Mutations

APOE R176C (ApoE2)

Mature Protein Numbering: R158C

Other Names: ApoE2

Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44908822 C>T
Position: (GRCh37/hg19):Chr19:45412079 C>T
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs7412
Coding/Non-Coding: Coding
DNA Change: Allele
Expected RNA Consequence: Allele
Expected Protein Consequence: Allele
Codon Change: CGC to TGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant has been associated with decreased risk of Alzheimer’s disease (AD), reduced AD neuropathology, and delayed AD onset. These protective effects appear to depend, at least in part, on ancestry, with people of European ancestry being the most protected, those of African ancestry less, and those of East Asian or Hispanic ancestry even less or not at all.

APOE2 was originally studied in the context of blood lipids and cardiovascular disease and characterized at the protein level as one of three inherited ApoE isoforms with unique cysteine/arginine combinations at two positions eventually identified as 130 and 176 (Weisgraber et al., 1981Zannis and Breslow, 1981). With cysteines at both positions, ApoE2 is the most acidic of the three species and was designated 2 based on its migration upon isoelectric focusing. APOE2 is thought to have arisen 200,000 to 300,000 years ago as a variant of the ancestral APOE allele, C176R (APOE4). Worldwide, its frequency is approximately seven percent, but its distribution is uneven. Whereas it is fairly common in Southeast Asia, Australia, and some African populations (up to 19 percent), it is absent from most indigenous American groups (Singh et al., 2006Abondio et al., 2019).

In the mid-1990s, APOE2 caught the attention of neuroscientists as it was underrepresented in AD patients, suggesting it reduced the risk of late-onset AD (Corder et al., 1994Smith et al., 1994West et al., 1994Farrer et al., 1997). Since then, multiple studies, including several large, genome-wide association studies, have confirmed its protective nature, at least in non-Hispanic Whites (see table below). Moreover, APOE2 appears to have a strong dose-dependent effect. While one APOE2 allele cuts AD risk down to about half of that of carriers of two APOE3 alleles, two alleles reduce it to 13 percent (Feb 2020 news; Aug 2019 conference news; Nov 2019 news; Reiman et al., 2020; table below). Of note, APOE2 carriers are still susceptible to AD (Stipho et al., 2018), but seem to have a milder phenotype (Groot et al., 2018).

Whether APOE2 affects the rate of cognitive decline in AD is uncertain (e.g., Katzourou et al., 2021), as are its effects on baseline cognition (for review see Li et al., 2020). Studies of cognitively healthy young to middle-aged individuals have shown minimal or null effects. Moreover, a study of nearly 10,000 English individuals aged 17–85  years identified an age-by-APOE2 interaction effect on cogntivie performance, but it did not survive correction for multiple testing (Rahman et al., 2024). On the other hand, cross-sectional studies of elderly non-demented individuals showed APOE2 carriers performed better on tests of memory, visuospatial skills, and global cognition than non-carriers, and longitudinal tests showed a slower decline of episodic memory, executive function, verbal learning, and global cognition (e.g., Kang et al., 2023). Also, APOE2 appears to delay cognitive decline in autosomal dominant AD, at least in carriers of the PSEN1 E280A (Paisa) variant (Vélez et al., 2015, Langella et al., 2023).

Neuropathology

Multiple studies have also examined the effects of APOE2, compared with APOE3, on neuropathology. In general, the presence of APOE2 has been tied to milder Aβ pathology (for review see Li et al., 2020). Amyloid-β accumulation has been consistently found to be lower in post-mortem brain tissues of both non-demented aged individuals and AD patients carrying APOE2 (e.g., Nagy et al., 1995Oyama et al., 1995Lippa et al., 1997Berlau et al., 2013Tiraboschi et al., 2004; Serrano-Pozo et al., 2015Reiman et al., 2020; Rohde et al., 2023). Moreover, PET imaging and fluid biomarker studies of cognitively healthy older adults have also found robust associations between APOE2 and decreased levels of Aβ pathology (e.g,, Morris 2010; Grothe et al., 2017; Jansen et al., 2015Palmqvist et al., 2015Salvadó et al., 2021a). Reducing Aβ pathology, however, may not be the only way APOE2 protects the brain. For example, in individuals with minimal Aβ accumulation, APOE2 carriers were still more likely to be cognitively intact compared with APOE3 homozygotes (Shinohara et al., 2016).

The relationship between APOE2 and tau pathology is still uncertain. Several analyses of post-mortem brain tissue revealed reduced neurofibrillary tangles in APOE2 carriers (e.g., Nagy et al., 1995Serrano-Pozo et al., 2015). Moreover, Reiman and colleagues reported a lower tau tangle burden in APOE2 individuals, even after controlling for neuritic Aβ plaques (Feb 2020 news; Reiman et al., 2020). However, some studies of living, non-demented older adults have failed to detect an association (Morris et al., 2010Salvadó et al., 2021a).  For example, using PET imaging in older adults without dementia, Salvadó et al. reported that, although APOE2 carriers had a lower global Aβ burden than APOE3 homozygotes, regional tau burden and tau accumulation over time were similar in the two groups. The authors proposed that the protective effect of the APOE2 allele may be primarily tied to resistance against Aβ deposition rather than tau pathology, consistent with the observation that APOE2 negatively correlated with tau pathology in Aβ-positive, but not Aβ-negative, individuals (Farfel et al., 2016). Using a larger sample and mediation analyses, however, a more recent study reported a direct association between APOE2 and reduced regional tau in the medial temporal lobe and early neocortical regions, beyond the effects of amyloid burden (Young et al., 2023).

Of note, in primary tauopathies, APOE2 may even be harmful. APOE2 was associated with increased risk of progressive supranuclear palsy (PSP), as reported in a preprint (Wang et al., 2024; Feb 2024 news), and APOE2 homozygosity was associated with more severe PSP pathology and corticobasal degeneration (Zhao et al., 2018). However, two other studies failed to confirm these associations (Sabir et al., 2019; Goldberg et al., 2020).

Studies of hippocampal volume, cortical thickness, brain connectivity patterns, and brain vascular health have yielded mixed results. Although a few studies have tied APOE2 to reduced hippocampal shrinkage (e.g., Hostage et al., 2013, Chiang et al., 2010), others have failed to detect a link (e.g., Grothe et al., 2017Serra-Grabulosa 2003Den Heijer et al., 2002). As reported in a preprint, APOE2 heterozygosity may delay hippocampal volume decline, but only in adults over 75 years of age (Chaloemtoem et al., 2024). Moreover, an association with greater cortical thickness has been observed multiple times (e.g., Shaw et al., 2007Liu et al., 2010; Fan et al., 2010), but not always (e.g., Groot et al., 2018). Also, whereas one study of brain connectivity found opposite aging trajectories in carriers of the APOE2 allele versus those carrying the AD risk allele APOE4 (Shu et al., 2016), another reported surprising similarities in the connectivity of individuals carrying either APOE2 or APOE4 alleles (Trachtenberg et al., 2012). No difference in FDG-PET imaging was detected, at least in one study (Grothe et al., 2017). Also of note, cognitively unimpaired APOE2 carriers were reported to have larger volumes of gray matter in brain regions typically affected by AD compared with non-carriers, and, in homozygotes, this also applied to regions related to successful aging (Salvadó et al., 2021b). However, a review of the literature concluded that APOE2’s association with several AD imaging markers, including brain structure, function, and metabolism, remained uncertain because of inconsistent results (Kim et al., 2022). One important factor that may contribute to these inconsistencies is the variabile reliability of many widely used APOE genotyping methods (Belloy et al., 2022).

Highlighting the uncertainties of how APOE2 protects the brain, a few studies have shown unexpected correlations between AD pathologies and symptoms in APOE2 carriers. For example, one study showed that APOE2 protection persisted even after controlling for AD neuropathological changes and comorbid pathologies (Qian et al., 2021). Moreover, in the oldest old, APOE2 carriers with intact cognition harbored a higher plaque burden than non-carriers (Berlau et al., 2009).

Interestingly, although APOE2 may be protective against some comorbid neurodegenerative proteinopathies presenting with AD (e.g., Walker and Richardson 2022), it does not seem to be protective against cerebrovascular-disease pathology compared with APOE3 (Goldberg et al., 2020). In fact, several studies have linked APOE2 to increased pathology, including white matter hyperintensities and microbleeds (e.g., Greenberg 1998Westlye et al., 2012Groot et al., 2018; Kim et al., 2022). The association may be due to direct effects of APOE2 on brain vasculature, effects on cardiovascular health which develop years before dementia onset, and/or result from a higher disease threshold in APOE2 carriers such that co-morbidities are more often required to overcome APOE2’s protective effect. Adding to the uncertainty of these considerations, at least one study reported APOE2 as being protective for white matter hyperintensities in cognitively healthy individuals (Salvadó et al., 2019).

A particularly interesting case is the connection between APOE2 and cerebral amyloid angiopathy (CAA), a condition that often co-exists with AD. Given that APOE2 is protective against Aβ deposition in brain parenchyma and CAA involves Aβ deposition in cerebral vessel walls, one might expect CAA risk to be lower in APOE2 carriers. However, in one study, allelic dose was not associated with a significantly lower odds ratio for CAA before or after adjustment for AD pathology (Reiman et al., 2020). In fact, several studies have found that APOE2 carriers are at higher risk of having this disease and with more severe pathology (Nelson et al., 2013Yu et al., 2015; for review see Li et al., 2020). Some studies suggest APOE2-associated accumulation of Aβ in vessels leads to vessel rupture and hemorrhages and, indeed, APOE2 has been tied to increased severity and frequency of hemorrhage in patients with CAA and lobar intracerebral hemorrhage (e.g., Brouwers et al., 2012O’Donnell et al., 2000Goldberg et al., 2020Hostettler et al., 2022; Wu et al., 2024), although these associations may vary with ancestry (Kittner et al., 2021). Of note, APOE2 is also a risk factor for stroke (e.g., Schilling et al., 2013). 

Studies of the lipoprotein and lipid profiles of the cerebrospinal fluid and brain tissue of APOE2 carriers have yielded varying results. ApoE levels appear to be elevated in cortices of ApoE2 carriers, but studies of cerebrospinal fluid (CSF) have been inconsistent (Li et al., 2020). One study found that CSF ApoE2 was the lowest of the three common isoforms in heterozygote individuals, before or after subdividing the samples according to Aβ42/Aβ40 ratios, a proxy for brain amyloid deposition (Minta et al., 2020). Also of note, similar lipidomic profiles were reported in APOE2 carriers and non-carriers in AD postmortem brains (Lefterov et al., 2019).

Other AD-relevant factors

Several studies have reported associations between APOE2 and other proteins and lipid species in blood, in the context of neurological function. For example, two reports noted increased levels of phospholipids in the blood of APOE2 carriers, a trait tied to lower risk of cognitive decline in cognitively normal individuals (Wong et al., 2019Zhao et al., 2020). Some findings have been unexpected. For example, two studies including blood samples from hundreds of thousands of individuals found that while APOE2 was associated with low levels of ApoA, a protein whose elevation has been tied to AD, it was also associated with low levels of insulin-like growth factor 1 (IGF-1), a protein whose reduction has been implicated in AD, and high levels of the marker of low-grade inflammation CRP which is associated with an elevated risk of neurodegenerative disease (Ferguson et al., 2020Wu et al., 2021). Also, although APOE2 associations with many biomarkers were in the opposite direction of biomarker associations with APOE4 as expected (e.g., LDL, IGF-1, CRP, alanine aminotransferase, and ApoA), a few associations were in the same direction (e.g. with hemoglobin A1c, lipoprotein A, and sex hormone-binding globulin). One study predicted that up to 30 percent of the protective effect of APOE2 may be mediated by plasma lipid species (Wang et al., 2022).

Genetic and environmental factors contribute to APOE2’s effects and may help explain differences in reported findings. In particular, differing effects have been reported between groups of different ancestries. As shown in the table below, the protective effect of APOE2 was not observed in Hispanics (Belloy et al., 2023Xiao et al., 2023), or found to be considerably weaker compared with Europeans or Whites (Blue et al., 2019; Rajabli et al., 2023). At least in one study, analysis of global ancestry was unable to explain this reduced effect (Belloy et al., 2023). Moreover, a large meta-analysis of East Asian cohorts indicated APOE2 had no effect on AD risk (Belloy et al., 2023) and another meta-analysis of Chinese cohorts suggested a lower incidence of AD associated with APOE3 than with APOE2 (Chen et al., 2022). Also, a large study of amyloid PET levels showed APOE2 has a much stronger protective effect in non-Hispanic Whites than in Asians (Ali et al., 2023). 

Many questions about how ancestry shapes APOE2's effects on AD risk remain. One challenge is disentangling the contributions of environmental factors. Indeed, modifiable risk factors which often vary between groups of different ancestries—such as lower education levels, smoking, and physical inactivity—appear to substantially attenuate the effects of APOE2 on dementia. Moreover, as reported in a preprint, the effectiveness of different methods to measure modifiable risks also varies between populations (Andrews et al., 2024).

Differences in APOE2's effects on AD risk may be shaped by nearby polymorphisms in the APOE region, as well as by variants in distant genes, including genes on other chromosomes. For example, a common variant of haptoglobin—a hemoglobin scavenger that also binds to ApoE and is thought to protect ApoE from oxidation—appears to modify both the deleterious effect of APOE4, as well as the protective effect of APOE2 (Bai et al., 2023). Moreover, two genome-wide analyses identified several APOE2 modifiers, revealing an enrichment in genes involved in inflammation, immunity, lipoprotein function, and cell-junction biology (Nazarian et al., 2022a; Nazarian et al., 2022b).

The reported influences of gender on APOE2's effects have been mixed. One meta-analysis showed that, in cognitively unimpaired non-Hispanic White adults, the APOE2/E3 genotype decreased AD risk more strongly in women than in men (Neu et al., 2017). In contrast, a  longitudinal study of two independent samples of non-Hispanic Whites, found that, relative to APOE3/E3, APOE2 protected against cognitive decline in men, but not women (Wood et al., 2023). Interestingly,  APOE2's protective effects on executive function in a large study of cognitively unimpaired individuals were found to be female-specific among Whites but male-specific among Blacks (Walters et al., 2023).

A large population-based study found that differences in brain structure between individuals—especially in areas particularly vulnerable to AD—may shape APOE2-associated protection against AD and related dementias (Savignac et al., 2022). Other phenotypes, such as personality traits, were tied to these structural variations and APOE2's effects. Gender also appeared to play a role in these associations, with social lifestyle modulating APOE2 protection in men and physical activity influencing protection in women. The effects of factors thought to influence cognitive reserve—such as years of education and literacy level—remain uncertain (e.g., Pettigrew et al., 2013; Pettigrew et al., 2023).

Non-AD Neurological Disorders

APOE2 has been found to be associated with increased risk for several neurological conditions, including post-traumatic stress disorder, age-related macular degeneration, progressive supranuclear palsy, corticobasal degeneration, and argyrophilic grain disease (for review see Li et al., 2020). APOE2 may also be associated with earlier onset or increased risk for cerebral palsy and Machado-Joseph Disease, albeit sample sizes have been small in these studies. Although no correlation between APOE and ALS risk has been detected, ALS patients homozygous for APOE2 showed decreased glucose metabolism in extra-motor areas compared with APOE3 homozygous patients (Canosa et al., 2019), and APOE2 was associated with more severe TDP-43 pathology in motor cortices of ALS post-mortem brains (Meneses et al., 2022). The effect of APOE2 on frontotemporal lobar degeneration (FTLD) risk is uncertain, with APOE2 exerting either no effect or increasing risk (e.g., Goldberg et al., 2020), as well as potentially increasing TDP-43 pathology, at least in FTLD with motor neuron disease (Meneses et al., 2022). Other neurological disorders whose associations with APOE2 have been studied—but results remain unclear—include Creutzfeldt-Jakob disease, multiple sclerosis, and Huntington’s disease (Li et al., 2020). In at least one study, no associations between APOE2 and Lewy body disease or hippocampal sclerosis were detected (Reiman et al., 2020). 

Non-neurological conditions

A wide range of non-neurological conditions have been reported to be positively or negatively associated with APOE2, including blood biochemistry and blood-cell traits, metabolic health, cardiovascular diseases, kidney dysfunction, cancer, fertility, and longevity (see, e.g., GWAS catalogLi et al., 2020Li et al., 2020Lumsden et al., 2020; Wu et al., 2021).

With some exceptions (see paragraph below on APOE2 homozygosity), APOE2 carriers tend to have normal or cardiovascular-protective profiles of lipids and lipoproteins in blood. Although findings vary between studies, compared with APOE3 carriers, on average, APOE2 carriers have lower levels of total cholesterol, low-density lipoproteins (LDL), and ApoB (e.g., Rasmussen et al., 2020Lumsden et al., 2020Karjalainen et al., 2020Ferguson et al., 2020Sebastiani et al., 2022; Pieri et al., 2022; Rasmussen et al., 2023; Compton et al., 2024). Indeed, a study of approximately half a million blood samples from the UK Biobank found that APOE2 accounted for a large percentage of the variance in blood cholesterol, LDL, and ApoB (approximately 6, 4, and 9 percent, respectively) (Wu et al., 2021). Consistent with these effects, APOE2 has been reported to decrease the risk of heart attack and angina, although not high blood pressure.

APOE2 carriers also appear to have elevated levels of ApoE, a trait correlated with a lower risk of dementia (Rasmussen et al., 2020), and reduced levels of fatty acids and sphingomyelins, the latter which have been associated with AD pathology (Compton et al., 2024). Mixed results have been reported for the association of APOE2 with levels of remnant cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol.

Interestingly, several of the differences in metabolite levels have been detected across a wide range of ages, including children and young adults, but appear to be attenuated in older carriers (Wu et al., 2021, Compton et al., 2024). Also of note, although in most cases, APOE2 and APOE4 appear to have opposite effects on traits related to fat metabolism, a couple of studies have reported similar effects for some metabolites, such as triglycerides and remnant cholesterol, and decreased lipoprotein A (Wu et al., 2021, Rasmussen et al., 2023).

Not surprisingly, multiple studies have shown an association between APOE2 and increased longevity. A higher frequency of the allele in elderly women compared with middle-aged women was first reported in 1993 (Cauley et al., 1993), and subsequent studies, including men and ranging from cross-sectional to longitudinal to genome-wide associations, have confirmed the association (for review see Li et al., 2020). Of note, the association seems to hold independently of AD, suggesting a systemic effect on aging (Shinohara et al., 2020).

However, APOE2 has also been associated with harmful peripheral phenotypes including kidney dysfunction (Kawanishi et al., 2013; Saito et al., 2020), reduced fertility (Martinez-Martinez et al., 2020), and more severe cancer phenotypes (Ostendorf et al., 2020). Moreover, two studies that included hundreds of thousands of white individuals found APOE2 homozygosity increased the risk for peripheral vascular disease (Lumsden et al., 2020, Rasmussen et al., 2023). Lumsden and colleagues also reported elevated risks for thromboembolism, arterial aneurysm, peptic ulcer, cervical disorders, and hallux valgus (Lumsden et al., 2020). Also, in one study, APOE2 dosage was found to be associated with diabetes and reduced levels of reticulocytes in blood (Wu et al., 2021). Interestingly, a study of the UK Biobank revealed APOE2 homozygotes with COVID had an increased hazard ratio for death, but it did not reach statistical significance (Ostendorf et al., 2022). In the same study, a COVID mouse model carrying APOE2 showed elevated viral loads and suppressed adaptive immune responses early after infection as compared to mice carrying APOE3.

A particularly well-studied link to APOE2 homozygosity is its association with hyperlipoproteinemia type III (HLPP3), also known as familial dysbetalipoproteinemia, characterized by the accumulation of remnants of triglyceride-rich lipoproteins, and early onset atherosclerosis and heart disease. Although it is often noted that the vast majority of HLPP3 patients are APOE2 homozygotes, the disease surfaces in only 5 to 10 percent of homozygous carriers. Current evidence points to HLPP3 being a complex disease, usually involving APOE2 homozygosity, but requiring other factors, such as obesity, hypothyroidism, estrogen deficiency, diabetes, or other genetic variants (e.g., Mahley 2016; Martinez-Martinez et al., 2020, Satny et al., 2023). Also of note, the prevalence of APOE2 homozygosity in HLPP3 patients may vary between populations. A large study in Germany, for example, identified only 16 percent of 350 HLPP3 patients as APOE2 homozygotes (Evans et al., 2013).

Biological effects of neurological relevance

Both Aβ-dependent and Aβ-independent mechanisms have been proposed to explain how APOE2 confers protection against AD, but much remains unclear or controversial (for reviews see Andrews et al., 2019Li et al., 2020; Raulin et al., 2022). At least for mouse studies, the age, brain region, type of AD mouse model, and endogenous ApoE levels are likely to be important contributors to inconsistencies in results (Li et al., 2020).

APOE2 has been associated with reduced Aβ production, slower Aβ aggregation, and more efficient degradation and clearance of the peptide, but most of these effects are still under investigation. For example, studies in human neurons derived from stem cells (iPSCs or ESCs) have shown that ApoE2 appears to be less efficient at stimulating APP transcription (Huang et al., 2019; Huang et al., 2017). However, a transcriptomic analysis of transgenic mice expressing human APOE showed no isoform-related differences in APP mRNA in the brain (Novy et al., 2021). Also, a study in human iPSC-derived neurons suggested that production of Aβ peptides is greatly reduced by ApoE2 (Brookhouser et al., 2021). Interestingly, this reduction may be the result of the direct binding of ApoE2 to γ-secretase within neurons, with the N-terminal region of ApoE modulating the inhibitory strength of the C-terminal region (Hou et al., 2023). However, studies in other experimental models have reported no effect on Aβ production (e.g., Irizarry et al., 2004; Castellano et al., 2011).

How the binding of ApoE2 to Aβ affects pathogenicity is also uncertain (for review see Li et al., 2020). Some studies have found that ApoE2 is more lipidated and binds Aβ with a higher affinity than do ApoE3 or ApoE4. Mice expressing human ApoE2 have higher levels of ApoE/Aβ complexes in their brains. It has also been reported that ApoE2 promotes Aβ clearance across the blood-brain barrier, as well as cellular uptake and degradation. Indeed, in an AD mouse model expressing human APOE4, production of ApoE2 by transduced ventricle-lining ependymal cells reduced amyloid deposition (Jackson et al., 2024).

Whether ApoE2 protects against Aβ oligomerization, which has been linked to neurotoxicity in AD, remains unclear. Nevertheless, several studies have shown ApoE2-associated anti-toxic effects, including protection against Aβ-induced cell death in cultured neurons (Miyata and Smith, 1996), and other brain-cell types, such as pericytes and endothelial cells (Wilhelmus et al., 2005Folin et al., 2006), reduced suppression of long-term potentiation by Aβ42 or AD brain lysate in hippocampal slices (Chen et al., 2010; Trommer et al., 2005), as well as decreased synaptic loss and neuritic dystrophy in mouse models that develop amyloid pathology (Hudry et al., 2013Lanz et al., 2003).

Some studies suggest APOE2 may also have effects on innate immunity, including microglial function (e.g., Serrano-Pozo et al., 2021; news Oct 2021; Zhou et al., 2023) and possibly the complement system (e.g., Panitch et al., 2021), as well as on the integrity of the brain-blood barrier (Li et al., 2020). Of note, a cell non-autonomous effect of ApoE2 on microglial activation was recently reported (Jackson et al., 2024). Microgliosis near plaques in AD mice expressing human APOE4 was reduced by exposure to ApoE2. Additional clues may emerge from the identification of genetic modifiers that counter APOE2’s protection against AD risk (Kim et al., 2020; Dec 2020 news).

As noted earlier, human data indicate that the relationship between APOE2 and tau pathology may depend on amyloid, and results from at least some experimental models support this possibility. In a study of human iPSC-derived neural cultures, for example, only APOE2-expressing cultures with altered Aβ42/40 ratios developed pathogenic tau (Brookhouser et al., 2021). Whether APOE2 affects tau pathology independently of Aβ in AD remains uncertain. Two studies using mouse models of tauopathy yielded different results: while one found similar levels of tau pathology and brain atrophy in a transgenic tauopathy model crossed with mice expressing human APOE2 or APOE3 (Shi et al., 2017), a study using a viral tauopathy model found more tau pathology in APOE2- than in APOE3-expressing mice (Zhao et al., 2018). The latter results support the reported increase in risk for primary tauopathies in humans. APOE2 may also have effects on other neurodegenerative pathologies. For example, in a synucleinopathy mouse model, researchers reported that ApoE2 reduced α-synuclein aggregation and neurodegeneration (Davis et al., 2020), while in a mouse model of TDP-43 pathology, it exacerbated motor function deficits, neuronal loss, and gliosis in the motor cortex (Meneses et al., 2022).

ApoE2’s effects on normal brain cell function have also been investigated. One study showed increased dendritic spine length and dendritic arborization in the cortex of one-month-old, but not older, APOE2 knockin mice as compared with APOE3 and APOE4 transgenics (Dumanis et al., 2009). The same study found no APOE isoform differences in spine density at any age in the hippocampus. In human cultured neurons derived from embryonic stem cells, ApoE2 was the least potent of the ApoE isoforms at stimulating synapse formation (Huang et al., 2019). Moreover, although aged APOE2 knockin mice performed better in a spatial memory test than APOE3 or APOE4 knockin mice, they showed similar or greater age-related changes in synaptic loss, neuroinflammation, and oxidative stress (Shinohara et al., 2016). Interestingly, lipidated ApoE2 enhanced synapse elimination by astrocytes in culture more than ApoE3 or ApoE4, a process that may reflect a protective removal of senescent synapses and debris (Chung et al., 2016). A study of the brain transcriptomes of male and female APOE-targeted replacement mice revealed patterns associated with APOE2 expression across young, middle, and old age (Zhao et al., 2020).  

Several preclinical and clinical studies are underway to evaluate APOE2’s therapeutic potential (Li et al., 2020Serrano-Pozo et al., 2021; Raulin et al., 2022, Jackson et al., 2024). For example, a viral vector driving expression of the allele is being tested for delivery to the central nervous system in APOE4 homozygotes who are at increased risk of developing AD (LX1001, Dec 2022 conference news). 

Other biological effects

Outside the brain, the effects of ApoE2 stem from the isoform’s reduced ability to bind to several cell surface receptors, particularly the LDL receptor, its downregulation of lipolysis, and its increased levels in blood compared with ApoE3. Decreased receptor binding reduces the liver’s ability to remove remnant lipoprotein particles—partially catabolized carriers of triglycerides including chylomicrons and very-low-density lipoprotein (VLDL) (for reviews see Mahley, 2016Martinez-Martinez et al., 2020). Also, ApoE2 has a lower capacity to promote hepatic lipase activity, and its high levels displace lipase co-factor ApoC-II which reduces the processing of lipoprotein particles, including VLDL to LDL and VLDL and intermediate-density lipoprotein (IDL) to high-density lipoprotein (HDL). Moreover, expression of ApoE2 in mouse myeloid cells has been reported to increase inflammasome activation and myelopoiesis (Igel et al., 2021). Despite these alterations, most APOE2 carriers have normal or hypolipemic profiles in blood, as previously noted, but additional genetic or environmental factors can precipitate pathology.

In addition to influencing blood, heart, and liver physiology, ApoE2 may affect reproductive physiology, as well as kidney and adipose tissue function, but the mechanisms underlying these effects remain uncertain (Martinez-Martinez et al., 2020).

Molecular underpinnings

Although R176 is eight amino acids beyond the ApoE receptor-binding site, the R176C substitution dramatically reduces receptor binding activity. Binding of ApoE2 to the LDL receptor, the most studied interaction, is very poor, as is binding to APOER2/LRP8 (for review see Li et al., 2020). However, binding to the LDL receptor-related protein (LRP1) and to heparan sulfate proteoglycans (HSPG) is less impaired, and binding to the VLDL receptor and TREM2 is normal. These different receptors have different requirements and functions: LDLR, VLDLR, LRP1, and HSPG have all been implicated in lipoprotein clearance and Aβ clearance, but only LDLR unequivocally requires lipid binding. Moreover, LRP1 appears to be also involved in neuroprotective signaling and synaptogenesis, while APOER2/LRP8 regulates trafficking of synaptic receptors, and TREM2 regulates microglial phenotypes and facilitates Aβ phagocytosis.

Many studies have examined the molecular underpinnings of ApoE2’s poor binding to LDL receptors, but open questions remain (see Chen et al., 2021 for review). One possibility is that the R176C substitution causes salt bridge rearrangements that reduce the positive charge in the receptor-binding region (Wilson et al., 1994; Dong et al., 1996). Alternatively, the R176C may alter ApoE’s initial lipid binding stage, preventing a conformational change that makes the receptor binding site accessible. R176 may be involved in unfolding ApoE, helping to pull apart two of the bundled helices in the N-terminal domain, helices 3 and 4, to allow dimerization between stretched-out monomers to form a mature lipoprotein particle (Chen et al., 2011). Of note, a high-resolution structural study suggested that once ApoE binds to lipids, it adopts an extended α-helical, antiparallel conformation on lipoproteins, consistent with the bundled helices opening up so the hydrophobic regions of the helices associate with lipid (Feb 2024 newsStrickland et al., 2024).

Although evidence from human brains is unavailable, ApoE2 appears to be more lipidated than ApoE3 or ApoE4 in human cerebrospinal fluid, as well as in astrocyte and microglial cell cultures (see Li et al., 2020; Martens et al., 2022 for reviews). Moreover, in vitro assays and the size of ApoE lipoprotein particles (e.g., Strickland et al., 2024) suggest ApoE2 is a better lipid acceptor. As proposed by Li and colleagues, this hyperlipidation may enable more efficient delivery of lipids to neurons, maintain synaptic plasticity during AD, clear Aβ via the blood-brain barrier more efficiently, and promote extracellular degradation of Aβ more effectively (Li et al., 2020).

Also of relevance to AD, ApoE2's reduced binding to HSPG may be protective against tau pathology. HSPG facilitates the dissemination and uptake of tau seeds into neurons, and limiting HSPG-ApoE binding reduces this spread. Indeed, this reduction has been implicated in AD protection associated with another ApoE variant, R154S (Christchurch), and insights into the molecular interactions involved in ApoE2-HSPG binding are beginning to emerge (e.g., Mah et al., 2023). Also of note, ApoE2 has been reported to have very low affinity for leukocyte immunoglobulin-like receptor B3 (LilrB3), a microglial receptor that binds tightly to ApoE4 and activates pro-inflammatory pathways (Zhou et al., 2023).

Research Models

Several rodent models expressing human APOE2 have been generated, including mice in which the murine Apoe gene is replaced with the human APOE2 allele, APOE2 Targeted ReplacementAPOE2 Knock-In, floxed (CureAlz), and APOE2 Knock-In (JAX). A particularly interesting mouse model was engineered to allow a switch from expressing APOE4 to APOE2 via activation of Cre recombinase (Aug 2023 conference news). Gene expression patterns in switched brain cells resembled those of APOE2 mice. Knock-in rat models, which develop hyperlipidemia, have also been produced (Wu et al., 2021). In addition, several groups have created isogenic induced pluripotent stem cells expressing the three major APOE isoforms, including APOE2 (e.g., Schmid et al., 2021). 

Note on nomenclature

APOE was first studied at the protein level and observed to have isoforms that migrated to different positions upon isoelectric focusing. The most common isoform was named ApoE3, while isoforms with one fewer positive charge were named ApoE2. Subsequent studies showed that, in most cases, these slower migrating species corresponded to R176C.

Table

STUDY Type Risk Allele/
Genotype
Risk Allele Freq N
Cases | CTRL
Association Results Ancestry
(Cohort)
Reference
GWAS Meta-analysis     472,868 (total) Beta=0.44 unit decrease
p=4x10-123
European Schwartzentruber et al., 2021a
GWAS Meta-analysis T (E2) 0.08 71,880b  | 383,378 Beta=21.20 z-unit decrease, p=1x10-99 European Jansen et al., 2019a
GWAS Meta-analysis     67,614b | 320,710 p=2x10-76 European, British Marioni et al., 2018a
Targeted E2/E2 +E2/E3 0.043 | 0.13 16,963 | 17,058 OR=0.53 [CI=0.48-0.58] p=2.44x10-40 Non-Hispanic White (NIAGADS/ADSP, AMP-AD, dbGAP, LONI) Belloy et al., 2023
Meta-analysis of meta-analyses E2/E2 +E2/E3   21,852 total OR=0.97 [CI=0.77-1.23]    p=0.80 East Asianc Belloy et al., 2023
Targeted E2/E2 +E2/E3 0.084 | 0.18 2,011 | 5,134 OR=0.69 [CI=0.57-0.84] p=2.56x10-4 Non-Hispanic Black (NIAGADS/ADSP, AMP-AD, dbGAP, LONI) Belloy et al., 2023
Targeted E2/E2 +E2/E3 0.073 | 0.097 2,189 | 3,549 OR=0.89 [CI=0.72-1.10]    p=0.29 Hispanic (NIAGADS/ADSP, AMP-AD, dbGAP, LONI) Belloy et al., 2023
Targeted
Meta-analysis
T (E2)   23,396 | 25,568
(116 studies)
OR=0.77d
CI [0.71-0.84] p<0.001
Chinese Chen et al., 2022
GWAS Meta-analysis T (E2)   21,982 | 41,944 p=6.4x10-53 European
(IGAP Rare Variants: Stage 1)
Kunkle et al., 2019e
GWAS T (E2)   21,392 | 38,164 p=5.9x10-44 Mixed ancestry
(ADGC Transethnic LOAD: All Samples)
Jun et al., 2017e
GWAS
Meta-analysis
T (E2)   17,536 | 36,175

p=2.91x10-23

(APOE-Stratified Analysis: All Samples)

(IGAP) Jun et al., 2016e
GWAS Meta-analysis T (E2)   17,008 | 37,154 p=1.2x10-22 European
(IGAP 2013: Stage 1)
Lambert et al., 2013e
GWAS Meta-analysis T (E2) 0.058 (total) 37,382 total OR=0.48
[CI=0.45-0.42]
p=4.35×10−86
Non-Hispanic White (ADGC) Rajabli et al., 2023f
GWAS Meta-analysis T (E2) 0.104 (total) 6,728 total OR=0.59
[CI=0.52-0.68]
p=5.65×10−14
African American (ADGC) Rajabli et al., 2023f
GWAS Meta-analysis T (E2) 0.056 (total) 8,899 total OR=0.67
[CI=0.57-78]
p=7.86×10−7
Hispanic (ADGC) Rajabli et al., 2023f
GWAS Meta-analysis T (E2) 0.040 (total) 3,232 total OR=0.44
[CI=0.37-52]
p=8.89×10−7
East Asian (ADGC) Rajabli et al., 2023f
EWAS     16,097 | 18,077 OR=2.31
p=3x10-105
European Sims et al., 2017a
GWAS T (E2) w/APOE4g   12,738 | 13,850 p=4.23x10-6 Mixed
(ADGC Transethnic LOAD: APOE4 carrierse)
Jun et al., 2017b
Targeted E2/E2 0.004 10,430 | 13,426

OR=0.52

CI [0.30-0.90]
p=0.02

AD Genetics Consortium (ADGC) Reiman et al., 2020
Targeted E2/E3 0.09 10,430 | 13,426

OR=0.63

CI [0.53-0.75]
p=2.2x10-7

AD Genetics Consortium (ADGC) Reiman et al., 2020
Targeted E2/E2 0.005 4,018 | 989 OR=0.13, 95%
CI [0.5-0.36]
p=6.3x10-5
AD Genetics Consortium (ADGC-Neuropath. confirmed) Reiman et al., 2020
Targeted E2/E3 0.052 4,018 | 989 OR=0.39
CI [0.30-0.50]
p=1.6x10-12
AD Genetics Consortium (ADGC-Neuropath. confirmed) Reiman et al., 2020
GWAS T (E2)   8,654 | 24,314 p=1.66x10-19 Mixed ancestry
(ADGC Transethnic LOAD: APOE4 Non-Carriers)
Jun et al., 2017e
GWAS Meta-analysis T (E2)   8,572 | 11,312 p=9.8x10-23 European
(IGAP 2013: ADGC Subset)
Lambert et al., 2013e
GWAS Meta-analysis T (E2)   7,184 | 26,968

p=3.17x10-13

(APOE-Stratified Analysis)

(IGAP, APOE4 non-carriers) Jun et al., 2016e
GWAS C (E3) 0.928632 2,741 | 14,739 OR=2.21
CI [1.79-2.64]
p=4x10-13
European Nazarian et al., 2019a
GWAS C (E3) 0.947 7,316 | 7,579 OR=2.17
CI [1.89-2.44]
p=3x10-33
European
(AD onset 58-79 years of age)
Lo et al., 2019a
GWAS C (E3) 0.93 2,399 | 4,160

OR=1.85 

CI [1.54-2.22]

p=6x10-12

European
(AD onset >80 years of age)
Lo et al., 2019a
GWAS T (E2) 0.057 5,705 | 7,067 OR=0.46
CI [0.40-0.52] p=2x10-31
European Wang et al., 2021a
GWAS T (E2) 0.024 | 0.041 4,230 | 3,109 OR=0.52
CI [0.43-0.64
] p=3.76x10-10
Non-Hispanic White (ADSP) Lee et al., 2023
GWAS T (E2) 0.065 | 0.12 1,137 | 1,707 OR=0.52
CI [0.43-0.62
] p=9.57x10-13
African American (ADSP) Lee et al., 2023
GWAS T (E2) 0.046 | 0.055 1,021 | 1,988 OR=0.77
CI [0.58-1.01] p=0.057
Hispanic (ADSP) Lee et al., 2023
GWAS T (E2)   1,968 | 3,928 p=1.3x10-8 African American
(ADGC)
Reitz et al., 2013
Targeted   0.05 1,238 | 1,790 HR=0.28
[CI=0.19 – 0.40]
European
(NIALOAD)
Blue et al., 2019
Targeted   0.06 1,329 | 1,738 HR=0.66
[CI=0.54 – 0.81]
Caribbean Hispanic
(CU Hispanics)
Blue et al., 2019
Meta-analysis T (E2) 0.071 2,689 total OR=1.22
CI [0.74-2.02]
p=0.4
Hispanic
(NACC, ADNI, HABS-HD)
Xiao et al., 2023

aData from GWAS Catalog rs7412, May 2022
bAD or AD family history
cMeta-analysis of two meta-analyses (Farrer et al., 1997, Choi et al., 2019).
dCompare to APOE3 in same cohort: OR=0.539, CI [0.504–0.576], p< 0.001
eData from the National Institute on Aging Genetics of Alzheimer’s Disease Data Storage Site (NIAGADS) rs7412, June 2022.
fData from MedRxiv preprint.
gFor more information on carriers of both APOE2 and APOE4 alleles, see [R176C];[C130R].

OR=odds ratio, GWAS=genome-wide association study, HR=hazard ratio. 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 GWAS of Caucasian or mixed ancestry cohorts 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: 18 Jun 2024

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References

Mutations Citations

  1. APOE C130R (ApoE4)
  2. PSEN1 E280A (Paisa)
  3. APOE R154S (Christchurch)
  4. APOE [R176C];[C130R] (ApoE2/4)

News Citations

  1. Paper Alert: Two ApoE2s Provide “Exceptional” Protection Against AD
  2. First Whole-Genome Sequencing of PSP Nets Six New Risk Loci
  3. Even In the Healthy, ApoE4 Stirs Up Trouble, Scientists Say
  4. In People Who Defy ApoE, New Alzheimer’s Risk Genes Found
  5. In Small Trial, Gene Therapy Spurs ApoE2 Production
  6. In Lipoparticles, ApoE Double Belt Keeps the Fat In
  7. Meet the Switching Mice: They Flip Their Glia APOE4 to APOE2

Therapeutics Citations

  1. LX1001

Research Models Citations

  1. APOE2 Targeted Replacement
  2. APOE2 Knock-In, floxed (CureAlz)
  3. APOE2 Knock-In (JAX)

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Other Citations

  1. APOE region

External Citations

  1. GWAS catalog
  2. Jackson et al., 2024

Further Reading

No Available Further Reading

Protein Diagram

Primary Papers

  1. . Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981 Sep 10;256(17):9077-83. PubMed.
  2. . Human very low density lipoprotein apolipoprotein E isoprotein polymorphism is explained by genetic variation and posttranslational modification. Biochemistry. 1981 Feb 17;20(4):1033-41. PubMed.

Other mutations at this position

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