Mutations

APOE Region

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., 2022Feb 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., 2019Belloy 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., 2020Li et al., 2022Liang 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., 2018Laws et al., 2003).

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., 2020Kulminski 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 as well. 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).

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), and frontotemporal dementia (e.g., Ferrari et al., 2017). 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.

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). Moreover, 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). 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: 09 Jan 2024

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References

News Citations

  1. Massive GWAS Meta-Analysis Digs Up Trove of Alzheimer’s Genes

Mutations Citations

  1. APOE C130R (ApoE4)
  2. APOE R176C (ApoE2)

Paper Citations

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