Case reports of unexpected memory retrieval in patients with severe dementia near death challenge the view that dementia is an irreversible consolidation problem, suggesting instead a retrieval problem. The likely mechanism involves fluctuating neuromodulators from the brain stem to the medial prefrontal cortex and hippocampus. Around death, neurotransmitter discharges change dramatically, and relatively resistant neuromodulator circuits can maintain optimal arousal and attention for memory processing, triggering episodes of lucidity. Corticotropin-releasing peptides may further increase mental clarity. No animal or human model exists to test this hypothesis, but similarities with delirium and lucid dreaming could provide windows for future research.
The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) activates signaling pathways (ERK1/2, mTOR, S6K1) in the hippocampus, rescuing long-term potentiation and memory deficits in two mouse models of Alzheimer's disease: mice infused with amyloid-β oligomers and aged APP/PS1 mice. The rescue depends on ERK signaling. HNK also corrects aberrant transcription in APP/PS1 mice. These results suggest HNK could be a therapeutic approach for Alzheimer's disease.