While the ‘Alzheimer’s gene’ is relatively common — the ApoE4 mutation is present in around 15% of the population — having two copies of the mutation is, thankfully, much rarer, at around 2%. Having two copies is of course a major risk factor for developing Alzheimer’s, and it has been thought that having a single copy is also a significant (though lesser) risk factor. Certainly there is quite a lot of evidence linking ApoE4 carriers to various markers of cognitive impairment.
And yet, the evidence has not been entirely consistent. I have been puzzled by this myself, and now a new finding suggests a reason. It appears there are gender differences in responses to this gene variant.
The study involved 131 healthy older adults (median age 70), whose brains were scanned. The scans revealed that in older women with the E4 variant, brain activity showed the loss of synchronization that is typically seen in Alzheimer’s patients, with the precuneus (a major hub in the default mode network) out of sync with other brain regions. This was not observed in male carriers.
The finding was confirmed by a separate set of data, taken from the Alzheimer's Disease Neuroimaging Initiative database. Cerebrospinal fluid from 91 older adults (average age 75) revealed that female carriers had substantially higher levels of tau protein (a key Alzheimer’s biomarker) than male carriers or non-carriers.
It’s worth emphasizing that the participants in the first study were all cognitively normal — the loss of synchronization was starting to happen before visible Alzheimer’s symptoms appeared.
The findings suggest that men have less to worry about than women, as far as the presence of this gene is concerned. The study may also explain why more women than men get the disease (3 women to 2 men); it is not (although of course this is a factor) simply a consequence of women tending to live longer.
Whether or not these gender differences extend to carriers of two copies of the gene is another story.
 . Gender Modulates the APOE ε4 Effect in Healthy Older Adults: Convergent Evidence from Functional Brain Connectivity and Spinal Fluid Tau Levels. The Journal of Neuroscience [Internet]. 2012 ;32(24):8254 - 8262. Available from: http://www.jneurosci.org/content/32/24/8254