Overview

Pathogenicity: Frontotemporal Dementia Spectrum : Uncertain Significance, Alzheimer's Disease : Not Classified, Parkinson's Disease : Not Classified, Dementia with Lewy Bodies : Not Classified, Multiple System Atrophy : Not Classified
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PP1, PP3, BS1, BS2, BP5
Clinical Phenotype Studied: Alzheimer's Disease, CBS, Corticobasal Degeneration, Dementia with Lewy Bodies, Frontotemporal Dementia, Progressive Supranuclear Palsy, pallido-nigro-luysial atrophy variant of progressive supranuclear palsy, PPA, nfvPPA, bvFTD, Parkinson's Disease, Multiple System Atrophy, Parkinson's Disease Dementia
Position: (GRCh38/hg38):Chr17:45991484 G>A
Position: (GRCh37/hg19):Chr17:44068850 G>A
Transcript: NM_005910; ENST00000351559
dbSNP ID: rs143624519
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to ACC
Reference Isoform: Tau Isoform Tau-F (441 aa)
Genomic Region: Exon 7
Research Models: 3

Findings

This variant may be a risk modifier for some neurodegenerative conditions, particularly diseases in the frontotemporal dementia (FTD) spectrum. The variant has also been studied in the context of Alzheimer's disease (AD), Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA).

The earliest report of A152T was in a 63-year-old man with an unclassified tauopathy characterized by progressive dementia with prominent speech impairment (Kovacs et al., 2011). His condition deteriorated over five years, and he developed myoclonus at end stage. His father reportedly had similar symptoms, although segregation with disease could not be determined.

Since then, several case studies of carriers diagnosed with diseases in the FTD spectrum, including bvFTD (Lee et al., 2013), progressive supranuclear palsy (PSP) (Lee et al., 2013), the non-fluent variant of primary progressive aphasia (nfvPPA) (Lee et al., 2013), corticobasal syndrome (CBS) (Lee et al., 2013), corticobasal degeneration (CBD) (Kara et al., 2012), pallido-nigro-luysial atrophy variant of PSP (PSP-PNLA) (Kara et al., 2012; Graff-Radford et al., 2013), and atypical tauopathy (Kara et al., 2012), have been reported. A152T carriers with Parkinson’s disease (Schulte et al., 2015), Parkinson's disease with dementia (Kara et al., 2012; Schulte et al., 2015), and Alzheimer's disease (Jin et al., 2012; Lee et al., 2013; Sala Frigerio et al., 2015; Barber et al., 2017), have also been described. Moreover, a study that sequenced AD patients with extreme biomarker levels in cerebrospinal fluid, reported five heterozygous carriers of the A152T mutation, one of whom had extremely low levels of Aβ42 (Benitez et al., 2013).

Evidence for co-segregation with disease in families is limited. In one family, the proband was diagnosed with AD with an age at onset of 57.5 years and the variant was absent from an unaffected sibling aged 69 years (Jin et al., 2012). In another family with PSP-PNLA, A152T was present in the proband and two sisters with some symptoms, and was absent from an unaffected sister (Kara et al., 2012). However, information on the affected sisters’ clinical phenotypes and ages at onset were not reported, nor was the age of the unaffected non-carrier.

Of note, in several families of a Basque population, A152T co-segregated with the pathogenic GRN mutation IVS6-1G>A (Pastor et al., 2015) which appeared to be responsible for most of the observed FTD phenotypes (Moreno et al., 2017). Twenty-one symptomatic patients who carried both mutations had clinical and neuropathological outcomes generally similar to individuals who carried just the GRN IVS6-1G>A mutation. Also, five individuals carrying only the A152T variant were identified, all asymptomatic, including three in their 80s, one in his 50s, and one in her early 40s. Robust tau pathology, atypical for GRN mutation carriers, was observed in half of the carriers of both mutations, however, which may reflect a contribution of A152T to pathology.

Cohort association studies have yielded mixed results, with several suggesting increased risk for diseases in the FTD spectrum (see table below). For example, a study that combined several independent cohort series from the U.S. and U.K., including 15,369 individuals, the A152T variant was associated with an elevated risk of FTD syndromes (Coppola et al., 2012). Similar results were obtained when only individuals of self-reported Caucasian ancestry were included in the analysis. Subsequent studies with smaller cohorts identified significant associations in some cases—FTD (Lopez et al., 2017), PSP syndrome (Lopez et al., 2017), and PPA (Ramos et al., 2018 30599136)—but not in others—FTD (Pastor et al., 2015) and CBS (Lopez et al., 2017).

Evidence for associations of A152T with neurodegenerative diseases outside the FTD spectrum has also not always been consistent and is more limited. Although Coppola and colleagues’ study found a significant association with AD (Coppola et al., 2012), others (Lopez et al., 2017; Benitez et al., 2013), including a study with more AD patients (Pastor et al., 2015), did not. One study reported associations with LBD and DLB (Labbé et al., 2015), while analyses of PD (Labbé et al., 2015; Pastor et al., 2015) and MSA (Labbé et al., 2015) failed to yield significant results. The association for a combined cohort of patients having either PD or Lewy body dementia (LBD) did not reach statistical significance (Coppola et al., 2012).

Although rare, the mutation is found at a higher frequency than most pathogenic mutations in public variant databases. In the gnomAD database, the global frequency was 0.0027 (gnomAD v.4.1.0, July 2025), with higher frequencies in some groups, such as non-Finnish Europeans (0.0032), and lower frequencies in others, such as East Asians (0.000089) and Ashkenazi Jews (0 carriers in 29,608 individuals). Of note, in HEX, a database of variants from Caucasian individuals age 60 or older who did not have a neurodegenerative disease diagnosis or disease-associated neuropathology at the time of death, the frequency was 0.001 (HEX, July 2025).

Neuropathology
Reflecting the variable clinical presentations of the A152T variant, neuropathological findings are similarly diverse. Abnormal tau accumulation appears to be the unifying feature in all cases for which postmortem findings are available. For instance, tau inclusions have been observed in von Economo neurons and fork cells of the frontoinsular and anterior cingulate cortices in two A152T carriers, one patient with PSP and another patient with corticobasal degeneration (Lin et al., 2019 31640778). Moreover, in a patient with PEP later reclassified as atypical tauopathy, neuropathological analysis revealed atypical tauopathy with neurofibrillary tangles, a mix of three-repeat and four-repeat tau isoforms, and a lack of TDP-43 pathology (Kara et al., 2012). In the same report, another individual with idiopathic PD plus dementia exhibited a mix of neurofibrillary tangles and Lewy bodies, consistent with his diagnosis (Kara et al., 2012). In other cases, the pathology is was indicative of PNLA, with prominent neuronal loss and tau deposition in the globus pallidus, subthalamic nucleus, and substantia nigra with lower levels of pathology in the motor cortex, striatum, pontine nuclei, and cerebellum (Kara et al., 2012; Graff-Radford et al., 2013).

Biological Effect

Tau aggregation
The effects of A152T on tau aggregation vary between model systems. An in vitro study found that the mutant protein aggregates with lower efficiency than wild-type protein but is more prone to oligomer formation (Coppola et al., 2012). Similarly, in a C. elegans model expressing A152T tau, soluble oligomeric tau was observed, but insoluble tau aggregates were not detected (Pir et al., 2016). Moreover, fractionation experiments in transgenic A152T mice revealed accumulation of soluble and oligomeric tau rather than insoluble tau (Maeda et al., 2016). A152T tau also remained soluble in an adeno-associated viral (AAV)  mouse model  in which mutant tau vectors were injected into the lateral ventricles (TauA152T-AAV; Carlomagno et al., 2019). Neural progenitor cells from induced pluripotent stem cells (iPSCs) of A152T mutation carriers, including one patient with PSP and one asymptomatic carrier, exhibited increased accumulation of total and phosphorylated tau (Silva et al., 2016). While fractionation analysis showed that A152T tau was less soluble than control tau via western blot, no tau aggregation was observed by immunofluorescence within cells.

In contrast, another transgenic mouse model expressing A152T tau exhibited fully developed neurofibrillary tangles throughout the nervous system in an age-dependent manner (Sydow et al., 2016), suggesting that insoluble tau may accumulate over time. Tau in these mice was also found to adopt a pathological conformation, as detected by the Alz-50 antibody (Sydow et al., 2016; Decker et al., 2016). Similarly, tau aggregation was observed in a transgenic zebrafish model expressing human A152T tau, with sarkosyl-insoluble tau detected in mutant fish but not in fish expressing human wild-type tau (Lopez et al., 2017). The mutant fish also exhibited positive immunostaining for MC1, which is a marker of conformational change in tau. Interestingly, however, minimal MC1 immunoreactivity was observed in mice expressing A152T tau via AAV vectors (Carlomagno et al., 2019).

To further elucidate the conformational properties of A152T tau, mutant oligomers were studied in vitro and found to have distinct properties from wild-type oligomers and oligomers generated from other MAPT mutations, such as less helical structure than their monomers and reduced thioflavin-T fluorescence when cross-seeded with wild-type oligomers, indicating reduced amyloid-like content (Bhopatkar et al., 2024).

Tau phosphorylation
In transgenic mice expressing full-length human A152T tau compared to non-transgenic control littermates, tau hyperphosphorylation in the CA3 region was prominent at multiple phosphorylation sites, including Ser235, Ser202, Ser396/Ser404, and Ser202/Thr205 (Sydow et al., 2016; Decker et al., 2016). In addition, in the aforementioned AAV model, mice expressing A152T were found to have hyperphosphorylation at the neighboring T153 residue (Carlomagno et al., 2019). Notably, this finding was also confirmed in postmortem tissue from A152T carriers with AD, PSP, LBD, corticobasal degeneration, and FTD with motor neuron disease. However, in another transgenic mouse model expressing human A152T tau, phosphorylation of tau was similarly higher compared to non-transgenic mice, but levels were comparable to those in mice transgenically expressing wild-type human tau, indicating that a greater propensity to phosphorylation may occur for human versus mouse tau or to tau that is overexpressed (Maeda et al., 2016).

In addition to hyperphosphorylation, A152T may create a novel phosphorylation site at threonine 152. This was supported by mass spectrometry studies in mutant C. elegans samples and in mouse brain tissue (Butler et al., 2018). However, in human iPSC-derived neurons from an A152T carrier, mass spectrometry failed to show a new phosphorylation site (Silva et al., 2016).

Microtubule abnormalities
The A152Tis variant impairs tau's ability to bind microtubules in vitro, resulting in less efficient microtubule assembly and impaired microtubule stability (Coppola et al., 2012). In mouse primary cortical neurons, A152T tau fused to Dendra2 (a photoconvertible fluorescent protein) diffused more rapidly from the axon through the axon initial segment into the somatodendritic compartment than wild-type tau, suggesting less effective microtubule binding and increased axon initial segment leakage (Butler et al., 2018). Similarly, in A152T transgenic mice, tau was mislocalized to the somatodendritic compartment in cortical, hippocampal, spinal, and cerebellar neurons (Sydow et al., 2016; Decker et al., 2016)—a finding that was also observed in A152T-expressing human iPSC-derived neurons (Silva et al., 2016).

Neuronal loss
Neuronal loss is observed across model systems expressing A152T. For instance, age-dependent neuronal loss was found in transgenic mice expressing A152T tau in a region-specific manner, with losses observed in the dentate gyrus and CA3 region, but not CA1, at 20 to 23 months of age but not four to six months (Maeda et al., 2016). In another transgenic mouse model expressing A152T tau in neurons, hTau40-AT, neuronal degeneration was also observed in the hippocampus and cortex (Decker et al., 2016; Sydow et al., 2016). These mice also exhibited increases in intracellular calcium at rest and after activity induction, and this was driven by extrasynaptic NMDA receptors. This increased calcium flux through extrasynaptic NMDARs led to activation of the CREB shut-off pathway and neurotoxicity. Neuronal loss was also observed in the cortex of mice expressing A152T tau via AAV vector injection (Carlomagno et al., 2019).

In a transgenic zebrafish model expressing human A152T tau, gross morphological abnormalities were observed compared to fish expressing wild-type human tau, as well as defects in pathfinding and branching of motor neurons; there were also decreases in total motor neuron number (Lopez et al., 2017). Increased cell death was also observed by TUNEL staining in A152T zebrafish versus wild-type fish.

Neuropathology was also observed in a C. elegans model expressing pan-neuronal A152T tau, where severe behavioral and cellular impairments were found, including paralysis, neurodegeneration of GABAergic motor neurons, aging-like morphological abnormalities in touch neurons, and an overall reduced lifespan relative to worms expressing wild-type tau (Pir et al., 2016). In addition, these worms also exhibited necrosis-mediated glutamatergic neuronal loss, which was driven by excitotoxicity and calcium dysregulation (Choudhary et al., 2018).

The A152T tau mutation promotes neuronal loss through stress-induced pathways in human iPSC-derived models. For example, human A152T-expressing iPSC-derived neurons were more vulnerable than control cells to cell death in pharmacological experiments where cellular stressors like rotenone, piericidin A, glutamate, and epoxomicin were applied (Silva et al., 2016). Likewise, increased neuronal cell death was observed following exposure to rapamycin (although not staurosporine or rotenone) in iPSC-derived cortical neurons from an A152T carrier who had PSP, and these effects were linked to increased expression of matrix metalloproteinases MMP-9 and MMP-2 via enhanced ERK pathway activation (Biswas et al., 2016).

In sum, calcium dysregulation, excitotoxicity, and stress-induced pathways have been implicated in neuronal loss associated with A152T.

Synaptic function
The A152T variant disrupts synaptic integrity and function across multiple model systems. In the hippocampus and cortex of transgenic A152T mice, presynaptic integrity was impaired, with reduced expression of synaptophysin, while PSD95 on the postsynaptic side seemed less affected (Sydow et al., 2016). Nonetheless, at advanced ages, the number of dendritic spines was reduced compared to wild-type mice, indicating eventual progression to postsynaptic defects.

These structural changes are paralleled by functional synaptic alterations in A152T mouse models. Transgenic A152T mice displayed increased basal synaptic transmission in the mossy fiber tract, but short-term and long-term plasticity did not differ from non-transgenic control mice (Decker et al., 2016). Similarly, in another transgenic A152T mouse model, increased basal synaptic transmission was observed in mossy fiber synapses compared to non-transgenic control mice, especially at older ages, but these effects were also seen in mice overexpressing wild-type tau, suggesting the effect may be due to overexpression of tau or expression of human tau rather than the mutation itself (Maeda et al., 2016). Moreover, while long-term plasticity did not differ between genotypes in this model, short-term plasticity (paired-pulse facilitation) was reduced in older transgenic (both wild-type and A152T) mice versus non-transgenic controls.

A152T mice also exhibit heightened epileptiform activity. Brain slices from mutant mice showed increased epileptiform activity following picrotoxin application, indicating heightened susceptibility (Decker et al., 2016). Furthermore, in another A152T mouse model, transgenic mutant mice exhibited increased spikes versus non-transgenic mice when evaluated with electroencephalograms (Maeda et al., 2016), corroborating the increased susceptibility found in the other study. In a later report using this same mouse model, intracranial EEG recording from the parietal cortex showed increased delta/theta (0.5-6 Hz) oscillation power compared to control mice, reflecting network dysfunction (Das et al., 2018).

Extending these findings to other models, C. elegans expressing pan-neuronal A152T tau showed synaptic impairments. In two separate studies, behavioral pharmacological experiments revealed impaired cholinergic presynaptic transmission (Butler et al., 2018; Pir et al., 2016). In addition, retrograde axonal transport of the RAB-3 protein, which is involved in synaptic transmission, was selectively perturbed in A152T-expressing worms (Butler et al., 2018). Also, the transgenic animals exhibited impairments in a short-term associative memory assay compared to wild-type worms.

In human iPSC-derived neurons genetically engineered to express A152T, synaptic function was also perturbed. Specifically, A152T-expressing differentiated excitatory neurons showed increased spontaneous neuronal activity compared to wild-type–expressing cells, which resulted in decreased calcium oscillations in inhibitory neurons present in the culture (Itsuno et al., 2024). This study further explored the mechanisms behind the hyperexcitability in excitatory neurons, finding that it is mediated by NMDA receptors via pharmacological studies. Additional experiments showed an increased interaction between tau and Fyn, which is a key protein that regulates NMDA receptors. Moreover, transcriptomic analysis demonstrated structural changes, such as upregulation of HOXB9 and IRX2, indicating a dedifferentiation phenotype.

Neuroinflammation
Transgenic A152T mice displayed astrocyte and microglia activation in the hippocampus and cortex, as detected with immunostaining markers such as GFAP, S100b, and Iba1 (Sydow et al., 2016). In a different transgenic A152T mouse model, astrocytosis but not microgliosis was observed based on immunostaining (Maeda et al., 2016). Similarly, in mice expressing A152T tau via AAV vector injection, significantly increased expression of GFAP was observed, and while Iba1 expression was also increased, the difference from controls was not significant (Carlomagno et al., 2019). Together, these data suggest that the A152T mutation does induce neuroinflammation, and these effects appear earlier in astrocytes than microglia.

Lipid droplet formation was impaired in a fly model expressing A152T tau versus wild-type tau, pointing to a disruption of normal glial function due to the mutation (Oct 2024 news;Goodman et al., 2024). Glia form lipid droplets, which are important for sequestering and removing toxic peroxidated lipids to minimize the negative impact of reactive oxygen species. This functional defect was proposed to potentially be the result of impaired mutant tau binding to microtubules.

Proteostasis abnormalities
The A152T variant disrupts proteostasis across diverse model systems. In a transgenic A152T mouse model, the autophagy-lysosome pathway was activated, but the ubiquitin-proteasome pathway was inhibited (Sydow et al., 2016). Likewise, a transgenic zebrafish model expressing A152T tau showed intact autophagy, but proteasome function was impaired (Lopez et al., 2017).

These disruptions in animal systems extend to human cellular models, where protein degradation pathways are also affected. In A152T human iPSC-derived neurons, proteostasis was markedly altered, with upregulation of ubiquitin-proteasome system components (UBI1) and autophagy-lysosomal pathway markers (LC3B-II, ATG12/5, SQSTM1/p62, LAMP1, LAMP2a; Silva et al., 2016). Proteins involved in the unfolded protein response and oxidative stress were also perturbed, but those involved in the heat-shock response were unchanged. Similarly, in another study of iIsogenic human iPSCs generated from fibroblasts of an A152T carrier, the mutant tau was found to be predisposed to proteolysis by caspases and other proteases, leading to greater tau pathology (Fong et al., 2013).

Further elucidating degradation mechanisms, researchers used a neuroblastoma cell line to systematically examine which autophagy pathways are used to degrade A152T tau by selectively silencing key proteins within each of the major pathways (Caballero et al., 2018). They found that A152T tau is preferentially degraded via macroautophagy and to a lesser extent by chaperone-mediated autophagy (CMA), but unlike wild-type tau, it is not degraded via endosomal microautophagy.

Together, data clearly point to disrupted proteostasis functions with A152T, though the specific pathways affected may differ by model system.

Mitochondrial abnormalities
In C. elegans expressing pan-neuronal A152T tau, mitochondria were mislocalized, and mitochondrial transport was defective (Pir et al., 2016).

In silico predictions
Although in one study A152T was predicted to be benign by PolyPhen2  (Sala Frigerio et al., 2015), its PHRED-scaled CADD score, which integrates diverse information in silico, was 22.8, above the commonly used threshold of 20 for predicting deleteriousness (CADD v1.7, Apr 2024).

Note on nomenclature
The A152T variant has also been reported as A469T, in reference to its position in the tau isoform with 776 amino acids (Uniprot P10636-9).

Table

Associations between A152T and Neurodegenerative Disorders

Pathogenicity

Frontotemporal Dementia Spectrum : Uncertain Significance*

*This variant may be a risk factor, a classification not included in the ACMG-AMP guidelines.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

Transgenic A152T mouse models have been developed expressing mutant human tau, allowing the investigation of A152T’s effects on cellular and behavioral outcomes. The hTau40-AT model expresses the 2N4R tau isoform driven by the neuron-specific Thy1.2 promoter (Decker et al., 2016; Sydow et al., 2016; Mar 2016 news). The hTau-A152T model expresses the 1N4R tau isoform preferentially in the forebrain (driven by the CaMKIIα promoter), and this model was also engineered with a “tet-off” system to allow the transgene to be suppressed when doxycycline is added to the diet (Maeda et al., 2016; Mar 2016 news). In addition to transgenic approaches, AAV models have also been established in mice in vivo (TauA152T-AAV; Carlomagno et al., 2019) and in brain slice cultures (Croft et al., 2019).

Non-mammalian transgenic models have also been used to explore pathophysiological outcomes of A152T. These include C. elegans (e.g., Pir et al., 2016, Butler et al., 2018, Choudhary et al., 2018), Drosophila (Goodman et al., 2024), and zebrafish (e.g., Lopez et al., 2017).

Cell-based models have been developed to investigate this variant’s pathological characteristics and impact on cellular function. A resource of human fibroblasts and neurally induced iPSCs expressing the A152T tau mutation is available (Karch et al., 2019; Oct 2019 news). Additionally, other A152T iPSC-derived lines have been described (e.g., Fong et al., 2013, Silva et al., 2016, Biswas et al., 2016, Itsuno et al., 2024).

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References

Research Models Citations

1. hTau-AT (hTau40-AT)
2. hTau-A152T
3. TauA152T-AAV

News Citations

1. A152T: A Different Kind of Tau Mutation 19 Mar 2016
2. Introducing: iPSC Collection from Tauopathy Patients 23 Oct 2019
3. New Role for Tau: Making Lipid Droplets in Glia? 22 Oct 2024

Paper Citations

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