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Background: About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates dementia risk by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (obesity, diabetes/prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. Objective: Our goal was to determine the effects of a high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of AD and assess the effects of menopause. Methods: First, 3-month-old AppNL-F and WT female mice were placed on either a control or a high fat diet until 10 months of age then assessed for metabolic outcomes. Next, we did a more extensive assessment in AppNL-F mice that were administered VCD (4-vinylcyclohexene diepoxide) or vehicle (oil) and placed on a control or high fat diet for 7 months. VCD was used to model menopause by causing accelerated ovarian failure. Results: Compared to WT controls, AD female mice had worse glucose intolerance. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. There were interactions between diet and menopause on some metabolic health serum biomarkers and the expression of hypothalamic markers related to energy balance. Conclusions: This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. [ABSTRACT FROM AUTHOR]

Background: Stress is a common modifiable risk factor for AD, which increases dementia risk 2‐fold. During the stress response, the hypothalamic‐pituitary adrenal (HPA) axis is activated which stimulates the release of stress hormones called glucocorticoids into the blood stream. Studies on early‐life stress have shown a glucocorticoid dependent vulnerability towards late‐life inflammation. However, adolescence may be a more critical period for stress‐induced vulnerability for late‐life neurodegenerative diseases given that adolescents experience longer circulating levels of glucocorticoids following stress exposure and greater stress responsivity. Additionally, sex is an important biological variable because there are sex differences in AD prevalence and stress vulnerability with women being affected more than men. We hypothesized that adolescent stress would exacerbate AD pathology later in life and that this effect will be stronger in females. Method: Male and female WT and Tg‐SwDI mice underwent a chronic social stress paradigm during adolescence (1‐1.5 months of age). The paradigm consists of alternating social isolation and change in group composition for 20 days. Mice were assessed longitudinally at 2, 4, and 6 months of age for anxiety‐like behavior, cognitive function, and social behavior. Brains were collected at 6 months of age to assess neuropathology. Result: Adolescent stress had an age‐dependent effect on anxiety‐like behavior and cognitive function whereby mice who experienced adolescent stress had greater anxiety and worse cognitive function as they aged compared to control mice. Further, there were sex differences in both anxiety‐like behavior and social behavior at 6 months of age, with females showing greater anxiety‐like behavior and social avoidance compared to male mice. Neuropathology assessments are ongoing. Conclusion: This data suggests that adolescent stress may exacerbate AD pathology later in life, with females being more susceptible than males to these effects. This data is in line with clinical studies showing that females are more likely to develop AD and suffer from anxiety disorders. [ABSTRACT FROM AUTHOR]

Background: About two‐thirds of those with Alzheimer's disease (AD) are women, most of whom are post‐menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid‐life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well‐known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic, cognitive, and pathological outcomes in the AppNL‐F knock‐in mouse model of Alzheimer's disease. Method: To model menopause, we used an accelerated ovarian failure model (4‐vinylcyclohexene diepoxide, VCD). This ovary‐intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL‐F mice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age. Result: Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). An interaction between HF diet and menopause led to an impaired episodic‐like memory. When examining the underlying pathology, we did not detect any changes in amyloid levels, however, we observe changes in neurogenesis and microglia response. Conclusion: Menopause and HF diet have independent and synergistic effects on metabolic, cognitive and pathological aspects of AD. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. [ABSTRACT FROM AUTHOR]

Harry H. Hiller, Second Promised Land: Migration to Alberta and the Transformation of Canadian Society (Montreal & Kingston: McGill-Queen's University Press, 2010), 568 pp. Cased. $100. ISBN 978-0-7735-3517-6. Paper. $29.95. [...]