Studies going back 20 years consistently indicate that the effects of ApoE4, the strongest genetic risk factor for late-onset AD, hit women harder than men across the lifespan. In a new meta-analysis, Arthur Toga and colleagues at the University of Southern California, Los Angeles, marshal clinical and genotype data on nearly 58,000 research participants, and come up with a more nuanced picture. For people between 55 and 85, the study suggests, having one copy of the E4 allele increases the risk of MCI and AD equally in women and men. Sex differences show up only at certain ages, where the risk kicks in earlier for women, and later for men. The study appears in the August 28 JAMA Neurology.

“The Neu et al. study appears to narrow the window through which we visualize increased AD susceptibility for women with [ApoE4],” wrote Dena Dubal and Camille Rogine of the University of California, San Francisco, in an accompanying editorial. But the work raises many questions, they wrote, including: What happens before and during this window to account for the risk? And do preventive efforts aimed at ApoE4 carriers need to start earlier in women than in men?

The work “reminds us that sex differences are relevant to the study of Alzheimer’s disease,” said Eric Reiman, Banner Alzheimer’s Institute, Phoenix. “Any differences might provide clues regarding disease mechanism and targets at which to aim treatments,” he wrote in an email to Alzforum (see full comment below). Reiman said the finding also emphasizes the value of including information about sex in prevention trials where relevant. “For instance, sex differences may be important for sample-size estimates for those prevention studies that use cognitive or clinical endpoints in younger persons with the ApoE3/4 genotype,” he wrote in an email to Alzforum.

The product of the ApoE gene, apolipoprotein E, abounds in the brain and participates in multiple AD-related processes, including Αβ production and clearance. The three ApoE alleles—E2, E3, and E4—confer different risks for AD. Most people have two copies of the E3 allele, which is neutral for AD risk. E4, carried by 25 percent of the population, increases the risk of AD, while the much rarer E2 protects. An influential 1997 meta-analysis established a sex difference in E4’s influence, showing that women with one E4 allele have a fourfold higher risk of AD than male carriers, who have about the same risk as E3/E3 men (Farrer et al., 1997). The sex difference also show up in biomarkers of pathology: Female ApoE carriers with MCI show increased cerebrospinal fluid tau concentrations and tau/Aβ ratios, compared with male carriers (Altmann et al., 2014May 2014 news). However, the influence of ApoE and sex on developing MCI and for moving from MCI to AD has been less studied.

To investigate the sex effect on a larger scale than previously possible, Toga and his group took advantage of the Global Alzheimer’s Association Interactive Network (GAAIN), an open-access resource that aggregates data from multiple independent studies of AD and MCI around the world (Nov 2016 news). By mining GAAIN data, first author Scott Neu could computationally aggregate nearly 60,000 subjects between the ages of 55 and 85 from 27 independent research studies, collating data on diagnosis, ApoE genotype, sex, and ethnicity. To minimize the variability in how AD is diagnosed across studies, the researchers asked each data set provider to recode his or her diagnoses into one of three pre-established categories—AD, MCI, or normal. The study excluded people with other neurological diseases, or with APP or presenilin mutations. Finally, because ApoE-associated risk varies with ethnicity, the investigators only looked at white (non-Hispanic) people of European descent. In the end, the study set comprised 31,340 subjects, divided into three case-control groups to compare genotypes in AD versus normal, MCI versus normal, and AD versus MCI. The researchers calculated the relative odds of AD for each genotype relative to the E3/E3 genotype, which they set at 1.

Over the entire age range, they did not detect a sex difference in E4 risk. Both men and women with E3/E4 genotype had about a threefold increase in risk for developing AD compared to their E3/E3 counterparts. For MCI, both sexes again showed similar risk, at about 1.6 times higher in E4 carriers than noncarriers. ApoE4 gave both men and women with MCI a twofold increased chance of deteriorating to AD. All categories of risk jumped in E4/E4 homozygotes, where the effect was equally high for both women and men. The protective effect of E2 did show a sex difference, with women seeing a greater reduction in risk than men.

The results suggest, contrary to previous data, that E4 affected men and women equally. But when the scientists broke out the risk by age, sex differences appeared. The ApoE4-associated risk of AD and MCI peaked earlier in women than in men, giving significant elevation between the ages of 65 and 75 for AD (4.37 times increased risk in women compared to 3.14 in men) and 55 and 70 for MCI (1.43 in women versus 1.07 in men). The E4-associated risk for AD or MCI among men peaked in the 75- to 85-year-old group.

“This finding supports the earlier, smaller studies that ApoE4 affected women more than men, but this is apparently not nearly as strong as previously thought,” said William Rebeck, Georgetown University, Washington, D.C. “People thought for years that APOE4 was a much bigger problem in women, but that apparently is not true,” he said.

Despite the large sample size, the study has significant limitations, which could skew the results. The authors discuss the variability in clinical diagnosis of MCI and AD across studies, and the lack of adjustment for other risk factors, such as education and family history of disease, as well as potential sex differences in lifestyle factors like cigarette smoking or alcohol use. The lack of distinction between different forms of MCI could also have influenced the results, said Charles Brainerd of Cornell University in Ithaca, New York. The diagnosis of AD itself is influenced by sex, said Mary Jo La Du, University of Illinois, Chicago. Women lag in diagnosis by about five years compared to men, she pointed out. Nevertheless, she said the sex difference must be robust to show up in this kind of study.

While the authors say they hope their work will stimulate more research on the basis of the sex difference, La Du fears the opposite. “I’m concerned people will look at these small differences and decide sex is not an important variable, despite years of evidence that it is,” she said. In contrast to human studies that rely on variable diagnoses to approximate pathology, animal work allows for the direct measurement of pathology and behavior and shows the interaction of sex and ApoE4 is profound, she added. 

In fact, the results for women’s risk agree with the 1997 meta-analysis, said Lindsay Farrer of Boston University, the lead author on that study. “The main finding of the new paper showing increased risk of AD among women between ages 65 and 75 is identical to what we reported for that same age period,” Farrer wrote in an email to Alzforum. The difference is that Farrer also detected a significant sex difference over the entire age range of his study. Subject selection might explain that, he wrote. “The onset ages of the subjects in our study were much more skewed toward younger ages, so that averaging over the entire range would yield a significant sex difference at all ages. Had we had a greater sampling of subjects with onset after age 80, the results may have been more similar to those of the new study, but I can’t be sure.”

The result has ramifications for clinical trials for preventive measures, and especially those targeting E4, Toga explained. “As we move to treating at ever-younger ages, it’s important to get a handle on risk as early as possible. This study suggests that women may have a slight increase in E4-associated risk at a much younger age than men.” That may warrant starting treatment earlier in women, especially those carrying E4, he said.

The implications for prevention trials in younger ApoE4 carriers need to be clarified, Reiman said. In the meantime, sex as a variable may be less important in ongoing trials enrolling ApoE4 homozygotes, he said (see Jul 2014 news, and full comment below). Men and women with two copies of ApoE4 show an exaggerated risk of AD, around 10 times higher than noncarriers, with no reported sex difference in this, or previous, studies. 

Defining an age of susceptibility may help narrow the focus on mechanistic studies looking at how sex interacts with Apoe4 to promote AD. “This is a major contribution to fine-tuning sex effects in age groups, and pushes risks earlier for women than men,” said Yadong Huang, University of California, San Francisco. “We should do similar studies in animals to define an age window where you see gender effect. This will help us to narrow down the best time to study mechanisms in mice,” Huang told Alzforum.

The increased risk in women comes on the heels of menopause. Although the investigators don’t know when precisely women in the study went through menopause, the mean age is 51. Could a loss of estrogen’s neuroprotective effects set off degenerative processes selectively in the E4 carriers? That is just one possible explanation, said Toga. “This is the value of studies like this. By beginning to put the temporal map together we get a more comprehensive picture, and begin to see patterns that pose new questions.” The ability to do this is in a computational way using pre-existing data helps speeds up that process, Toga said.—Pat McCaffrey

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  1. Surprisingly, the effects of sex on ApoE4-related risk of Alzheimer's disease have not been well examined. The studies most referenced are from the 1990s, despite the huge growth in information about ApoE genotype and AD since then. Now, in a meta-analysis of 27 studies and over 30,000 individuals, Neu et al. show that, grouping all ages together, there is no difference in ApoE4-related risk in women than in men: ApoE3/4 women, Odds Ratio=3.1; ApoE3/4 men, OR=3.3. Logistic regression analysis did show that the ApoE4 effect occurs earlier in women, resulting in a higher OR in ApoE3/4 women than men in the age group 65 to 75 (4.4 versus 3.1). This finding supports the earlier, smaller studies that ApoE4 affected women more than men, but this effect is apparently not nearly as strong as previously thought.

    There were other findings here that help define the risk associated with ApoE2. ApoE2 was associated with decreased risk of AD (as expected), but ApoE2 women were protected better than men (OR = 0.5 compared to 0.7). Female and male ApoE2/4 individuals had an increased risk of AD (OR=2.1-2.3), consistent with the view that ApoE4 has a stronger negative risk than ApoE2 has a protective risk. In both sexes, ApoE genotype had a much smaller effect on MCI, perhaps because non-AD patients can be found more in this group. No sex effect on ApoE4-related conversion from MCI to AD was observed. Together, these data help define a broader set of individuals who would benefit from any ApoE4-related therapeutic approaches.

  2. In this meta-analysis of data from nearly 58,000 cases and controls, the authors report no overall sex differences in clinical AD risk in ApoE4 heterozygotes or homozygotes 55–85 years of age. But they did see higher odds ratios in women at younger ages (i.e., 65–75). Furthermore, they found that the ApoE2 allele had a greater protective effect in ApoE4 carriers than noncarriers. While one cannot exclude an impact of ascertainment bias on this primarily retrospective case-control study, I find it interesting and important for several reasons:

    It reminds us that sex differences are relevant to the study of Alzheimer’s disease, and that any differences might provide clues regarding disease mechanisms and targets at which to aim treatments.

    It suggests the value in incorporating information about sex in prevention trials, when relevant. For instance, sex may be important for sample-size estimates for those prevention studies that use cognitive or clinical endpoints in younger persons with the ApoE3/4 genotype and to ensure comparable proportions of males and females in the active and placebo treatment groups. On the other hand, sex may be less important for ApoE4 homozygotes or those with the ApoE2/4 genotype, and its implications for prevention trials in younger ApoE4 carriers using biomarker endpoints needs to be clarified.

    It highlights the value of the rapidly growing Global Alzheimer’s Association Interactive Network (GAAIN), permitting researchers to initially survey and then analyze data from the largest number of relevant subjects. This federated data resource—and shared data from prospective cohort and case-control studies in general—will have great value for the entire field.​

  3. This new study has about twice as many cases and the same number of controls as our 1997 study. The main finding of the new paper showing increased risk of AD among women between ages 65 and 75 is identical to what we reported for that same age period. The notable difference between studies is that the portion of our sample on which the sex-difference in risk was based was among clinic- and autopsy-based samples, which tend to be younger than subjects ascertained in community-based samples.

    Community-based data sets were included in their study, whereas we had such samples but excluded them from this specific analysis because of ascertainment bias. This probably explains why we saw an attenuated finding at even earlier ages (as low as age 50) but did not observe a diminishing effect of the sex difference at later age. It would be interesting to see what they find only among the clinic- and autopsy-based portion of their sample. Take-home message (for me) is that it is nice to have our findings confirmed 20 years later. ​

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References

News Citations

  1. NIH to Ensure Equal Study of Sexes in Preclinical Research
  2. EMIF, GAAIN: Online Gateways to Reams of Alzheimer’s Data
  3. Novartis to Partner with Banner Health on ApoE4 Prevention Trial

Paper Citations

  1. . Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA. 1997 Oct 22-29;278(16):1349-56. PubMed.
  2. . Sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014 Apr;75(4):563-73. Epub 2014 Apr 14 PubMed.

External Citations

  1. Global Alzheimer’s Association Interactive Network

Further Reading

No Available Further Reading

Primary Papers

  1. . Apolipoprotein E Genotype and Sex Risk Factors for Alzheimer Disease: A Meta-analysis. JAMA Neurol. 2017 Aug 28; PubMed.
  2. . Apolipoprotein E ε4 and Risk Factors for Alzheimer Disease-Let's Talk About Sex. JAMA Neurol. 2017 Aug 28; PubMed.