Thalamic pathology and memory loss in early Alzheimer’s disease: moving the focus from the medial temporal lobe to Papez circuit

Aggleton, John P., Pralus, Agathe, Nelson, Andrew J. D. and Hornberger, Michael ORCID: (2016) Thalamic pathology and memory loss in early Alzheimer’s disease: moving the focus from the medial temporal lobe to Papez circuit. Brain, 139 (7). pp. 1877-1890. ISSN 0006-8950

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It is widely assumed that incipient protein pathology in the medial temporal lobe instigates the loss of episodic memory in Alzheimer’s disease, one of the earliest cognitive deficits in this type of dementia. Within this region, the hippocampus is seen as the most vital for episodic memory. Consequently, research into the causes of memory loss in Alzheimer’s disease continues to centre on hippocampal dysfunction and how disease-modifying therapies in this region can potentially alleviate memory symptomology. The present review questions this entrenched notion by bringing together findings from post-mortem studies, non-invasive imaging (including studies of presymptomatic, at-risk cases) and genetically modified animal models. The combined evidence indicates that the loss of episodic memory in early Alzheimer’s disease reflects much wider neurodegeneration in an extended mnemonic system (Papez circuit), which critically involves the limbic thalamus. Within this system, the anterior thalamic nuclei are prominent, both for their vital contributions to episodic memory and for how these same nuclei appear vulnerable in prodromal Alzheimer’s disease. As thalamic abnormalities occur in some of the earliest stages of the disease, the idea that such changes are merely secondary to medial temporal lobe dysfunctions is challenged. This alternate view is further strengthened by the interdependent relationship between the anterior thalamic nuclei and retrosplenial cortex, given how dysfunctions in the latter cortical area provide some of the earliest in vivo imaging evidence of prodromal Alzheimer’s disease. Appreciating the importance of the anterior thalamic nuclei for memory and attention provides a more balanced understanding of Alzheimer’s disease. Furthermore, this refocus on the limbic thalamus, as well as the rest of Papez circuit, would have significant implications for the diagnostics, modelling, and experimental treatment of cognitive symptoms in Alzheimer’s disease.

Item Type: Article
Additional Information: © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Uncontrolled Keywords: anterior thalamic nuclei,dementia,limbic thalamus,memory,retrosplenial cortex
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
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Depositing User: Pure Connector
Date Deposited: 24 Sep 2016 00:08
Last Modified: 21 Oct 2022 06:30
DOI: 10.1093/brain/aww083

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