Imagine a grand mansion where different rooms represent various aspects of Alzheimer’s disease (AD). One room explores the connection between sex differences and AD, while another delves into the impact of depression. In this study, researchers took a closer look at these rooms to gain a deeper understanding of how they interact. By comparing a group of individuals with pathologically confirmed AD to a control group without dementia, they discovered intriguing findings. While women in the control group experienced higher levels of depression, this discrepancy disappeared when considering only those with AD. However, both men and women with AD had higher rates of depression compared to the control group. Surprisingly, the increase in depression frequency was more pronounced in men with AD than women. These results suggest that there may be unique factors in the development of depression in men with AD. Further exploration is needed to uncover the underlying mechanisms behind this sex-specific difference. This study underscores the importance of considering sex as a critical factor in aging studies and raises questions about potential therapeutic interventions tailored to address the distinct needs of men and women living with AD.

IntroductionSex differences in Alzheimer’s disease (AD) may contribute to disease heterogeneity and affect prevalence, risk factors, disease trajectories and outcomes. Depression impacts a large number of patients with AD and has been reported to be more prevalent in women. We aimed to better understand the interaction between sex, depression and AD neuropathology, which could have implications for detection of symptoms, earlier diagnosis, therapeutic management, and enhanced quality of life.MethodsWe compared 338 cases with clinicopathologically confirmed AD (46% women) to 258 control cases (50% women), without dementia, parkinsonism or a significant pathological diagnosis. Depression was assessed both, using the Hamilton Depression Scale (HAM-D), and as being reported in their medical history combined with treatment with antidepressant medication.ResultsIn the control group, women showed a higher depression severity, and a higher proportion of women were found to meet the cut-off score for depression on the HAM-D (32 vs. 16%) and having an history of depression (33 vs. 21%), while these sex differences were not observed in AD. Further, in both groups, female sex independently predicted the presence of depression, with covariates for age and cognitive status. AD subjects had higher mean HAM-D scores, were more likely to meet cutoff scores for depression (41 vs. 24%) and have a history of depression than controls (47 vs. 27%). When comparing the increase in frequency of depression in controls versus AD, the difference was significantly greater in men (AD men – control men: 24%) than in women (AD women – control women: 9%). Although subjects with depression were more likely to have higher levels of AD neuropathology, these differences were not observed when investigating the control or AD group separately.DiscussionControl women had a higher likelihood and severity of depression than control men, but this sex difference was not noted when considering only those with pathologically defined AD, emphasizing the importance of considering sex in aging studies. AD was associated with higher rates of depression and men may be more likely to report or be diagnosed with depression once they develop AD indicating the importance of more frequent depression screenings in men.

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