a GWAS study of 866 Caucasians reported a significant association of the polymorphism with changes in the volumes of AD-relevant subcortical regions, including the hippocampus, amygdala, putamen, and nucleus accumbens (p=0.0002, Meng et al., 2020). However, in a Korean cohort, the variant was only minimally associated with AD pathologies evaluated by brain imaging (adjusted p > 0.4, Seo et al., 2020).

Also, a couple of studies have found correlations between c.-286T>G and amyloid pathology, but their sample sizes were small. A study of 114 British individuals, for example, found an association between the TT genotype and a higher level of parenchymal Aβ deposition, independent of APOE4 allele status (p<0.05, Lambert et al., 2005). Moreover, in an American cohort including 313 individuals, the c.-286G allele was associated with elevated levels of total Aβ peptide in cerebrospinal fluid (p<0.05), but not with the Aβ42/Aβ40 ratio (Kauwe et al., 2009).

Other neurological effects

Several studies have reported the c.-286T allele being negatively correlated with cognitive function and neurological health in non-demented, elderly individuals. Ma and colleagues, for example, reported reduced performance in tests of general cognition, episodic memory, processing speed, and executive function by Chinese APOE4 carriers who were homozygous for the c.-286T allele compared with individuals carrying the G allele (Ma et al., 2016a). The authors also found a reduction in grey matter volume in the inferior temporal gyrus and fusiform gyrus, which correlated with cognitive phenotype. The same group also reported negative effects on brain connectivity, in particular associated with the default mode network (Ma et al., 2016b), and a subsequent study found alterations in fronto-parietal connectivity (Zhang et al., 2020).

Consistent with these findings, other studies of Chinese non-demented individuals have reported TT carriers as more frequently having decreased attention and executive function, as well as disrupted white matter connections (Shu et al., 2015, Chang et al., 2017). Moreover, accelerated age-related reduction of thickness of the left parahippocampal gyrus has been observed in TT carriers compared with G-allele carriers (Chen et al., 2015). Providing evidence from a European population, a study of individuals from the Helsinki Birth cohort revealed an association of the c.-286G allele with higher total cognitive ability, independent of the major APOE2/3/4 isoforms (Rantalainen et al., 2016). More recently, a GWAS of European Americans revealed an association of the T allele with reduced levels of ApoE in plasma, a trait that correlated with worse cognitive function (Aslam et al., 2023). The effect appeared to be independent from other variants in the APOE region. A previous study, also in individuals of European ancestry, reported lower ApoE plasma levels associated with a higher risk of dementia, and specifically AD (Rasmussen et al., 2020).

On the other hand, one study of a longitudinal cohort of American men found no association between the polymorphism and cognitive performance (Prada et al., 2014), and another study of a small cohort of eldery Chinese reported a weak association of the GG genotype with an increased risk of cognitive impairment compared with TT and TG genotypes and suggested an interaction with cadmium plasma levels (Ye et al., 2023). Moreover, a study of over a million individuals identified c.-286T as one of 765 genome-wide SNPs contributing to educational attainment (Lee et al., 2018).

In addition, a few studies have analyzed the association of c.-286T>G with neurological disorders unrelated to AD. For example, a study including 510 Chinese patients suffering from Parkinson’s disease (PD) and 510 controls found a correlation between the T allele and increased susceptibility to PD (Huang et al., 2020). Also, a study of 60 Mexican families with schizophrenia concluded that the c.-286G allele on an APOE3 background was associated with the disease (Tovilla-Zarate et al., 2009). Moreover, a few small studies suggest c.-286T>G may influence outcomes in traumatic brain injury, but the effect remains uncertain (Panenka et al., 2017, Reuter-Rice et al., 2018, Abrahams et al., 2018). One small study found the c.-286G allele associated with ischemic stroke, but not with the severity of intracranial atherosclerosis, in contrast to converse associations detected for APOE4 (Abboud et al., 2008). Although a study of a small sample of subarachnoid hemorrhage patients did not reveal an association with c.-286T>G, it did identify association with a haplotype that included the variant (Kaushal et al., 2007). 

Conflicting findings have been reported for c.-286T>G association with risk for macular degeneration (Fritsche et al., 2009, McKay et al., 2011), glaucoma (Lam et al., 2006, Saglar et al., 2014, Guo et al., 2015), and obstructive sleep apnea (Kalra et al., 2008, Kripke et al., 2010).

Non-neurological effects

The c.-286T>G polymorphism has also been examined in the context of a wide range of non-neurological conditions, with traits related to cardiovascular health among the most intensively studied. In a French cohort, the polymorphism was reported to be associated with a moderately elevated risk of myocardial infarction and the effect was independent of the APOE2/3/4 alleles (Lambert et al., 2000). Similarly, an independent, and possibly additive, effect of the variant on the severity of coronary artery disease was described in patients from the U.K. (Ye et al., 2003). In addition, in a cohort of Finnish individuals, those with premature coronary heart disease had a higher frequency of c.-286T and APOE4 alleles, when analyzed separately or combined, than healthy controls (Viitanen et al., 2001). Of note, whereas one study found that Swedish women carrying both the APOE4 and c.-286T alleles suffered from higher cardiovascular mortality (Fredriksson et al., 2007), a study of Danish individuals over age 85 failed to identify increased risk of cardiovascular mortality associated with either APOE4 or c.-286T homozygosity (Heijmans et al., 2001). Similarly, a study of a Chinese Han population showed no association of c.-286T>G with hypertension (Zhang et al., 2015).

Also, the SNP has been reported to have a dose-dependent effect on ApoE blood levels (Lambert et al., 2000), as well as influence other blood lipoprotein and lipid profiles (Moreno et al., 2003, Klos et al., 2006, Pare et al., 2007, Ken-Dror et al., 2010, Rudkowska et al., 2013, Radwan et al., 2014, Pirim et al., 2019, Gallois et al., 2019, Harshfield et al., 2021). For example, a GWAS study of over 6,000 Finnish men identified associations between c.-286T>G and serum HDL/phospholipid levels, as well as levels of serum polyunsaturated fatty acids (Gallois et al., 2019). Moreover, associations in non-Hispanic whites with low-density lipoprotein cholesterol (LDL-C), total cholesterol, and triglyceride levels were identified after adjusting for the APOE 2/3/4 isoforms (Radwan et al., 2014, Pirim et al., 2019). In some studies, however, the independence of the effects of c.-286T>G have been less clear. For example, in a group of healthy men in the U.K., c.-286T was associated with higher levels of plasma LDL-C and ApoB, but only in APOE4 carriers (Ken-Dror et al., 2010). In addition, at least some effects of the SNP may depend on whether blood metabolites are measured before or after eating (Moreno et al., 2003), as well as on diet composition (Moreno et al., 2004).

The c.-286T>G polymorphism may associate with other conditions as well. Some studies, for example, have reported associations with altered glucose metabolism (e.g., Clark et al., 2009, Komurcu-Bayrak et al., 2011), although one study reported no effect on type 2 diabetes risk (Geng et al., 2011).  Moreover, conflicting findings have been reported for c.-286T>G association with renal cell carcinoma (Moore et al., 2009, Lv et al., 2015). Additional reports include associations with chronic kidney disease (Yoshida et al., 2009), bone structural traits influenced by diet (Tolonen et al., 2011), and leprosy (Wang et al., 2018). Interestingly, a GWAS including over 125,000 individuals identified c.-286T>G as a SNP that affected HDL cholesterol levels associated with short sleep time (Noordam et al., 2019). Not surprisingly, associations with longevity have also been reported (Lu et al., 2014, Ryu et al. 2016).

Biological effects

Most studies of this variant in the APOE promoter indicate the T allele reduces transcription of the gene relative to the G allele. Decreased levels of ApoE have been found in postmortem brain tissue and in blood of carriers of the c.-286T allele, particularly in TT homozygotes (Lambert et al., 1998b, Lambert et al., 2000, Moreno et al., 2003, Lambert et al., 2005, Choi et al., 2019). Consistent with these findings, Artiga and colleagues reported that substituting the c.-286T allele with a G in transfected human hepatoma cells resulted in a 169 percent increase in transcription (Artiga et al., 1998a). Subsequent in vitro experiments yielded similar results (Campillos et al., 2003, Ramos et al., 2005, Maloney et al., 2010, Choi et al., 2019), although the effect was undetectable in one study (Tycko et al., 2004).

The consequences of these findings are still under investigation. The T allele's association with reduced transcription and increased AD risk in APOE4 homozygotes, for example, led Choi and colleagues to propose that increasing ApoE4 levels could be of therapeutic value (Choi et al., 2019). However, after evaluating multiple studies in humans and animal models, the APOE4 NIA/ADSP Consortium concluded the opposite, at least for individuals of European and African ancestry (Vance et al., 2024). The authors of this report also recommended collecting more data on Asian populations.

Some studies indicate that regulation of APOE transcription by c.-286T>G may vary between cell types and species. Campillos et al., for example, found different effects of c.-286T>G on APOE transcription in lymphocytes or erythroleukemia cells compared with hepatoma or astrocytoma cells (Campillos et al., 2003), while Maloney and colleagues reported transcriptional differences between human neuroblastoma and rat PC12 cells (Maloney et al., 2010). Also of note, c.-286T is within the HuC functional domain of the APOE promoter which, spanning nucleotides -366 to -101, acted as a negative regulatory element in a reporter assay using uninduced human neuronal cells and a positive regulatory element in uninduced human glial cells (Maloney et al., 2007). In contrast, the corresponding mouse sequence (which did not overlap completely with the human sequence) had no apparent effect in neuronal cells and a negative effect in glial cells.

One factor that may contribute to such differences is the heterogeneous nuclear ribonucleoprotein hnRNPA1 (A1) whose expression varies between cell types (Campillos et al., 2003). Using DNA-affinity chromatography and mass spectrometry to analyze the binding of proteins in nuclear extracts of human T lymphocytes to the APOE promoter, the authors found A1 specifically binding to the T, but not G, allele of c.-286T>G as part of a transcriptional regulatory complex (Campillos et al., 2003). Interestingly, A1 appeared to promote an increase in transcriptional activity, reducing the differences in basal transcriptional activity between c.-286T and c.-286G. Consistent with this observation, two cell lines that express high levels of A1 constitutively, Jurkat T-lymphocytes and CB7 erythroleukemia cells, showed no significant differences in the basal activity of a promoter bearing c.-286T versus c.-286G, while in cells that express lower levels of A1, human HepG2 hepatoma cells and human U87 astrocytoma cells, allelic differences were robust.

In addition, the c.-286T>G SNP may interact with other polymorphisms to modulate APOE transcription (Maloney et al., 2010). In human neuroblastoma cells, the reduced transcription associated with the c.-286T allele was modulated by c.-558A>T, another promoter variant. In the presence of c.-558A, which increased transcription, c.-286T intensified the upregulation, while c.-286G muted it. Based on electrophoretic mobility shift assays, Southwestern blots, and consensus sequence analyses, Maloney and colleagues predicted the c.-558A variant has greater affinity for the SP1 transcription factor than c.-558T, while c.-286G has greater affinity for GATA family transcription factors than c.-286T. Moreover, in vitro reporter assays revealed the c.-558A/c.-286T genotype increased expression, presumably via SP1 binding to c.-558A, whereas c.-558A/c.-286G and c.-558T/c.-286G led to moderate levels of transcription, presumably because GATA factor(s) binding to c.-286G overrode the effects of the more distal c.-558A>T site. The lowest levels of transcription were observed with the c.-558T/c.-286T genotype, in which binding of transcription factors to both sites was predicted to be minimal. Linkage disequilibrium between these two variants appears to be weak (for c.-558T/c.-286T D’=0.153, r²=0.005; Rasmussen et al., 2020).

DNA methylation has surfaced as yet another piece of the c.-286T>G regulatory puzzle. Ma and colleagues found that methylation of the APOE gene, which correlated with decreased APOE transcription, was highest in TT homozygotes, intermediate in heterozygotes, and lowest in GG homozygotes (Ma et al., 2015). Interestingly, age affected the influence of c.-286T>G on methylation. For carriers of the G allele, GG and TG genotypes, older age was associated with lower methylation levels of the APOE promoter. In contrast, TT homozygotes had elevated methylation levels regardless of age.

c.-286T>G may also have transcriptional effects that depend on AANCR, an RNA enhancer which includes c.-286T>G in its sequence (Watts et al., 2022). In some cells and under stress, AANCR is fully transcribed and promotes APOE expression, whereas in others, it is only partially transcribed adopting a configuration that represses expression. Of note, expression of AANCR in astrocytes is highly correlated with APOE expression (Zhang et al., 2016).

This variant's PHRED-scaled CADD score (9.36), which integrates diverse information in silico, did not reach 20, a commonly used threshold to predict deleteriousness (CADD v.1.6, Nov 2022).

Table

Table1: AD Association

^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) rs405509, June 2022
^cData from GWAS Catalog rs405509, May 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.
For Caucasian and mixed ancestry cohorts, 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).

Table 2: AD association taking APOE4 into account

^aData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) rs405509, June 2022
^bAllele frequency in APOE4/APOE4 | Total allele frequency

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 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)
2. APOE c.-558A>T (rs449647)

Paper Citations

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Other Citations

1. APOE region

External Citations

1. Artiga et al., 1998a
2. GWAS catalog

Further Reading

No Available Further Reading