Altered SPMs and age-associated decrease in brain DHA in APOE4 female mice: Brain SPMs and DHA, sex, ageing and APOE genotype

An Apolipoprotein E4 (APOE4) genotype is the most important, common genetic determinant for Alzheimer’s disease (AD), and female APOE4 carriers present with an increased risk compared to males.
The study quantified cortical and hippocampal fatty acid and phospholipid profiles along with select eicosapentaenoic acid (EPA)- and docosahexaenoic acid (DHA)-derived specialised proresolving mediators (SPMs) in 2-, 9- and 18-month-old APOE3 and APOE4 male and female mice.
A 10% lower cortical DHA was evident in APOE4 females at 18 months compared to 2 months, with no significant decrease in APOE3 or APOE4 males. This decrease was associated with a reduction in DHA-phosphatidylethanolamine. Older APOE4 females had a 15% higher oleic acid content compared to young mice. Although no sex*APOE genotype interactions were observed for SPMs expressed as a ratio of their parent compound, higher cortical (±) 18 HEPE, resolvin D3, protectin D1, 10S,17S-diHDHA, maresin 1, 17S-HDHA and 14S-HDHA were evident in females, and lower cortical 17R-resolvin D1, 10S,17S-diHDHA and (±) 18 HEPE in APOE4.
Our findings show a strong association between age, female sex and an APOE4 genotype, with decreased cortical DHA and a number of SPMs, that together may contribute to the development of cognitive decline and AD pathology