Conserved cell‐type specific signature of resilience to Alzheimer’s disease nominates role for excitatory cortical neurons
Abstract
Background Alzheimer’s disease (AD), the leading cause of dementia, affects millions of people worldwide. With no disease‐modifying medication currently available, the human toll and economic costs are rising rapidly. Under current standards, a patient is diagnosed with AD when both cognitive decline and pathology (amyloid plaques and neurofibrillary tangles) are present. Remarkably, some individuals who have AD pathology remain cognitively normal. Uncovering factors that lead to “cognitive resilience” to AD is a promising path to create new targets for therapies. However, technical challenges discovering novel human resilience factors limit testing, validation, and nomination of novel drugs for AD. Method In this study, we use single‐nuclear transcriptional profiles of postmortem cortex from human individuals with high AD pathology who were either cognitively normal (resilient) or cognitively impaired (susceptible) at time of death, as well as mouse strains that parallel these differences in cognition with high amyloid. Result Our cross‐species discovery approach highlights a novel role for excitatory layer 4/5 cortical neurons in promoting cognitive resilience to AD, and nominates several resilience genes that include ATP1A1, GABRB1, PTK2, and ROCK2. Nominated resilience genes were tested for replication in orthogonal data sets and confirmed to be correlated with cognitive resilience. Additionally, we identified several potential mechanisms of resilience, including regulati…
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Omics and large cohort dataset analyses have identified potential cell signatures and molecular mechanisms of resilience, including high processing of energetic pathways involving mitochondrial metabolism and glycolysis, axonal and dendritic growth, and a general increase in protein processing.
“Advancements in omics and large cohort dataset analyses have enabled the identification of potential cell signatures and molecular mechanisms of resilience, including high processing of energetic pathways involving mitochondrial metabolism and glycolysis, axonal and dendritic growth, and a general increase in protein processing [11, 90, 91].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [91]
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Anderson, A. G., Rogers, B. B., Loupe, J. M., Rodriguez-Nunez, I., Roberts, S. C., White, L. M., Brazell, J. N., Bunney, W. E., Bunney, B. G., Watson, S. J., et al. (2023) · Cell Genomics · doi:10.1016/j.xgen.2023.100263 · Cited by 82 · see citing works
“PHF24 is a modulator of GABAB receptor activity 86 andwas recently identified in a study of AD resilience genes.(87) ADAMTS1 has been implicated in AD both biochemically(88) and genetically.”
BackgroundJury-Garfe, N., Redding-Ochoa, J., You, Y., Martínez, P., Karahan, H., Chimal-Juárez, E., Johnson, T. S., Zhang, J., Resnick, S., Kim, J., et al. (2024) · Acta Neuropathologica · doi:10.1007/s00401-024-02775-1 · Cited by 22 · see citing works
“…analyses have enabled the identification of potential cell signatures and molecular mechanisms of resilience, including high processing of energetic pathways involving mitochondrial metabolism and glycolysis, axonal and dendritic growth, and a general increase in protein processing [11, 90, 91].”
BackgroundSelf-citationRate of tau propagation is a heritable disease trait in genetically diverse mouse strains
Welikovitch, L. A., Dujardin, S., Dunn, A. R., Fernandes, A. R., Khasnavis, A., Chibnik, L. B., Kaczorowski, C. C., & Hyman, B. T. (2023) · iScience · doi:10.1016/j.isci.2023.105983 · Cited by 5 · see citing works
Self-citationJury, N., You, Y., Martínez, P., Redding‐Ochoa, J., Karahan, H., Johnson, T. S., Zhang, J., Kim, J., Troncoso, J. C., & Lasagna‐Reeves, C. A. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.07.27.550884 · Cited by 3 · see citing works
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- Authors
- Telpoukhovskaia, M., Hadad, N., Gurdon, B., Dai, M., Ouellette, A. R., Neuner, S., Dunn, A. R., Hansen, S. L., Wu, Y., Dumitrescu, L., O'Connell, K. M., Dammer, E. B., Seyfried, N. T., Muzumdar, S., Gillis, J., Robson, P., Zhang, J., Hohman, T. J., Philip, V. M., Menon, V., & Kaczorowski, C. C.
- Affiliations
- Jackson Laboratory (US)
- Icahn School of Medicine at Mount Sinai (US)
- Vanderbilt University (US)
- Vanderbilt University Medical Center (US)
- The Jackson Laboratory Bar Harbor ME USA
- Emory University (US)
- Cold Spring Harbor Cold Spring Harbor NY USA
- University of Toronto (CA)
- The Jackson Laboratory for Genomic Medicine (US)
- Columbia University Irving Medical Center (US)
- Tufts University (US)
- Corresponding author
- Telpoukhovskaia, Maria
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2022-12
- Volume
- 18
- Issue
- S4
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- OpenAlex
- W4312086286
- Cited by
- 4
- References
- 0
- Citations by year
- 2024: 1 · 2023: 3
- FWCI
- 0.62
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Alzheimer s & Dementia (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, cognitive resilience
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