Explaining variability in early stages of [18F]‐flortaucipir tau‐PET binding: Focus on sex differences

Abstract INTRODUCTION Female sex is associated with increased [18F]‐flortaucipir signal, which may be affected by amyloid pathology, age, and off‐target binding in skull and meninges. METHODS In this cross‐sectional study comprising 52 females and 52 matched males, we examined sex‐related differences in regional tau‐positron emission tomography (PET) with and without considering off‐target binding. We assessed the respective contributions of sex, age, amyloid‐PET burden, and off‐target binding to tau‐PET signal. We explored associations between age at menopause and hormone replacement therapy (HRT) use with regional tau‐PET signals. RESULTS Female sex was associated with increased regional tau both independently and interactively with amyloid, but amyloid‐independent associations were largely reduced when controlling for off‐target binding. Age but not age*sex interactions explained a small but significant amount of tau‐PET signal in temporoparietal regions. Considering the sample size and limited range of amyloid‐PET burden, no clear associations between regional tau‐PET signals and age at menopause or HRT use could be found. DISCUSSION Female sex is associated with increased [18F]‐flortaucipir signal mainly through its interaction with amyloid.