Alzheimer’s Genetic Risk Tracked Across Sex and Race

A recent study led by Assistant Professor of Neurology Dr. Logan Dumitrescu examined how sex affects Alzheimer’s genetic risk, and how those effects differ between race. The genetic association study is the largest known study of its kind, using harmonized data from more than 32,000 research participants aged 60 and older.  

Apolipoprotein E (APOE), a protein involved in fat metabolism, is the strongest genetic risk factor for Alzheimer’s disease. In humans, APOE comes in three variants. APOE-e3, the most common, is considered neutral with respect to Alzheimer’s risk.   Though less common, APOE-e4 is carried by half of people who develop Alzheimer’s disease after age 65 and is known to increase risk. Past research has found that APOE-e4 increases Alzheimer’s risk more among women, but up until this study, it has been unclear whether this difference occurs across races.   

APOE-e2, the least common variant, is considered to lower risk of cognitive impairment later in life. However, it has been unclear whether APOE-e2 protection varies with sex or with race.  

The study found that APOE-e4 has stronger negative effects in females than in males and did not significantly differ among races. Surprisingly, the risk reduction from APOE-e2 among men and women were similar overall. However, when it comes to the intersection of sex and race, APOE-e2 showed a female-specific protective effect among White participants and a male-specific protective effect among Black participants.  

“These are informative and somewhat surprising results,” said Dr. Dumitrescu, “highlighting the fact that, while APOE-e2 and APOE-e4 have opposing effects on cognition and Alzheimer’s disease risk, they are not simply two sides of the same coin, as they are differently modified by sex and race, which has implication for precision medicine, clinical trial inclusion, and underlying biological etiology.”