Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases
Open accessAbstract
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects. Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
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Tau-mediated neurodegeneration arises from multiple pathological mechanisms including loss of normal function, gain of toxic function, aggregation, and mislocalization.
“Tau-mediated neurodegeneration arises from multiple pathological mechanisms, including loss of normal function [37–42], gain of toxic function [43–46], aggregation [44, 47–49], and mislocalization [50–52].”
From Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease (2026) · cites this paper as [42]
The Discussion describes impaired microtubule stabilization as a loss of function and increased, potentially toxic tau oligomers as a gain of function; it also discusses aggregation. These findings concern the p.A152T variant, and no passage in our copy supports mislocalization as a mechanism (searched: mislocalization of tau). (LLM, conf=0.86)
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- Authors
- Coppola, G., Chinnathambi, S., Lee, J. J., Dombroski, B. A., Baker, M. C., Soto-Ortolaza, A. I., Lee, S. E., Klein, E., Huang, A. Y., Sears, R., Lane, J. R., Karydas, A. M., Kenet, R. O., Biernat, J., Wang, L.-S., Cotman, C. W., DeCarli, C. S., Levey, A. I., Ringman, J. M., Mendez, M. F., Chui, H. C., Le Ber, I., Brice, A., Lupton, M. K., Preza, E., Lovestone, S., Powell, J., Graff-Radford, N., Petersen, R. C., Boeve, B. F., Lippa, C. F., Bigio, E. H., Mackenzie, I., Finger, E., Kertesz, A., Caselli, R. J., Gearing, M., Juncos, J. L., Ghetti, B., Spina, S., Bordelon, Y. M., Tourtellotte, W. W., Frosch, M. P., Vonsattel, J. P. G., Zarow, C., Beach, T. G., Albin, R. L., Lieberman, A. P., Lee, V. M., Trojanowski, J. Q., Van Deerlin, V. M., Bird, T. D., Galasko, D. R., Masliah, E., White, C. L., Troncoso, J. C., Hannequin, D., Boxer, A. L., Geschwind, M. D., Kumar, S., Mandelkow, E.-M., Wszolek, Z. K., Uitti, R. J., Dickson, D. W., Haines, J. L., Mayeux, R., Pericak-Vance, M. A., Farrer, L. A., Ross, O. A., Rademakers, R., Schellenberg, G. D., Miller, B. L., Mandelkow, E., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- University of Pennsylvania (US)
- Mayo Clinic (US)
- University of California, San Francisco (US)
- Cornell University (US)
- University of California, Irvine (US)
- University of California, Davis (US)
- Emory University (US)
- University of Southern California (US)
- Centre National de la Recherche Scientifique (FR)
- King's College London (GB)
- Drexel University (US)
- Northwestern University (US)
- University of British Columbia (CA)
- Western University (CA)
- Indiana University Bloomington (US)
- Harvard University (US)
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- The University of Texas Southwestern Medical Center (US)
- Johns Hopkins University (US)
- Vanderbilt University (US)
- Boston University (US)
- The University of Texas at Arlington (US)
- University of Pittsburgh (US)
- ORCID
- Coppola, Giovanni
- Chinnathambi, Subashchandrabose
- Dombroski, Beth A.
- Baker, Matt C.
- Lee, Suzee E.
- Klein, Eric
- Huang, Alden Y.
- Sears, Renee
- Lane, Jessica R.
- Kenet, Robert O.
- Biernat, Jacek
- Cotman, Carl W.
- DeCarli, Charles S.
- Levey, Allan I.
- Ringman, John M.
- Mendez, Mario F.
- Chui, Helena C.
- Brice, Alexis
- Lupton, Michelle K.
- Preza, Elisavet
- Lovestone, Simon
- Powell, John
- Petersen, Ronald C.
- Boeve, Bradley F.
- Lippa, Carol F.
- Bigio, Eileen H.
- Mackenzie, Ian
- Finger, Elizabeth
- Kertesz, Andrew
- Caselli, Richard J.
- Gearing, Marla
- Ghetti, Bernardino
- Spina, Salvatore
- Bordelon, Yvette M.
- Frosch, Matthew P.
- Beach, Thomas G.
- Albin, Roger L.
- Lieberman, Andrew P.
- Trojanowski, John Q.
- Bird, Thomas D.
- Galasko, Douglas R.
- Masliah, Eliezer
- White, Charles L.
- Troncoso, Juan C.
- Hannequin, Didier
- Boxer, Adam L.
- Kumar, Satish
- Mandelkow, Eva-Maria
- Uitti, Ryan J.
- Dickson, Dennis W.
- Haines, Jonathan L.
- Mayeux, Richard
- Farrer, Lindsay A.
- Ross, Owen A.
- Rademakers, Rosa
- Schellenberg, Gerard D.
- Miller, Bruce L.
- Geschwind, Daniel H.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-05-03
- Volume
- 21
- Issue
- 15
- Pages
- 3500-3512
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3392107
- OpenAlex
- W2097717784
- Cited by
- 240
- References
- 7
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 14 · 2023: 13 · 2022: 13 · 2021: 13 · 2020: 24 · 2019: 21 · 2018: 26 · 2017: 26 · 2016: 26 · 2015: 17 · 2014: 10 · 2013: 16 · 2012: 1
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Human Molecular Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Max Planck Digital Library (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- DZNE Pub (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Funders
- University of Pennsylvania
- Emory University (P50AG025688, AG025688)
- Northwestern University (AG13854)
- Arizona Department of Health Services (P30 AG19610, P50 AG025688, 05-901, U24 AG21886, 211002)
- Louisiana State University
- CurePSP
- Wellcome Trust (081864)
- National Institute for Health and Care Research
- European Commission (242257)
- Agence Nationale de la Recherche
- Arizona Biomedical Research Commission (P30 AG19610, 05–901, 211002)
- National Institutes of Health (05-901, UL1TR000150, 211002, AG023501, AG05142, AG13854, AG19610, AG025688)
- School of Medicine, Emory University
- Medical Research Council
- National Institute on Aging (211002, P30-AG-19610, P30AG010133, RC1AG035610, AG13854, AG 025688, AG 05142, U01AG016976, AG-19610, P50AG016570, P50-AG 16570, P50-AG05142, P01AG017586, R37AG011762, U01AG032984, U24 AG21886, AG023501, K23AG039414, R37 AG11762, 16570, P50AG005142, P30AG019610, R01AG031278, 05-901, P30AG013854, P50AG025688, R01AG026938, R01AG038791, AG038791, P01AG019724, U24AG021886, P50AG023501)
- National Institute of Mental Health (05-901, R01MH059566, R01MH059571, 211002, R01MH060879, R01MH059565, R01MH060870, R01MH061675, R01MH059586, R01MH059588, R01MH067257, P30 AG19610, R01MH059587)
- National Human Genome Research Institute (U01HG006375)
- National Institute of Neurological Disorders and Stroke (R01NS078086, R01NS065782, P50NS072187)
- National Center for Research Resources (UL1RR025741)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- MAPT, tau protein, rare variants, frontotemporal dementia, Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, microtubule binding, tau oligomers, neurodegenerative disease risk, genetic susceptibility
- MeSH terms
- Aged, Alzheimer Disease, Genotype, Haplotypes, Humans, Middle Aged, Risk, Genetic Variation, tau Proteins, Genetic Predisposition to Disease, Frontotemporal Dementia
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