Analysis of data from more than 8,000 people, most of them older than 60, has revealed that, among the 5,000 people initially tested cognitively normal, carrying one copy of the “Alzheimer’s gene” (ApoE4) only slightly increased men’s risk of developing MCI or Alzheimer’s — but nearly doubled women’s risk (healthy men with APOE4 were 27% more likely to develop MCI or Alzheimer’s compared to those without the gene, while female carriers had an 81% greater risk).
Among the 2,200 who were initially diagnosed with mild cognitive impairment, women were more likely to progress to Alzheimer’s (116% greater risk vs 64% for men), but the difference wasn’t significant. However, it was significant when only comparing carriers of 2 copies of the common ApoE3 variant with carriers of one ApoE3 copy and one ApoE4 copy (there are three variants of the ApoE gene: E3 is the most common; E4 is the ‘bad’ one; E2 is actually protective). Analysis of imaging and biomarker data from 1,000 patients confirmed the gender difference.
A gender difference was first suggested in a 1997 paper, but the research had never been followed up until recently. The current study was preceded by a 2012 imaging study, that found that female ApoE4 carriers had brain connectivity significantly different from normal, while male carriers’ brains were little different than normal.
While it’s not known why there should be such differences, biomarkers suggested that the increased female risk has something to do with tau pathology. Previous research has also indicated that ApoE4 interacts with estrogen.
The finding suggests why Alzheimer’s is so much more common in women — not just because they tend to live longer, but because they are, indeed, more at risk. It also tells us that research referencing the ApoE gene should separate by gender.
 Sex modifies the APOE-related risk of developing Alzheimer disease. Annals of Neurology. 75(4), 563 - 573.(2014).