Gene That Increases Risk Of Alzheimer's Found To Disrupt Memory Replay

The gene variant ApoE4 is a major genetic risk factor for Alzheimer's disease, and it may interfere with memory formation by compromising memory playback

Everyone carries two alleles for the apolipoprotein gene ApoE4, one from your father and one from your mother. While we still don't know exactly what causes Alzheimer's disease, possessing the allele ApoE4 is the strongest known genetic risk factor (outside of familial Alzheimer's disease). It's not clear exactly why or how it increases risk, but statistics clearly demonstrate a link.  Having one or even two alleles of E4 doesn't definitively mean you'll develop Alzeimer's, but around 65-80% of Alzheimer's patients possess an ApoE4 allele.

Below is a table highlighting the risk for each of the 3 variant combinations:  

Credit: Alzheimer's drug discovery foundation 

Focusing on the hippocampus

The hippocampus is responsible for encoding certain types of new memory, and it's particularly affected by Alzheimer's. Research at the Gladstone Institutes has now uncovered that ApoE4 lowers 2 key types of neural activity in the hippocampus: sharp wave ripples (ripples) and slow gamma activity. Both processes are involved with consolidating new, and accurate memories. 

"When we experience something new, cells in the hippocampus fire in a particular order. Later, these same cells fire over and over again in the same order to replay the event, which helps consolidate the memory so we don't forget it. Slow gamma activity that occurs during the ripples organizes the firing of these cells. If this activity is disrupted, the playback will be disorganized, compromising the memory"

The importance of slow gamma activity

When the researchers compared mice with the regular ApoE3 protein, ApoE4 mice had fewer of these 'ripples' and reduced gamma activity too. When they engineered mice with ApoE4 expressed in every cell except those specific hippocampal neurons, they found that the slow gamma activity was the major factor at play. The gamma co-ordinating of neuron firing seemed to be the crucial factor in memory consolidation. This means that in humans the effect of ApoE4 is likely similar, which could open up new avenues of treatment.

"Our research suggests that disrupted slow gamma activity during ripples is a major consequence of apoE4 expression that likely impairs memory consolidation. With this knowledge, we can now work toward correcting or restoring slow gamma activity in the hippocampus to prevent or alleviate memory loss in Alzheimer's disease"

Find out more about the research from the Gladstone researchers themselves: 

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