Sex Differences in Blood-Based Biomarkers for Alzheimer's Disease Show Clinical Utility

It is a well known fact that men and women age differently. There have been several studies that have looked at differences in tissue, molecular clocks, and longevity profiles from simple, clinical blood tests. Women generally live longer, but tend to be more frail due to certain chronic conditions as they age. Men perform better physically, but tend to have more chronic conditions later in life. Untangling the web of underlying causes is challenging.

In Alzheimer's Disease (AD), sex differences are well known across pathophysiology and clinical presentation. For example, women show greater vulnerability to certain AD risk factors including the presence of the APOE ε4 allele, higher tau burden, more neurodegeneration, and faster disease progression. Interestingly, women show resilience to pathology in early stages of the disease. 

These early stages are the focus of clinical trials, where amyloid plaques are targeted for destruction before clinical symptoms occur. Marta Milà-Alomà has been investigating sex effects that could improve trial enrichment. In this study, Marta and her colleagues investigated whether sex directly modifies plasma biomarkers that are used clinically for monitoring AD pathology and progression.

This study revealed that there are statistically significant sex differences in levels of plasma biomarkers tested:

1) One protein, GFAP (glial fibrillary acidic protein), was higher in women whether they were cognitively impaired or not. GFAP is a secondary biomarker of neuroinflammation. 
 

2) Men who were cognitively unimpaired (CU) had lower amounts of GFAP and amyloid Aβ42, and a higher ratio of p-tau217/Aβ42 which is a measure of amyloid positivity or pathology

3) Cognitively impaired women (CI) had more GFAP, p-tau217, and higher amyloid positivity (p-tau217/Aβ42)

4) In CU women, amyloid positivity could be used to predict cognitive decline 

These differences were not explained by BMI (body mass index) or by prevalence of certain comorbidities, which suggests that other intrinsic biological differences may exist. Future studies that focus on sex-based biological profiles including hormonal, metabolic, and vascular contributions, may improve biomarker interpretation and help optimize clinical trial participant selection and monitoring.

This paper is available through Alzheimer's & Dementia: 

Milà-Alomà et al (2026) Sex differences in Alzheimer's disease plasma biomarker levels and clinical utility. Alz & Dement. 22:e71244
DOI: 10.1002/alz.71244