Sex differences in the association between tau PET and cognitive performance in a non-Hispanic White cohort with preclinical AD

Introduction: We investigated how the associations between tau and cognitive measures differ by sex in the preclinical Alzheimer's disease (AD) stage.

Methods: A total of 343 cognitively unimpaired, amyloid-positive individuals (205 women, 138 men) who self-identified as non-Hispanic White from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) Study were included. We assessed sex-stratified associations between ¹⁸ F-flortaucipir positron emission tomography (PET) standardized uptake value ratio (SUVR) in the meta-temporal region and Preclinical Alzheimer's Cognitive Composite (PACC) and Computerized Cognitive Composite (C3) components.

Results: We observed that higher tau level was significantly associated with worse cognitive performance only in women: PACC and its components except for Mini-Mental State Examination (MMSE) and C3 components: First Letter Name Recall (FNLT) and One-Card Learning Reaction Time (OCL RT). These associations except for FNLT were apolipoprotein E (APOE) ε4 independent.

Discussion: Women show stronger associations between tau PET and cognitive outcomes in preclinical AD. These findings have important implications for sex-specific tau-targeted preventive AD clinical trials.

Highlights: The tau positron emission tomography (PET) signal in the meta-temporal region was associated with poor cognitive performance in preclinical Alzheimer's disease (AD). After sex stratification, the associations between regional tau PET and cognitive outcomes were observed only in women. The associations between tau PET and some cognitive outcomes were independent of apolipoprotein E (APOE) ε4.