Overview

Clinical Phenotype: Alzheimer's Disease, Multiple Conditions
Position: (GRCh38/hg38):Chr19:44908756 C>A
Position: (GRCh37/hg19):Chr19:45412013 C>A
Transcript: NM_000041; ENSG00000130203
dbSNP ID: rs121918393
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CGC to AGC
Reference Isoform: APOE Isoform 1
Genomic Region: Exon 4

Findings

This variant appears to be protective against Alzheimer’s disease (AD). Although still under investigation, its beneficial effects may apply to multiple forms of AD, including autosomal dominant and APOE4-associated AD.

R154S (Christchurch) gained attention in the AD field when it was identified, in homozygous form on an APOE3 backbone, in a Colombian woman also carrying the presenilin 1 (PSEN1) variant E280A (Paisa), the most common cause of familial early onset AD (Nov 2019 news; Arboleda-Velazquez et al., 2019). The woman was part of the large kindred in the Colombian region of Paisa after which the variant was named. Unlike other Paisa carriers who typically develop dementia in their 40s, this woman had only modest short-term memory loss at age 72 and mild dementia at 75.

Strikingly, PET imaging followed by postmortem analysis revealed an unusually high burden of amyloid-β plaque in her brain, with tau pathology restricted to medial temporal and occipital regions. Areas typically involved in AD, including the frontal cortex and hippocampus, were mostly spared, with neurons considered extremely vulnerable to tau-induced neurodegeneration remaining mostly intact, and only mild levels of astrocyte degeneration and vascular deterioration (Sep conference news 2022; Sepulveda-Falla et al., 2022; Henao-Restrepo et al., 2022).

Brain regions free of tau pathology harbored homeostatic astrocytes and microglia expressing genes involved in acute immune responses. In contrast, the occipital cortex was laden with microglia having a transcriptional profile similar to a chronic inflammatory state described in a mouse model of amyloidosis. Moreover, in both astrocytes and microglia, ApoE expression was highest in the frontal cortex and lowest in the occipital cortex, with intermediate expression in the hippocampus. Also, the occipital cortex and amygdala contained Aβ plaques within blood vessels, also known as cerebral amyloid angiopathy (CAA), which correlated with the extent of tau pathology and contrasted with the widespread CAA seen in most Paisa carriers. Glucose metabolism levels in areas associated with AD, such as the precuneus, were similar to those of age matched, non-E280A carriers, as was the level of neurofilament light chain in plasma, an indicator of neuronal damage.

Based on these findings, it was proposed that the Christchurch variant may be protective against AD, blocking the inflammatory process linking Aβ plaques to tau tangles, at least in Paisa carriers. Indeed, subsequent experiments in mice supported this proposal: an amyloidosis mouse model injected with tau fibrils and carrying the Christchurch mutation had fewer plaques and tangles than non-carrier mice and, in particular, tau seeding and spreading were reduced (see Biological Effects below).

Although early studies suggested Christchurch heterozygosity is not  protective of Paisa-associated AD, a subsequent, larger study identified several signs of protection. In the original 2019 study, four Paisa carriers who carried one copy of Christchurch were reported to have developed cognitive impairment at ages similar to non-Christchurch carriers (Arboleda-Velazquez et al., 2019) and a subsequent study of 340 Paisa carriers, including 11 Christchurch heterozygotes, also failed to identify a protective effect (Cochran et al., 2023). However, a study of 1077 Paisa carriers, including 27 Christchurch heterozygotes, found the median age at onset of cognitive impairment was 52 years (95% CI, 51-58) in the Christchurch carriers compared with 47 years (95% CI, 47-49) in the Christchurch noncarriers (Quiroz et al, 2024, Aug 2023 conference news). Brain imaging of two of these individuals revealed relatively preserved metabolism in brain regions typically affected by AD compared with Christchurch noncarriers, and in one individual, ¹⁸F-flortaucipir PET imaging showed decreased tau pathology. In addition, post-mortem examination of brain samples from four carriers of both Christchurch and Paisa variants revealed reduced vascular amyloid pathology compared with carriers of only the Paisa variant.

Effects on non-Paisa carriers | Non-neurological Conditions | Biological Effects | Biological Effects in the Context of AD | Note on nomenclature

Effects on non-Paisa carriers

Importantly, Christchurch may also be protective against pathologies associated with C130R (APOE4), the strongest genetic risk factor for late-onset AD. In human neurons derived from induced pluripotent stem cells (iPSCs) and the P301S tauopathy mouse model, homozygous, but not heterozygous, Christchurch rescued APOE4-associated tau pathology (Nelson et al., 2023; December 2023 news). In the mouse model, it also protected against neurodegeneration and neuroinflammation in a gene dose-dependent manner.

The effects of Christchurch in the context of APOE3, and absent the Paisa mutation, remain uncertain. A study of 37 carriers identified in 500,00 UK Biobank participants—including 30 APOE3 homozygotes, five APOE3/E4 heterozygotes, and one APOE3/E2 heterozygote—was unable to detect an effect on AD risk because of the low number of carriers (He et al., 2023). None of the Christchurch carriers had AD (ages 57-82, mean age = 69), but AD incidence in the control group was only 0.51 percent. No significant differences in diagnoses for cerebral amyloid angiopathy or vascular dementia between carriers and non-carriers were observed. Of note, studies in APOE3 mice revealed that Christchurch is protective of AD-like pathologies induced by other means—APP/PS1 mutations and tau injections—that do not involve either the Paisa variant or APOE4 (Chen et al., 2023; December 2023 news)

Surprisingly, a report of two heterozygous siblings in Spain suggested Christchurch may be deleterious in some cases (Hernandez et al., 2021). These two carriers suffered from AD with ages at onset of 53 and 66, with no known mutations in PSEN1, PSEN2 or APP, nor in the coding or intronic sequences of 90 genes related to neurodegenerative conditions, including AD. Autopsy findings from one of the siblings showed AD pathology similar to that reported in other genetic forms of AD, including cerebral amyloid angiopathy and “cotton wool” plaques. The authors suggested the variant might be pathogenic. Also, cerebrovascular disease was reported in a 65-year-old Spanish carrier (Civeira et al. 1996).

Non-neurological Conditions

The effects of the Christchurch variant on lipid metabolism remain unclear. Several case studies over the last three decades suggested it is a risk factor for hyperlipoproteinemia type III (HLPP3). The condition, a.k.a. familial dysbetalipoproteinemia, is characterized by elevated cholesterol and triglyceride levels in blood, and early onset atherosclerosis and heart disease. A 2017 compilation of reported cases identified 34 of 48 carriers with diagnosed HLPP3 (Koopal et al., 2017). However, some studies have failed to confirm this association, while others have suggested Christchurch’s effects may be shaped by other genetic and environmental factors.

One of the more recent studies, including more than 4,000 Spanish individuals, identified 18 index carriers, all of whom had hyperlipidemia (Bea et al., 2023). Fifteen were patients from a lipid clinic (n=3,667), while three were from a control population (n=822). The latter three were found to have combined hyperlipidemia despite being in the control group. An analysis of first-degree relatives of index patients identified 27 carriers total. Compared to non-carriers, carriers had elevated levels of very-low-density lipoprotein cholesterol (VLDLc) and elevated VLDLc/ApoB ratios. ApoB is the main protein in low-density lipoprotein (LDL) particles.

On the other hand, cardiovascular disorders, medication use, as well as blood and urine-based biomarkers in the 37 Christchurch carriers from the UK Biobank were similar to those of age-matched non-carriers. In this study, the only significant difference between carriers and non-carriers was a reduction in plasma levels of ApoB and lower median ApoB/ApoA1 ratios (He et al., 2023). As noted by the authors, together, these alterations suggest a decreased risk for major adverse cardiovascular events.

Some researchers have proposed that the full expression of HLPP3 with cardiovascular symptoms in Christchurch carriers depends on multiple factors, including body weight and the presence of the APOE2 variant (Rolleri et al., 2003). HLPP3 has been observed in Christchurch carriers lacking an APOE2 variant (e.g., Pocovi et al., 1996; Civeira et al., 1996; Feussner et al., 1998), but the presence of APOE2 may increase the probability of full-fledged HLPP3 (Rolleri et al., 2003). Indeed, early studies had reported carriers with the APOE3, but not the APOE2, allele who had cholesterol and triglyceride plasma levels that were close to normal (Wardell et al., 1987; Pocovi et al, 1996; Hubácek et al., 2005).

The Christchurch variant was first described in a 43-year-old man from Christchurch, New Zealand suffering from HLPP3 (Wardell et al., 1987). He was one of seven patients whose ApoE proteins migrated on an isoelectric focusing gel to the position of the R176C (APOE2) variant which had been associated previously with recessive HLPP3. Upon cysteamine treatment, which adds a positive charge to cysteine residues, a shift in the migration of the carrier’s APOE proteins was observed that differed from that expected for the APOE2 allele. Subsequent peptide mapping and amino acid analysis revealed that this individual had only one copy of APOE2, while his other allele carried the Christchurch variant on an APOE3 background. The carrier had a family history of high lipid levels in blood, including his sister and two daughters, one of whose APOE protein was examined and found to carry the variant. Wardell et al. pointed out the Christchurch variant likely contributed significantly to disease since the patient’s VLDL contained approximately five-fold more of the Christchurch than the APOE2 variant. The mutation was subsequently sequenced at the DNA level in an HLPP3 patient from Utah (Emi et al., 1988).

The variant was subsequently reported in several individuals worldwide, including multiple unrelated Spanish subjects and some of their relatives (Pocovi et al., 1996; Civeira et al., 1996; Valveny et al., 1997; Solanas-Barca et al., 2012; Lamiquiz-Moneo et al., 2016, Bea et al., 2023), two kindreds from Italy (Rolleri et al., 2003) and one from Colombia (Arboleda-Velasquez et al., 2019), two siblings in France (Vialletes et al., 2000), two patients in the Czech Republic (Hubácek et al, 2005), as well as individuals in Germany (Feussner et al., 1998), Canada (Hegele 1999), and the UK (He et al., 2023). 

In addition, some studies have suggested the Christchurch variant may be a risk factor for other lipid disorders or none at all. For example, two French siblings carrying the variant and APOE2 were diagnosed with hyperlipoproteinemia type V, a disease characterized by severe hypertriacylglycerolemia  (Vialletes et al., 2000; Dalongeville, 2000) and one Spanish individual was diagnosed with isolated hypercholesterolemia, a.k.a. hyperlipoproteinemia type IIa (Bea et al., 2023). On the other hand, the prevalence of dyslipidemia, cardiovascular disease, and hypertension in 37 Christchurch carriers from the UK Biobank was similar to those of age-matched non-carriers, although levels of ApoB—the main protein found in low-density lipoprotein (LDL)—were lower (He et al., 2023).

The Christchurch variant varies in frequency, and perhaps in its effects, across different populations. Globally, the variant is very rare, with a frequency of 0.000013 in the gnomAD variant database, including only two carriers, both heterozygotes of Latino/Admixed American ancestry (v2.1.1, Dec 2023). Moreover, the large UK Biobank study reported a higher, but still very low, frequency of 0.00004 which included 36 Europeans and one individual of admixed American ancestry (He et al., 2023). In addition, two studies of German individuals concluded the variant is very rarely found in patients with dyslipidemia (Feussner et al., 1998; Evans et al., 2013). However, it appears to be considerably less rare in some Spanish populations, particularly amongst dyslipidemic patients (Civeira et al. 1996; Pocovi et al., 1996), with the largest study reporting an overall frequency of 0.0040 (Bea et al., 2023). 

Biological Effects

The Christchurch variant is found in the receptor-binding region of ApoE. An in vitro assay using a bacterial-expressed mutant ApoE revealed a 60 percent reduction in binding to LDL receptors compared with ApoE3 (Lalazar et al., 1988). Similarly, others have reported 45-60 percent reductions (Koopal et al., 2017), as well as reduced VLDL affinity for the LDL receptor (Bea et al., 2023).

In addition, Christchurch binds less tightly to heparan sulfate proteoglycans (HSPGs) than wild-type ApoE (Wardell et al., 1987; Arboleda-Velazquez et al., 2019; Mah et al., 2023). R154 has been proposed to be one of eight amino acids lining a shallow groove that makes direct contact with HSPG sulfo groups (Libeu et al., 2001), and the substitution of an uncharged serine for a positively charged arginine is expected to reduce ApoE’s affinity for negatively charged HSPGs. Binding kinetics suggest that ApoE binds to HSPGs in two stages: a fast electrostatic step, which is disrupted by the Christchurch substitution, followed by a slower conformational change (Mah et al., 2023). 

Biological Effects in the Context of AD

Of particular interest to AD pathology, HSPG facilitates the dissemination and uptake of tau seeds into neurons, and limiting HSPG-ApoE binding reduces this spread (Holmes et al., 2013;May 2018 news; Stopschinski et al., 2018; Rauch et al., 2018). The spatial restriction of tau pathology in the PSEN1 E280A carrier suggested the Christchurch variant might blunt tau spreading, potentially through impaired HSPG binding (Nov 2019 news; Arboleda-Velazquez et al., 2019). Consistent with this possibility, both tau seeding and spreading were reduced in mice with AD-like pathologies carrying the Christchurch variant. Specifically, knockin mice with a humanized copy of APOE3 including the Christchurch mutation (APOE3ch) crossed with the amyloidosis model APPPS1 (APPPS1:APOE3ch) and injected with AD-brain derived tau extracts, had less neuritic plaque-associated tau in both their ipsilateral and contralateral hippocampi and cortices than APPPS1:APOE3 controls (Chen et al., 2023). Moreover, in this same study, bone marrow-derived macrophages with microglia-like properties from APOE3ch mice, showed increased phagocytosis and degradation of tau fibrils compared to those of APOE3 mice, and tau uptake was competitively inhibited by heparin, suggesting HSPG involvement. These cells also secreted fewer tau seeds. Furthermore, in human cells,  iPSC-derived astrocytes carrying Christchurch mitigated tau propagation within iPSC-derived neurons and were less prone to becoming reactive compared to the isogenic, non-carrier iPSCs from which they were generated (Murakami et al., 2024).

Similarly, in the case of APOE4-mediated pathogenicity, Christchurch homozygosity protected against tau uptake and phospho-tau accumulation in isogenic iPSC neurons, at least in part, via reduced HSPG binding (Nelson et al., 2023). 

Hoping to mimic Christchurch’s effects, researchers have generated an antibody, 7C11, that blocks ApoE-HSPG binding (Marino et al., 2023, Aug 2023 conference news, October 2023 news). The antibody preferentially binds to the ApoE4 isoform and when systemically administered to APOE4 knockin mice it reduced the number of brain cells with detectable p-tau396, an early marker of tau pathology and a component of toxic tau seeds prone to aggregate. Also, 7C11 reduced tau pathology in retinas of MAPT*P301S mice treated with recombinant human ApoE.

The Christchurch variant also appears to affect amyloid pathology. In vitro experiments revealed that Aβ42 aggregated less in the presence of human recombinant ApoE carrying the Christchurch variant than in the presence of wildtype ApoE3 (Arboleda-Velazquez et al., 2019). This prompted the authors to speculate that the Colombian homozygote’s extensive amyloid burden may have been even worse in the absence of the variant. Consistent with this prediction, Aβ plaque burden in 6-month-old APPPS1:APOE3ch mice was decreased compared to that of control APPPS1:APOE3 mice (Chen et al., 2023).

Interestingly, Christchurch’s effects on amyloid pathology appear to be linked to its effects on tau pathology, at least in mice (Chen et al., 2023). The size and number of Aβ plaques in 9.5-month-old APPPS1:APOE3ch mice injected with AD-tau were considerably reduced compared to those of tau-injected APPPS1:APOE3 controls. Also, in the Christchurch mice, more phagocytic microglia clustered around individual Aβ plaques and synaptic loss was diminished. Importantly, protection against tau pathology was not observed in APOE3Ch mice injected with tau but lacking amyloid pathology. Also, phagocytosis of tau fibrils by microglia-like bone marrow-derived macrophages in culture was enhanced by co-treatment with low levels of Aβ, as well as vice versa: tau fibrils enhanced Aβ uptake. Moreover, secretion of tau was reduced in the Christchurch macrophages possibly reflecting the decreased tau spread seen in vivo. The authors concluded that Christchurch’s ability to reduce Aβ pathology may enable, at least in part, the suppression of tau seeding and spreading.

Consistent with its apparent ability to temper Aβ and tau pathologies in APOE3 or APOE4 mouse models, Christchurch has also been reported to reduce gliosis and neurodegeneration in mice. In P301S/APOE4 animals, Christchurch carriers had fewer Iba1-positive microglia, GFAP-positive astrocytes, and disease-associated microglia and astrocytes, and these reductions were dependent on gene dosage (Nelson et al., 2023). Reduced microgliosis was also observed in homozygous APPPS1:APOE3ch mice (Chen et al., 2023). Moreover, Christchurch homozygosity, and to a lesser extent heterozygosity, dampened hippocampal and dentate gyrus atrophy in P301S/APOE4 mice (Nelson et al., 2023).

Also, in tauopathy mice, the transcriptional profiles of excitatory neuron subpopulations were increased in the presence of Christchurch, while profiles of disease-associated oligodendrocytes were decreased, with both changes occurring in a gene dose-dependent manner (Nelson et al., 2023). Moreover, in tauopathy mice carrying two copies of Christchurch, increases in the transcriptional profiles of homeostatic astrocytic and microglial populations were observed, while disease-associated profiles for both glial cells were reduced. Also, Christchurch reduced tau phosphorylation (p-tau396) in cerebral organoids generated from iPSCs from the homozygous Christchurch carrier who also carried the Paisa mutation (Perez-Corredor et al., 2024). The reduction was associated with elevated levels of β-catenin and increased expression of cadherin/Wnt signaling pathways. Interestingly, in experiments using a Wnt reporter cell line, ApoE3 Christchurch activated Wnt signaling when combined with Wnt3a ligands, while wildtype ApoE3 inhibited it.

Complementing and extending these observations, another study, reported in a preprint, concluded that Christchurch promotes a microglial response that reduces amyloid pathology, and inhibits the same response in the context of tau pathology where it is harmful (Tran et al., 2024). In this study, Christchurch was introduced into the mouse ApoE gene, and these mice were crossed to 5xFAD and to PS19 tauopathy mice. Christchurch reduced plaques in the former, but not tau pathology in the latter. Single-cell and spatial transcriptomics revealed Christchurch promoted microglia to adopt a disease-associated signature (DAM) around plaques in the 5xFAD mice, while dampening the DAM response and a disease-associated astrocyte signature in PS19 mice.  This is consistent with another preprint showing that Christchurch may confer resilience against tau pathology by dampening microglial interferon responses (May 2024 news, Naguib et al., 2024).

Cells that are particularly vulnerable to AD pathology appear to be protected by the presence of Christchurch. Single-nuclei RNA sequencing of brain cells of the homozygous Colombian carrier, for example, revealed a transcriptional cluster in the hippocampus and the frontal, but not occipital, cortex distinctive of RORB+ excitatory neurons (Sepulveda-Falla et al., 2022, Sep conf news 2022). These neurons were previously identified as being very vulnerable to tau-induced neurodegeneration (Jan 2021 news). In addition, Christchurch homozygosity appeared to rescue vulnerable GABA-positive cells, which are normally less prevalent in APOE4 iPSC-derived neuronal cultures (Nelson et al., 2023). Also, in mice with tauopathy, neurons appeared to be partially protected against APOE4-driven neurodegeneration by Christchurch expression in microglia and astrocytes which may benefit from the variant’s expression more than neurons do. Interestingly, R154 has been implicated in ApoE4 binding to a microglial receptor that activates pro-inflammatory  pathways (Zhou et al., 2023).

Also of note, in humans, single-nucleus RNA sequencing of brain tissue from the Christchurch homozygote who also carried PSEN1 E280A revealed increased expression of LRP1 in astrocytes of the frontal, but not the occipital, cortex (Feb 2024 news; Almeida et al., 2024). LRP1 encodes an APOE receptor implicated in tau spreading which may also facilitate clearance of tau paired helical filaments. This study also found upregulation of a gene encoding an isomerase reported to decrease tau inclusion toxicity, FKBP1B, and downregulation of a gene encoding a co-chaperone reported to promote accumulation of neurotoxic tau, FKBP5. Changes in the expression of other genes that may be related to Christchurch’s protective effects included downregulation of PSEN1 and upregulation of the protective retromer gene VPS35 and of two genes involved in heparan synthesis, B3GAT3 and EXTL2.

Christchurch may also help counter ApoE4 toxicity by lowering the ratio of potentially neurotoxic ApoE fragments to full-length ApoE, as suggested by observations in iPSC-derived neurons (Nelson et al., 2023). In addition, the increase in ApoE acidity resulting from the substitution of an arginine with a serine in this variant has been noted as potentially protective of endolysosomal trafficking—a process that can be stalled by the loss of solubility of proteins with isoelectric points close to the pH of early endosomes, such as ApoE4 (Vance et al., 2024).

The effects of Christchurch on lipids and lipoprotein particles in plasma and cerebrospinal fluid (CSF) have also been examined. Consistent with some observations in humans, APOE3ch mice had an HLPP3-like phenotype, including elevated levels of cholesterol, VLDL, and to a lesser extent LDL, in plasma (Chen et al., 2023). Also, ApoE levels were increased. In contrast to humans (He et al., 2023), however, ApoB levels in the plasma of these mice were increased (Chen et al., 2023). In CSF and brain lysates, however, lipoprotein and lipoprotein-related protein levels were similar to those of control mice expressing humanized APOE3. Interestingly, both the plasma and CNS effects differed between males and females.

Whether and how the peripheral effects of Christchurch impact its central effects on AD pathology remains uncertain. For example, while one study found elevated ApoB plasma levels associated with early onset AD (e.g., Wingo et al., 2019; May 2019 news), another found no association with late-onset disease (e.g., Tynkkynen et al., 2016).

In silico analyses, including SIFT, Polyphen-2, and MutationTaster, predicted the Christchurch variant to be damaging (Lamiquiz-Moneo et al. 2016). In addition, its PHRED-scaled CADD score, which integrates diverse information in silico, was above 20, also suggesting a deleterious effect (CADD v.1.6, May 2022). A comparison of ApoE amino acid sequences from 63 mammals revealed R154 is highly conserved (Frieden et al., 2015).

Note on nomenclature

Some papers include ApoE2 in the name of this variant because its isoelectric migration is very similar to that of R176C (ApoE2). Also, in other papers, APOE3 has been included in the variant’s name to denote the isoform backbone in which the variant was identified.

Research Models

The Christchurch mutation has been introduced into isogenic iPSC lines that are homozygous for the common alleles APOE2, APOE3, and APOE4 (Haidar et al., 2024). The set is available at the European Bank of iPSCs.

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References

Mutations Citations

1. PSEN1 E280A (Paisa)
2. APOE C130R (ApoE4)

News Citations

1. Can an ApoE Mutation Halt Alzheimer’s Disease? 4 Nov 2019
2. Does One Copy of the Christchurch ApoE Variant Slow Alzheimer’s? 12 Aug 2023
3. APOE Christchurch Variant Tames Tangles and Gliosis in Mice 17 Dec 2023
4. To Deliver Itself From Cell to Cell, Phospho-Tau Uses UPS 19 May 2018
5. New Therapeutic Strategy—Mimic the ApoE Christchurch Mutation? 24 Oct 2023
6. Protective ApoE Variant Quells Interferon Responses in Tauopathy 21 May 2024
7. Selective Vulnerability News: RORB Neurons Are First Victims of Tangles 21 Jan 2021
8. Different Cellular Mechanisms in Familial and Sporadic Alzheimer’s? 29 Feb 2024
9. Is APOB a Risk Gene for Early Onset Alzheimer’s? 30 May 2019

Research Models Citations

1. Tau P301S (Line PS19)
2. APPPS1

Paper Citations

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