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Integrated multimodal cell atlas of Alzheimer’s disease

Gabitto, Mariano I., Travaglini, Kyle J., Rachleff, Victoria M., Kaplan, Eitan S., Long, Brian, Ariza, Jeanelle, Ding, Yi, Mahoney, Joseph T. +86 more·2023
DOI 10.1101/2023.05.08.539485

Preprint — published as 10.1038/s41593-024-01774-5 · Paper page

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Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org .

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  • AD DEGs were consistent with published results both for region-specific DEGs and for DEGs computed jointly over all regions for multiple AD variables, and were further corroborated by comparisons with various independent studies.

    “AD DEGs were consistent with published results both for region-specific DEGs and for DEGs computed jointly over all regions for multiple AD variables, and were further corroborated by comparisons with various independent studies11,12,15,19,47–53”

    From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [15]

    The Discussion (page unavailable) describes a “near complete lack of overlap” in gene-expression results across studies and says differences in brain regions preclude proper comparisons with this temporal-cortex analysis. It notes that some individual effects were recapitulated, but does not report the claimed consistency of region-specific and jointly computed, all-region AD DEGs across multiple variables. (LLM, conf=0.85)

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  • A comprehensive molecular characterization of region-specific differences in Alzheimer's disease is currently lacking.

    “Although some brain regions relevant to AD have been studied individually at scale or jointly in samples from a few individuals8–16, a comprehensive molecular characterization of region-specific differences in AD is currently lacking”

    From Single-cell multiregion dissection of Alzheimer’s disease (2024) · cites this paper as [15]

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Authors
Gabitto, M. I., Travaglini, K. J., Rachleff, V. M., Kaplan, E. S., Long, B., Ariza, J., Ding, Y., Mahoney, J. T., Dee, N., Goldy, J., Melief, E. J., Brouner, K., Campos, J., Campos, J., Carr, A. J., Casper, T., Chakrabarty, R., Clark, M., Cool, J., Valera Cuevas, N. J., Dalley, R., Darvas, M., Ding, S.-L., Dolbeare, T., Mac Donald, C. L., Egdorf, T., Esposito, L., Ferrer, R., Gala, R., Gary, A., Gloe, J., Guilford, N., Guzman, J., Hirschstein, D., Ho, W., Jarksy, T., Johansen, N., Kalmbach, B. E., Keene, L. M., Khawand, S., Kilgore, M., Kirkland, A., Kunst, M., Lee, B. R., Malone, J., Maltzer, Z., Martin, N., McCue, R., McMillen, D., Meyerdierks, E., Meyers, K. P., Mollenkopf, T., Montine, M., Nolan, A. L., Nyhus, J., Olsen, P. A., Pacleb, M., Peña, N., Pham, T., Pom, C. A., Postupna, N., Ruiz, A., Schantz, A. M., Shapovalova, N. V., Sorensen, S. A., Staats, B., Sullivan, M., Sunkin, S. M., Thompson, C., Tieu, M., Ting, J., Torkelson, A., Tran, T., Wang, M.-Q., Waters, J., Wilson, A. M., Haynor, D., Gatto, N., Jayadev, S., Mufti, S., Ng, L., Mukherjee, S., Crane, P. K., Latimer, C. S., Levi, B. P., Smith, K., Close, J. L., Miller, J. A., Hodge, R. D., Larson, E. B., Grabowski, T. J., Hawrylycz, M., Dirk Keene, C., & Lein, E. S.
ORCID
Publisher
openRxiv
Published
2023-05-09
DOI
10.1101/2023.05.08.539485
Cited by
27
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Type
Preprint

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