New study reveals sex differences in cerebrospinal fluid biomarkers of Alzheimer’s disease prior to symptom onset

A study led by the Barcelonaβeta Brain Research Center (BBRC), the research center of the Pasqual Maragall Foundation, show important sex differences in Alzheimer’s disease (AD) biomarkers in individuals who do not yet experience cognitive symptoms. The work was conducted in collaboration with the Women’s Brain Foundation, whose mission includes advancing research on sex and gender differences to move toward precision medicine in brain health, and partners in the United States.

The study analysed over 900 cognitively unimpaired participants, including participants in the ALFA+ cohort, part of the ALFA study (ALzheimer's and FAmilies) at the BBRC, supported by the ”la Caixa” Foundation, which follows 400 cognitively unimpaired participants at risk for Alzheimer’s disease, and participants in the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center (N=548) at Wisconsin University.

Participants underwent Aβ PET imaging at baseline and follow-up, and provided CSF samples covering core AD pathology as well as markers of neurodegeneration, synaptic function, glial reactivity, neuroinflammation and vascular dysregulation.

Across both cohorts, women showed higher levels of synaptic biomarkers, most notably neurogranin, whereas men had higher concentrations linked to neurodegeneration, astroglial reactivity (it can be defined as the brain’s alarm-and-repair mode) and vascular dysregulation. 

Despite these biological differences, core CSF measures such as Aβ42/40 and p-tau/Aβ42 ratios identified Aβ PET-positive individuals with similarly high accuracy in women and men. Notably, the associations between several CSF biomarkers and Aβ load on PET were stronger in women, suggesting potential sex-specific nuances for prognosis or monitoring during the preclinical stage.

“We found that the levels of some CSF biomarkers differ between men and women, but both sexes can be classified equally well when it comes to detecting amyloid in the brain, supporting their use in clinical trials without the need for sex-specific cutoffs. However, their associations with amyloid burden can vary by sex, which may have implications for their prognosis or monitoring applications”, says Dr. Marta Milà, postdoctoral researcher at Northern California Institute for Research and Education (NCIRE) and associated researcher at the BBRC.

Dr. Antonella Santuccione Chadha, CEO and Founder of the Women’s Brain Foundation, added: “Understanding sex differences in biomarker patterns brings us closer to precision medicine in Alzheimer’s, where prevention and treatment strategies can be tailored for men and women.”

Together, these findings reinforce the robustness of current CSF tools for early detection while encouraging sex-aware interpretation when tracking disease biology over time. This study highlights the importance of integrating sex as a biological variable in Alzheimer’s research and paves the way for more personalized approaches to brain health.

Reference article: Milà-Alomà M, Van Hulle C, Brugulat-Serrat A, Casals Brodú M, González-Escalante A, Sánchez-Benavides G, Shekari M, Castro-Aldrete L, Minguillón C, Novakova Martinkova J, Tartaglia MC, Quijano-Rubio C, Kollmorgen G, Schumacher Dimech A, Cirillo D, Quevenco FC, Iulita MF, Fauria K, Gispert JD, Ferretti MT, Santuccione Chadha A, Johnson SC, Suárez-Calvet M; ALFA study. Sex differences in Alzheimer's disease CSF biomarkers and their association with Aβ pathology on PET in cognitively unimpaired individuals. Alzheimers Res Ther. 2025 Oct 30;17(1):235. doi: 10.1186/s13195-025-01844-1. PMID: 41168813; PMCID: PMC12573942.