Recent Alzheimer’s disease (AD) research has taken a new approach by looking at how various factors like genetics, sex, and lifestyle choices come together to impact the progression and severity of the disease. The most significant risk factor for late-onset AD is the gene APOE4. When combined with a high-fat, high-sugar Western diet, APOE4 carriers had worse outcomes, and the effects differed for males and females.

In this study, scientists fed a Western diet to mice specially bred to have two copies of APOE4. While both sexes showed cognitive impairments, the effect was more pronounced in males. Males also had larger livers and signs of oxidative stress and brain inflammation. Female APOE4 carriers did not have these signs, yet they still had cognitive impairments.

The study suggests that male APOE4 carriers are more vulnerable to the harmful effects of a Western diet than females. It is also further evidence that AD risk factors affect males and females differently, and it is critical to research both sexes.

Instead of having a single cause, it is becoming increasingly clear that Alzheimer’s disease (AD) results from the convergence of risk factors such as genetics, sex, and lifestyle. While it’s important to study each factor separately, examining how these factors interact may provide a deeper understanding of the biological processes leading to AD.

APOE4 is the most significant genetic risk factor for developing AD, and the gene’s impact is more pronounced in females. Alongside genes and sex, lifestyle factors are also implicated in AD. Obesity, for example, accelerates and worsens AD-related changes in animal models and is a modifiable risk factor in humans. A contributor to obesity is prolonged consumption of a Western diet, which is high in saturated fats and sugars.

To explore how a Western diet might interact with sex and APOE4 status, researchers engineered mice to have two copies of the APOE4 gene and then fed them a Western diet for nine months. They compared these mice to those fed a standard diet and to mice that are non-APOE4 carriers.

In non-carriers, a Western diet led to larger livers. Among APOE4 carriers, only the males experienced liver enlargement. A Western diet also triggered oxidative stress and brain inflammation, but only in male APOE4 carriers.

Irrespective of APOE4 status, all mice on a Western diet had higher blood glucose levels. Altered glucose metabolism can contribute to diabetes, a condition linked to an elevated risk for AD. Surprisingly, the greatest changes were observed in APOE4 females, yet they experienced no change in liver size and no signs of oxidative stress or brain inflammation.

Both male and female APOE4 carriers exhibited cognitive impairments after consuming a Western diet, but the impact was more significant in males, suggesting that males might be more susceptible to the adverse consequences of a Western diet than females. These effects, such as impaired liver function and glucose metabolism, could lead to inflammation and oxidative stress in the brain and, ultimately, cognitive impairment.

Why female APOE4 carriers experienced cognitive impairment despite not having the same metabolic issues as males remains unclear. Further research is needed in this area.

This study indicates that an approach like precision medicine, which considers how genetics, sex, and lifestyle factors interact, could be highly beneficial in preventing and treating AD. It also highlights the ongoing need to study AD in both sexes.

Published in International Journal of Molecular Sciences.

Sex Differences in Metabolic Indices and Chronic Neuroinflammation in Response to Prolonged High-Fat Diet in ApoE4 Knock-In Mice

Paula Grammas, Ph.D., Tribute Senior Living