Basic Science and Pathogenesis

Alzheimer's disease (AD) is a neurodegenerative disease that affects 6.5 million Americans aged 65 or older. Of the 6.5 million Americans with AD, 4.2 million of them are female^, demonstrating that females are at higher risk for AD than males. One genetic risk factor for AD is APOE genotype. Apolipoprotein E (APOE) has three predominant alleles in humans: APOE2, APOE3, and APOE4. Individuals that are homozygous for APOE4 have up to a 15-fold increase in AD risk compared to APOE3 homozygous individuals. A third, modifiable risk factor for AD is diet. A high fat, 'Western' style diet has been shown to be associated with AD.

12-week-old human APOE3 and APOE4 knock-in mice of both sexes were fed a standard chow or Western diet for 16 additional weeks (total 6 months old) to investigate the effects of diet, sex, and APOE genotype. Hippocampus were isolated and processed for mitochondrial frozen respirometry and immunoblotting.

When fed a chow diet, there were no differences in respiration capacities between the APOE3 and APOE4 genotypes within the sexes. Chow-fed females of both genotypes displayed significantly decreased mitochondrial complex I- and IV- dependent respiration capacities in the hippocampus compared to chow-fed males. On a Western diet, APOE4 males displayed significantly decreased mitochondrial complex I- and IV- dependent respiration capacities as well as significant decreases in all electron transport chain complex proteins compared to APOE3 males.

Our findings suggest that female APOE4 KI mice exhibit reduced mitochondrial function under chow-fed conditions compared to male APOE4 KI mice, while a Western diet leads to mitochondrial maladaptation in male APOE4 KI mice. A Western diet in female mice is likely to further exacerbate the observed sex differences in mitochondrial function, resulting in a more significant decrease in respiration capacities in APOE4 females compared to APOE3 females and/or APOE4 males. Further research is needed to examine the effects of a Western diet on mitochondrial function in APOE4 female mice.