The role of sex differences in depression in pathologically defined Alzheimer’s disease

Abstract

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.

Sex differences in the relationship between depression and Alzheimer’s disease—mechanisms, genetics, and therapeutic opportunities

“…AD represents the most prevalent form of dementia, and nearly all patients experience neuropsychiatric symptoms, with depression being one of the most common psychiatric disorders, in conjunction with cognitive and memory deficits ( Lyketsos et al, 2011 ; Santos et al, 2016 ; Depp et al, 2023 ; Rodriguez Salgado et al, 2023 ; Tremblay et al, 2023 ). Importantly, depression not only manifests as an early symptom of AD dementia but also increases the risk of AD, and conversely, depressive disorders can also arise in response to cognitive decline due to AD ( Elser et al, 2023 ; Liao et al, 2023 ), suggesting a crucial and bidirectional association between AD and depression.…”

“…Notably, both depression and AD display a significant sex disparity, with a higher prevalence observed among women ( Wang et al, 2022a ), but existing research on sex differences in the association between AD and depression produces incongruent findings. A recent study noted men appearing to be more susceptible to developing depressive symptoms following the onset of AD ( Tremblay et al, 2023 ), which may arise from overlapping symptoms between AD dementia and depression, as well as the absence of consensus criteria to diagnose AD-related depression. Likewise, another study revealed that men diagnosed with depression have a higher risk of developing AD ( Elser et al, 2023 ), but men may be less inclined to seek healthcare compared with women, resulting in consistent underestimation of the prevalence of depression among men.…”

“…Alzheimer’s disease (AD) is a leading neurodegenerative disorder, characterized by cognitive deficits, behavioral changes, and memory loss ( Nebel et al, 2018 ; Depp et al, 2023 ). Recognized as a multifactorial disorder with diverse etiologies ( Guo et al, 2022 ; Uras et al, 2023 ), emerging evidence highlights sex differences as a significant contributor to AD’s heterogeneity, influencing prevalence, disease progression, risk factors, and outcomes ( Tremblay et al, 2023 ). Women, who represent about two-thirds of AD patients, exhibit a faster cognitive decline and higher susceptibility to AD ( Hampel et al, 2018 ; Levine et al, 2021 ; Martinkova et al, 2021 ; Cui et al, 2023 ).…”

“…Depressed individuals are over twice as likely to develop AD dementia compared to those without depression ( Elser et al, 2023 ), underlining a notable link between the two conditions. Interestingly, both depression and AD are more common in women ( Wang et al, 2022a ), yet studies suggest that men with depression might be at a higher risk of developing AD, and they are more likely to show depressive symptoms following AD onset ( Fuhrer et al, 2003 ; Dal Forno et al, 2005 ; Underwood et al, 2019 ; Tremblay et al, 2023 ).…”