Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Reference Assembly: GRCh37/hg19
Position: Chr19:45411941 T>C
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs429358
Coding/Non-Coding: Coding
DNA Change: Allele
Expected RNA Consequence: Allele
Expected Protein Consequence: Allele
Codon Change: TGC to CGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4
Research Models: 2

Findings

This variant, one of the three common alleles of the APOE gene, is the major known risk factor for late-onset Alzheimer’s disease (LOAD). It is found in at least half and as much as 75 percent of all LOAD patients. Unlike other variants associated with a high risk of disease, APOE4 is common, with a global frequency of 14 to 25 percent. The risk it confers appears to vary between populations, with people of East Asian ancestry being more vulnerable, those of European ancestry less, and those of African or Hispanic ancestry even less (see table below). The largest datasets are from studies of Caucasian populations, in which APOE4 increases AD risk in a dose-dependent manner with one allele raising risk about threefold, and two alleles elevating it 10- to 15-fold (for reviews, see Belloy et al., 2019; Yamazaki et al., 2019; Serrano-Pozo et al., 2021; Koutsodendris et al., 2021; Martens et al., 2022).

APOE4 was originally studied in the context of blood lipids and cardiovascular disease and first 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., 1981; Zannis and Breslow, 1981). With arginines at both positions, ApoE4 is the most basic of the three species and was designated 4 based on its migration upon isoelectric focusing (see Nomenclature Notes below). It is likely that APOE4 is the ancestral form of APOE which gave rise to APOE2 and APOE3 (Hanlon and Rubinsztein 1995; Seixas et al., 1999; Fullerton et al., 2000; Abondio et al., 2019). 

APOE4’s ties to LOAD date back to the early 1990s, when a linkage study of multiple affected families revealed a disease-associated locus on chromosome 19, which then led to pinpointing of the APOE4 allele (Corder et al., 1993; Saunders et al., 1993; Strittmatter et al., 1993; Poirier et al., 1993). Since then, several large association studies have confirmed and extended these findings (Coon et al., 2007; Grupe et al., 2007; GWAS catalog). Overall, the population risk that can be attributed to APOE4 has been estimated at 20 percent (Reyes-Dumeyer et al., 2022), following a semi-dominant pattern of inheritance with moderate penetrance (Genin et al., 2011). APOE4 status alone still outperforms polygenic risk scores in predicting dementia risk, despite the steady improvement of the latter, including multiple genome-wide variants (Yu et al., 2023).

APOE4 also modifies the age of AD onset, with carriers’ symptoms emerging about five years earlier than those of non-carriers (Sando et al., 2008; De Rojas et al., 2021). Consistent with the earlier onset of symptoms, amyloid and tau pathologies were shifted towards younger ages, six and two years, respectively, in a longitudinal PET study (Therneau et al., 2021). APOE4 also seems to accelerate onset in individuals with familial LOAD (Reyes-Dumeyer 2022) or AD associated with Down syndrome, despite the already severe amyloid burden caused by chromosome 21 trisomy (Bejanin et al., 2021; July 2021 news). Moreover, individuals with sporadic early onset AD are more likely to be homozygous for APOE4 (Hammers et al., 2023). Also, in autosomal-dominant AD (ADAD), data from PSEN1 E280A (Paisa) carriers revealed an age-related acceleration of cognitive decline associated with APOE4 (Langella et al., 2023). However, the allele's effects on ADAD may vary based on mutation type (Almkvist et al., 2022).

Whether and under what circumstances APOE4 affects disease progression remains uncertain, although most studies suggest it accelerates it. For example, faster cognitive decline has been reported in carriers versus non-carriers (e.g., Jutten et al., 2021; Qian et al., 2021; but see Katzourou et al., 2021), as well as shorter disease duration (e.g., Vermunt et al., 2019). Imaging studies suggest APOE4 accelerates the atrophy of brain areas affected by AD, increases the rate of amyloid deposition, and enhances and accelerates tau deposition (for review see Koutsodendris et al., 2021, Steward et al., 2023). It also seems to speed up cognitive decline independently of neuropathology (Qian et al., 2021; Qian et al., 2023). Alterations in brain lipid metabolism associated with the APOE4 genotype may emerge early, possibly preceding amyloid plaques (Apr 2023 conference news).

Interestingly, APOE4-related AD appears to be distinct from APOE4-unrelated AD (Vogel et al., 2021; Apr 2021 news; Frisoni et al., 2021). Proteomic, transcriptomic, and metabolomic analyses of cerebrospinal fluid, brain tissue, plasma, and cerebral organoids derived from patient stem cells have all revealed APOE4-dependent profiles, including a unique signature of disease progression (e.g., Zhao et al., 2020a and 2020b; Konijnenberg et al., 2020; Nov 2021 conference news; Madrid et al., 2021; Chang et al., 2022; Das et al., 2023; Dammer et al., 2023; Brase et al., 2023; Frick et al., 2023; see Raulin et al., 2022 for review).  Hallmarks of APOE4-related AD include particularly  high levels of tau pathology and atrophy in the medial temporal lobe (Emrani et al., 2020; La Joie et al., 2021), association of AD phenotypes with plasma inflammation markers (Tao et al., 2023), as well as altered blood-brain barrier function, cerebral blood flow, and meningeal lymphatics (Montagne et al., 2020; May 2020 news; Chen et al., 2021; Sep 2022 conference news, Sun et al., 2023; Jun 2023 news). Of note, some of these alterations—for example those in brain connectivity—may be due to compensatory mechanisms that shape brain function early on (e.g., Cacciaglia et al., 2022).

Moreover, age and genetic factors, including gender, modify APOE4’s effects on AD risk, having a stronger influence on people between the ages of 60 and 75, and on women, whose risk peaks at an earlier age than that of men (Farrer et al., 1997; Bickeböller et al., 1997; Altmann et al., 2014; Neu et al., 2017; Sep 2017 news; Nemes et al., 2023; Belloy et al., 2023). Sex differences are also observed in biomarkers of pathology, particularly in cerebrospinal fluid tau, with women having higher levels than men in amyloid-positive individuals (Hohman et al., 2018; May 2018 news). Disease stage is also relevant, with one study showing higher CSF phospho-tau levels in women than men, but only during pre-dementia stages of disease (Babapour Mofrad et al., 2020). In addition, women carriers appear to be particularly susceptible to tau pathology (Feb 2019 news; Nov 2019 news). Interestingly, differences in brain structure between individuals—especially in the hippocampus and default network which are particularly vulnerable to AD—appear to also help shape APOE4-associated AD risk (Savignac et al., 2022).

Clues to the molecular underpinnings of gender-associated differences are beginning to emerge. For example, a study in mice suggested follicle-stimulating hormone, which rises in post-menopausal females, may contribute to APOE4 vulnerability (Xiong et al., 2023).  Also, a genetic variant that regulates microglial activation was identified as a gender-specific modifier of APOE4 AD risk (July 2022 news; Jiang et al., 2022).

Environmental factors also modify APOE4’s effects. For example, infections, in particular by the herpes virus, may boost AD risk (Apr 2021 conference news), while a healthy lifestyle may reduce it (e.g., Jia et al., 2023). However, many such effects are complex and not well understood. Healthy lifestyle choices, for example, may need to be adopted early in life to be protective against APOE4-associated risk (e.g., Aug 2019 news). Indeed, alterations tied to APOE4 expression at the molecular, cellular, and behavioral levels have been detected decades before disease onset (e.g., Oct 2015 news; Dec 2021 news).

The role of other variants in APOE4 pathogenicity

APOE4’s effect on AD risk is modulated by other genetic factors and some studies suggest these modifiers are abundant. Several have been traced to the APOE region, which includes APOE and a few neighboring genes, while others are far-flung, including variants in other chromosomes (e.g., Kim et al., 2020; Dec 2020 news; Ebenau et al., 2021; Huq et al., 2021; Nazarian et al., 2022; Nazarian et al., 2022; Sep 2022 news).

An example of a nearby modulator is APOE R269G, a rare variant within APOE itself that is co-inherited with APOE4. In a large association study including more than 500,000 participants, it was associated with a twofold reduction in AD risk (June 2022 news; Le Guen et al., 2022). Although its biological effect is unknown, it is suspected to have a direct effect on ApoE function, possibly altering lipid binding and/or oligomerization.

Klotho-VS, a set of two polymorphisms, F352V and C370S, in the longevity gene Klotho, offers an example of a distant modulator. In heterozygous form, Klotho-VS cuts APOE4 AD risk by approximately a third (Erickson et al., 2019; Belloy et al., 2020; Apr 17 news). It appears to accomplish this by lowering amyloid-dependent tau accumulation (Aug 2020 news; Neitzel et al., 2021). Even in non-demented APOE4 carriers, Klotho-VS has been associated with reduced amyloid and tau pathologies (Belloy et al., 2021; Driscoll et al., 2021; Ali et al., 2022; see also Grøntvedt et al., 2022). The relationships between Klotho-VS, ApoE, and AD are complex, however. For example, Klotho heterozygosity has also been reported to slow down cognitive decline specifically in male AD patients who do not carry APOE4 (Chen et al., 2023). 

Other variants that may temper APOE4’s damaging effects include the APOE R154S (Christchurch) variant (Nelson et al., 2023), P522R in the phospholipase Cγ2 (PLCG2) gene (van der Lee et al., 2019; May 2019 news; Kleineidam et al., 2020), variants in Wnt signaling genes (Lin et al., 2021; Sep 2021 news), a variant in the IL1RL1 gene that alters microglial activation (July 2022 news; Jiang et al., 2022), a common variant of haptoglobin, a hemoglobin scavenger that also binds to ApoE and is thought to protect ApoE from oxidation (Bai et al., 2023), and polymorphisms in genes and inter-genic regions neighboring APOE (see APOE region).

Of note, APOE4 may itself act as a modulator of the effects of variants. For example, the penetrance of loss-of-function variants in the SORL1 gene, another strong genetic risk factor for AD, appears to be increased by the presence of APOE4 alleles in a dose-dependent manner (Schramm et al., 2022).   

Interestingly, ancestry plays an important role in determining APOE4 consequences (table below shows data from comparative studies). Since the mid-1990s, there have been reports of a weaker effect of APOE4 on AD risk in people of African ancestry compared with Caucasians (Maestre et al., 1995; Tang et al., 1996; Farrer et al., 1997). Also, APOE4 has been found to confer higher risk in East Asians, and lower risk in Hispanics, compared with whites (see Harerimana et al., 2022 for review). Large studies including tens of thousands of individuals support these observations (e.g., Belloy et al., 2023; Rajabli et al., 2023; Choi et al., 2019). Ancestry-based differences have also been reported in the association of APOE4 with AD endophenotypes, such as amyloid PET levels (Ali et al., 2023).

Efforts to identify the genetic regions responsible for differences in AD risk have revealed nearby sequences, also known as local ancestry regions (LAR), in the APOE region (e.g., Rajabli et al., 2018; Babenko et al., 2018; Rajabli et al., 2022), with some studies pinpointing variants of interest (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 is a likely candidate. For example, a study of single-nuclei RNA in the frontal cortices of APOE4 homozygotes indicated that carriers of European LARs expressed higher levels of APOE4 than carriers of African LARs (Griswold et al., 2021). 

Many questions about how ancestry shapes APOE4's effects on AD risk remain. One challenge is dissecting the roles of different ancestries in admixed populations, such as Hispanic groups. The effects of African and European local and global ancestries have been examined in Hispanics, as well as the potential contributions of Amerindian ancestry, sometimes yielding conflicting results (Blue et al., 2019; Marca-Ysabel et al., 2021; Belloy et al., 2023). Moreover, 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, Mukadam et al., 2022). Differences in demographic variables, sample sizes, analytical and statistical methodologies, measures of cognition, and racial bias in assessing dementia have been proposed as factors accounting for these discrepancies. Also of note, methodological limitations are potentially relevant to many APOE association studies. For example, the variability in the reliability of widely used APOE genotyping methods may result in irreproducible findings (Belloy et al., 2022).

APOE4 is more prevalent in Africans and Oceanians than in Europeans, particularly non-Finnish Europeans, with Asians and Hispanics/Latinos having the lowest frequency (Kamboh et al., 1995; Wang et al., 2021; gnomAD v2.1.1, Sep 2022).

Non-AD neurological disorders

APOE4 has also been associated with non-AD pathologies and conditions. Some of them often accompany AD (see Belloy et al., 2019), such as cerebral amyloid angiopathy (CAA; e.g., Premkumar et al., 1996;  Rannikmäe et al., 2014; Reiman et al., 2020), the more severe inflammatory form of CAA (Grangeon et al., 2022), and AD psychosis (DeMichele-Sweet et al., 2021). Also, APOE4 homozygosity has been associated with a modest increase in risk for ischemic cerebrovascular disease (Rasmussen et al., 2023), a condition which can co-occur with CAA. Other conditions are independent of AD, including some neuropathologies associated with transactive response DNA-binding protein of 43 kDa (TDP-43), such as limbic-predominant age-related TDP-43 encephalopathy (LATE) and hippocampal sclerosis (e.g., Yang et al., 2018; Dugan et al., 2021), as well as negative outcomes after traumatic brain or spinal cord injury (e.g., McKee and Daneshvar, 2015; Atherton et al., 2022). Moreover, one study reported APOE4 increasing the risk of impaired cognition and multiple neurodegenerative proteinopathies (Walker and Richardson 2022). 

Interestingly, in Parkinson’s disease (PD), APOE4 has been associated with a change in the progression of the disease. APOE4 appears to accelerate cognitive decline (Paul et al., 2016; Tan et al., 2020; Liu et al., 2021) and, in carriers with a high amyloid burden, hasten motor deterioration (Pu et al., 2021). Also of note, although a substantial number of PD patients develop AD pathology, a preprint suggests APOE4 may drive PD dementia by a mechanism independent of AD pathology (Wu et al., 2023). 

Multiple studies have reported associations between APOE4 and dementia with Lewy bodies (e.g., Hardy et al., 1994; Tsuang et al., 2013; Guerreiro et al., 2017; Dec 2017 news). However, while some studies suggest this association is due to the common co-occurrence of of Lewy body (LB) pathology with AD pathology (e.g., Kaivola et al., 2022), others suggest APOE4 affects the two pathologies independently of each other (e.g., Tsuang et al., 2013). Consistent with the former possibility, a large GWAS meta-analysis, indicated APOE4 is associated with risk of AD⁺LB^– and AD⁺LB⁺ compared with AD^–LB^–, but not with risk of AD^–LB⁺ compared with AD^–LB^– or risk of AD⁺LB⁺ compared with AD⁺LB^– (Talyansky et al., 2023). Also, at least one TDP-43opathy appears to be unaffected by APOE4: a large meta-analysis including 4,000 amyotrophic lateral sclerosis cases and 10,000 controls found no association between the allele and the disease (Govone et al., 2014).

Associations between APOE4 and age-related cognitive decline have been described in multiple reports (e.g., Davies et al., 2014; Raj et al., 2016; Corley et al, 2022; Tomassen et al., 2022), with all cognitive domains tested, particularly memory, being affected (e.g., Kang et al., 2023, Pettigrew et al., 2023, Sun et al., 2023; Jun 2023 news). Interestingly, some of the declines appeared to be mitigated by cognitive reserve (Pettigrew et al., 2023) and APOE4's negative impact on baseline memory appears to be stronger in women than in men (Walters et al., 2023). Also, in a study of several cohorts with different neurodegenerative and cerebrovascular disorders, APOE4 carriers performed consistently worse on tests of verbal memory and visuospatial skills, regardless of their diagnoses (Dilliott et al., 2021). 

Although several studies have indicated APOE4 is not associated with decreased cognitive function in healthy individuals (e.g., Davies et al., 2018, Rietman et al., 2022), some have found associations with neuropathological and functional changes. One study, for example, reported alterations in the functional connectivity of the default mode network in young carriers (Kucikova et al., 2023). Another found APOE4 associated with the accelerated loss of slow-wave sleep during aging (Himali et al., 2023). Moreover, a preprint describing a large imaging study of healthy UK Biobank participants tied APOE4 to localized reductions in white matter integrity (Heise et al., 2023). 

In some instances, however, APOE4 may be neurologically protective. For example, some studies suggest APOE4 confers a slight cognitive advantage early in life, which declines with age (Lu et al., 2021; Oct 2021 news), and others indicate it decreases the risk of age-related macular degeneration (e.g., Fritsche et al., 2016; Rasmussen et al., 2022).

Non-neurological conditions

APOE4 was initially shown to play a role in lipid transport and cardiovascular disease (see Mahley et al., 2009; Mahley 2016). Its preference for interacting with very low-density lipoprotein (VLDL) in blood is thought to accelerate these particles’ uptake. This in turn causes a downregulation of cell surface receptors that bind ApoE which then leads to an increase in circulating cholesterol-rich LDL particles. Large association studies of white individuals in general population cohorts revealed moderately increased LDL-cholesterol, remnant cholesterol, ApoB, and triglyceride levels in plasma, and decreased ApoE, high-density lipoprotein (HDL) cholesterol, and ApoA in APOE4 versus APOE3 homozygotes (Rasmussen et al., 2019, Rasmussen et al., 2023). Interestingly, differences in remnant cholesterol and triglyceride levels decreased with age, with no statistically significant differences detected in groups of individuals over 70 years of age. Additional studies have shown associations of APOE4 with other metabolic alterations (e.g., Li et al., 2020; Ferguson et al., 2020). 

APOE4 carriers have a higher risk of other medical conditions as well. For example, they are more likely to get infected by SARS-CoV-2 and die with COVID than non-carriers (Jan 2021 news; Ostendorf et al., 2022). As assessed in a COVID mouse model and in vitro experiments, potential mechanisms underlying this vulnerability include elevated viral loads, suppressed adaptive immune responses early after infection, and detrimental effects on astrocytes and neurons. Also, APOE4 carriers may be more likely than non-carriers to develop neurovascular complications associated with COVID (May 2023 conference news). They may also be more prone to accumulate chromosomal alterations with age (Leshchyk et al., 2023).

A few studies have also revealed protective effects, such as a better prognosis for melanoma (Ostendorf et al., 2020) and a lower risk for obesity and non-alcoholic fatty liver disease (e.g., Palmer et al., 2021, Huebbe et al., 2023). Interestingly, one study suggested that, although APOE4 carriers with high levels of AD neuropathology at death had higher mortality risk than non-carriers, APOE4 carriers with low levels of AD neuropathology had a lower mortality risk than non-carriers (Pirraglia et al., 2023).

Also, it has been suggested that APOE4 may provide an evolutionary advantage in highly infectious environments, such as those experienced by early humans (e.g., van Exel et al., 2017; Garcia et al., 2021, Smith and Ashford, 2023, Trumble et al., 2023). In non-industrialized, subsistence communities, APOE4 was associated with increased fertility, better immune activation during infection, and lower levels of baseline inflammation, which may outweigh the neurological and cardiovascular risks identified in industrialized populations. Moreover, even in European populations, extreme climate conditions, which influence cholesterol demand, and an increased need for vitamin D may have fueled APOE4 selection (see Harerimana et al., 2022 for review).

Biological Effect

ApoE4 has been implicated in a remarkable number of alterations associated with AD, including gain- and loss-of-function effects (see Yamazaki et al., 2019; Belloy et al., 2019; Serrano-Pozo et al., 2021; Koutsodendris et al., 2021; Martens et al., 2022; Steele et al., 2022 for reviews). It appears to contribute to both hallmark AD pathologies, amyloid plaques (e.g., Nov 2021 news; July 2021 news; May 2019 conference news; Jul 2018 news; Jun 2018 news; Jan 2017 news) and neurofibrillary tangles (e.g., Sep 2017 news; June 2018 news; Apr 2021 news; Saroja et al., 2022; Nov 2022 news; Jan 2023 news). In addition, it has been blamed for altering lipid transport and metabolism in brain cells (e.g., Nov 2021 conference news; Mar 2021 news; Aug 2019 news; Apr 2019 conference news; Jul 2018 conference news, Apr 2023 conference news) and fueling neuroinflammation (Nov 2021 conference news; Jul 2018 conference news; Aug 2019 news; Asante et al., 2022; Parhizkar and Holtzman 2022; Kloske et al., 2023), abnormal cellular stress responses (e.g., Martens et al., 2022), neurodegeneration (e.g., May 2021 news; Apr 2021 news; Oct 2019 news), and blood-brain barrier breakdown (e.g., Jun 2020 news; May 2020 news; Jul 2018 conference news; Sep 2022 conference news).

ApoE4 has also been reported to reduce neurogenesis (e.g., Oct 2020 news; Aug 2018 news), alter neuronal structure and function (e.g., Koutsodendris et al., 2021), disrupt endocytosis and intracellular trafficking (e.g., Martens et al., 2022; July 2021 news; Oct 2020 news), impair mitochondrial function, energy metabolism (Mahley 2023) and mitophagy (e.g., Hou et al., 2023), as well as modify transcription (e.g., Theendakara et al., 2018), including enhancing the expression of APP (Jan 2017 news, Huang et al., 2017). At a tissue level, it appears to alter brain glucose metabolism (e.g., Johnson, 2020; Yassine and Finch, 2020) and cause neural network dysfunction (e.g., Koutsodendris et al., 2021).

Although it is unclear which of these myriad alterations play primary roles in the disease process, several occur during the initial stages of disease. Through multiple mechanisms, ApoE4 is thus thought to initiate a cascade of early alterations leading to later pathological changes (Koutsodendris et al., 2021; Martens et al., 2022; Steele et al., 2022).

How a single amino acid substitution triggers this cascade remains uncertain. ApoE4 binds lipids more poorly, heparin more tightly, and is more prone to self-aggregation than ApoE3, but the structural underpinnings of these differences have yet to be elucidated. Initial studies predicted an interaction between R79 and Glu273 mediated by ApoE4’s arginine in the C130 position, resulting in a tighter interaction between the N-terminal and C-terminal domains of the protein (Hatters et al., 2005, Xu et al., 2004). However, the importance of this bridge has been called into question and other models hint at increased flexibility of the bundle of helices in the N-terminal domain (see Chen et al., 2020 for review).

Of note, even under highly controlled conditions, with ApoE4 in monomeric form, the protein appears to adopt multiple configurations (Stuchell-Brereton et al., 2023). Moreover, ApoE4 is predicted to change conformation depending on its lipidation status, association with other molecules (including other ApoE proteins), post-translational modifications, and microenvironment. Insights into ApoE4’s behavior under these diverse conditions are beginning to emerge. For example, one study indicated lipid-free ApoE4 forms V-shaped dimers with the N-terminal domains coming together at an angle that likely fuels aggregation and is different from that formed by ApoE3 and ApoE2 dimers (Nemergut et al., 2023).

Interestingly, the cellular source of ApoE4 appears to be important in determining its consequences. In glial cells, ApoE4 has been reported to disrupt lipid metabolism, altering cholesterol and cholesterol ester production and export, as well as increasing lipid droplet accumulation (e.g., Aug 2019 news, March 2019 news, Nov 2021 news, Nov 2022 news, Sep 2023 news, Windham and Cohen, 2023, Nov 2023 news). It also has been shown to impair endolysosomal trafficking, alter mitochondrial metabolism, and upregulate innate immune pathways.

ApoE4-expressing microglia have distinct immune and metabolic transcription profiles associated with aging, amyloid and tau pathologies, inflammatory challenge, and brain plasticity. These are characterized by enhanced glycolysis (Lee et al., 2023), altered regulation of genes involved in extracellular matrix organization and chondroitin sulfate biosynthesis (Brase et al., 2023), and changes in the expression of genes that define homeostatic versus disease-associated states (Lee et al., 2023, Yin et al., 2023, Liu et al., 2023, Oct 2023 news). Moreover, microglial efferocytosis—the clearance of apoptotic cells and debris in the brain—has been identified as a genetic risk hub for AD, with ApoE4 affecting multiple steps in this process (Romero-Molina et al., 2022).

Several studies have reported that ApoE4 microglia have sluggish phagocytosis and heightened inflammatory responses compared with their ApoE3 counterparts (e.g., June 2018 news, Aug 2019 news, Sep 2019 news), and appear to be locked in a state of homeostasis unable to clear plaque or tangles efficiently (Sep 2022 conference news, Oct 2023 news). In addition, ApoE4 has been suggested to facilitate pro-inflammatory activation in microglia by binding tightly to the microglial leukocyte immunoglobulin-like receptor B3 (LilrB3) (Zhou et al., 2023). 

ApoE4 has also been reported to alter glial-neuronal interactions: driving tau-mediated neurodegeneration via glia-derived ApoE4 (Shi et al., 2019; Oct 2019 news; Wang et al., 2021; Apr 2021 news, Haney et al., 2023), disrupting immune signaling associated with neuroinflammation (e.g., Aug 2019 news; Tcw et al., 2022; Serrano-Pozo et al., 2021; Parhizkar and Holtzman 2022; Chernyaeva et al., 2023), and perturbing neuron-astrocyte coupling of lipid metabolism (e.g., Qi et al., 2021; Oct 2023 conference news). Moreover, in the context of tau pathology, microglial ApoE4 appears to induce lysosomal abnormalities and ramp up synapse phagocytosis (Gratuze et al., 2022; Nov 2022 news). Astrocytic ApoE4 may also affect synapses, decreasing dendritic spine density and altering their architecture (Watanabe et al., 2023). In addition, ApoE4 may disrupt axon myelination by affecting oligodendrocyte health and differentiation (Cheng et al., 2022, Blanchard et al., 2022, Mok et al., 2022), impair microglial surveillance of the activity of neuronal networks (Victor et al., 2022), and possibly interfere with the regulation of neuronal gene expression via astrocyte-derived miRNAs (Li et al., 2021).

ApoE4 has also been reported to fuel neurodegeneration directly within neurons. Although neurons normally produce much less ApoE than glial cells, with age, certain neurons increase production. This correlates with elevated expression of antigen-presenting genes, tau pathology, and ultimately cell death. In APOE4 knockin mice, this ApoE surge occurred earlier than in controls (May 2021 news), and a preprint reported early hyperexcitability in a subpopulation of hippocampal excitatory neurons (Jang et al., 2023). In a tauopathy mouse model, removing ApoE4 from neurons drastically reduced neurofibrillary tangles, tau-mediated gliosis, and myelin loss (Feb 2023 news; Koutsodendris et al., 2023). Moreover, human APOE4 neurons transplanted into the hippocampi of APOE4 knockin mouse generated Aβ and phospho-tau aggregates, and elevated the levels of pro-inflammatory microglia, as reported in a preprint (Rao et al., 2023). Interestingly, tau pathology in these mice was dependent on the presence of microglia. 

Several mechanisms have been suggested to explain ApoE4’s effects in neurons. For example, ApoE4 can be aberrantly cleaved in neurons to generate toxic C-terminal fragments. These fragments can cause mitochondrial dysfunction, tau pathology, and neuronal death (Koutsodendris et al., 2021). Moreover, one study found ApoE can inhibit Aβ production by binding to γ-secretase in neurons, and ApoE4 is less capable of doing so compared with ApoE3 and ApoE2 (Hou et al., 2023). Also, a preprint suggested ApoE4 may drive tau aggregation in neurons by disrupting the function of neuroproteasomes—proteasomes localized to neuronal plasma membranes that degrade newly synthesized proteins, including tau (Paradise et al., 2023).

Vascular cell function seems to be affected by ApoE4 as well. In pericytes, for example, ApoE4 appears to cause alterations that disrupt the blood-brain barrier (e.g., Bell et al., 2012; May 2012 news; May 2020 news; Montagne et al., 2021) and, in a 3D cell-culture model system, it promoted cerebral amyloid angiopathy (Blanchard et al., 2020; Jun 2020 news). In addition, ApoE4 is associated with changes in gene expression in endothelial cells, pericytes, and perivascular fibroblasts (Sep 2022 conference news, Sun et al., 2023). Vascular cell function may also be affected indirectly by expression of ApoE4 in astrocytes. In AD mice with ApoE4-deficient astrocytes, for example, gliosis was dampened, and cerebrovascular integrity and function were improved, although Aβ deposition shifted from the brain parenchyma to the vasculature (Xiong et al., 2023). Moreover, observations reported in a preprint revealed that, in mice, macrophages closely apposed to neocortical microvessels, a.k.a. border associated macrophages, produce ApoE4 and react to it, releasing reactive oxygen species that result in resticted cerebral blood flow (Apr 2023 conference news, Iadecola et al., 2023).

Interestingly, although ApoE produced systemically, by the liver and peripheral macrophages, is excluded from the brain, increasing evidence suggests it is tied to neurological health. For example, a study of more than 100,000 Danes found that APOE genetic variants associated with low ApoE levels in plasma were also more likely to be associated with an increased risk for dementia, and for AD in particular (Rasmussen et al., 2020). Low plasma levels appear to correlate with APOE4 carriership (e.g., Martinez-Morillo et al., 2014), and one study reported low levels associated with CSF AD biomarkers in patients with mild cognitive impairment and AD (Giannisis et al., 2022). However, as reported in a preprint, heparin-bound ApoE4 may be increased in plasma, together with other heparin-binding proteins tied to AD (Guo et al., 2023).

Although some experiments in mice have failed to detect effects of peripheral ApoE in the brain (e.g., Huynh et al., 2019), several have done so. For example, in mice transplanted with primary human hepatocytes, peripheral ApoE was found to affect cognitive behaviors, synaptic health, neuroinflammation, insulin signaling, and cerebrovascular function (Giannisis et al., 2022; Liu et al., 2022; see also Golden and Johnson 2022). Analyses of brain tissue and plasma proteome profiling of conditional mouse models expressing human APOE4 only in the liver, as well as from a human endothelial cell model, suggest these various effects stem from vascular dysfunction (Liu et al., 2022). Also of note, breeding these conditional mice with an AD mouse model exacerbated amyloid pathology.

Moreover, peripheral effects on carrier health could also have indirect, AD-related consequences. For example, C-reactive protein (CRP) released during peripheral inflammation may contribute to APOE4-related AD neurodegeneration (Tao et al., 2021, Royall et al., 2017). Moreover, APOE4 carriers’ elevated risk of cardiovascular disease may select for populations of older carriers enriched in metabolic traits that enabled them to survive the risk past mid-life. These traits may modify LOAD risk and/or expression (Wu et al., 2021). Also of note, APOE4 appears to influence the composition of the gut microbiome (e.g., Zajac et al., 2022) which in turn may affect the progression of at least some neurodegenerative pathologies (e.g., Seo et al., 2023, Jan 2023 news).

In addition to its effects on AD pathology, ApoE4 may fuel other types of neurodegenerative damage. Indeed, ApoE interacts with multiple amyloid proteins in addtion to Aβ (for review see Loch et al., 2023). For example, a post-mortem study indicated increased ApoE accumulation in the Lewy bodies of APOE4 carriers with Lewy body dementia, and other studies suggest ApoE4 exacerbates α-synuclein pathology, increasing the seeding of aggregates that are particularly toxic to neurons  (e.g., Feb 2020 news;  Zhao et al., 2021; Jin et al., 2022). In mouse models of synucleinopathy, ApoE4 worsened neurodegeneration, inflammation, memory loss, and motor deficits.

Therapeutic Candidates

Multiple approaches to therapeutically counter the harmful effects of ApoE4 are being examined, ranging from directly targeting the protein, to mitigating its downstream effects (see Serrano-Pozo et al., 2021; Yang et al., 2021; Raulin et al., 2022 for reviews). Direct strategies include reducing ApoE4 levels, enhancing the protein’s lipidation, and blocking its interactions with Aβ peptides or APP. For example, an antibody that preferentially binds to aggregated, poorly lipidated ApoE, a form often adopted by ApoE4, was reported to reduce amyloid pathology and improve cerebrovascular function in mice (Feb 2021 news; May 2019 conference news; Apr 2018 news).

Approaches to target downstream effects include blocking a proton leak channel to circumvent ApoE4-mediated stalling of early endosomes (July 2021 news), identifying drugs that normalize transcriptional signatures linked to ApoE4 (Oct 2021 news), boosting lipid efflux from glial cells (Nov 2023 news) and targeting downstream signaling cascades disrupted by ApoE4 (Dec 2021 news).

Also, other researchers are attempting to boost ApoE2/ApoE3 activity, either by using gene therapy to express the benign isoforms in APOE4 carriers (e.g., LX1001, Dec 2022 conference news, Jackson et al., 2023), or by designing small molecules to mold ApoE4 into a conformation that more closely resembles those of ApoE2/ApoE3 (e.g., Wang et al., 2018, June 2018 news, Nemergut et al., 2023, ALZ-801). 

Of note, taking into account APOE4 carriership is proving important for the development and deployment of multiple AD therapies, even those that do not target ApoE. For example, recent studies have shown that the efficacy, side effects, and likely the optimal timing, of anti-Aβ immunotherapies are all shaped by the presence of APOE4 (Ossenkoppele and van der Flier, 2023). 

Research Models

Multiple APOE4 research models have been developed, including rodent models and patient-derived induced pluripotent stem cell (iPSC) lines (e.g., Nov 2022 news; Schmid et al., 2021; Raman et al., 2020).  APOE4 knock-in mice, transgenic mice and rats, and mice carrying APOE4 together with AD-relevant mutations are available. 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). Also of note, a 3D human brain model derived from APOE4 carrier iPSCs was described in a preprint (Stanton et al., 2023). With six brain cell types embedded in a 3D hydrogel, it is engineered to mimic immuno-glial-neurovascular interactions.

Nomenclature Notes

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 additional positive charge were named ApoE4. Subsequent studies showed that, in most cases, these faster migrating species corresponded to C130R.

Table

APOE4-Associated AD Risk Across Groups of Different Ancestries*

*Only data from reports comparing AD risk among groups of different ancestries using the same analyses tools, in the same study, were included.
^aReference E3/E3.
^bMeta-analysis of two meta-analyses (Farrer et al., 1997, Choi et al., 2019).
^cData from MedRxiv preprint.
^dMeta-analysis of multiple studies.
^eReference: E4 non-carriers.
^fDiagnosed with dementia/ADRD, not specifically AD.

OR=odds ratio, HR=hazard ratio, RR=risk ratio.
Statistically significant associations (as assessed by the authors) are in bold.

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References

News Citations

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2. Dysregulated Lipid Metabolism Comes to the Fore at AD/PD 27 Apr 2023
3. Forget Typical Alzheimer's: AI Finds Four Types. 30 Apr 2021
4. Do Lipids Lubricate ApoE's Part in Alzheimer Mechanisms? 5 Nov 2021
5. Even Without Amyloid, ApoE4 Weakens Blood-Brain Barrier, Cognition 9 May 2020
6. Shooting Themselves in the Foot? Microglia Block “Good” State with ApoE4 9 Sep 2022
7. New Look at Sex and ApoE4 Puts Women at Risk Earlier than Men 1 Sep 2017
8. Study Finds Sex Influences CSF Tau Levels in ApoE4 Carriers 11 May 2018
9. Is a Woman’s Brain More Susceptible to Tau Pathology? 8 Feb 2019
10. ApoE4 and Tau in Alzheimer’s: Worse Than We Thought? Especially in Women 1 Nov 2019
11. Receptor Decoy Raises Risk of Alzheimer’s—But Only in Women 26 Jul 2022
12. More Data on Herpes and Alzheimer’s Disease 16 Apr 2021
13. Healthy Lifestyle Hedges Dementia Risk, but Not if Genetic Risk Runs High 27 Aug 2019
14. Young ApoE4 Carriers Wander Off the ‘Grid’ — Early Predictor of Alzheimer’s? 23 Oct 2015
15. Young ApoE4 Carriers Have Reversed AD Proteomic Signature 1 Dec 2021
16. In People Who Defy ApoE, New Alzheimer’s Risk Genes Found 29 Dec 2020
17. Up, and Down—Haptoglobin Moves APOE4 Risk in Mysterious Ways 30 Sep 2022
18. Two ApoE Mutations Decrease Risk for Alzheimer's Disease 10 Jun 2022
19. Klotho Variant Cuts ApoE4’s Alzheimer Risk by a Third 17 Apr 2020
20. Klotho VS Variant Preserves Memory by Preventing Tangles 14 Aug 2020
21. The Mutation You Want: It Protects the Brain, Extends Life 31 May 2019
22. In Oldest Old, Rare Longevity Variants Suppress Common Pathogenic Ones 18 Sep 2021
23. First Genome-Wide Association Study of Dementia with Lewy Bodies 15 Dec 2017
24. Not All Bad? APOE4 Sharpens Memory in Older People 9 Oct 2021
25. APOE Tied to Increased Susceptibility to SARS-CoV-2 29 Jan 2021
26. Could Juicing Up Trafficking Abolish ApoE4’s Alzheimer’s Risk? 17 Jul 2021
27. On The Docket at AD/PD: The Many Crimes of ApoE4 1 May 2019
28. ApoE Has Hand in Alzheimer’s Beyond Aβ, Beyond the Brain 14 Jul 2018
29. In Human Neurons, ApoE4 Promotes Aβ Production and Tau Phosphorylation 15 Jun 2018
30. ApoE Risk Explained? Isoform-Dependent Boost in APP Expression Uncovered 20 Jan 2017
31. ApoE4 Makes All Things Tau Worse, From Beginning to End 20 Sep 2017
32. Squelching ApoE in Astrocytes of Tau-Ravaged Mice Dampens Degeneration 10 Apr 2021
33. Sans TREM2, ApoE4 Drives Microgliosis and Atrophy in Tauopathy Model 18 Nov 2022
34. Meddling Microbiome Worsens Tauopathy and Neurodegeneration 13 Jan 2023
35. Droplets of Unsaturated Fats Burden Human ApoE4 Astrocytes 12 Mar 2021
36. ApoE4 Glia Bungle Lipid Processing, Mess with the Matrisome 16 Aug 2019
37. At AD/PD Conference, New Alzheimer’s Genes Reinforce Known Pathways 19 Apr 2019
38. Does ApoE in Neurons Drive Selective Vulnerability in Alzheimer’s? 21 May 2021
39. In Tauopathy, ApoE Destroys Neurons Via Microglia 17 Oct 2019
40. Human Blood-Brain Barrier Model Blames Pericytes for CAA 15 Jun 2020
41. Alzheimer's Risk Genes Nip at Hippocampus Throughout Life 30 Oct 2020
42. Alzheimer’s Disease-Related Proteins Needed for Neurogenesis 3 Aug 2018
43. In Astrocytes, ApoE4 Bungles Endocytosis, PICALM Picks Up the Slack 28 Oct 2020
44. Lipid-Laden, Sluggish Microglia? Blame Aβ. 6 Sep 2023
45. Do APOE4’s Lipid Shenanigans Trigger Tauopathy? 23 Nov 2023
46. In Amyloid and Tangle Models, APOE4 Paralyzes Microglia 26 Oct 2023
47. Among AD Mutations, Only ApoE4 Seems to Hobble Microglia 14 Sep 2019
48. Cracking the Cholesterol-AD Code: Metabolites and Cell Type 21 Oct 2023
49. Secreted by Neurons, ApoE4 Makes Tangles and Degeneration Worse 24 Feb 2023
50. ApoE4 Makes Blood Vessels Leak, Could Kick Off Brain Damage 17 May 2012
51. Macrophages Blamed for Vascular Trouble in ApoE4 Carriers 13 Apr 2023
52. Toxic α-Synuclein: Egged on by ApoE4, Thwarted by ApoE2? 7 Feb 2020
53. Would ApoE Make a Better Therapeutic Target Than Aβ? 26 Feb 2021
54. Antibodies Against Microglial Receptors TREM2 and CD33 Head to Trials 10 May 2019
55. Human ApoE Antibody Nips Mouse Amyloid in the Bud 5 Apr 2018
56. Can an Old Diuretic Drug Disarm APOE4, Prevent Alzheimer’s? 15 Oct 2021
57. In Small Trial, Gene Therapy Spurs ApoE2 Production 14 Dec 2022
58. Cornucopia: LOADs of New Mouse Models Available 5 Nov 2022
59. Meet the Switching Mice: They Flip Their Glia APOE4 to APOE2 23 Aug 2023

Mutations Citations

1. PSEN1 E280A (Paisa)
2. APOE R269G
3. APOE R154S (Christchurch)

Therapeutics Citations

1. LX1001
2. ALZ-801

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Other Citations

1. Jun 2023 news

External Citations

1. GWAS catalog

Further Reading

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