A major genetic risk factor for Alzheimer’s disease – the E4 variant of the apolipoprotein E (APOE) gene – manifests itself more often in women than in men, researchers reported.
In a cohort of cognitively healthy older men and women, carrying the E4 variant was associated with deficits in brain connectivity in women, but not in men, according to Michael Greicius, MD, of the Stanford University School of Medicine in Palo Alto, Calif., and colleagues.
The sex difference was also apparent, in a separate cohort, in levels of the Alzheimer’s-associated protein tau in cerebrospinal fluid, Greicius and colleagues reported in the June 13 issue of the Journal of Neuroscience.
It has long been known that more women than men will eventually develop the disease, and the new findings may help explain why, Greicius said in a statement.
“This disparate impact of ApoE4 status on women versus men might account for a big part of the skewed gender ratio,” he said.
It might also have implications for prognosis, he and colleagues noted, in that men who carry the E4 variant should not be assumed to be at higher than normal risk of Alzheimer’s.
Greicius and colleagues conducted functional-connectivity magnetic resonance imaging (fcMRI) on 131 healthy people, with a median age of 70, to examine connections in the brain’s so-called default mode network.
The default mode network is in play when a person is awake but not focused on a task. Greicius and colleagues have previously shown that elements of the network – which usually have a synchronous firing pattern – are less tightly linked in Alzheimer’s and the linkage deteriorates as the disease progresses.
The volunteers were all cognitively healthy, and genetic testing showed that 43 carried at least one copy of the E4 variant, while the rest had two copies of the E3 allele. The other variant, E2, appear to protect against Alzheimer’s and so volunteers carrying it were excluded from the study.
Greicius and colleagues found that – as expected – carrying at least one copy of the E4 variant was associated with “significantly decreased connectivity” in the default mode network, compared with volunteers carrying two copies of the E3 variant.
But further testing showed an interaction of the APOE genotype and sex, Greicius and colleagues reported. Specifically:
In a large region including the cuneal cortex, precuneus, and posterior cingulate gyrus, the loss of connectivity was greater in women carrying an E4 variant than in those with two copies of E3.
Male E4 carriers showed decreased posterior default mode connectivity only in a small cluster in the left superior parietal cortex compared with men carrying two copies of the E3 variant.
And women carrying E4 showed reduced functional connectivity compared with male E4 carriers in the cuneus/precuneus cluster of the posterior default mode network.
To confirm the findings, the researchers turned to a second cohort – participants in the Alzheimer’s Disease Neuroimaging Initiative who were cognitively healthy and had data on cerebrospinal measurements.
As in the original cohort, volunteers carrying the E2 variant were excluded, leaving 93 participants, including 26 who carried either one or two copies of the E4 variant.
Analysis of the cerebrospinal fluid showed an interaction of sex and APOE genotype that was significant at P=0.024.
Specifically, the total tau levels were highest in female E4 carriers, at an average of 99 picograms per milliliter, and lowest in women with two copies of the E3 variant, at 65 picograms per milliliter on average. The difference was significant at P=0.046.
“It was only possible to see these differences in tau levels when we separated the patients by gender,” Greicius said.
There were no significant differences between male E4 carriers and those with two copies of E3, between female and male E4 carriers, or between women and men carrying two copies of the E3 variant.
The study was supported by the Hillblom Foundation, the John Douglas French Alzheimer’s Disease Foundation, the JNA Foundation, and the NIH.
The journal said the authors declared no competing interests.
Primary source: Journal of Neuroscience
Source reference: Damoiseaux JS, et al “Gender modulates the APOE 4 effect in healthy older adults: Convergent evidence from functional brain connectivity and spinal fluid tau levels” J Neurosci 2012; 32(24): 8254 – 8262.