Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.

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  1. In 2019, Arboleda-Velasquez et al. reported the remarkable case of a woman who harbored the highly penetrant PSEN1-E280A Alzheimer’s mutation, but was spared the disease for 28 years beyond the mean age of onset that occurred in the late 40s of the other family members within this very large kindred. The first notable feature in her evaluation came from brain imaging, which revealed extensive amyloid throughout her brain but quite limited tau pathology. This decoupling of amyloid deposition and tau pathology coincident with being spared from clinical dementia was confirmed when she came to autopsy (Sepulveda-Falla, et al., 2022). As predicted by the live-imaging studies, her brain was filled with amyloid plaques, but tau tangles were confined to the occipital cortex, a very unusual distribution. These observations suggested that the mechanism by which she was spared tau pathology was very likely related to inhibition of tau spread. In the Arboleda-Velasquez lab the search was on for a genetic explanation of her condition. They found an unusual variant in APOE (APOE3-R136S) first reported in Christchurch New Zealand and named for that city where any connection to Alzheimer’s disease was not even suspected.

    The original report made the case that APOE3-R136S was linked to this unusual phenotype, but it was widely acknowledged that the hypothesized link needed substantiation. Afterall, it was only one case, and it seemed that the expression of the clinical phenotype required APOE3-R136S homozygosity as observed in this subject. No other family member was known with APOE3-R136S homozygosity, but APOE3-R136S heterozygotes were known. One would like to see gene dosage effects to substantiate a claim of causation. Although the original cohort of APOE3-R136S carriers in the family did not show a delayed onset, a more recent re-evaluation of these cases and the discovery of additional heterozygotes suggested a modest delay in disease onset (personal communication, Arboleda-Velasquez). However, a more definitive link of the APOE variant to the phenotype did not exist until the publication of Nelson et al. 

    In this elegant study, Nelson and colleagues asked whether APOE3-R136S is protective against APOE4-driven deleterious effects observed in late-onset Alzheimer’s disease. They used a tauopathy mouse model and human iPSC-derived neurons carrying either homozygous or heterozygous APOE4-R136S in contrast to the proband patient, whose background genotype was APOE3. In these experiments, homozygosity protected against tau pathology and neuroinflammation, whereas heterozygosity only protected against the neuroinflammation.

    With greater confidence in the original observation concerning APOE3-R136S protection, the next steps require an understanding of the mechanism with a focus on how tau spread might occur. We and others have implicated HSPGs in tau spread (Rauch et al., 2018); however, most studies of tau spread do not address the physico-chemical state of the prion-like tau moiety that spreads. Hence, a better understanding of the precise uptake mechanism utilized for different tau structures that template misfolding in recipient cells is needed, whether uptake occurs through LRP1 (Rauch et al., 2020) or macropinocytosis (Diamond, 2023) or some other mechanism. Interestingly, many of the implicated molecules form a potential disease nexus that includes tau, HSPGs, LRP1, APOE, and amyloid, where interventions might be pinpointed.

    An open question is in which cell type the components of this complex operate. Nelson et al. raised some provocative effects of APOE3-R136S on protective astrocyte pools. A second paper by the Holtzman group nicely demonstrated the protective effects of APOE3-R136S. It located the functional significance of the variant on microglia using a humanized knock-in mouse expressing human APOE3-R136S crossed with an Aβ-depositing model (Chen et al., 2023). Insoluble tau fibrils derived from human AD brain extract were injected to assess Aβ-induced tau seeding and spreading. One surprise was that APOE3ch reduced overall amyloid plaque deposition as well as reducing peri-amyloid plaque tau seeding and spreading. Importantly, myeloid cell phagocytosis and degradation of human tau fibrils were enhanced in the presence of APOE3-R136S and was linked to reduced binding of APOE3-R136S to HSPG and LRP1 in vitro. Apparently, the relatively reduced binding of APOE3-R136S permitted increased uptake and degradation of tau fibrils in microglia.

    Finally, the extraordinary serendipity of this APOE protective variant deserves mention. Outside of the context of this very large PSEN1 E280A family, it is difficult to imagine that the variant would have been detected, particularly in the homozygous state. Unsurprisingly, this variant was not detected in a recent GWAS study (Cochran et al., 2023), and the distinct coalescent paths through which second variants enter families with rare large effect-size single gene mutations make GWAS detection of protective variants challenging. Nevertheless, the value of these large families for discovery is indisputable, and strategies for finding such protective variants should be developed (Kosik, 2023). 

    References:

    Sepulveda-Falla D, Sanchez JS, Almeida MC, Boassa D, Acosta-Uribe J, Vila-Castelar C, Ramirez-Gomez L, Baena A, Aguillon D, Villalba-Moreno ND, Littau JL, Villegas A, Beach TG, White CL 3rd, Ellisman M, Krasemann S, Glatzel M, Johnson KA, Sperling RA, Reiman EM, Arboleda-Velasquez JF, Kosik KS, Lopera F, Quiroz YT. 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.

    Nelson MR, Liu P, Agrawal A, Yip O, Blumenfeld J, Traglia M, Kim MJ, Koutsodendris N, Rao A, Grone B, Hao Y, Yoon SY, Xu Q, De Leon S, Choenyi T, Thomas R, Lopera F, Quiroz YT, Arboleda-Velasquez JF, Reiman EM, Mahley RW, Huang Y. The APOE-R136S mutation protects against APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Nat Neurosci. 2023 Dec;26(12):2104-2121. Epub 2023 Nov 13 PubMed.

    Rauch JN, Chen JJ, Sorum AW, Miller GM, Sharf T, See SK, Hsieh-Wilson LC, Kampmann M, Kosik KS. Tau Internalization is Regulated by 6-O Sulfation on Heparan Sulfate Proteoglycans (HSPGs). Sci Rep. 2018 Apr 23;8(1):6382. PubMed.

    Rauch JN, Luna G, Guzman E, Audouard M, Challis C, Sibih YE, Leshuk C, Hernandez I, Wegmann S, Hyman BT, Gradinaru V, Kampmann M, Kosik KS. LRP1 is a master regulator of tau uptake and spread. Nature. 2020 Apr;580(7803):381-385. PubMed.

    Diamond MI. Travels with tau prions. Cytoskeleton (Hoboken). 2024 Jan;81(1):83-88. Epub 2023 Nov 11 PubMed.

    Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread. Cell. 2024 Jan 18;187(2):428-445.e20. Epub 2023 Dec 11 PubMed.

    Cochran JN, Acosta-Uribe J, Esposito BT, Madrigal L, Aguillón D, Giraldo MM, Taylor JW, Bradley J, Fulton-Howard B, Andrews SJ, Acosta-Baena N, Alzate D, Garcia GP, Piedrahita F, Lopez HE, Anderson AG, Rodriguez-Nunez I, Roberts K, Dominantly Inherited Alzheimer Network, Absher D, Myers RM, Beecham GW, Reitz C, Rizzardi LF, Fernandez MV, Goate AM, Cruchaga C, Renton AE, Lopera F, Kosik KS. 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.

    Kosik KS. Search Strategies for Alzheimer Protector Genes. Ann Neurol. 2023 Oct;94(4):613-617. Epub 2023 Aug 26 PubMed.

    View all comments by Kenneth Kosik

  2. As demonstrated by our original APOE Christchurch publication (Arboleda-Velasquez et al., 2019), case reports can be exceptionally sensitive in uncovering new mechanisms, offering unique insights into biology, pathophysiology, and, in this instance, resistance within the context of a “genetics of health” paradigm.

    We should acknowledge the wealth of information that can emerge from n=1 studies. While there is a substantial need for extensive research to sway skeptics, these papers compellingly present evidence of the robust and multifaceted protective effects of APOE-Ch. It is worth noting the challenging path the original case report faced during peer review elsewhere before its eventual publication in Nature Medicine. At the time, it appeared that some reviewers were reluctant to disseminate these findings widely. Reflecting on this in hindsight, it is clear that the Christchurch case could have emerged in 2017 already.

    Discovering a protective effect, especially one with such significant impact leading to complete rescue, is both thrilling and humbling. It raises the question of whether the field should have pursued APOE as a therapeutic target in earnest much earlier. Compared to amyloid and tau, APOE has received less attention for therapeutics. To those considering our finding unexpected, the protective effects of APOE2 reported decades ago could have served as a notice. 

    Our original report showcased protection in the context of the severe E280A PSEN1 mutation in an APOE3/3 background. Therefore, Nelson et al. demonstrating robust protection of Christchurch in APOE4/E4 mice is highly encouraging, suggesting broad effects with potential implications for millions of APOE4 carriers at risk of or already affected by Alzheimer's.

    The work by Chen et al. delves into the impact of ApoECh on amyloid-related pathology, shedding light on an aspect of the original report that has been somewhat overlooked—the influence on amyloid. PET imaging of the case revealed extensive amyloid pathology, while the presence of tauopathy was lower than anticipated. Despite this, we conducted investigations into the potential impact of ApoECh on amyloid fibrillation and oligomerization, findings originally included in our report. These results, though somewhat divergent from the main narrative, have now undergone independent validation, reaffirming their significance. 

    Regarding the therapeutic potential of mimicking the Christchurch mutation, Nelson et al.'s results emphasize that APOE Christchurch can safeguard mice even when present in only one copy, highlighting the potential effectiveness of APOE-Ch based therapeutics. Chen et al.'s results suggest that ApoE-Ch's efficacy might stem from its influence on multiple mechanisms encompassing both amyloid and tau pathologies, not just from a single process. Instead, the protection could be the culmination of various effects on ApoE, pivotal in numerous stages of the condition. ApoE Christchurch's potency could be attributed to its dual impact, serving as a formidable combination in combating Alzheimer's.

    Marino and Perez et al. recently unveiled antibodies that emulate the impact of ApoE Christchurch. Their preclinical studies demonstrated efficacy in tauopathy models. The recent paper from the Holtzman group underscores the necessity of exploring the antibody's performance in amyloid models, highlighting a pivotal next step in understanding its broader therapeutic potential.

    The two recent papers shed light on the significance of diminished ApoE Christchurch interactions with heparan sulfate proteoglycans, a crucial element in its protective effect against Alzheimer's. While this concept was proposed in the original report, this new work supplies experimental evidence validating it. Moreover, Chen et al.'s findings implicate microglia in the mechanisms of protection, a facet not evident in previous analyses.

    References:

    Arboleda-Velasquez JF, Lopera F, O'Hare M, Delgado-Tirado S, Marino C, Chmielewska N, Saez-Torres KL, Amarnani D, Schultz AP, Sperling RA, Leyton-Cifuentes D, Chen K, Baena A, Aguillon D, Rios-Romenets S, Giraldo M, Guzmán-Vélez E, Norton DJ, Pardilla-Delgado E, Artola A, Sanchez JS, Acosta-Uribe J, Lalli M, Kosik KS, Huentelman MJ, Zetterberg H, Blennow K, Reiman RA, Luo J, Chen Y, Thiyyagura P, Su Y, Jun GR, Naymik M, Gai X, Bootwalla M, Ji J, Shen L, Miller JB, Kim LA, Tariot PN, Johnson KA, Reiman EM, Quiroz YT. 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.

    Marino C, Perez-Corredor P, O'Hare M, Heuer A, Chmielewska N, Gordon H, Chandrahas AS, Gonzalez-Buendia L, Delgado-Tirado S, Doan TH, Vanderleest TE, Arevalo-Alquichire S, Obar RA, Ortiz-Cordero C, Villegas A, Sepulveda-Falla D, Kim LA, Lopera F, Mahley R, Huang Y, Quiroz YT, Arboleda-Velasquez JF. APOE Christchurch-mimetic therapeutic antibody reduces APOE-mediated toxicity and tau phosphorylation. Alzheimers Dement. 2024 Feb;20(2):819-836. Epub 2023 Oct 4 PubMed.

    View all comments by Joseph Arboleda-Velasquez

  3. Protective missense variants in APOE—or those that change an amino acid in the protein sequence of APOE—are very rare. Nonetheless, they are incredibly important because understanding how they nearly abrogate an increased risk of AD may pave the way to new therapeutics against the devastating disease. This is why both Nelson et al. and Chen et al.—who probe protective mechanisms of the Christchurch variant—are exciting and impactful as we imagine new APOE-directed therapies for AD.

    Nelson et al., 2023, found that homozygous insertion of the R136S variant into APOE4 rescued APOE4-driven Tau pathology, neurodegeneration and neuroinflammation. Using the PS19 mouse tauopathy model alongside human iPSC-derived neurons strengthened their data, since both models showed convergent findings. It’s remarkable that insertion of the R136S variant into APOE4 decreased APOE4-linked neuronal uptake of tau, possibly through decreasing heparin binding. Could this, in part, explain why the individual who was a homozygous carrier of the E3-Christchurch variant showed minimal tau burden and was resistant to autosomal-dominant AD?

    The data inspire us toward specific modifications that may target heparin binding by APOE to protect against AD. Would this afforded protection need to be specific to APOE4-induced pathology? Maybe not, as the R136S variant was originally observed in the APOE3 gene. Perhaps its protective reach on tau is even further and broader than APOE4.

    Indeed, Chen et al., 2023, used a humanized knock-in of APOE3 with and without the Christchurch variant, in the absence and presence of an Aβ-depositing model (APP/PS1 mice). They studied how injected tau seeded and spread through mice brains with or without amyloid. They found that E3-Christchurch reduced plaque-associated tau pathology. In vitro they show that myeloid cells (precursors to microglia) expressing E3-Christchurch showed more tau fibril uptake and less of its release, suggesting that microglia might degrade more tau and also keep it from spreading.

    It’s particularly exciting that this study identifies and delineates an interaction between Aβ and tau—with Aβ either amplifying or enabling the E3-Christchurch-mediated protective effects on tau. This reminds us of the individual homozygous for E3-Christchurch carrying a gene for autosomal-dominant AD who had heavy amyloid but very little tau burden in her brain. How might Aβ “prime” the brain to facilitate a protective effect of the E3-Christchurch variant against tau?

    Both studies are important, well-executed, and provide deeper mechanistic insight into the E3-Christchurch variant. Future studies probing the role of E3-Christchurch on cognition and its substrates will be particularly illuminating. The protected individual with the E3-Christchurch variant had mild cognitive deficits despite carrying an autosomal-dominant AD mutation. Did the E3-Christchurch mutation directly or indirectly modify systems and circuits underlying learning and memory—leading to minimal clinical deficits?

    View all comments by Dena Dubal

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This paper appears in the following:

News

  1. APOE Christchurch Variant Tames Tangles and Gliosis in Mice

Mutations

  1. APOE R154S (Christchurch)