To Understand Sex Differences in Alzheimer’s Disease, We Need to Understand Risk Factors Across the Lifespan

By July 10, 2017Uncategorized

By Elizabeth Mormino, PhD, Stanford University, SWHR Interdisciplinary Network on Alzheimer’s Disease Member

The long course of Alzheimer’s disease: Put simply, Alzheimer’s disease (AD) can be conceptualized as two stages: a clinically silent stage, where brain pathologies are present, but symptoms are absent; and a symptomatic stage, where individuals show signs of dementia (this typically involves memory impairment as well as an inability to live independently). Although there is debate regarding what criteria should be used to classify the clinically silent stage, there is consensus in the field that the pathological drivers of AD, the brain accumulation of amyloid and tau proteins, begin decades before symptoms occur. We can measure these pathologies in humans by using either brain scans or lumbar puncture. Research studies have shown that individuals with no symptoms of dementia but who have evidence of AD pathology are at elevated risk for being diagnosed with AD during a later follow-up visit [1]. These individuals with evidence of pathology but no symptoms are currently being targeted in prevention trials to determine if reducing pathology during the clinically silent stage prevents symptoms of dementia [2]. Given the failure of multiple clinical trials in symptomatic AD patients, there is hope that targeting the disease as early as possible, even before symptoms are present, will be a successful strategy against AD.


Risk factors for AD: Despite the fact that over 5 million Americans currently live with AD, it is very difficult to predict who will develop the disease. The most established risk factors are older age and the presence of the APOE4 gene (possession of the APOE4 genotype is known to increase amyloid buildup in the brain). Interestingly, some work has suggested that women are more at risk for AD than men, even after accounting for women’s longer lifespans. However, a greater incidence of AD is not always identified in studies [3], suggesting that if women are at elevated risk of AD compared to men, the reasons are complex and multifactorial.


Importance of sex-specific risk factors for AD across the lifespan: Regardless of whether women are at greater risk for AD, there are undoubtedly different sets of risk factors that impact women versus men. Importantly, these factors are likely to exert changes at different points in the lifespan, which is particularly relevant when considering how sex-specific risk factors may interact with AD pathologies (see Figure). For instance, many factors that show sex differences, such as education during early life, hormonal changes, and vascular changes influence risk of dementia. It is therefore possible that these risk factors that act differently in women and men interact with AD pathological events at different points along the lifespan to ultimately influence risk of AD in late life. For instance, brain accumulation of amyloid and tau proteins are present in midlife [4] and may interact with risk factors that are different in women and men during that portion of the lifespansuch as menopause. The interaction between risk factors, AD pathology, and sex in midlife may be particularly true for women that possess the APOE4 risk gene, since APOE4 is known to shift the age of amyloid buildup earlier (see Figure).


Goal of early identification and prevention: With the recent ability of scientists to measure amyloid and tau accumulation in living people [5], there is a unique opportunity to understand AD pathology throughout the lifespan and before symptoms are present. With these tools, we should aim to develop algorithms that predict future risk, and design treatment strategies that prevent the symptomatic stage of AD altogether. In this pursuit, and because of their known influence, consideration of sex-specific factors that influence AD pathologies is essential to the goal of early identification and prevention of the disease.

ALTZ_PrevFigure: Summary of time course of AD pathologies across the lifespan. Amyloid accumulation occurs at earlier ages in individuals with the APOE4 genotype (purple line compared to orange line). Tau accumulation in brain regions essential for memory are common in middle age (green line). Examples of sex-related differences throughout the lifespan are superimposed (blue, yellow, and pink rectangles), and show different degrees of overlap with the occurrence of pathological processes.


There is still more to be done in investigating new AD risk factors and discerning how established risk factors vary by sex and gender. The Society for Women’s Health Research Interdisciplinary Network on Alzheimer’s Disease is committed to advocating for these goals in order to inform prevention and treatment, providing guidance for research, clinical trials, and policy. Click here to learn more about our work.




  1. Rowe, C.C., et al., Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann Neurol, 2013. 74(6): p. 905-13.
  2. Sperling, R.A., et al., The A4 study: stopping AD before symptoms begin? Sci Transl Med, 2014. 6(228): p. 228fs13.
  3. Mielke, M.M., P. Vemuri, and W.A. Rocca, Clinical epidemiology of Alzheimer’s disease: assessing sex and gender differences. Clin Epidemiol, 2014. 6: p. 37-48.
  4. Braak, H. and E. Braak, Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging, 1997. 18(4): p. 351-7.
  5. Johnson, K.A., et al., Tau positron emission tomographic imaging in aging and early Alzheimer disease. Ann Neurol, 2016. 79(1): p. 110-9.


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