by Paul Govern

A new study of genetic risks for cognitive impairment later in life uses data from 32,426 research participants ages 60 and older to elaborate these risks across sex and across the intersection of sex and race. The study, the largest of its kind to date, was reported July 17 in JAMA Neurology. 

“Learning more about how these genetic risks play out across sex and race can help guide research into the causes of cognitive decline in Alzheimer’s disease,” said the leader of the study, computational geneticist Logan Dumitrescu, PhD, MS, assistant professor of Neurology at Vanderbilt University Medical Center.

The risk variants at issue in the study occur in APOE, the gene that encodes the brain’s principal cholesterol carrier, apolipoprotein E. In humans APOE comes in three variants. APOE3, the most common, is considered neutral with respect to Alzheimer’s risk.

APOE4 is the strongest genetic risk factor for cognitive impairment later in life and is carried by half of people who develop Alzheimer’s disease after age 65. It’s known to increase risk more for women than for men, but apparently, it’s been unclear whether this difference obtains across races. While common, APOE4 is considerably less common than APOE3.

APOE2, which is less common still, is considered to lower risk of cognitive impairment later in life, but apparently, it’s been unclear whether APOE2 protection varies either with sex or with race.

• The study finds that APOE4 has stronger negative effects on baseline memory and language capability in women than in men and establishes that this sex difference is similar for whites and Blacks.
• The study finds that risk reduction from APOE2 is similar for men and women overall, but when it comes to the intersection of sex and race, the researchers write that “the APOE2 protective effect was female-specific among white individuals but male-specific among Black individuals.”

“These are instructive and somewhat puzzling results,” Dumitrescu said, “with APOE4 seen as interacting with age-related changes in sex biology across races, while surprisingly APOE2 presents this see-saw with respect to the intersection of sex and race, which cries out for a yet larger study.”

Data for the study comes from four cognitive aging research cohorts, with 38% of participants found to carry at least one copy of APOE4 and 14% carrying at least one copy of APOE2. Cognitive performance was measured periodically, and separate scores were highlighted for memory, executive function and language capability.

Joining Dumitrescu to lead the study were co-lead authors Skylar Walters, MS, statistical genetic analyst II, and graduate student Alex Contreras. Others from VUMC on the study include Jaclyn Eissman, Amalia Peterson, MD, Katherine Gifford, PsyD, Angela Jefferson, PhD, and Timothy Hohman, PhD. The study was supported by the National Institutes of Health (AG10161).