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.

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Comments

  1. This is a fascinating report of an individual harboring a rare combination of genetic mutations/variants (i.e., PSEN1 E280A + APOE3 Christchurch homozygosity). These genetic features together putatively resulted in a phenotype of extreme resilience to AD, as symptom onset in this patient was delayed by three decades compared to other PSEN1 E280A mutation carriers. The fact that such a case was not only identified, but also deeply phenotyped with multimodal longitudinal imaging and cognitive testing during life, as well as neuropathological and multi-omic analysis at death, is a testament to the impressive ongoing international collaborations between these research centers.

    While this study is chock-full of fascinating insights and analyses, there is an emphasis placed on the patient's striking occipital-predominant pattern of tau pathology. Both in vivo and neuropathological analyses confirm prominent occipital tau pathology with a relative sparing of frontal and medial parietal regions, which are brain areas that are typically compromised in PSEN1-E208A mutation carriers. The finding of primarily occipital tau expression in a resilient individual is reminiscent of our recent tau subtyping work, which described a “posterior” subtype with prominent occipital tau-PET binding and an attenuated rate of cognitive decline relative to the other tau subtypes (Vogel et al., 2021). 

    Future work will be needed to ascertain whether this similarity is a coincidence or if there is a consistent link between occipital phenotypes and slower clinical progression. The present finding potentially linking occipital CAA to occipital tau is in accordance with a recent postmortem analysis (Rabin et al., 2022) and represents a compelling lead worth pursuing further.

    However, the focus on the occipital predominance of tau pathology somewhat overshadows what, in our opinion, might be the main message of this work: This individual displayed reduced tau pathology relative to other PSEN-E208A carriers in almost every region. Close visual inspection of figures 1C and 2D seem to indicate that this is true both in terms of ante-mortem longitudinal tau PET accumulation and the total amount of tau pathology at death. This is in spite of having excessive and widespread brain amyloid deposition consistent with the genotype.

    This global resilience in the face of one of the most aggressive forms of AD underscores the apparently profound effect the APOE gene has on the time course of the AD pathophysiological process.

    This paper includes many other interesting analyses. We look forward to future work comparing results from the omics analyses to those of other individuals carrying different APOE haplotypes and causal AD mutations. We hope these analyses will ultimately help us achieve a better understanding of AD pathogenesis and may eventually lead to the identification of targets for boosting resilience against AD pathology.

    References:

    Vogel JW, Young AL, Oxtoby NP, Smith R, Ossenkoppele R, Strandberg OT, La Joie R, Aksman LM, Grothe MJ, Iturria-Medina Y, Alzheimer’s Disease Neuroimaging Initiative, Pontecorvo MJ, Devous MD, Rabinovici GD, Alexander DC, Lyoo CH, Evans AC, Hansson O. Four distinct trajectories of tau deposition identified in Alzheimer's disease. Nat Med. 2021 May;27(5):871-881. Epub 2021 Apr 29 PubMed.

    Rabin JS, Nichols E, La Joie R, Casaletto KB, Palta P, Dams-O'Connor K, Kumar RG, George KM, Satizabal CL, Schneider JA, Pa J, Brickman AM. Cerebral amyloid angiopathy interacts with neuritic amyloid plaques to promote tau and cognitive decline. Brain. 2022 Aug 27;145(8):2823-2833. PubMed.

    View all comments by Oskar Hansson

  2. This is a very important case report because it brings the neuropathological findings of a woman who had a PSEN1 mutation with extremely high presented and expected age of clinical onset in the fifth decade, who remained practically asymptomatic until her eighth decade of life. Previous work showed that a rare ApoE3 Christchurch variant could be protecting her against dementia. Now this careful neuropathological examination adds to the history by showing that, indeed, the levels of APOE in her brain are different from those in other members of this family who have come to autopsy, and by confirming an unexpected distribution of tau pathology.

    In 2020, my and Martin Kampmann’s labs at UCSF showed that RORB+ excitatory neurons have a higher vulnerability to AD pathology than other excitatory neurons. This work corroborates our findings and adds a spotlight on the importance of this neuronal class for AD pathogenesis.

    Postmortem examination remains the gold standard for diagnosing neurodegenerative diseases. Methodological improvements in the last years have greatly enhanced the potential and impact of research using the human postmortem brain. Hopefully studies like this will help to highlight the value of investing in autopsy programs in ADRD research.

    View all comments by Lea T. Grinberg

  3. This is an exciting follow-up report from the homozygote APOE3ch case reported in 2019 (Nov 2019 news). Notably, the authors highlight the histological differences in the pattern of tau accumulation and the single-cell gene-expression profiles along the cortical mantle compared to other AD forms.

    The study advances histological analyses to clarify how the Christchurch mutation might confer a protective effect against developing AD pathology—as the previous report had mainly focused on neuroimaging. The authors confirm that the APOE3ch case accumulates tau at a lower degree in most of the cerebral cortex, except for the occipital lobe, where they noted significant accumulations. These results align with recent findings (Jul 2022 news) in which we showed a tight spatial intersection between tau cortical spreading and the spatial gradient of APOE expression. As the occipital cortex displays low topological APOE expression, it is not surprising that the potential beneficial effect of the APOE Christchurch mutation is sparse in that cerebral region.

    Additionally, the authors highlight the selective vulnerability of excitatory RORB+ neurons, which significantly differ from expression profiles in other AD presentations.

    Understanding the mechanism by which APOE-specific mutations might affect genetic profiles and AD pathology in individual cases is essential to grasp the big picture of AD risk. Whereas the current results highlight the genetic co-expression between APOE and other genes in a cell-specific manner, it would be necessary to further evaluate such associations in APOE3 non-Christchurch participants.

    In summary, this study highlights the pathological implications of specific forms of APOE and opens new avenues for developing APOE-centered treatments in AD.

    View all comments by Jorge Sepulcre-Bernad

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This paper appears in the following:

News

  1. In Brain With Christchurch Mutation, More ApoE3 Means Fewer Tangles

Mutations

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