ArticleHuman molecular genetics2012
Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases.
Article in Human molecular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT01804452 (Observational Longitudinal Study of Magnetic Resonance Imaging, Specimen Biomarkers, and Clinical Progression in Progressive Supranuclear Palsy and Corticobasal Degeneration), which is not on this map. Cited by 147 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Observational Longitudinal Study of Magnetic Resonance Imaging, Specimen Biomarkers, and Clinical Progression in Progressive Supranuclear Palsy and Corticobasal Degeneration
Who cites it
147 citing papers in PubMed, 234 citations in OpenAlex.
- Fyn kinase: a key mechanistic regulator and therapeutic target in tauopathy and neurodegenerative diseases.Translational neurodegeneration · 2026Review
- Amyloid exacerbates tau and alpha-synuclein pathologies, behavioral impairments, and neuroinflammation in a mixed dementia model.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease.bioRxiv : the preprint server for biology · 2026Article
- Evaluating MAPT p.A152T as a risk factor for the 3R tauopathy Pick's disease.Brain communications · 2026Article
- Alzheimer's disease: genetic background in the era of next-generation sequencing technologies.Brain communications · 2026Review
- Tau protein: Physiological functions and multifaceted roles in neurodegenerative and psychiatric disorders.Genomic psychiatry : advancing science from genes to society · 2025Article
- Article
- Gene Expression Signatures of Immaturity, Decreased pH, and Neural Hyperexcitation in the Hippocampus of Alzheimer's Disease Model Mice.Neuropsychopharmacology reports · 2025Article
- Profiling the impact of different tau species on glial cell biology.Frontiers in cell and developmental biology · 2025Article
- Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress.Nature neuroscience · 2024Article
- MAPT mutations associated with familial tauopathies lead to formation of conformationally distinct oligomers that have cross-seeding ability.Protein science : a publication of the Protein Society · 2024Article
- Tau in neurodegenerative diseases: molecular mechanisms, biomarkers, and therapeutic strategies.Translational neurodegeneration · 2024Review
- Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases.Molecular neurodegeneration · 2024Review
- Peripheral GFAP and NfL as early biomarkers for dementia: longitudinal insights from the UK Biobank.BMC medicine · 2024Article
- Disentangling tau: One protein, many therapeutic approaches.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2024Review
- Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses.Aging and disease · 2024Review
- The MAPT p.E342K and p.R406W mutations are associated with progressive supranuclear palsy with atypical features.Parkinsonism & related disorders · 2024Article
- Molecular Mechanism of Tau Misfolding and Aggregation: Insights from Molecular Dynamics Simulation.Current medicinal chemistry · 2024Review
- A novelFrontiers in neurology · 2024Article
- Alzheimer's Disease: Models and Molecular Mechanisms Informing Disease and Treatments.Bioengineering (Basel, Switzerland) · 2024Review
87 more citing papers are in PubMed but not listed here.
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Authors and funding
75 authors at 20 institutions in 4 countries.
Funding
Abstract
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.