Why study sex differences in Alzheimer’s disease and in the context of Down syndrome?
The topic of sex differences is increasingly recognized as a top priority in neurology research, particularly in the context of precision medicine and personalized care strategies. Women account for around two-thirds of patients with Alzheimer’s disease, as well as their caregivers. Work from recent years has shown that biological sex can influence key aspects of Alzheimer’s disease, including molecular pathways, cognitive progression, and risk factor profiles. While there is growing literature about sex differences in Alzheimer’s disease manifestations, little is known about this topic in the genetic forms of the disease, which are key populations for preventive clinical trials.
What have we done in this study?
Our study recruited the most significant clinical cohort of adults with Down syndrome (628 participants) with multimodal biomarkers (plasma, CSF, MRI, PET) to examine whether clinical and biomarker changes of Alzheimer’s disease differed between men and women. We deemed it important to conduct this study on Down syndrome because these individuals represent the largest genetically determined population at risk of Alzheimer’s disease (>90% in the 7th decade), and because we found an important gap in the literature, with discrepant results on Alzheimer’s disease risk by sex, and no study on sex differences across different biomarker modalities.
Our work revealed similarities and differences by sex across Alzheimer’s disease manifestations. We found similar prevalence and age at diagnosis of Alzheimer’s disease between men and women with Down syndrome, but men showed lower scores in an episodic memory test from age 45. Amyloid (A), tau (T), and neurodegeneration (N) biomarkers were comparable in men and women. When we explored the association between sex and APOE ε4 (a major risk factor of Alzheimer’s disease), we found that the ε4 allele modified the association between sex and clinical diagnosis, with an earlier age at diagnosis by 3 years in women, but not in men. Our exploratory analyses considering sex, APOE ε4, and biomarkers showed that women ε4 carriers exhibited lower CSF Aβ42/Aβ40 ratio and lower hippocampal volume compared with women without this allele, in line with the clinical difference. Given that sample sizes, after stratification were small, these exploratory results need further confirmation in other cohorts.
Relevance of the study
To our knowledge, this is the largest study providing an integrated view of the association between sex and Alzheimer’s disease manifestations in a genetic form of the disease. These results are relevant for clinical research and for upcoming trials that consider this population and use biomarkers for patient selection. In light of the growth of precision medicine, we believe it important to account for, report, and publish sex-stratified data, even when no sex differences are found, to avoid bias in the literature.
This work results from a global collaboration with clinical centres in Spain, the UK, Sweden, and the USA. It was inspired by the scientific leadership of the Women’s Brain Project, a non-profit organization advocating for precision medicine from a sex and gender lens.