Sex differences in plasma biomarkers for identifying Aβ pathology in CN and MCI individuals: Implications for Clinical Trials

Background Our objective was to investigate whether sex influences plasma biomarker levels and performance in identifying Aβ‐PET‐positivity in CU and MCI ADNI participants. Method The study included 417 participants (Table1) with known Aβ‐PET status and plasma Aβ42/Aβ40 (IP‐LC‐MS/MS), and pTau181, tTau and NfL (Simoa HD‐X). We used ANCOVA to examine the effect of age, sex and APOEε4 on plasma biomarkers, and the interactions between sex, APOEε4 and age. ROC analyses were performed to determine the added value of each plasma biomarker, alone or in combination, to a base model of risk factors age and APOEε4 in the entire sample. The models were then applied to subsets of women and men separately, and the AUCs were compared with DeLong test. The same models were run separately for CU and MCI individuals, and Random Forest (RF) analyses were performed to assess each variable’s importance. Result In CUs, women had higher Aβ deposition but lower plasma pTau181 than men. In contrast, MCI men had lower plasma Aβ42/40 than MCI women. In CU men, there was a steeper increase of pTau with age (Figure1), whereas APOEε4 had a stronger effect on pTau in MCI women. ROC analyses indicated that in CUs, addition of Aβ42/40 to risk factors performed better than using risk factors alone for both sexes. In MCIs, the addition of any plasma biomarker improved the base model in men, but not in women (Figure2). In RF analyses, plasma Aβ42/40 had the strongest importance for model accuracy in CU men and women. In women with MCI, Aβ42/40 and tau have similar importance and were only slightly superior to risk factors, while in men, Aβ42/40 had the strongest importance. Conclusion Sex differences were observed in plasma Aβ42/40 and pTau, and in the impact of risk factors, which varied by clinical stage. In MCIs, the classification performance varied by sex, with a greater added value of plasma biomarkers, particularly Aβ42/40, in men. These findings emphasize the need to consider sex differences when using plasma biomarkers for clinical trials, especially in MCIs. Further studies are necessary to elucidate the underlying mechanisms and implications of these observations.