World Alzheimer’s Day: The Importance of Studying Sex Differences

By Paula Duarte-Guterman and Liisa Galea

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September 21 is World’s Alzheimer’s Day. An estimated 564,000 Canadians are currently living with dementia, a degenerative disease that results in severe cognitive decline and the World Health Organization recently published their guidelines for risk reduction for dementia. Alzheimer’s disease is the most common form of dementia. In the brain, there is a progressive loss of brain cells and the addition of pathological features (plaques and tangles). One of the first brain areas affected by Alzheimer’s disease is the hippocampus, an area important for the formation of new memories. The hippocampus is a unique structure because it continues to produce new neurons in the brain throughout life. This year exciting research demonstrated that the number of these new neurons in the hippocampus diminished with Alzheimer’s disease pointing to an important mechanism of the disease which will hopefully have implications for the development of therapies. However it is not known whether the number of new neurons is reduced similarly in males and females. This is becoming increasingly important because Alzheimer’s disease affects females and males differently. Females share a greater burden of the disease compared to males, with two-thirds of Alzheimer’s disease patients being females. Interestingly, this demographic may be dependent on geographic location with a sex disparity more evident in European compared to North American populations. More importantly, females with Alzheimer’s disease show greater brain pathology and cognitive decline than males with Alzheimer’s disease. For this reason, health researchers have been increasingly interested in understanding why Alzheimer’s disease impacts females more so than males.

Work at UBC, with WHRI members, is exploring sex differences in Alzheimer’s pathological features in the brain. In our latest work, we analysed data from the Alzheimer’s disease Neuroimaging Initiative (ADNI). ADNI is a large North American cohort study investigating the progression of Alzheimer’s disease using a variety of cognitive tests, neuroimaging and blood markers. In this group of people, females had higher levels of tau, a protein related to Alzheimer’s disease, compared to males. This protein also increased in certain people with a gene (APOE4) related to Alzheimer’s but the increase was much steeper in females compared to males. Surprisingly although females had worse brain pathology than males, females performed better in memory tests and had larger hippocampal volumes compared to males. This may delay diagnosis in females because the progression of Alzheimer’s disease may be different between the sexes. This work also underscores that Alzheimer’s Disease can show different neuropathology that may require the need for different treatments between males and females.

While sex and genetics are important, experiences and lifestyle choices can impact cognitive aging and risk of Alzheimer’s disease. Mild cognitive impairment is often an initial step in the progression toe Alzheimer’s disease, with anywhere from 10-50% of people with mild cognitive impairment developing Alzheimer’s disease. Therefore, researchers are trying to identify what factors may drive or reduce the risk from mild cognitive impairment to Alzheimer’s disease. For example in females, pregnancy and motherhood can have long term effects on brain and cognition. Having more than 5 children increases the risk of Alzheimer’s disease by 1.7 fold compared to females who had 1-4 children, however miscarriages may result in reduced risk for Alzheimer’s disease. Exercise may be able to help brain aging. Work by Teresa Liu-Ambrose and her team at UBC indicates that females with mild cognitive impairment may have a greater benefit from physical activity on memory than males. Research is ongoing to determine what type of exercise and for how long will afford the best benefit to combat cognitive decline in either males or females. Lastly, new work from our lab, in collaboration with researchers at Baycrest Hospital in Toronto, shows that males with mild cognitive impairment were more likely to show reduced memory with stress than females with mild cognitive impairment. These new findings underscore how important it is to study the effects of Alzheimer’s and mild cognitive impairment in both males and females to deliver the best possible prescription treatments.

Studying the risks and protective factors (genetic, experiences, lifestyle) in both sexes is important for understanding how the disease progresses and to better design specific treatments and interventions. These studies indicate why it is so important to fund and research the influence of Alzheimer’s disease in both males and females. It is possible that different treatments may be necessary in females and males and between genotypes. Although the WHO guidelines have a number recommendations to reduce your risk for dementia including increasing physical activity, reducing tobacco and alcohol intake and maintaining a balanced diet and healthy weight, there is unfortunately no attention paid to whether biological sex may impact these recommendations. Research in this area will help determine what makes females more vulnerable to Alzheimer’s disease as they age and which treatments or combination of treatments might be beneficial.

Relevant papers for further reading

Moreno-Jimenez EP et al. Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer’s disease. Nature Medicine 25:554 (2019)

Nebel RA et al. Understanding the impact of sex and gender in Alzheimer’s disease: A call to action. Alzheimer’s & Dementia 14:1171. (2018)

Duarte-Guterman P et al. Sex and APOE genotype influence AD neuropathology but not epigenetic age across diagnosis. bioRxiv 741777; doi: https://doi.org/10.1101/741777

Falck RS et al. Impact of exercise training on physical and cognitive function among older adults: a systematic review and meta-analysis. Neurobiology of Aging 79:119 (2019)

Barha CK et al. Sex-specific relationship between long-term maintenance of physical activity and cognition in the Health ABC Study: Potential role of hippocampal and dorsolateral prefrontal cortex volume. J Gerontol A Biol Sci Med Sci. doi: 10.1093/gerona/glz093 (2019)

Duarte-Guterman P et al. The long and short term effects of motherhood on the brain. Frontiers in Neuroendocrinology 53:100740 (2019)

Jang H et al. Differential effects of completed and incomplete pregnancies on the risk of Alzheimer disease. Neurology 0:e1 (2018)

Murphy KJ et al. Sex differences in cortisol and memory following acute social stress in amnestic mild cognitive impairment bioRxiv 757484; doi: https://doi.org/10.1101/757484 (2019)

WHO Guidelines. Risk Reduction of Cognitive Decline and Dementia. Geneva: World Health Organization; Licence: CC BY-NC-SA 3.0 IGO. https://cdn.prod-carehubs.net/n1/802899ec472ea3d8/uploads/2019/05/Dementia-Guidelines_30042019-Final-embargoed.pdf (2019)