Study shows well-established protective gene for Alzheimer’s only safeguards against cognitive decline in men

A new study led by Sunnybrook researchers has found that APOE ε2, a gene variant known to be protective against Alzheimer’s disease, is only protective in men and not women. The research was published in Alzheimer’s & Dementia: The Journal of the Alzheimer's Association today.

“Previous research has shown that women have an increased risk of developing Alzheimer’s disease,” says Dr. Jennifer Rabin, senior author of the study and a scientist in the Hurvitz Brain Sciences Program at Sunnybrook Research Institute. “Although factors such as longer survival may contribute to why women are more likely to develop the disease, recent research suggests biological mechanisms may also impact sex differences in Alzheimer’s risk and progression.”

APOE ε2 is one of three inherited gene variants that can affect the chances of a person developing Alzheimer’s disease. Having the APOE ε2 variant decreases risk, whereas having the APOE ε4 variant increases risk. APOE ε3, the most common variant, is believed to have a neutral effect on the disease.

The collaborative study team, which included researchers from Canada and the United States, looked at whether sex modifies the association between the protective APOE ε2 gene variant and cognitive decline, using publicly available data from cognitively unimpaired adults that were part of four observational research sources.

The authors found that across two independent samples of participants, men with APOE ε2 were more protected against cognitive decline compared to women with the same APOE ε2 variant. In addition, men with APOE ε2 were more protected compared to men with the neutral gene variant (APOE ε3/ε3). However, this was not the case in women. In women, those with APOE ε2 were no more protected than those with the neutral gene variant (APOE ε3/ε3). The reasons for these sex-specific effects remain unclear. However, one possibility is that declining estrogen levels that occur with menopause may be a contributing factor given that estrogen has neuroprotective effects.

“These results suggest that the longstanding view that APOE ε2 provides protection against Alzheimer’s disease may require reevaluation,” says Madeline Wood, a graduate student at Sunnybrook and lead author of the study. “Our findings have important implications for developing sex-specific strategies to prevent and treat Alzheimer’s disease, particularly given that women are at a higher risk than men.”

The authors say the next step in their research is to continue to replicate the findings in large and diverse samples and to further investigate the sex-specific effects of APOE ε2 on Alzheimer’s disease biomarkers.

Funding for this study was supported by The Harquail Centre for Neuromodulation, the Dr. Sandra Black Centre for Brain Resilience & Recovery, Canadian Institutes of Health Research, and the Alzheimer’s Society of Canada.

Media Contact:
Samantha Sexton
Communications Manager, Sunnybrook Research Institute
Samantha.sexton@sunnybrook.ca