Sex differences in plasma p‐tau181 accumulation is associated with subsequent tau‐PET signal

Abstract

AbstractBackgroundPET and post‐mortem studies show that women consistently exhibit higher medial‐temporal and neocortical tau compared to men, independent of age or diagnostic status. What remains unclear is whether such sex differences are also observed in the plasma biomarkers and related to future tau‐PET deposition. We examined baseline and longitudinal phosphorylated‐tau (plasma p‐tau181‐UGOT), which was derived prior to a tau‐PET scan, in order to determine whether changes in p‐tau181 are associated with higher regional tau‐PET in women relative to men.MethodWe selected 313 participants (clinically normal, n = 169; MCI/dementia, n = 144) from ADNI (Female% = 146(46%); AgeMean = 71(±7)years; APOEe4 = 105(34%); Ab+ = 162(52%)) with at least two timepoints of plasma p‐tau181‐UGOT measured in ADNI1/2/GO (time‐pointsMean = 3.7(±1)). Cross‐sectional Ab‐PET and tau‐PET (Flortaucipir) scan were collected in ADNI3 ((time‐difference from baseline plasmaMean = 7.1y(±1.9)). Two a priori tau‐PET partial volume corrected (PVC) regions were selected: entorhinal (EC) and inferior temporal (IT). We used linear regression to examine the influence of baseline p‐tau181 and sex on subsequent tau‐PET, adjusting for time gap between plasma‐PET and tau‐PET. Linear mixed‐effects models probed how retrospective change in plasma tau were associated with regional tau‐PET and sex, covarying for neocortical Ab‐PET, diagnosis, APOEe4 and age. We also examined interactions between sex and variables of interest.ResultBaseline p‐tau181 was strongly associated (b = 0.86 and b = 0.53) with subsequent tau‐PET, although sex did not display main effects in the model, nor did sex moderate the plasma‐PET association. Longitudinal p‐tau181 was not associated with subsequent tau‐PET. Women with accumulating p‐tau181 exhibited higher subsequent tau‐PET burden in EC and IT regions than men (p = 0.04 and p = 0.03, respectively; Figure 1). Higher‐order interactions between sex and tau‐PET with APOEe4, diagnosis or Ab‐PET were not significant, although, women diagnosed with MCI/dementia and elevated Ab seemed to drive the interaction (Figure 2).ConclusionElevated tau‐PET burden in women may be more strongly associated with prior increases in plasma p‐tau181 relative to men. Given the pre‐established association between p‐tau181 and Ab, this could be initial evidence that early events related to the deposition of Ab predict later cortical tau deposition in a sex‐specific manner. Given the novelty of examining longitudinal plasma measures, further investigation is necessitated beyond this preliminary evidence.