Gene Factors Into Sex-Related Differences in Cognition Loss in Presence of T2D

Among patients with type 2 diabetes (T2D) and weight issues, cognitive advantages that women hold over men when both are affected are preserved into later life but are eroded for women carrying apolipoprotein E ε4 alleles.

Among patients with type 2 diabetes (T2D) patients and weight issues, women tend to maintain certain advantages over men on certain cognitive assessments as they age, but women with apolipoprotein E (APOE) ε4 see those advantages eroded, according to a new study.

Results of the study, published in Alzheimer’s & Dementia: Translational Research & Clinical Interventions, looked at patients with T2D who were overweight or obese. The study found women performed better than men in verbal learning and processing speed (P < .001). However, women with the APOE ε4 genotype suffered steeper cognitive declines in verbal learning (P = .02) and processing speed (P = .007) than those without the alleles; men were not affected by having the allele or not.

The rates of decline overall for men and women were similar (P ≥ .10). Also, the sexes performed equivalently in executive function assessments (P = .22).

Numerous studies have reported that women’s cognitive performance exceeds men’s when it comes to verbal learning and memory, with some having reported that cognitive decline for females is less steep during the aging process. However, numerous risk factors can have a negative impact on cognition, including diabetes and obesity.

A previous report by the authors, from the Action for Health in Diabetes (Look AHEAD) cohort with diabetes and obesity, showed women with better average performances in cognition. One surprising result from the study was that the prevalence of mild cognitive impairment or dementia was 45% lower among women than men throughout the cohort’s entire age range from 55 to 86. The prior analysis, however, could not distinguish the reason as being the result of a slower rate of cognitive aging in women, from relative cognitive benefits having emerged prior to cognitive assessments, or perhaps both.

The new study followed up on Look AHEAD by examining longitudinal assessments of cognitive functions. The researchers obtained 2 to 4 cognitive assessments across up to 10 years from 2799 adults with T2D who had been enrolled in a clinical trial of weight loss intervention. Individuals were part of a randomized controlled trial that began recruiting in 2001. Weight loss interventions ended by 2012.

The faster rate of cognitive aging among women with the APOE ε4 allele relative to male carriers suggests that the allele accelerated decline, the authors said.

“Because APOE ε4 is the strongest risk factor for dementia due to Alzheimer’s disease (AD), it is possible that greater underlying AD pathology in women compared to men explains this observation,” the authors wrote.

Furthermore, since women with T2D are known to have higher risk for stroke and cardiovascular disease than men, and the Look AHEAD cohort women had a higher burden of cerebrovascular disease, it is possible that the underlying pathology may have prevented any further expansion of cognitive benefits for females over time, they wrote.

The authors also suggested that having the APOE ε4 genotype may have cut against any benefits that lifestyle intervention may have provided perimenopausal women. They speculated there may be an adverse interaction between endogenous estrogen and the APOE ε4 genotype on glucose metabolism in the brain.


Espeland, MA, Yassine, H, Hayden, KD, et al. Sex‐related differences in cognitive trajectories in older individuals with type 2 diabetes and overweight or obesity. Alzheimer's Dement. 2021;7:e12160. doi:10.1002/trc2.12160