The dual-path hypothesis for the emergence of anosognosia in Alzheimer's disease

Although neurocognitive models have been proposed to explain anosognosia in Alzheimer's disease (AD), the neural cascade responsible for its origin in the human brain remains unknown. Here, we build on a mechanistic dual-path hypothesis that brings error-monitoring and emotional processing systems as key elements for self-awareness, with distinct impacts on the emergence of anosognosia in AD. Proceeding from the notion of anosognosia as a dimensional syndrome, ranging from the lack of concern about one's own deficits (i.e., anosodiaphoria) to the complete lack of awareness of deficits, our hypothesis states that (i) unawareness of deficits would result from a failure in the error-monitoring system, whereas (ii) anosodiaphoria would more likely result from an imbalance between emotional processing and error-monitoring systems. In the first case, a synaptic failure in the error-monitoring system, in which the cingulate cortex plays a major role, would have a negative impact on error (or deficits) awareness, preventing patients from becoming aware of their condition. In the second case, an impairment in the emotional processing system, in which the amygdala and orbitofrontal cortex play a major role, would prevent patients from monitoring the internal milieu for relevant errors (or deficits) and assigning appropriate value to them, thus biasing their impact on the error-monitoring system. Our hypothesis stems from two scientific premises. One comes from preliminary results in AD patients showing a synaptic failure in the error-monitoring system and decline of awareness at the time of diagnosis. Another comes from the somatic marker hypothesis, which proposes that emotional signals are critical to adaptive behavior. Further exploration will be of great interest to illuminate the foundations of self-awareness and improve our understanding of the underlying mechanisms of anosognosia in AD.