ApoE4 and Dementia Without Alzheimer's Disease

The gene referred to as apolipoprotein E4 (ApoE4) is a recognized risk factor for Alzheimer's disease.  If you carry this gene, it doesn't guarantee that you'll get Alzheimer's disease, but the odds are greater.  Therefore, genetic testing companies like 23andMe and Ancestry.com will test for the #4 variant of ApoE.  If they find that you carry this gene, the companies are required by law to explain to you that this does not guarantee you will get Alzheimer's disease, but they must recommend that you to seek counseling on your path forward.

So what does ApoE4 do that's so bad?  About a year ago, we posted a list offenses, noting that each offense played its own role in a very complex disease.

Recall that, like all genes, ApoE4 is the design description for a protein.  In this case, it's a protein that helps transport cholesterol through the blood.  But what's wrong with variant #4?  Two things we noted have come up again in recent research published in the journal Nature ("APOE4 leads to blood–brain barrier dysfunction predicting cognitive decline"): promoting inflammation and damaging the blood-brain barrier.  We have been discussing both of these in recent posts.

The more we learn about inflammation, the more we realize how pervasive its effects are on many of the body's maintenance mechanisms -- and on many diseases.  But what I found interesting in the recent research linked above was how the ApoE4 protein is associated with damage to the blood-brain barrier -- most notably in the hippocampus and temporal regions.

We discussed the blood-brain barrier in the post on dietary salt.  The blood-brain barrier is part of the brain's own immune system, and it blocks the entry of pathogens into the brain.  Breakdown of the blood-brain barrier has been associated with Alzheimer's disease.

The research reported in Nature brought something new to the table.  While a correlation between breakdown in the blood-brain barrier and Alzheimer's disease seems to be established, it may be that there can also be cognitive decline here without Alzheimer's disease.

In their study population, the researchers conducted brain scans for beta amyloid and abnormal tau proteins among subjects carrying the ApoE4 gene.  (Beta amyloid plaques and accumulation of tau-related tangles are important biomarkers for Alzheimer's disease.)  They identified those individuals who did not have Alzheimer's disease.  Nevertheless, there were cases of cognitive decline in this population, suggesting that there are more ways in which this problem gene can cause dementia than just through Alzheimer's disease.