Research Spotlight: Understanding the Role of Biological Sex in Age-Related Neurological Diseases

Anna K. Bonkhoff, MD and Natalia S. Rost, MD, MPH, of the Department of Neurology at Massachusetts General Hospital, are the lead and senior author, respectively, of a paper published in Science Advances titled “Sex differences in age-associated neurological diseases—A roadmap for reliable and high-yield research.” Cost-effectiveness of broadly neutralizing antibodies for HIV prophylaxis for infants born in settings with high HIV burdens."

How would you summarize your study for a lay audience?

Most neurological diseases have subtle yet distinct differences due to biological sex. For example, female stroke patients, on average, present with a higher stroke severity, and Parkinson’s disease is more frequent and severe in men.

In our review, we focused on sex differences in Alzheimer’s disease (AD) and acute ischemic stroke (AIS), to articulate how we can accelerate research in this area, turn potential pitfalls into solutions, and discover promising avenues for future research.

These findings can help prioritize further investment in that are in development to help achieve the goal of eliminating transmission of HIV to children worldwide.

What question were you investigating?

We wanted to understand how biological sex affects the human brain across health and disease and how we can use this knowledge to develop more effective and personalized neurological care.

What approach did you use?

To build the foundation to understand the potential origins of sex differences, we performed a systematic literature review and summarized our findings on the effects of sex-specific genes, hormones, and aging on the brain. 

Then, we homed in on AD and AIS, articulating what is known about how sex differences affect these diseases. We aimed to discuss and situate findings from historical studies and comprehensively present recent data. We included insights from and links between preclinical and clinical work. 

What did you find?

Biological sex can have many effects on the human brain. These effects, primarily mediated through sex chromosomes and hormones, may become even more pronounced during aging and in the presence of brain disease.  

Biological women have two X chromosomes, while biological men have one X and one Y chromosome. The X chromosome is large and rich in genes. In contrast, the Y chromosome is smaller and contains fewer genes. Emerging research indicates that genes from the X chromosome are more highly expressed in brain tissue. Recent research also suggests new locations on the X chromosome that increase the risk of AD. 

Sex hormones, such as estrogen, progesterone, and testosterone play major roles in the development of AD and outcome of AIS, particularly by influencing inflammation during aging. In AD, for example, brain immune cells may increase tau-related damage more dramatically in females. At the same time, these same immune cells may have female-specific anti-inflammatory and protective functions in AIS. 

What are the implications?

Closer ties between preclinical and clinical work and an intensified dialogue between researchers investigating the younger and older brain across many neurological diseases may enrich and accelerate research and facilitate novel insights.  

Eventually, this approach to sex differences in the healthy and diseased brain may improve our understanding of the brain in general. It holds promise to achieve optimal brain health and treatment of brain disease for each patient. 

What are the next steps?

Future work should focus on building large and comprehensive datasets that capture data with more detail, including reproductive history, measurement of sex hormones, and patient-reported outcomes. Data gathered in clinical routine care should also be made more readily available for analysis by collaborative research teams.  

It would also be useful to re-evaluate testing instruments, such as the Mini Mental State Examination used for AD, to ensure that the tools are similarly sensitive in men and women to prevent missed diagnoses and capture meaningful outcomes for all patients.  

Overall, biological sex could help inform preventative and therapeutic regimens for diseases. 

Authorship: In addition to Bonkhoff and Rost, Mass General Brigham authors include Gillian Coughlan, Valentina Perosa, Kenda Alhadid, Markus D. Schirmer, Robert W. Regenhardt, Susanne van Veluw, Rachel Buckley, and Michael D. Fox. 

Paper cited: Bonkhoff, A et al. “Sex differences in age-associated neurological diseases—A roadmap for reliable and high-yield research”Science Advances DOI:10.1126/sciadv.adt9243

Funding: Schirmer is supported by the Heitman Stroke Foundation and NIA R21AG083559. Regenhardt is in part supported by research grants from NIH-NINDS (R25NS065743), Society of Vascular and Interventional Neurology, and Heitman Foundation for Stroke. Fox was supported by the Ellison/Baszucki Foundation, the Nancy Lurie Marks Foundation, the Kaye Family Research Endowment, and the National Institutes of Health (Grant Nos. R01MH113929, R21MH126271, R56AG069086, R01MH115949, and R01AG060987). Rost is in part supported by NIH-NINDS (U19NS115388).

Disclosures:Regenhardt has served on a DSMB for a trial sponsored by Rapid Medical and has served as site PI for studies sponsored by Penumbra and Microvention. Rost has received compensation as scientific advisory consultant from Omniox, Sanofi Genzyme and AbbVie Inc.