Study addresses the debate around gender, genetics and Alzheimer’s disease

Written by Francesca Lake

When it comes to mutations in APOE, the long-standing yet controversial view is that women carriers of the ε4 allele are at a greater risk for late-onset Alzheimer’s disease (AD) than their male counterparts. However, a new meta-analysis has challenged this theory.
Various studies have shown either that gender confers an increased risk, or none at all.

The analysis saw researchers from the Keck School of Medicine at the University of Southern California, Los Angeles (CA, USA) analyze the relationship between gender , APOE genotype and risk of mild cognitive impairment (MCI) and AD using data covering nearly 58,000 patients in 27 research studies.

They demonstrated that one copy of the ε4 allele conferred no difference in risk of AD or MCI between the ages of 55 and 85. AD risk was increased for women in the 65–75 age group compared to men, and MCI risk was increased for women between the ages of 55 and 70. The effect of other alleles on risk was also examined.

The researchers postulated that the physiologic changes associated with menopause and estrogen loss could be behind the gender differences.

The study was limited by variability in the methods used to describe AD and MCI in the data sets, and the lack of detail pertaining to risk factors and lifestyle in the data sets. The analysis was also restricted to a non-hispanic, white population, preventing generalization of the results.

“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 AD,” noted the authors. “For example, if women are at increased risk for AD at younger ages, it is plausible that treatments for women may need to be initiated earlier, especially in those who carry an APOE ε4 allele.”

The results were further discussed in an accompanying Editorial by Dena Dubal and Camille Rogine (University of California, San Francisco, CA, USA). “The Neu et al. study appears to narrow the window through which we visualize increased AD susceptibility for women with APOE3/E4. This finding raises the question: what is going on within and beyond this 10- to 15-year period?” they commented. “What if we could identify young women at high risk for AD decades before its onset, based on APOE4 status combined with other biomarkers, and offer a treatment derived from newfound, sex biology–based, APOE ε4 pathways?”

Sources: Neu SC, Pa J, Kukull W et al. Apolipoprotein e genotype and sex risk factors for Alzheimer disease: a meta-analysis. JAMA Neurol. doi:10.1001/jamaneurol.2017.2188 (2017) (Epub ahead of print); Dubal D, Rogine C. Apolipoprotein E ε4 and risk factors for Alzheimer disease—let’s talk about sex. JAMA Neurol. doi:10.1001/jamaneurol.2017.1470 (2017);