Scientists haven’t pinpointed a definitive cause for Alzheimer’s disease—a fatal brain disorder that robs people of their memory and cognitive abilities. But now researchers have uncovered an intriguing clue about why more women than men develop the condition. A particular gene variant, found in a quarter of the population and long known to raise people’s risk for the disease, seems less menacing in men, new research shows. The findings could have implications for potential gender-specific treatments, some Alzheimer’s investigators suggest.
Though a small percentage of Alzheimer’s cases arise from genetic mutations that cause obvious disease before the age of 65, the vast majority of people who develop the condition do so later in life from undefined triggers, some thought to be genetic. In 1993, scientists found that people who inherit a gene variant called apolipoprotein E4 (APOE4) are more prone to the common form of Alzheimer’s that strikes in late life . There’s also a “risk-neutral” variant (APOE3) and a much rarer version of the gene (APOE2) that decreases a person’s risk for Alzheimer’s. Shortly thereafter, other research groups replicated the finding and some data hinted that APOE4 raises Alzheimer’s risk more in women than in men. Indeed, when scientists combed through a massive data set containing 5930 Alzheimer’s patients and 8607 dementia-free elderly from 40 independent studies, they reported in 1997 that females with the APOE4 variant were four times more likely to have Alzheimer’s compared with people with the more common, neutral form of the gene . However, in men, APOE4 seemed virtually harmless.
“It was a pretty big effect,” says Michael Greicius, a neurologist at Stanford University Medical Center in California, of the analysis. Yet the findings didn’t create much of a stir at the time.
In fact, Greicius had been practicing for 5 years before learning of the data in 2008. After dozing off for the first few slides of someone’s talk, he perked up when the 1997 findings showed up. He recalls thinking “there might be something to it.”
Greicius became more convinced of the gender effect a few years ago when his group performed a neuroimaging study in healthy older adults. The brain scans revealed that even in the absence of symptoms, women with the APOE4 variant had poor connectivity in brain networks typically afflicted by Alzheimer’s , compared with those without APOE4; brain connectivity in male APOE4 carriers looked almost normal. Some studies in mouse models of Alzheimer’s disease have also found that female rodents had more severe behavioral and neurological defects than their brothers.
To nail the issue, Greicius and colleagues analyzed data from 2588 people with mild cognitive impairment and 5496 healthy elderly who visited national Alzheimer’s centers between 2005 and 2013. They noted the participants’ APOE genotype—a person can have two, one, or zero copies of APOE4—and gender, and logged which of the people who already had mildly impaired cognitive abilities ended up with full-blown Alzheimer’s, and who among the healthy developed mild cognitive impairment or Alzheimer’s.
In the group with mild memory deficits, both male and female APOE4 carriers progressed to Alzheimer’s disease more readily than those without the risk gene. However, among healthy seniors, women who inherited the APOE4 variant were twice as likely as noncarriers to develop mild cognitive impairment  or Alzheimer’s disease, whereas APOE4 males fared only slightly worse than those without the gene variant. In a separate group of 980 seniors participating in the Alzheimer’s Disease Neuroimaging Initiative, spinal fluid measures of the protein tau, also implicated as a contributor to the brain disorder, seemed more indicative of Alzheimer’s in APOE4 women than APOE4 men. Greicius’s Stanford team reported its findings online today in Annals of Neurology.
Because the study was large and longitudinal, meaning it looked at the same group of people over time, other scientists consider the new study more powerful than the 1997 analysis, which did not check if people in the control group later became impaired. The new paper “confirms the gender effect of APOE4 in a more robust way,” says Yadong Huang, a neuroscientist at the Gladstone Institute of Neurological Disease in San Francisco, California.
The findings will likely have implications for future studies of potential Alzheimer’s treatments. In previous clinical trials, some side effects have been more harmful to APOE4 carriers than noncarriers, but very few studies have subdivided these groups by gender. It’s also possible that some compounds will prove more effective for men than for women, Huang suggests.
In addition, the new findings are likely to spur research into biological mechanisms that might explain APOE4’s gender bias. Prior research points to hormones. The APOE gene contains stretches of DNA that estrogen can bind, and mouse studies show the hormone can regulate APOE expression in a tissue-specific manner . And in people, cells age faster in APOE4 women than in carriers—yet less so in women on hormone therapy .