The APOE gene, the strongest genetic risk factor for Alzheimer’s disease, may play a more prominent role in disease development among women than men, according to new research from the Vanderbilt Memory and Alzheimer’s Center.
The research confirmed recent studies that carrying the APOE ε4 allele has a greater association with Alzheimer’s disease among women compared to men, and went one step further by evaluating its association with amyloid and tau levels.
The study published May 7 in JAMA Neurology adds to mounting evidence that the higher prevalence of Alzheimer’s disease among women may not simply be a consequence of living longer.
Almost two-thirds of Americans with Alzheimer’s are women. The research, based on a meta-analysis of both cerebral spinal fluid (CSF) samples from study volunteers from four datasets and autopsy findings from six datasets of Alzheimer-diseased brains, is the most robust evidence to date that the APOE gene may play a greater role in women than men in developing Alzheimer’s pathology, said Timothy Hohman, PhD, assistant professor of Neurology and the study’s lead author.
“In Alzheimer’s disease, we have not done enough to evaluate whether or not sex is a contributing factor to the neuropathology,” Hohman said. “We haven’t fully evaluated sex as a biological variable. But there is good reason to expect in older adulthood that there would be hormonal differences between the sexes that could impact disease.”
The study looked at whether APOE in men and women was primarily associated with the amyloid pathway — the proteins that form plaques in the brain — or with the tau pathway — the proteins that form tangles in the brain.
The association with the amyloid pathway was the same in men and women. However, the APOE association was much greater for women with the tau pathway. This is opposite of what researchers expected because of APOE’s established role in amyloid processing.
“The prevailing hypothesis of disease in Alzheimer’s is that amyloid comes online first and downstream is where we see tau changes that ultimately drive neurodegenerative changes,” Hohman said.
Further analysis revealed that the sex difference with tau levels was present in amyloid-positive individuals — those with higher levels of amyloid plaque as determined by their CSF amyloid levels. The research suggests that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis.
The greater association with tau occurred in CSF samples, but not with the autopsy datasets.
The reason for the contradiction between CSF samples and autopsy datasets could be because Braak staging — the method for quantifying the degree of tau tangle pathology at autopsy — measures a different aspect of tau pathology than what is measured in CSF .
“The way Braak staging works is you are actually looking at where in the cortex you see tangles at autopsy,” Hohman explained. “So it is not a measure of how many tangles are there. It is a measure of where those tangles are located.”
Another possibility is that CSF tau may be an indicator of a more general neurodegenerative process that is not specific to tangle pathology.
“This study is at least moving toward bringing sex as a biological variable into our analyses and thinking about sex differences. Do we see differences in disease that could tell us something about the biology of the disease and could help both sexes in terms of coming up with treatment approaches? I think that the right treatment approach for a female above the age of 65 may end up being different than what it is for a male. Really the only way to find out is to look.”
The research was supported by the National Institutes of Health, the Alzheimer’s Disease Genetics Consortium (funded by the National Institute on Aging) and the Vanderbilt Memory and Alzheimer’s Center.
