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

Abstract

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.

Keywords: anterior thalamic nuclei; dementia; limbic thalamus; memory; retrosplenial cortex.

Research into episodic memory loss in Alzheimer’s disease has repeatedly focused on the hippocampus. Aggleton et al. argue that this approach is too narrow, and ignores the early involvement of other brain sites, most notably the anterior thalamic nuclei, which are also vital for episodic memory.

Figure 1

Illustrations showing the location of the anterior thalamic nuclei within Papez circuit and the limbic system. ( A ) Schematic drawing of Papez circuit (in black). ( B ) Schematic diagram of the key connections between the anterior thalamic nuclei and laterodorsal thalamic nucleus with sites implicated in Alzheimer’s disease. ATN = anterior thalamic nuclei; HPC/SUB = hippocampal formation, including subiculum; LD = laterodorsal thalamic nucleus; MMB = mammillary bodies; MTT = mammillothalamic tract; PARAHPC = parahippocampal region; PFC = prefrontal cortex; RSC = retrosplenial cortex.

Figure 2

Post-mortem pathology in the anterior thalamus in patients with Alzheimer’s disease. The coronal images are taken with permission from Braak and Braak (1991 b ). ( A ) Conspicuous patches of amyloid deposition in the anteroventral thalamic nucleus. ( B ) Presence of neurofibrillary changes adjacent to the anteroventral thalamic nucleus. ( C ) Dense deposition of neurofibrillary tangles in the anterodorsal thalamic nucleus. Av = anteroventral thalamic nucleus; Ad = anterodorsal thalamic nucleus; Pt = parataenial nucleus; SM = stria medullaris; Va = ventral anterior nucleus.