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.

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  1. This elegant study provides proof-of-principle evidence that the cascading component of the “amyloid cascade hypothesis” can be unhinged. The study shows that a lot of amyloid plaque accumulation does not necessarily lead to tau pathology and neurodegeneration. Namely, amyloid can be the smoke and not the fire.

    What is the fire that has been doused by the APOE3ch mutation? The study shows that the mutation prevents uptake by neurons. So, from a neuron’s perspective, ApoE Christchurch is equivalent to an APOE null. Here, three lines of evidence provide an answer. One, the recent Neuron paper by Tessier-Levigne’s group that shows that PS1 mutations cause endosomal traffic jams by intraneuronal accumulation of APP fragments (enlarged endosomes), which typically occurs by blocking endosomal recycling (Kwart et al., 2019). Two, papers by Joachim Herz, which show that APOE nulls accelerates endosomal recycling (e.g. Xian et al., 2019). Three, recent papers showing that blocking endosomal recycling increases tau pathology (Young et al., 2018) and the early manifestations of neurodegeneration (Temkin et al., 2017), independent of APP.

    Together, one can plausibly speculate that the APOE3ch mutation effectively normalizes the endosomal recycling defects caused by PS1 mutations, preventing tau pathology, neurodegeneration, and dementia, even with extracellular accumulation of amyloid plaques.

    References:

    Kwart D, Gregg A, Scheckel C, Murphy EA, Paquet D, Duffield M, Fak J, Olsen O, Darnell RB, Tessier-Lavigne M. A Large Panel of Isogenic APP and PSEN1 Mutant Human iPSC Neurons Reveals Shared Endosomal Abnormalities Mediated by APP β-CTFs, Not Aβ. Neuron. 2019 Oct 23;104(2):256-270.e5. Epub 2019 Aug 12 PubMed.

    Xian X, Pohlkamp T, Durakoglugil MS, Wong CH, Beck JK, Lane-Donovan C, Plattner F, Herz J. Reversal of ApoE4-induced recycling block as a novel prevention approach for Alzheimer's disease. Elife. 2018 Oct 30;7 PubMed.

    Young JE, Fong LK, Frankowski H, Petsko GA, Small SA, Goldstein LS. Stabilizing the Retromer Complex in a Human Stem Cell Model of Alzheimer's Disease Reduces TAU Phosphorylation Independently of Amyloid Precursor Protein. Stem Cell Reports. 2018 Mar 13;10(3):1046-1058. Epub 2018 Mar 1 PubMed.

    Temkin P, Morishita W, Goswami D, Arendt K, Chen L, Malenka R. The Retromer Supports AMPA Receptor Trafficking During LTP. Neuron. 2017 Apr 5;94(1):74-82.e5. PubMed.

    View all comments by Scott Small

  2. This paper is exciting and remarkable for various reasons.

    1. PET imaging showed very high amyloid load, but little tau pathology and glucose metabolism in the healthy range, supporting a greater role of tau than amyloid in cognitive injury in AD. The critical role of tau pathology in AD is particularly intriguing as ApoE, at least in microglia, was recently shown to play such a critical role in tauopathies by Shi et al. (2019). It is also remarkable that this protective effect was seen while the hippocampal volume was lower than the range seen in unimpaired carriers and more in the range seen in younger MCI carriers.
    2. This shows the importance and relevance of animal studies in which dominant familial AD mutations are being crossed with mice expressing different human ApoE isoforms for both early and late-onset AD. This result is consistent with the ability of ApoE3, but not ApoE4, to protect against Aβ-induced cognitive impairments without altering Aβ levels in mice overexpressing human APP with familial AD mutations and expressing human apoE3 and apoE4, as we reported in 2000 (Raber et al., 2000). Interestingly, combined expression of ApoE2 or ApoE4 with human APP-overexpressing mice revealed a several-fold greater load of Aβ plaques, insoluble brain Aβ levels, Aβ oligomers, and density of neuritic plaques, in APP/E2 than APP/E4 mice, while APP/E4 mice, but not APP/E2 mice, exhibited cognitive impairments (Pankiewicz  et al., 2014). 
    3. Although the paper refers to E3 as being neutral with regard to AD risk and phenotype, AD risk is a relative risk compared with that of E3 homozygote carriers. Especially as age is such a strong risk factor of AD, this is an important distinction.
    4. Lowering of ApoE expression is mentioned as a therapeutic option. While understandable based on the rescue of AD-like phenotypes in ApoE knockout mice expressing dominant familial AD mutations, there are ApoE isoform differences in ApoE levels; therefore a reduction in ApoE levels would be expected to have very different effects in carriers of the different genotypes.
    5. The case study describes an individual who had a history of statin use. Statins can affect cognition. Based on the contraindicating effects of statins on cognitive performance in humans (Schultz et al., 2018) and rodent studies (Villasana  et al., 2013), one wonders what the role of statins might have been in the observed cognitive effect in this case study.
    6. The authors show elegantly that the protective effect might involve reduced binding to HSPG and LDLR. Antibodies directed to the ApoE binding region to HSPG can mimic this effect, supporting ApoE as a therapeutic target. The preserved glucose metabolism and other pathways and mechanisms not assessed in this study might also play a role in this protection. Clearly, unbiased omics approached are warranted to identify all pathways underlying the differential effects of ApoE isoforms to facilitate the identification of diagnostic markers and the development of novel ApoE genotype-dependent therapeutic targets for AD and other age-related cognitive disorders.
    7. In summary, together with other reports, these data support that tau and ApoE might be especially good therapeutic targets in AD. This is definitely encouraging and exciting news for carriers of dominant AD mutations, such as those with mutations in PSEN1 and the AD research community. As the individual in the case report had the APOE3-Christchurch throughout life, and in the bigenic mice described earlier ApoE was also expressed throughout life, a pressing question is at what age/time point ApoE needs to be targeted in vivo to be protective against familial AD mutations like PSEN1.

    References:

    Shi Y, Manis M, Long J, Wang K, Sullivan PM, Remolina Serrano J, Hoyle R, Holtzman DM. Microglia drive APOE-dependent neurodegeneration in a tauopathy mouse model. J Exp Med. 2019 Nov 4;216(11):2546-2561. Epub 2019 Oct 10 PubMed.

    Raber J, Wong D, Yu GQ, Buttini M, Mahley RW, Pitas RE, Mucke L. Apolipoprotein E and cognitive performance. Nature. 2000 Mar 23;404(6776):352-4. PubMed.

    Pankiewicz JE, Guridi M, Kim J, Asuni AA, Sanchez S, Sullivan PM, Holtzman DM, Sadowski MJ. Blocking the apoE/Aβ interaction ameliorates Aβ-related pathology in APOE ε2 and ε4 targeted replacement Alzheimer model mice. Acta Neuropathol Commun. 2014 Jun 28;2:75. PubMed.

    Schultz BG, Patten DK, Berlau DJ. The role of statins in both cognitive impairment and protection against dementia: a tale of two mechanisms. Transl Neurodegener. 2018;7:5. Epub 2018 Feb 27 PubMed.

    Villasana LE, Rosenthal RA, Doctrow SR, Pfankuch T, Zuloaga DG, Garfinkel AM, Raber J. Effects of alpha-lipoic acid on associative and spatial memory of sham-irradiated and 56Fe-irradiated C57BL/6J male mice. Pharmacol Biochem Behav. 2013 Jan;103(3):487-93. Epub 2012 Oct 7 PubMed.

    View all comments by Jacob Raber

  3. The finding that this individual with a PS1 E280A mutation did not develop symptoms of cognitive impairment due to AD until her early 70s is very intriguing. The fact that she also has the ApoE3 Christchurch mutation, has very high amyloid deposition, but less tau pathology than one would expect brings up a lot of interesting possibilities.

    Since the person has a high amyloid load but less tau pathology, one wonders whether the effect of this ApoE variant is somehow decreasing the ability of ApoE to initiate a microglial-mediated inflammatory response to tau pathology. While this cannot be determined from the information presented in this individual at this point, we have observed in mouse models of tauopathy that ApoE2 results in less neuroinflammation in the brain than with ApoE4 and that ApoE plays a key role in the extent of tau pathology development and tau-mediated neurodegeneration. 

    The fact that ApoE3 Christchurch does not bind to the LDLR receptor or HSPG very well suggests several mechanisms to further explore regarding how ApoE may be modulating inflammation, tauopathy progression, and neurodegeneration.

    View all comments by David Holtzman

  4. While much of the genetic study of AD focuses on risk factors and causes of the disease, it is at least as important to identify corresponding protective factors. This study takes this approach by focusing on factors that protect/delay onset of disease by focusing on subjects who are protected from the AD presenilin mutation PSEN1/E280A. This led to the identification of a PSE1/E280A-expressing person who has two copies of the APOE3 Christchurch (R138S) mutation, and did not develop AD three decades after the expected disease onset.

    These findings have important AD pathology and ApoE-related therapeutic ramifications. Pathologically, the AD protective effects of R136S are associated with high Aimage plaque deposition but limited tau burden and neurodegeneration, suggesting that tau plays a more important role than Aβ in driving neurodegeneration.

    Therapeutically, these findings suggest that either genetic engineering of ApoE3 by mutating it to R136A and/or corresponding pharmacological approaches could potentially be used to counteract the effects of ApoE4. Such an approach is complimentary to the suggested treatment with the AD protective ApoE2.

    However, additional in vitro and in vivo studies are required for unraveling the mechanisms underlying the protective effect of ApoE3 Christchurch, such as why only the homozygous form of this molecule is protective.

    View all comments by Daniel Michaelson
    • User Profile Image John Hardy
      Institute of Neurology, UCL
    • Posted:

    One should always be aware that this is a single case report. It remains possible there are other reasons for this woman’s protection. However, there are precedents for other APOE variants that change risk of AD (Kamboh et al., 1999; Medway et al., 2014).

    A welcome consequence of this finding is that it may help bolster work on the mechanisms of APOE risk.

    References:

    Kamboh MI, Aston CE, Perez-Tur J, Kokmen E, Ferrell RE, Hardy J, DeKosky ST. A novel mutation in the apolipoprotein E gene (APOE*4 Pittsburgh) is associated with the risk of late-onset Alzheimer's disease. Neurosci Lett. 1999 Mar 26;263(2-3):129-32. PubMed.

    Medway CW, Abdul-Hay S, Mims T, Ma L, Bisceglio G, Zou F, Pankratz S, Sando SB, Aasly JO, Barcikowska M, Siuda J, Wszolek ZK, Ross OA, Carrasquillo M, Dickson DW, Graff-Radford N, Petersen RC, Ertekin-Taner N, Morgan K, Bu G, Younkin SG. ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer's disease. Mol Neurodegener. 2014 Mar 10;9:11. PubMed.

    View all comments by John Hardy

  6. Due to the known nature of their mutations, autosomal-dominant cohorts are powerful models to understand Alzheimer's pathobiology. Any time an ADAD carrier significantly deviates from their expected trajectory, there is the possibility to gain remarkable insight into protective mechanisms.

    The work by Arboleda-Velasquez and colleagues describes an ADAD mutation carrier who has maintained relatively preserved cognition beyond the expected age they would decline. This individual has high levels of Aβ measured with PET, but relatively low and atypical presentation of tau pathology.

    The association of preserved cognition and altered tau PET presentation with the APOE3ch mutation is fascinating. This result further emphasizes just how strongly tau pathology measured with PET is coupled to cognition. Exploring the impact this unique variant has on APOE functioning and its downstream consequences could open the door to new therapeutic approaches to treat the disease.

    View all comments by Brian Gordon

  7. We’d like to pick up on several of the interesting themes raised in these studies as based on our own work in this area.

    In a study of 1,557 brains in the NACC v 10 database (which we presented  at AAIC, 2019, and which we’ve now submitted) we found that E2 was associated with significantly reduced risk of neuritic plaques, diffuse plaques, and Braak stage. Odds Ratios in E2 v E3/E3 contrasts were around .50 for these three neuropathologies  and ORs in E2 v E4 contrasts were around .90, again for the three AD pathologies. In a mediation analysis we found that E2 had direct effects on tau Braak stage, as well as indirect effects via amyloid.

    However, there were sharp limits to E2 neuroprotection. When the E2 isoform was in the presence of the e4 isoform, i.e., in the E2/E4 genotype, E2 was not protective (see also Oveisgharan et al., 2018). This genotype “behaved” like other E4 carrier cases in terms of promoting pathology. Second and unexpectedly, E2 demonstrated trends for increases in FTLD related pathologies (including TDP-43 and select tauopathies).

    We’ve also conducted microarray transcriptional profiling studies in human postmortem neocortex to identify E2-associated pathways. We found that E2 was linked to increased expression of transcripts in an integrin/extracellular matrix KYOTO pathway (Conejero-Goldberg et al., 2014). The potential importance of this finding (and the HSPG binding related to the APOE mutation) is that matrix neurobiology might play a role in tau propagation as suggested by Lendvai et al., 2012. 

    References:

    Conejero-Goldberg C, Gomar JJ, Bobes-Bascaran T, Hyde TM, Kleinman JE, Herman MM, Chen S, Davies P, Goldberg TE. APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. Mol Psychiatry. 2014 Feb 4; PubMed.

    Lendvai D, Morawski M, Négyessy L, Gáti G, Jäger C, Baksa G, Glasz T, Attems J, Tanila H, Arendt T, Harkany T, Alpár A. Neurochemical mapping of the human hippocampus reveals perisynaptic matrix around functional synapses in Alzheimer's disease. Acta Neuropathol. 2012 Sep 9; PubMed.

    Oveisgharan S, Buchman AS, Yu L, Farfel J, Hachinski V, Gaiteri C, De Jager PL, Schneider JA, Bennett DA. APOE ε2ε4 genotype, incident AD and MCI, cognitive decline, and AD pathology in older adults. Neurology. 2018 Jun 12;90(24):e2127-e2134. Epub 2018 May 11 PubMed.

    View all comments by Terry Goldberg

  8. This is a very interesting finding, and parallels recent findings from the Kaczorowski lab (in mice). In our recent study, we took the approach to map modifiers that protect/delay onset of cognitive deficits in a genetically diverse population of transgenic mice carrying human familial AD mutations in APP and PSEN1 (Neuner et al., 2019). In this way, we identified genetic variants in the receptor binding domain of mouse Apoe associated with cognitive resilience (Figure 2). Specifically, strains of mice with ADAD mutations that were resilient to cognitive decline despite high amyloid burden had two copies of the C57BL/6J allele at the ApoE locus. Our results are consistent with the present report, that variants in ApoE modify the impact on ADAD mutations on cognition (even absent effects on amyloid).

    Perhaps more importantly, since most AD mouse models are maintained on a pure C57BL/6J background, we speculate that preclinical studies that failed to translate to human clinical trials may be due to studies being run in mice that harbor protective variants at ApoE that modify the impact of ADAD mutations.

    References:

    Neuner SM, Heuer SE, Huentelman MJ, O'Connell KM, Kaczorowski CC. Harnessing Genetic Complexity to Enhance Translatability of Alzheimer's Disease Mouse Models: A Path toward Precision Medicine. Neuron. 2019 Feb 6;101(3):399-411.e5. Epub 2018 Dec 27 PubMed.

    View all comments by Catherine Kaczorowski

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This paper appears in the following:

News

  1. Can an ApoE Mutation Halt Alzheimer’s Disease?
  2. Two ApoE Mutations Decrease Risk for Alzheimer's Disease
  3. Protective ApoE Variant Quells Interferon Responses in Tauopathy
  4. Can Heparin Delay Alzheimer’s Disease?

Mutations

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