Sex differences in Alzheimer's disease plasma biomarker levels and clinical utility

Sex differences in Alzheimer's disease (AD) plasma biomarkers remain understudied despite higher AD risk in women.

We examined sex differences in plasma amyloid beta (Aβ)42/40, phosphorylated tau (p-tau)217, p-tau217/Aβ42, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) in cognitively unimpaired (CU) and cognitively impaired (CI) Alzheimer's Disease Neuroimaging Initiative participants. For Aβ42/40, p-tau217, and p-tau217/Aβ42, we evaluated amyloid positron emission tomography positivity classification performance and associations with cognitive trajectories using sex interactions and sex-stratified models.

Among CU participants, men had lower Aβ42 and GFAP, and higher p-tau217/Aβ42. Among the CI group, GFAP, p-tau217 and p-tau217/Aβ42 were higher in women. Overall classification performance was similar across sexes; however, p-tau217 and p-tau217/Aβ42 showed higher specificity and positive predictive value in CU women, with the opposite pattern observed in CI participants. In CU participants, p-tau217 and p-tau217/Aβ42 predicted modified Preclinical Alzheimer Cognitive Composite decline only in women.

Sex-specific plasma biomarker cutoffs may not be necessary. However, sex influences biomarker levels, classification metrics, and prognostic value, highlighting the importance of considering sex differences when interpreting biomarker results and optimizing trial enrichment strategies.