Aliria Rosa Piedrahita de Villegas surprised scientists when she remained sharp 30 years past her expected age of Alzheimer’s disease onset, as dictated by an autosomal-dominant E280A Paisa presenilin mutation. Her resilience was attributed to having two copies of an ApoE3 variant, called Christchurch. At the Alzheimer’s Association International Conference, held July 16-20 in Amsterdam, Yakeel Quiroz of Massachusetts General Hospital, Boston, claimed one copy was sufficient to protect others in Piedrahita de Villegas’ kindred. Among 1,000 Paisa carriers in that extended family who live near Antioquia, Colombia, Quiroz found 12 who also had a copy of Christchurch. They staved off MCI for seven years longer than noncarriers. Though the delay to AD diagnosis was shorter, just four years, this still put their age at onset past the normal range for Paisa carriers.

Like Piedrahita de Villegas, one Christchurch heterozygote had abundant amyloid plaques yet few neurofibrillary tangles. “This is the first evidence that having one copy of Christchurch may give some protection against the Paisa mutation, even if it’s not as strong as in the homozygous case,” Quiroz told Alzforum. However, another study led by Nicholas Cochran, HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, of the same cohort found no delay in cognitive decline in heterozygous Christchurch carriers. The discrepancy comes down to different age-at-onset estimates, the scientists say.

  • Twelve people who carry the Paisa presenilin mutation also have a copy of ApoE-Christchurch.
  • Their AD progression was delayed four to seven years.
  • They had fewer tangles, less brain atrophy than Christchurch noncarriers.
  • A separate study found no delay in their disease progression.
  • An antibody that mimics the ApoE variant eased tau pathology in mice.

The Christchurch effect might even lead to a therapy. Working with Quiroz, Joseph Arboleda-Velasquez and Claudia Marino of Massachusetts Eye and Ear in Boston have recapitulated the tau-squelching effects using an antibody that makes ApoE behave like the Christchurch variant. When mice expressing human ApoE were injected with the antibody their brains made less hyperphosphorylated tau.

Since 2014, Quiroz and colleagues have studied more than 6,000 members of this extended family through the Colombia-Boston (COLBOS) collaboration. Among this kindred, about 1,200 carry the Paisa presenilin variant. Most turn amyloid positive on PET scans by age 28 and tau positive a decade later. On average, they develop mild cognitive impairment by 44 and dementia by 49 with just a year or two of variation in age at onset (Acosta-Baena et al., 2011). 

Despite carrying this pernicious mutation, Piedrahita de Villegas was sharp until age 72. When she died, a month before her 78th birthday, she had but mild dementia symptoms. Subsequent whole-exome sequencing of her DNA revealed she had two copies of the Christchurch mutation. This variant of ApoE3 binds poorly to heparan sulfate proteoglycans (HSPGs), extracellular matrix molecules that help propagate tau seeds (Aug 2013 conference news). Despite an immense burden of amyloid plaques throughout her brain, she had neurofibrillary tangles only in her hippocampus and occipital cortex (Nov 2019 news; Sep 2022 news). In stark contrast, typical Paisa carriers from the Colombian kindred are riddled with tangles, especially in their precuneus, by the time they get MCI in their 40s. They typically die before age 60.

Did ApoE-Christchurch protect others in Piedrahita de Villegas’ extended family? In 2019, Quiroz and colleagues had reported four Paisa carriers with one copy of Christchurch. All became cognitively impaired at the normal age. Last March, Cochran, and co-first authors Juliana Acosta-Uribe at UC Santa Barbara, and Bianca Esposito of the Icahn School of Medicine at Mount Sinai, New York, reported that among 340 Paisa carriers in the Colombian kindred, 11 were heterozygous for APOE-Christchurch. They developed MCI and dementia at the expected ages as well (Cochran et al., 2023). 

More Plaques, Fewer Tangles. Amyloid and tau PET scans of a Paisa/Christchurch carrier (right columns) show he had more amyloid yet almost no neurofibrillary tangles when he was diagnosed with MCI at 51 than a typical Paisa carrier diagnosed at age 44 (left columns). [Courtesy of Yakeel Quiroz, Massachusetts General Hospital.]

To cast a wider net, Quiroz and colleagues turned to banked blood samples from 1,000 Paisa carriers and 1,000 noncarriers among the Colombian kindred, sequencing their APOE genes. Among the latter, 100 carried a single Christchurch copy. Twelve of the Paisa carriers did, and 10 of these were the same people analyzed by Cochran.

Quiroz and colleagues comprehensively reviewed their medical records and found that the 12 had delayed AD onset, albeit by less than Piedrahita de Villegas. On average, they were diagnosed with MCI at 51 and dementia at 53, delays of seven and four years, respectively.

Why were the ages at onset later than those estimated by Cochran and colleagues? Quiroz chalks that up to revisions of the ages at onset after more detailed clinical review. In support of that, some have lived until age 60, five years longer than Christchurch noncarriers.

So far, two men with Paisa/Christchurch variants have had PET scans and they support the premise that one copy of the ApoE variant protects. One man was diagnosed with MCI at 51 when his semantic fluency and executive function began to fail. That year, he flew to Boston for structural MRI and amyloid and tau PET scans. Compared to Paisa carriers with a typical MCI age at onset of 44, he had less hippocampal atrophy and almost no tau pathology. Tangles were limited to regions affected during early stage AD, such as the entorhinal cortex, even though he had more amyloid plaques than Christchurch noncarriers of the same age (image above). A follow-up PET scan at age 53 showed only scant spread of tangles to the surrounding medial temporal lobe (image below). By 54, he had progressed to mild dementia.

Slow Spread. In a man carrying Paisa and a copy of ApoE-Christchurch, tau PET scans taken two years apart captured minimal neurofibrillary tangle growth from his entorhinal cortex throughout his medial temporal lobe. [Courtesy of Yakeel Quiroz, Massachusetts General Hospital.]

The other man started having trouble recalling words at age 52, prompting an MCI diagnosis. He developed mild dementia at 57 and progressed to moderate AD by 62. Two years later, he had MRI and FDG PET scans in Colombia. His hippocampus had minimal atrophy and his precuneus metabolism was normal compared to Paisa carriers with MCI in their 40s (image below). Metabolism tanks in the precuneus of Christchurch noncarriers by this age. His preserved metabolism mirrored that seen in Piedrahita de Villegas’s brain.

Preserved Precuneus. Glucose metabolism waned in the precuneus in a Paisa carrier (top), but not in a carrier with one copy of ApoE3-Christchurch (bottom). [Courtesy of Yakeel Quiroz, Massachusetts General Hospital.]

Intriguingly, the benefits of the Christchurch variant may be dependent upon other mutants, such as Paisa. In a few case studies, this APOE variant did not protect against early-onset sporadic AD or cerebrovascular disease in Paisa noncarriers, noted Rik Ossenkoppele and Colin Groot, Amsterdam University Medical Center (Hernandez et al., 2021; Civeira et al., 1996). “These findings point to a complex interplay between APOE and the PSEN1 E280A mutation, which could be exploited to produce new treatment targets for AD,” they wrote (comment below).

Toward a Therapy
In that vein, Quiroz, Arboleda-Velasquez, and Marino are developing an antibody mimicking this isoform.

The Christchurch mutation lies where ApoE binds to HSPGs. These extracellular matrix molecules encourage the dissemination and uptake of tau seeds into neurons, and limiting HSPG-ApoE binding curbs this spread (May 2018 news; Stopschinski et al., 2018). Of all known ApoE isoforms, Christchurch binds most weakly to HSPGs, perhaps explaining the low tangle loads in people with the variant. To block ApoE-HSPG binding, Arboleda-Velasquez and colleagues generated 7C11 an antibody that docks on ApoE’s HSPG-binding site.

To make the antibody, the researchers created an antigen containing a peptide corresponding to the ApoE3 HSPG-binding domain and injected it into mice. One animal produced the antibody, which strongly latched onto ApoE3 and, surprisingly, bound ApoE4 even more tightly. Both isoforms have identical HSPG-binding domains. “Perhaps different conformations or polarities of the ApoE isoforms drive the different affinities,” Marino suggested. 7C11 thwarted most ApoE-HSPG binding, as measured by heparin-affinity chromatography.

Still, targeting the HSPG binding site may have unintended off-target effects. “This antibody might also impede the interaction of ApoE with other proteins required for homeostatic functions, such as the LDL receptor protein, as it binds in the same region,” wrote Victor Montal, Hospital de la Santa Cru, Spain (comment below).

Would the antibody prevent HSPG-induced tau pathology in vivo? The researchers injected 7C11 into the abdomens of 16-month-old APOE4 knock-in mice. By this age, the mice have many phospho-tau aggregates within their neurons, even though they have no tau mutations (Brecht et al., 2004). Compared to controls, mice given 7C11 had about half as many p-tau396-positive cells. This form of p-tau is thought to be an early marker of tau pathology and correlates with denotes toxic tau seeds prone to aggregate (Rosenqvist et al., 2018). The results suggest that the antibody’s ability to mimic Christchurch protects against tau pathology.

Whether 7C11 might work in people remains to be seen. Marino found it bound to postmortem samples of middle temporal gyri from two Colombian Paisa carriers—one APOE3/3, the other APOE4/4.

Groot and Ossenkoppele cautioned that it might not work for everyone. "Given the inconsistent results between protective effects of APOEch in PSEN1 E280A mutation homozygotes, heterozygotes, and noncarriers, and the small sample sizes, there is a reasonable likelihood that APOEch mimicking therapeutics might only benefit specific cases," they wrote.—Chelsea Weidman Burke


  1. The presentation by Dr. Quiroz at the featured research symposium organized by the atypical AD PIA was one of our personal highlights of AAIC. The talk covered the previous discovery of an individual from a large kindred living in the region of Paisa in Colombia, who was a PSEN1 E280A mutation carrier and an APOE3-Christchurch (APOEch) homozygote. This individual proved to be extremely resilient to the detrimental effects of the PSEN1 E280A mutation, and was only displaying mild cognitive symptoms 30 years after the estimated age of onset of clinical symptoms (Arboleda-Velasquez et al., 2019). PET imaging of this APOEch homozygote revealed an extended temporal decoupling between amyloid and tau pathology, since this individual showed only modest tau PET (18F-Tauvid) uptake in the presence of very high and widespread amyloid PET burden (11C-PiB; Sepulveda-Falla et al., 2022). Postmortem examinations of the same individual also revealed only mild astrocyte degeneration and vascular deterioration in the presence of significant amyloid burden (Henao-Restrepo et al., 2023) suggesting that, in PSEN1 E280A mutation carriers, APOEch may block the inflammatory response linking amyloid and tau pathology.

    At AAIC, Dr. Quiroz presented new work from her team showing that APOEch heterozygotes with a PSEN1 mutation also show increased resilience against both clinical symptoms—five- to seven-year delay of MCI and dementia compared to other PSEN1 E280A mutation carriers from the same kindred—and cerebral tau pathology. These findings are very intriguing, because they suggest that the protective effects of APOEch do not require homozygosity and can, to a lesser extent, also be found in APOEch heterozygotes in the context of a PSEN1 E280A mutation. This might be very important because APOEch has also been observed in two individuals with sporadic AD at a relatively young age, in one case with cerebrovascular disease, suggesting that APOEch did not yield protection when there was no PSEN1 E280A mutation present (Hernandez et al., 2021; Civeira et al., 1996). Earlier reports on the effects of APOE in PSEN1 E280A mutation carriers suggest that, as is the case in sporadic AD, APOEε2 carriership is protective against developing AD symptoms, while APOEε4 might lead to an earlier symptom onset, although this effect was not statistically significant (Vélez et al., 2015). Together with the findings on APOEch, these findings point to a complex interplay between APOE and the PSEN1 E280A mutation, which could be exploited to produce new treatment targets for AD.

    The R136S Christchurch mutation of the APOE gene is located in a domain that governs the interaction between apolipoprotein E (ApoE) and heparan sulfate proteoglycans (HSPG). APOE alleles and mutations are differentially associated with ApoE and HSPG binding, with APOEε4 (the main genetic risk factor for sporadic AD) having higher binding compared to the protective APOEε2 allele and the APOEch mutation. This inspired the investigators to test the efficacy of an antibody that binds to APOEε4 and alters its function by decreasing binding to HSPG, aiming to mimic the protective effects of APOEch. When administered to a mouse model of tauopathy, the antibody reduced tau pathology, which suggests that APOEch-inspired therapeutic agents might show promise as a disease-modifying treatment in AD. As a cautionary note, given the inconsistent results between protective effects of APOEch in PSEN1 E280A mutation homozygotes, heterozygotes, and noncarriers, and the small sample sizes, there is a reasonable likelihood that APOEch mimicking therapeutics might only benefit specific cases. However, this discovery represents a new avenue of research into therapeutics that alter APOE-related pathways to combat AD, which will require further examination in more complete models of AD and in-human trials.


    . Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report. Nat Med. 2019 Nov;25(11):1680-1683. Epub 2019 Nov 4 PubMed.

    . Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis. 1996 Dec 20;127(2):273-82. PubMed.

    . Gliovascular alterations in sporadic and familial Alzheimer's disease: APOE3 Christchurch homozygote glioprotection. Brain Pathol. 2022 Sep 21;:e13119. PubMed.

    . Heterozygous APOE Christchurch in familial Alzheimer's disease without mutations in other Mendelian genes. Neuropathol Appl Neurobiol. 2021 Jun;47(4):579-582. Epub 2020 Nov 5 PubMed.

    . Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol. 2022 Sep;144(3):589-601. Epub 2022 Jul 15 PubMed.

    . APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease. Mol Psychiatry. 2015 Dec 1; PubMed.

  2. The series of papers related to the ApoE3-Christchurch mutation from Drs. Arboleda-Velasquez and Quiroz, is a clear example of how a case report of a single-residue mutation (Nov 2019 news; Sepulveda-Falla et al., 2022) might help to, first, understand part of the pathophysiology of the disease, and then to develop promising drugs for AD.

    I am also quite excited to see the field moving beyond anti-amyloid therapies. This is important, especially with the current FDA-approved drugs showing adverse results in APOE4 (and more strongly in homozygous) participants. We need to move forward, and, as in the cancer field, develop more personalized therapies for the entire spectrum of AD subjects.

    The study by Marino and colleagues adds to a corpora of recent studies that target ApoE to treat AD (Martens  et al., 2022). Dr. Holtzman’s group has shown promising results with other lipid-free ApoE antibodies and the removal of ApoE in glia (Liao et al., 2018; Mahan et al., 2022). Moreover, it was recently shown by Dr. Huang’s group that the specific degradation of neuronal ApoE4 might have even stronger protective effects (Koutsodendris et al., 2023) compared to removal of glial ApoE. Consequently, the use of antibodies to block the interaction of ApoE with adversarial players, such as heparan sulfate proteoglycans, adds an interesting alternative to counter the pathologic effects of ApoE, but with a key difference: The antibody approach does not degrade ApoE, and, as a result, it can still fulfill its homeostatic functions.

    That said, I do think the current approach has some caveats that should be further explored. Their 7C11 antibody, which blocks the HSPG binding site, might also impede the interaction of ApoE with other proteins required for homeostatic function, such as the LDL receptor protein, which binds in the same region. Moreover, the binding area of the three complementarity-determining regions might go beyond the HSPG binding site affecting other functions of ApoE. In addition, it is very possible that the docking of an antibody to ApoE has allosteric effects along the protein,  affecting its structure, and its function, e.g., lipid binding, in other ApoE regions. Also, as reported by the authors, when using the full-length ApoE, which includes the highly heterogeneous C-terminal region (Stuchell-Brereton et al., 2023), antibody affinity profiles decrease considerably, probably due to the large size of antibodies (compared to nanobodies or small-molecules) and reduced access to the binding site caused by the hindrance of the C-terminal.

    Overall, I think exciting times are ahead in the race to cure AD, and the development of new and appealing pharmacological strategies, such as the one described here by Marino and colleagues, is a clear example that the field is moving forward. ApoE is too central in too many AD-related pathways just to be ignored as a promising therapeutic target.


    . Distinct tau neuropathology and cellular profiles of an APOE3 Christchurch homozygote protected against autosomal dominant Alzheimer's dementia. Acta Neuropathol. 2022 Sep;144(3):589-601. Epub 2022 Jul 15 PubMed.

    . ApoE Cascade Hypothesis in the pathogenesis of Alzheimer's disease and related dementias. Neuron. 2022 Apr 20;110(8):1304-1317. Epub 2022 Mar 16 PubMed.

    . Targeting of nonlipidated, aggregated apoE with antibodies inhibits amyloid accumulation. J Clin Invest. 2018 May 1;128(5):2144-2155. Epub 2018 Mar 30 PubMed.

    . Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis. Mol Neurodegener. 2022 Feb 2;17(1):13. PubMed.

    . Neuronal APOE4 removal protects against tau-mediated gliosis, neurodegeneration and myelin deficits. Nat Aging. 2023 Mar;3(3):275-296. Epub 2023 Feb 20 PubMed.

    . Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proc Natl Acad Sci U S A. 2023 Feb 14;120(7):e2215371120. Epub 2023 Feb 7 PubMed.

  3. Evidence indicates that APOE Christchurch plays a protective role by disrupting the connection between APOE and HSPG. This disruption, in turn, leads to a reduction in tau phosphorylation at S396—a significant and pathological phospho-tau site associated with AD.

    The diminished interaction between APOe4-HSPG, as demonstrated through the use of antibodies, correlates with decreased tau pathology. This suggests a dose-dependent relationship, where heterozygosis offers partial protection due to the absence of protection from the other allele. Given this context, the results Quiroz presented at AAIC align remarkable well and were not unexpected.

    Looking ahead, the prospect of a mechanism, such as an antibody, that can disrupt APOE-HGF links holds immense promise, particularly if proven safe and effective in clinical applications.

    In terms of future directions, it would be valuable to investigate similar links in APOE4 individuals of African descent. Understanding these connections is crucial, especially considering that the risk posed by APOE4 is not as pronounced in individuals of African ancestry compared to those of European descent.

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Mutations Citations

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

News Citations

  1. Tales of Traveling Tau: Is Transfer Between Neurons Normal?
  2. Can an ApoE Mutation Halt Alzheimer’s Disease?
  3. In Brain With Christchurch Mutation, More ApoE3 Means Fewer Tangles
  4. To Deliver Itself From Cell to Cell, Phospho-Tau Uses UPS

Research Models Citations

  1. APOE4 Targeted Replacement

Paper Citations

  1. . Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011 Mar;10(3):213-20. PubMed.
  2. . Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred. Alzheimers Dement. 2023 Sep;19(9):3835-3847. Epub 2023 Mar 23 PubMed.
  3. . Heterozygous APOE Christchurch in familial Alzheimer's disease without mutations in other Mendelian genes. Neuropathol Appl Neurobiol. 2021 Jun;47(4):579-582. Epub 2020 Nov 5 PubMed.
  4. . Apo E variants in patients with type III hyperlipoproteinemia. Atherosclerosis. 1996 Dec 20;127(2):273-82. PubMed.
  5. . Specific glycosaminoglycan chain length and sulfation patterns are required for cell uptake of tau versus α-synuclein and β-amyloid aggregates. J Biol Chem. 2018 Jul 6;293(27):10826-10840. Epub 2018 May 11 PubMed.
  6. . Neuron-specific apolipoprotein e4 proteolysis is associated with increased tau phosphorylation in brains of transgenic mice. J Neurosci. 2004 Mar 10;24(10):2527-34. PubMed.
  7. . Highly specific and selective anti-pS396-tau antibody C10.2 targets seeding-competent tau. Alzheimers Dement (N Y). 2018;4:521-534. Epub 2018 Oct 14 PubMed.

Further Reading