Female specific risk factors for the development of Alzheimer’s disease neuropathology and cognitive impairment: Call for a precision medicine approach

Udeh-Momoh, Chinedu; Watermeyer, Tamlyn

doi:10.1016/j.arr.2021.101459

Cited by 34 publications

(27 citation statements)

References 247 publications

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“…Reduction in GSH from the liver is an indirect measure of oxidative stress. GSH reduction in the liver has been strongly correlated with aging and neurodegeneration and occurs in the presence of progressive mitochondrial damage to mtDNA [ 40 , 41 , 42 ]. As oxidative stress in the brain increases, hepatic GSH levels drop due to an efflux of the antioxidant into the brain where it participates in redox signaling and helps restore cellular homeostatic levels [ 43 ].…”

Section: Resultsmentioning

confidence: 99%

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

Mattar

Majchrzak

Iannucci

et al. 2022

IJMS

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Late-onset Alzheimer’s disease (LOAD) likely results from combinations of risk factors that include both genetic predisposition and modifiable lifestyle factors. The E4 allele of apolipoprotein E (ApoE) is the most significant genetic risk factor for LOAD. A Western-pattern diet (WD) has been shown to strongly increase the risk of cardiovascular disease and diabetes, conditions which have been strongly linked to an increased risk for developing AD. Little is known about how the WD may contribute to, or enhance, the increased risk presented by possession of the ApoE4 allele. To model this interaction over the course of a lifetime, we exposed male and female homozygote ApoE4 knock-in mice and wild-type controls to nine months of a high-fat WD or standard chow diet. At eleven months of age, the mice were tested for glucose tolerance and then for general activity and spatial learning and memory. Postmortem analysis of liver function and neuroinflammation in the brain was also assessed. Our results suggest that behavior impairments resulted from the convergence of interacting metabolic alterations, made worse in a male ApoE4 mice group who also showed liver dysfunction, leading to a higher level of inflammatory cytokines in the brain. Interestingly, female ApoE4 mice on a WD revealed impairments in spatial learning and memory without the observed liver dysfunction or increase in inflammatory markers in the brain. These results suggest multiple direct and indirect pathways through which ApoE and diet-related factors interact. The striking sex difference in markers of chronic neuroinflammation in male ApoE4 mice fed the high-fat WD suggests a specific mechanism of interaction conferring significant enhanced LOAD risk for humans with the ApoE4 allele, which may differ between sexes. Additionally, our results suggest researchers exercise caution when designing and interpreting results of experiments employing a WD, being careful not to assume a WD impacts both sexes by the same mechanisms.

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Section: Resultsmentioning

confidence: 99%

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

Mattar

Majchrzak

Iannucci

et al. 2022

IJMS

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“…A trend effect of sex was found on episodic and relational memory, but the effect of sex on the relationship between risk, lifestyle factors and cognition was not investigated. Sex is an important biological variable in the development of AD (Udeh-Momoh and Watermeyer, 2021; Luckey et al, 2021). Strikingly, however, very little is known on its moderating effect on these relationships in mid-life.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in the associations between risk for late-life AD, protective lifestyle factors and cognition in mid-life

Deng

Ritchie

et al. 2023

Preprint

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It is now acknowledged that Alzheimer's Disease (AD) processes are present decades before the onset of clinical symptoms, but whether lifestyle activities can protect against these early AD processes in mid-life remains poorly understood. Furthermore, the impact of sex as a biological variable on associations between dementia risk, protective lifestyle activities and cognition is unknown. In this study, we aimed to replicate findings from our two recent studies [Deng et al. (2022) and Heneghan et al. (2022)] on the contribution of mid-life modifiable activities to cognition in individuals with dementia risk, in a larger independent cohort of the PREVENT–Dementia research program (N = 461 vs N = 208 used previously). Second, we investigated associations between biological sex, dementia risk, protective lifestyle activities and cognitive performance. Participants (40–59 years; N = 461) completed cognitive and clinical assessments cross-sectionally. Mid-life activities were measured with the Lifetime of Experiences Questionnaire. Known risk factors for sporadic late-onset AD (Apolipoprotein E ϵ4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score [CAIDE]) were investigated. Replicating our key previous findings (Deng et al., 2022 and Heneghan et al., 2022), we found that episodic and relational memory was (a) significantly negatively associated with the CAIDE risk score, (b) positively associated with stimulating lifestyle activities, and (c) that females performed significantly better than males in episodic and relational memory. The key novel finding of this study was that inherited dementia risk (i.e., APOE ϵ4 genotype) modulated the association between sex, lifestyle and cognition. Only for APOE ϵ4+ females, not APOE ϵ4-, higher occupational attainment was associated with better episodic and relational memory. Conversely, only for APOE ϵ4+ males, not APOE ϵ4-, higher occupational attainment was associated with worse episodic and relational memory. These findings suggest that modifiable lifestyle activities offset cognitive decrements due to inherited AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of Alzheimer's disease. Furthermore, these findings suggest an urgent need for targeted research on female-specific risk factors, to inform personalised strategies for AD prevention and the promotion of female brain health.

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“…Smoking is also a stronger risk factor for MI in women than in men ( 26 ). Thus, the observed sex differences in the COPD-CABG associations may be a result of their shared risk factors, thus highlighting the importance of smoking cessation in women undergoing revascularization ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

“…For instance, CABG was a stronger risk factor for Alzheimer’s disease in women than in men. This is could be explained by the common risk factor profiles associated with CVD and Alzheimer’s, including hypertension, diabetes and obesity ( 27 ). Another possibility could be that women are more susceptible to cognitive impairment caused by the operation and the anesthesia themselves.…”

Section: Discussionmentioning

confidence: 99%

Sex differences in coronary artery bypass grafting-related morbidity and mortality

Nurkkala

Kauko²,

Palmu³

et al. 2022

Front. Cardiovasc. Med.

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BackgroundCoronary artery bypass grafting (CABG) is associated with both cardiovascular disease (CVD) and non-CVD traits. In addition, women’s prognosis after coronary events and revascularizations is worse than in men. As the course of CVD in women differs from that of men, we performed a phenome-wide analysis on the sex differences in CABG -related morbidity and mortality.Materials and methodsWe performed an untargeted analysis on the sex differences in predictors and outcomes of CABG. We studied a sample of 176,680 FinnGen participants, including 5,950 individuals who underwent CABG (4,988 men and 962 women) and were followed between 1998 and 2019. Over 1,100 different traits were analyzed for both sexes and the results were adjusted with age, smoking status and BMI. Cox proportional hazards models with sex-trait interactions were used to estimate the associations between (1) traits and incident CABG; and (2) CABG and incident traits.ResultsIn women, CABG was more strongly related to greater increases in risk of diseases such as hypertension, Alzheimer’s, aortic aneurysms, gout, and chronic kidney disease compared to risk increases observed in men (all interaction p-values < 0.03). After CABG, men had 2.5-fold (p = 3.1E−15) and women 6.3-fold (p = 9.4E−08) greater risk of cardiac death compared to same-sex individuals who did not undergo CABG (p for interaction 8.2E−4). Moreover, the risk of death in women remained higher even 12 years after CABG, whereas the long-term risk of death in men was not increased, compared to same-sex individuals who did not undergo CABG.ConclusionThe adverse outcomes after CABG, both quantity and quality, also appear to differ between men and women. In women, CABG is related to greater long-term increases in risk of cardiac death and several other disease states than in men. Consideration should therefore be given to whether women receive adequate long-term post-operative therapy and follow-up as CABG is not associated with equally improved cardiovascular disease prognosis in women than in men.

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Female specific risk factors for the development of Alzheimer’s disease neuropathology and cognitive impairment: Call for a precision medicine approach

Cited by 34 publications

References 247 publications

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

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

Sex differences in the associations between risk for late-life AD, protective lifestyle factors and cognition in mid-life

Sex differences in coronary artery bypass grafting-related morbidity and mortality

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