Green GS, Fujita M, Yang HS, Taga M, Cain A, McCabe C, Comandante-Lou N, White CC, Schmidtner AK, Zeng L, Sigalov A, Wang Y, Regev A, Klein HU, Menon V, Bennett DA, Habib N, De Jager PL. Cellular communities reveal trajectories of brain ageing and Alzheimer's disease. Nature. 2024 Sep;633(8030):634-645. Epub 2024 Aug 28 PubMed.
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Washington University in St. Louis, School of Medicine
This fascinating and timely study really deepens our understanding of cellular dynamics in aging and Alzheimer’s disease. The use of single-cell RNA-Seq on such a large cohort of brains is impressive and allows for an unprecedented look at the specific microglial and astrocyte states involved in disease progression.
The discovery of distinct AD-related and -resilient aging trajectories is particularly intriguing and aligns with the idea that glial cells are key players in both the onset and progression of neurodegeneration. The identification of these specific phenotypes within the AD trajectory opens new possibilities for targeted therapeutic interventions that could modify disease progression by focusing on these glial populations at different stages.
This study is an important step forward in understanding the cellular changes that underlie Alzheimer’s.
View all comments by Jonathan KipnisGenentech, Inc.
This paper is a significant achievement. Along with recent datasets from the Allen Brain Institute and MIT, it represents the latest generation of Alzheimer's nuc-Seq atlases notable for the large number of samples and cells analyzed. The insights emerging at this scale, which were not evident in the previous generation of smaller studies, include more robust statistical findings, finer resolution on cell type clusters, and, importantly, the ability to look at more subtypes of patients, and stratify patients along disease trajectories.
For this trajectory analysis, Green et al. present BEYOND, a simple, clever, new method based on the composition of the various cell clusters within each sample. Because of the diversity and size of their dataset, they were able to describe two aging trajectories. The first one was associated with Alzheimer's pathology; it includes glial activation and the development of Aβ and tau pathology.
Surprisingly, and quite interestingly, they also identified an "alternative brain aging" trajectory characterized by a different cellular composition, lack of classical Alzheimer's pathology, and, importantly, slower cognitive decline. They validated the existence of this alternative pathway using a bulk RNA-Seq dataset. Further study of this trajectory may yield new biology that could help explain healthy brain aging.
References:
Gabitto MI, Travaglini KJ, Rachleff VM, Kaplan ES, Long B, Ariza J, Ding Y, Mahoney JT, Dee N, Goldy J, Melief EJ, Agrawal A, Kana O, Zhen X, Barlow ST, Brouner K, Campos J, Campos J, Carr AJ, Casper T, Chakrabarty R, Clark M, Cool J, Dalley R, Darvas M, Ding S-L, Dolbeare T, Egdorf T, Esposito L, Ferrer R, Fleckenstein LE, Gala R, Gary A, Gelfand E, Gloe J, Guilford N, Guzman J, Hirschstein D, Ho W, Hupp M, Jarksy T, Johansen N, Kalmbach BE, Keene LM, Khawand S, Kilgore M, Kirkla. Integrated multimodal cell atlas of Alzheimer's disease. 2024 Feb 15 10.1101/2023.05.08.539485 (version 3) bioRxiv.
Mathys H, Boix CA, Akay LA, Xia Z, Davila-Velderrain J, Ng AP, Jiang X, Abdelhady G, Galani K, Mantero J, Band N, James BT, Babu S, Galiana-Melendez F, Louderback K, Prokopenko D, Tanzi RE, Bennett DA, Tsai LH, Kellis M. Single-cell multiregion dissection of Alzheimer's disease. Nature. 2024 Aug;632(8026):858-868. Epub 2024 Jul 24 PubMed.
View all comments by Brad FriedmanAllen Institute for Brain Science
This is one of four contemporary large-scale efforts to apply single-cell profiling to the neocortex in a cohort of AD donors. The other three are our own (coming out in November in Nature Neuroscience), Li-Huei Tsai’s in Cell last year, and Evan Macosko’s in the same Cell issue (Gazestani et al., 2023; Mathys et al., 2023).
All four identified known increases in disease-associated microglia and astrocytes, though with increased molecular resolution. And all point to unexpected vulnerability in inhibitory neurons. Sst- and Lamp5-positive cells were more consistently identified; though there were hints of this since the 1980s!
They also all try to assess AD as a continuum/trajectory, either using quantitative measures of neuropathology, or, in the case of Green et al., using the cellular proportions themselves. We mapped these and other AD datasets to a common cellular taxonomy to compare results more easily across studies.
The big limitation of all our studies is that they are descriptive. We can point to associations between molecular and cellular changes and AD (and even order these changes with trajectories), but we cannot say anything about what causes what. Green et al.’s big advance is applying mediation modeling to overcome this.
This proposes a hypothesis about how molecular and cellular changes relate to one another and tests that against the data. In Green et al.’s case, plaques trigger microglia to adopt an inflammatory state, which triggers p-tau deposition, which triggers astrocytes to adopt a reactive state, which triggers neurodegeneration. Because more variance was explained by this “mediation,” it supports this chain of events. It’s a chain the field expected, but a good proof of principle for the technique, which can now be applied to other hypotheses for AD.
References:
Gazestani V, Kamath T, Nadaf NM, Dougalis A, Burris SJ, Rooney B, Junkkari A, Vanderburg C, Pelkonen A, Gomez-Budia M, Välimäki NN, Rauramaa T, Therrien M, Koivisto AM, Tegtmeyer M, Herukka SK, Abdulraouf A, Marsh SE, Hiltunen M, Nehme R, Malm T, Stevens B, Leinonen V, Macosko EZ. Early Alzheimer's disease pathology in human cortex involves transient cell states. Cell. 2023 Sep 28;186(20):4438-4453.e23. PubMed.
Mathys H, Peng Z, Boix CA, Victor MB, Leary N, Babu S, Abdelhady G, Jiang X, Ng AP, Ghafari K, Kunisky AK, Mantero J, Galani K, Lohia VN, Fortier GE, Lotfi Y, Ivey J, Brown HP, Patel PR, Chakraborty N, Beaudway JI, Imhoff EJ, Keeler CF, McChesney MM, Patel HH, Patel SP, Thai MT, Bennett DA, Kellis M, Tsai LH. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology. Cell. 2023 Sep 28;186(20):4365-4385.e27. PubMed.
View all comments by Kyle TravagliniBroad Institute of MIT and Harvard
Broad Institute
In this paper, Green et al. use single-cell analyses of 1.6 million cells and the BEYOND framework, along with mediation modeling, to explore the cellular dynamics of AD. They attempt to distinguish the progression to AD (referred to as "prAD") from alternative brain aging (ABA) and reconstruct the possible sequence of events, more specifically to astrocytic and microglial roles in the causal chain of the disease. One strength of this study is its exploration of cellular disease progression as a result of coordinated cellular communities rather than focusing solely on individual subpopulations or molecular changes. Additionally, the study benefits from a relatively large sample size, replication in bulk-inferred samples, and the use of multiple quantitative AD-related traits instead of focusing on a single trait.
The disease-associated subpopulations of microglia that the authors define are molecularly consistent with definitions in our recent meta-analysis (Gazestani et al., 2023). The authors further extend the work by constructing an AD cascade model, placing Mic.12 (our GPNMB_EYA2 subpopulation) upstream of Aβ and Mic.13 (our LPL_CD83 subpopulation) downstream of Aβ, but upstream of tau and cognitive decline. It is interesting to see that the trajectories of cellular change reported, and pseudotime assignment, were robust to different algorithms, enabling the use of similar frameworks to understand molecular processes in other datasets.
The biggest challenge of this work—unavoidable in a postmortem study design—is the need to retrospectively predict temporal dynamics based upon a single endpoint. It will be interesting and important to see if these trajectories are recapitulated in animal models—where sampling can occur longitudinally across the model disease course—or in humans, either through serial PET imaging, or in rare human brain biopsy specimens (where patients can be followed longitudinally after sampling). Future studies should also explore neuronal subpopulations and molecular changes (genes and eQTLs) in-depth, where aging and tissue collection methods play a significant role.
References:
Gazestani V, Kamath T, Nadaf NM, Dougalis A, Burris SJ, Rooney B, Junkkari A, Vanderburg C, Pelkonen A, Gomez-Budia M, Välimäki NN, Rauramaa T, Therrien M, Koivisto AM, Tegtmeyer M, Herukka SK, Abdulraouf A, Marsh SE, Hiltunen M, Nehme R, Malm T, Stevens B, Leinonen V, Macosko EZ. Early Alzheimer's disease pathology in human cortex involves transient cell states. Cell. 2023 Sep 28;186(20):4438-4453.e23. PubMed.
View all comments by Vishal SarsaniMake a Comment
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