Human brain aging heterogeneity observed from multi-region omics data reveals a subtype closely related to Alzheimer’s disease
Open accessAbstract
INTRODUCTION: The interconnection between brain aging and Alzheimer’s disease (AD) remain to be elucidated. METHODS: We investigated multi-omics (transcriptomics and proteomics) data from multiple brain regions (i.e., the hippocampus (HIPP), prefrontal cortex (PFC), and cerebellum (CRBL)) in cognitively normal individuals. RESULTS: We found that brain samples could be divided into ADL (AD-like) and NL (normal) subtypes which were correlated across brain regions. The differentially expressed genes in the ADL samples highly overlapped with AD gene signatures and the changes were consistent across brain regions (PFC and HIPP) in the multi-omics data. Intriguingly, the ADL subtype in PFC showed more differentially expressed genes than other brain regions, which could be explained by the baseline gene expression differences in the PFC NL samples. DISCUSSION: We conclude that brain aging heterogeneity widely exists, and our findings corroborate with the hypothesis that AD-related changes occur decades before the clinical manifestation of cognitive impairment in a sub-population.
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Adding neuroimaging data enriches stratification by revealing distinct progression patterns across biomarker-defined subgroups.
“The addition of neuroimaging data further enriches stratification efforts by revealing distinct progression patterns across biomarker-defined subgroups347,401,402.”
From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [402]
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Grubman, A., Chew, G., Ouyang, J. F., Sun, G., Choo, X. Y., McLean, C., Simmons, R. K., Buckberry, S., Vargas-Landin, D. B., Poppe, D., et al. (2019) · Nature Neuroscience · doi:10.1038/s41593-019-0539-4 · Cited by 956 · see citing works
Yankner, B. A., Lu, T., & Loerch, P. (2008) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathmechdis.2.010506.092044 · Cited by 677 · see citing works
Neff, R. A., Wang, M., Vatansever, S., Guo, L., Ming, C., Wang, Q., Wang, E., Horgusluoglu-Moloch, E., Song, W.-M., Li, A., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb5398 · Cited by 306 · cited 2× · see citing works
“We applied the hierarchical and two other clustering methods, namely, K-means and WSCNA to define the subtype structures [36].”
MethodSelf-citationWingo, A. P., Dammer, E. B., Breen, M. S., Logsdon, B. A., Duong, D. M., Troncosco, J. C., Thambisetty, M., Beach, T. G., Serrano, G. E., Reiman, E. M., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-09613-z · Cited by 211 · cited 5× · see citing works
“We selected 78 samples [19 normal (CDR = 0, braak score: bbscore ≤ 3, CERAD = “NL”) and 59 LOAD (CDR ≥ 1, bbscore ≥ 5, CERAD = “definite AD”)] to define AD signature from this dataset using the same pipeline in our previous study [5].”
BackgroundMethodResultInfluentialCortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons
Yu, L., Tasaki, S., Schneider, J. A., Arfanakis, K., Duong, D. M., Wingo, A. P., Wingo, T. S., Kearns, N., Thatcher, G. R. J., Seyfried, N. T., et al. (2020) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.1807 · Cited by 127 · see citing works
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Ren, F., Wei, J., Chen, Q., Hu, M., Yu, L., Mi, J., Zhou, X., Qin, D., Wu, J., & Wu, A. (2025) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2025.07.030 · Cited by 97 · see citing works
- Authors
- Peng, S., Wang, E., Wang, M., Wang, X., Yu, K., Fu, Y., Poudel, S., Ho, L., Narayan, S., Huffman, D. M., Gaiteri, C., Bennet, D. A., Ehrlich, M. E., Haroutunian, V., Peng, J., Zhang, B., & Tu, Z.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- St. Jude Children's Research Hospital (US)
- Albert Einstein College of Medicine (US)
- SUNY Upstate Medical University (US)
- Rush University Medical Center (US)
- James J. Peters VA Medical Center (US)
- Corresponding author
- Tu, Zhidong
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2024-03-05
- OpenAlex
- W4392454005
- Cited by
- 1
- References
- 5
- Citations by year
- 2025: 1
- Type
- posted content
- Language
- en
- Open access
- green
- dx.doi.org
- Licence
- cc-by-nc-nd
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG017917, P30 AG72975, P30-AG 10161, R01‐AG17917, R01 AG15819, U01‐AG61356, U01AG046152, R01AG015819, P30AG010161, U01AG061356, U01‐AG46152, P30AG072975)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- brain aging, Alzheimer's disease, aging heterogeneity, prefrontal cortex, hippocampus, cerebellum, transcriptomics, proteomics, multi-omics integration, differentially expressed genes, cognitively normal individuals, early biomarkers, gene expression signatures
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