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Men and women with the apolipoprotein E ɛ4 (APOE4) allele have essentially the same risk of developing Alzheimer's disease from ages 55 to 85, but women between 65 and 75 with APOE4 have a higher risk than men of the same genotype and age group, a meta-analysis found.

Across an age span of 55 to 85 years, men (OR 3.09, 95% CI 2.79-3.42) and women (OR 3.31, 95% CI 3.03-3.61) with APOE ɛ3/ɛ4 showed a similar increase in Alzheimer's disease risk, according to Arthur Toga, PhD, of the University of Southern California in Los Angeles, and colleagues.

Between ages 65 and 75, however, women with APOE ɛ3/ɛ4 had a higher risk of Alzheimer's disease than men (women: OR 4.37, 95% CI 3.82-5.00; men: OR 3.14, 95% CI 2.68-3.67; P=0.002), they reported online in

"Collectively, our findings, along with previous work, warrant further investigation into a likely complex set of risk factors with consideration of sex-specific treatments for cognitive decline and Alzheimer's disease," they wrote. "For example, if women are at increased risk for Alzheimer's disease at younger ages, it is plausible that treatments for women may need to be initiated earlier, especially in those who carry an APOE ɛ4 allele."

The three most common alleles of the APOE gene are ɛ2, ɛ3, and ɛ4. Carrying the ɛ4 allele increases risk for Alzheimer's disease; conversely, the ɛ2 allele is associated with lower Alzheimer's disease risk.

The investigators performed a meta-analysis of 27 studies of 31,340 non-Hispanic white individuals between ages 55 and 85, working directly with each data set provider to classify each patient into categories of normal, mild cognitive impairment, and Alzheimer's disease. They excluded patients with a clinical history of stroke, cerebrovascular disease, Lewy bodies, amyloid precursor protein or presenilin gene mutations, or comorbidity with any other known neurological disease.

From pooled data, they calculated ORs for each sex and APOE genotype. For each sex, they used a continuous age variable and 5 indicator variables representing the 5 APOE genotypes (ɛ2/ɛ2, ɛ2/ɛ3, ɛ3/ɛ4, and ɛ4/ɛ4), with APOE ɛ3/ɛ3 as the referent. They also conducted another pooled analysis, adding a sex indicator variable and 5 additional covariates that were the products of the sex variable with each APOE genotype variable to look for interactions.

They discovered that, contrary to long-held views, men and women with the APOE ɛ3/ɛ4 genotype had nearly the same odds as developing Alzheimer's disease from 55 to 85 years. At ages 65 to 75, however, women with one copy of APOE4 were at increased risk of Alzheimer's disease.

Overall, the APOE ɛ2/ɛ3 genotype produced a protective effect on women (OR 0.51, 95% CI 0.43-0.61), decreasing their Alzheimer's disease risk more (P=0.01) than men (OR 0.71, 95% CI 0.60-0.85).

The investigators saw no difference in risk of mild cognitive impairment between men with APOE ɛ3/ɛ4 (OR 1.55, 95% CI 1.36-1.76) and women (OR 1.60, 95% CI 1.43-1.81) at ages 55 to 85. However, women who carried the ɛ4 allele had an increased risk of mild cognitive impairment between ages 55 and 70 (women: OR 1.43, 95% CI 1.19-1.73; men OR 1.07, 95% 0.87-1.30, P=0.05).

They also saw no significant differences between men and women in risk of converting from mild cognitive impairment to Alzheimer's disease from ages 55 to 85.

Though individuals with APOE ɛ4/ɛ4 had increased risk compared with individuals with ɛ3/ɛ4, the researchers saw no significant differences between men and women with ɛ4/ɛ4.

In an accompanying editorial, Dena Dubai MD, PhD, and Camille Rogine of the University of California in San Francisco noted that this study appeared to narrow the window to view increased susceptibility for women with APOE ɛ3/ɛ4.

"Unexpectedly, [the authors] identified ages during which clinical, sex-based vulnerabilities emerge," they wrote. "In the decades preceding this window, are deleterious APOE ɛ4 mechanisms preferentially operating in women?"

Because Alzheimer's disease is a long pathophysiological process, the findings that women with APOE ɛ3/ɛ4 from age 65 to 75 have increased risk might mean that invisible effects of APOE4 are in play much earlier, Dubai and Rogine noted.

"Sex matters in brain health," they added. "Understanding what makes one sex more vulnerable (or more resilient) unravels exciting, new pathways we can target in novel treatments for one or both sexes."

This study is limited by variability of the data sets the researchers used. They relied on the data set providers' expertise to translate diagnoses into the investigators' definitions of Alzheimer's disease and mild cognitive impairment. They also did not have information about risk factors like education and family history of dementia, or sex-dependent differences due to smoking, hormonal changes, or alcohol use.

The investigators also were not able to fully exclude Hispanic participants. This might have affected their results slightly, because the odds of developing Alzheimer's disease are different in Hispanic populations. "Considering these limitations, our results should not be generalized beyond white non-Hispanic individuals in North America and Europe," they wrote.