Background Whether the association of cardiovascular diseases (CVDs) with dementia differs by sex remains unclear, and the role of socioeconomic, lifestyle, genetic, and medical factors in their association is unknown. Methods We used data from the UK Biobank, a population-based cohort study of 502,649 individuals. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between CVD (coronary heart diseases (CHD), stroke, and heart failure) and incident dementia (all-cause dementia, Alzheimer's Disease (AD), and vascular dementia (VD)). The moderator roles of socioeconomic (education, income), lifestyle (smoking, BMI, leisure activities, and physical activity), genetic factors (APOE allele status), and medical history were also analyzed. Results Compared to people who did not experience a CVD event, the HRs (95%CI) between CVD and all-cause dementia were higher in women compared to men, with an RHR (Female/Male) of 1.20 (1.13, 1.28). Specifically, the HRs for AD were higher in women with CHD and heart failure compared to men, with an RHR (95%CI) of 1.63 (1.39, 1.91) and 1.32 (1.07, 1.62) respectively. The HRs for VD were higher in men with heart failure than women, with RHR (95%CI) of 0.73 (0.57, 0.93). An interaction effect was observed between socioeconomic, lifestyle, genetic factors, and medical history in the sex-specific association between CVD and dementia. Conclusion Women with CVD were 1.5 times more likely to experience AD than men, while had 15% lower risk of having VD than men.

Summary Background Associations between endogenous estrogen exposure indicators and risk of subtypes of dementia have been unclear. Methods Databases (PubMed, EMBASE and Web of Science) were searched electronically on 1st July and updated regularly until 12nd November 2021. Observational studies of English language were selected if reported an effect estimate [e.g., odds ratio (OR), rate ratio (RR) or hazard ratio (HR)] and 95% CI for the association between any exposure (age of menarche, age at menopause, reproductive period, estradiol level) and any endpoint variable [all-cause dementia, Alzheimer's disease (AD), vascular dementia (VD), cognitive impairment (CI)]. Random-effects models and dose-response meta-analyses were used to calculate estimates and to show the linear/nonlinear relationship. PROSPERO CRD42021274827. Findings We included 22 studies (475 9764 women) in this analysis. We found no clear relationship between late menarche (≥14 vs <14 years) and dementia, CI in categorical meta-analysis compared to a J-shape relationship in dose-response meta-analyses. Later menopause (≥45 vs <45 years) was consistently associated with a lower risk of all-cause dementia (pooled RR: 0.87, 95%CI: 0.78–0.97, I 2 =56.0%), AD (0.67, 0.44–0.99, I 2 =78.3%), VD (0.87, 0.80–0.94) and CI (0.82, 0.71–0.94, I 2 =19.3%) in categorical meta-analysis, showing similar results in dose-response meta-analyses. An inverse relationship between longer reproductive duration (≥35 vs <35 years) and dementia was observed in dose-response meta-analysis. In addition, estradiol levels after menopause were inversely correlated with the risk of AD and CI. Interpretation In this study, later menopause and longer reproductive period were associated with a lower risk of dementia, while the relationship for menarchal age was J-shaped. There was an inverse relationship between higher postmenopausal estrogen levels and risk of AD and CI. Longitudinal study are needed to further explore the association between life-time estrogen exposure and risk of subtypes of dementia. Funding Start-up Foundation for Scientific Research in Shandong University.

Background Whether the association of type 2 diabetes (T2DM) with dementia was differed by sex remains unclear, and the roles of age at onset of disease, insulin use and diabetes’ complications in their association are unknown. Methods This study analyzed data of 447 931 participants from the UK Biobank. We used Cox proportional hazards models to estimate sex-specific hazard ratios (HRs) and 95% confidence intervals (CI), and women-to-men ratio of HRs (RHR) for the association between T2DM and incident dementia [all-cause dementia, Alzheimer's disease (AD), and vascular dementia (VD)]. The roles of age at onset of disease, insulin use and diabetes’ complications in their association were also analyzed. Results Compared to people with no diabetes at all, people with T2DM had increased risk of all-cause dementia (HR 2.85, 95% CI 2.56–3.17). The HRs between T2DM and AD were higher in women than men, with an RHR (95%CI) of 1.56 (1.20, 2.02). There was a trend that people who experienced T2DM before age 55 had higher risk of VD than those who had T2DM after age 55. In addition, there was a trend that T2DM had higher effect on VD that occurred before age 75 years than events that occurred after age 75. Patients with T2DM using insulin had higher risk of all-cause dementia than those without insulin, with an RHR (95%CI) of 1.54 (1.00–2.37). People with complications had doubled risk of all-cause dementia, AD and VD. Conclusions Adopting a sex-sensitive strategy to address the risk of dementia in patients with T2DM is instrumental for a precision medicine approach. Meanwhile, it is warranted to consider patients' age at onset of T2DM, insulin use status and complications conditions.

AimsTo examine the effect of a healthy lifestyle score derived from seven lifestyle factors recommended by the diabetes management guidelines on all‐cause and cause‐specific dementia in individuals with type 2 diabetes mellitus (T2DM), and how diabetes duration and insulin use status modify their association.Materials and MethodsThis study analysed data of 459 840 participants from the UK Biobank. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals for the association of an overall healthy lifestyle score with all‐cause and cause‐specific dementia of Alzheimer's disease, vascular dementia and non‐Alzheimer non‐vascular dementia.ResultsUsing diabetes‐free participants who scored 5‐7 as the reference group, in diabetes‐free participants, we observed higher healthy lifestyle score was related to lower risk of all‐cause and cause‐specific dementia. However, in people with T2DM, those scored 2‐3, 4 and 5‐7 all had around the two‐time risk of all‐cause dementia (HR: 2.20‐2.36), while those scored 0‐1 had over a three‐time risk (HR: 3.14, 95% confidence interval 2.34‐4.21). A dose‐response trend was observed with vascular dementia (each 2‐point increase: 0.75, 0.61‐0.93) and no significant association with Alzheimer's disease (0.95, 0.77‐1.16). The reduced risk of all‐cause and cause‐specific dementia with higher lifestyle score was observed in patients with a diabetes duration less than 10 years, or in patients with no insulin use.ConclusionIn people with T2DM, higher healthy lifestyle score was associated with lower risk of all‐cause dementia. Diabetes duration and insulin use moderated the association between healthy lifestyle score and risk of dementia.

Background Diabetes and dementia share common lifestyle risk factors, while few studies have examined the effect of seven healthy lifestyle factors as recommended by the diabetes management guidelines on all-cause and cause-specific dementia in individuals with type 2 diabetes (T2DM). Also, the roles of diabetes duration and insulin therapy in their association remain unclear. Methods This study analyzed data of 459 840 participants from the UK Biobank. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of an overall healthy lifestyle score (derived from smoking, social connection, alcohol consumption, physical activity, sedentary, sleep duration and diet) with all-cause and cause-specific dementia of Alzheimer's disease (AD), Vascular dementia (VD) and Non-Alzheimer non-vascular dementia (NAVD), using people without T2DM as the reference group. We also analyzed the role of diabetes duration and insulin use on the association between lifestyle score and dementia. Results During a mean follow-up of 12.1 years, 5 268 incident dementia events were recorded. Using diabetes-free participants who had a lifestyle score of 5–7 as reference group, in diabetes-free participants, we observed a clear trend that higher healthy lifestyle score was related to lower risk of all-cause and cause-specific dementia. However, in people with T2DM, we did not observe such a trend with all-cause dementia. People with lifestyle score of 2–3, 4 and 5–7 all had around two-time risk of all-cause dementia (HR: 2.20–2.36), while those with a score of 0–1 had over three-time risk (HR: 3.14, 95% CI 2.34–4.21). After separating the analyses with dementia subtypes, a dose-response trend was only observed with VD (each two-point increase: 0.75, 0.61–0.93), and no significant association with AD (0.95, 0.77–1.16). The reduced risk of all-cause dementia, AD, VD, and NACD with higher lifestyle score was only observed in patients with diabetes duration less than 10 years, or in patients with no insulin use. Conclusions In people with T2DM, higher healthy lifestyle score was associated with lower risk of all-cause dementia, while the relationship with cause-specific dementia was inconsistent. A dose-response trend was only observed with VD, not with AD. The beneficial effect of healthy lifestyle was only observed in people with diabetes duration less than 10 years, or in those with no insulin use.