Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease
Open accessAbstract
Alzheimer's disease (AD) causes unrelenting, progressive cognitive impairments, but its course is heterogeneous, with a broad range of rates of cognitive decline 1. The spread of tau aggregates (neurofibrillary tangles) across the cerebral cortex parallels symptom severity 2,3. We hypothesized that the kinetics of tau spread may vary if the properties of the propagating tau proteins vary across individuals. We carried out biochemical, biophysical, MS and both cell- and animal-based-bioactivity assays to characterize tau in 32 patients with AD. We found striking patient-to-patient heterogeneity in the hyperphosphorylated species of soluble, oligomeric, seed-competent tau. Tau seeding activity correlates with the aggressiveness of the clinical disease, and some post-translational modification (PTM) sites appear to be associated with both enhanced seeding activity and worse clinical outcomes, whereas others are not. These data suggest that different individuals with 'typical' AD may have distinct biochemical features of tau. These data are consistent with the possibility that individuals with AD, much like people with cancer, may have multiple molecular drivers of an otherwise common phenotype, and emphasize the potential for personalized therapeutic approaches for slowing clinical progression of AD.
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Cases with most marked propagation potential had the fastest clinical course and characteristic patterns of post-translational modifications.
“In examining the clinical records, we found that those cases with the most marked propagation potential also had the fastest clinical course and had characteristic patterns of post-translational modifications (10, 11).”
From All the Tau We Cannot See (2023) · cites this paper as [10]
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Carosi, J. M., Denton, D., Kumar, S., & Sargeant, T. J. (2021) · Cell Death & Differentiation · doi:10.1038/s41418-020-00727-2 · Cited by 16 · see citing works
- Authors
- Dujardin, S., Commins, C., Lathuiliere, A., Beerepoot, P., Fernandes, A. R., Kamath, T. V., De Los Santos, M. B., Klickstein, N., Corjuc, D. L., Corjuc, B. T., Dooley, P. M., Viode, A., Oakley, D. H., Moore, B. D., Mullin, K., Jean-Gilles, D., Clark, R., Atchison, K., Moore, R., Chibnik, L. B., Tanzi, R. E., Frosch, M. P., Serrano-Pozo, A., Elwood, F., Steen, J. A., Kennedy, M. E., & Hyman, B. T.
- Affiliations
- Harvard University (US)
- Massachusetts General Hospital (US)
- Boston Children's Hospital (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Corresponding author
- Hyman, Bradley T.
- ORCID
- Venue
- Nature Medicine
- Published
- 2020-06-22
- Volume
- 26
- Issue
- 8
- Pages
- 1256-1263
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7603860
- OpenAlex
- W3035823399
- Cited by
- 438
- References
- 56
- Citations by year
- 2026: 47 · 2025: 69 · 2024: 58 · 2023: 66 · 2022: 81 · 2021: 84 · 2020: 31
- FWCI
- 39.55
- Type
- journal article
- Language
- en
- Update notices
- correction (2021-01-29)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- PubMed Central (acceptedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute on Aging (1RF1AG059789, 1RF1AG058674, 1P30AG062421, 1K08AG064039)
- JPB Foundation
- The Tau consortium
- Alzheimer’s Association (2018-AARF-591935)
- the Martin L. and Sylvia Seevak Hoffman Fellowship for Alzheimer’s research
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (P2ELP3_184403)
- Cure Alzheimer’s Fund
- 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, tau protein, hyperphosphorylated tau, post-translational modification, neurofibrillary tangles, clinical heterogeneity, cognitive decline, personalized treatment
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cerebral Cortex, Female, Humans, Male, Middle Aged, Phosphorylation, Severity of Illness Index, Neurofibrillary Tangles, tau Proteins, Age of Onset, Genetic Heterogeneity, Cognitive Dysfunction, Protein Aggregation, Pathological
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