Corticothalamic circuit and executive dysfunction in Alzheimer's disease and related tauopathies

Alzheimer's disease (AD) is the leading cause of dementia worldwide. AD is characterized by the extracellular accumulation of amyloid‐β (Aβ), in the form of soluble oligomers, insoluble fibrils and plaques, and by intracellular aggregation of hyperphosphorylated tau (p‐tau) into neurofibrillary tangles. This latter feature places AD amongst the several tauopathies described to date. In primary tauopathies, tau is the major and prominent component of the pathology, whereas in secondary tauopathies, tau aggregation is regarded as a downstream response to other pathological events, such as Aβ aggregation in AD. At later stages, in both primary and secondary tauopathies, accumulation of abnormal tau is associated with neuronal degeneration, synaptic loss and cognitive impairment.

Although progressive memory loss remains the most recognized clinical manifestation of AD, impairments in other cognitive domains also develop. Executive dysfunction (i.e. encompassing deficits in planning, decision‐making and cognitive flexibility) often emerges during the earliest stages of the disease, with some patients presenting non‐amnestic and predominantly dysexecutive forms of AD. This reflects the heightened vulnerability of the prefrontal cortex (PFC), a region critically involved in higher‐order cognitive processes, and suggests that subtle synaptic dysfunction precedes explicit neuronal loss.

At the cellular level, AD is understood as a disorder of synaptic failure rather than simply a consequence of protein aggregation. Both Aβ and tau interfere with synaptic homeostasis through distinct yet converging mechanisms, including disruption of calcium signalling, impairment of neurotransmitter release and destabilization of cytoskeletal architecture. These alterations build up to compromise the efficiency of neuronal communication, particularly in circuits that require sustained and high‐frequency activity, such as those underlying working memory and executive control.

Among the crucial circuits governing higher cognitive functions, the connectivity between the PFC and the thalamus plays a central role in coordinating attention, cognitive flexibility, executive functions and decision‐making. This thalamocortical loop operates as a dynamic relay system, modulating the flow of information necessary for adaptive decision‐making. Despite its functional relevance, the precise mechanisms by which Aβ and tau pathology affect the thalamocortical circuit have remained largely unexplored.

In a recent issue of The Journal of Physiology, Zhong et al. (2026) combined optogenetics and ex vivo electrophysiology to investigate the functional integrity of the PFC‐to‐thalamus circuit in two distinct AD transgenic mouse models (the P301S tauopathy model and the 5xFAD amyloidosis model) at early stages of pathology (∼4 months). By expressing channelrhodopsin‐2 (ChR2) in PFC neurons and recording light‐evoked excitatory postsynaptic currents (oEPSCs) in the mediodorsal thalamus (MD), the authors initially established that the PFC–MD is the strongest connection among PFC–thalamic projections (Zhong et al., 2026). Next, high‐frequency stimulation revealed an exacerbated short‐term depression of oEPSCs in both transgenic models, indicating impaired maintenance of synaptic transmission from PFC to MD during sustained activity, despite the absence of changes in basal synaptic strength or intrinsic neuronal excitability (Zhong et al., 2026). The authors also found reduced projections from the PFC to the MD in the P301S mice, based on the reduced ChR2 signal at synaptic terminals of the MD, which was transported from PFC principal neurons, but whether such a reduction is also found in the 5xFAD mice remains an open question. Together, these data indicate that the PFC–MD connection is compromised in both transgenic models.

Considering the role of tau in microtubule stability and axonal transport, Zhong et al. (2026) also analysed whether inhibiting kinases involved in pathological tau phosphorylation could rescue the observed deficit in synaptic transmission. Pharmacological inhibition of the serum and glucocorticoid‐regulated kinase 1 (SGK1) or glycogen synthase kinase 3β (GSK3β) successfully restored the short‐term depression in the P301S tau model, but not in the 5xFAD model (Zhong et al., 2026). Given that tau hyperphosphorylation is not observed consistently in 5xFAD mice, these findings suggest that Aβ and tau disrupt the PFC–MD circuit by different mechanisms, with the Aβ‐associated mechanism remaining to be elucidated.

The PFC–MD projections depend on precise temporal fidelity and sustained synaptic transmission, making them particularly vulnerable to early synaptic perturbations in neurodegenerative conditions. Defining how tau and Aβ differentially compromise synaptic information transfer within this circuit is crucial for understanding the implications for disorders where one predominates, such as in frontotemporal dementia (FTD; a primary tauopathy), or where they act synergistically, as in AD.

Preclinical evidence shows that Aβ and tau act cooperatively to cause circuit and behavioural dysfunction in transgenic mice that develop amyloid and tau pathology concomitantly (APP/PS1+Tau) (Pickett et al., 2019). Importantly, they showed accumulation of pathological tau in presynaptic terminals, supporting the role of tau in mediating synaptic dysfunction (Pickett et al., 2019). In line with the data from Zhong et al. (2026), Pickett et al. (2019) also found that reduction in p‐tau corrected behavioural deficits, synaptic tau levels and transcriptional alterations in the APP/PS1+Tau mice.

Clinical evidence from patients with mild cognitive impairment and AD indicates that Aβ deposition emerges preferentially within core regions of the default mode network, including medial prefrontal areas, reflecting network‐level susceptibility (Palmqvist et al., 2017). Additionally, degeneration of the mediodorsal thalamic nucleus is a relatively late event in AD and appears structurally dissociated from the early vulnerability observed in prefrontal regions. It is important to note that Aβ begins to accumulate decades before symptoms emerge, whereas tau accumulates temporally closer to cognitive impairment, and the brain region where it accumulates is more predictive of loss of function. Connectivity‐based models suggest that tau pathology propagates along neuronal circuits and that this process can be accelerated by concomitant Aβ accumulation (Vogel et al., 2020).

Prefrontal tau accumulation is correlated with executive dysfunction across clinically and aetiologically distinct tauopathies, such as chronic traumatic encephalopathy (Alosco et al., 2024), early and late‐onset AD, especially with predominant dysexecutive symptoms (Tanner et al., 2022; Therriault et al., 2021), and FTD (Ghirelli et al., 2020). It has also been shown that the functional connectivity between areas of the limbic cortico‐striato‐thalamic–cortical circuit is reduced in a behavioural variant of FTD, which may be associated with more severe behavioural disturbances (Liu et al., 2023). Moreover, a recent study revealed that symptomatic FTD mutation (i.e., C9orf72, GRN or MAPT) carriers have significantly smaller volumes and widespread higher mean diffusivity (i.e., an MRI‐derived marker consistent with reduced microstructural integrity) of thalamic subregions compared with non‐carriers, which were overall most prominent in regions involved in associative and limbic functions, including the mediodorsal subregion (Soskic et al., 2025). Collectively, these findings support the translational relevance of the PFC–MD circuit and underscore the importance of studying its vulnerability in neurodegenerative disorders, particularly in tauopathies (Fig. 1).

Figure 1. Prefrontal cortex to mediodorsal thalamus circuit disruption in Alzheimer's disease and related pathologies.

Schematic of PFC→MD connectivity in healthy conditions and in the context of tau and Aβ pathology. Healthy conditions show intact circuit connectivity, whereas both tau and Aβ pathologies are associated with impaired synaptic connectivity within the PFC→MD pathway. These alterations can be linked to executive dysfunction and neurodegeneration, with possible synergistic interactions between tau and Aβ. Abbreviations: Aβ, amyloid‐β; MD, mediodorsal thalamus; PFC, prefrontal cortex; p‐tau, hyperphosphorylated tau. Created with BioRender [EY29OC73BR].

Accordingly, the hypothesis that MD degeneration follows PFC dysfunction is consistent with the temporal progression of pathology. However, this interpretation should be approached cautiously. Evidence from non‐Alzheimer's tauopathies, as cited, highlights that tau deposition is correlated with executive dysfunction in diverse conditions. In this context, disruption of the MD–PFC circuit might be a consequence of widespread pathology rather than a primary driver of early disease, reflecting the emergence of large‐scale thalamocortical network dysfunction as neurodegeneration becomes more globally distributed. Future longitudinal studies comparing different disease stages are warranted to clarify this question.

In conclusion, the evidence reported by Zhong et al. (2026) showed that P301S and 5xFAD mice develop impaired short‐term plasticity in PFC‐to‐MD pathways attributable, in part, to tau kinase‐induced disruption of axonal transport. Data from this study, along with previous findings, encourage future studies to elucidate the mechanisms connecting functional and circuit‐level dysfunction, particularly within the PFC–MD pathway, because this might provide key insights into early disease processes and reveal new targets for dysexecutive function caused by AD and other tauopathies.

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Competing interests

None declared.

Author contributions

L.F.d.S.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. D.C.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. R.A.S.L.‐F.: conception or design of the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; agreement to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.

Funding

L.F.d.S. is funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), 3300382483424060. D.C. funded by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), E‐26/200.203/2004. R.A.S.L.‐F. is funded by Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), E‐26/200.054/2024.

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