Sex-specific patterns in tau spreading throughout the Braak stages in the Alzheimer’s disease spectrum

Background Increasing evidence suggests that the trajectory of Alzheimer’s disease (AD) pathologies, such as amyloid and tau, differ between the sexes. Objective Given the higher susceptibility of females to dementia, we aimed to investigate the sex differences in the primary accumulation of tau and its subsequent spread to later cortical brain regions. Methods We included 315 participants in this study: 221 cognitively unimpaired individuals with normal amyloid (n = 140, A- CU) or abnormal amyloid (n = 81, A+ CU), and 94 cognitively impaired individuals with abnormal amyloid (A+ CI). Each individual received two to six tau positron emission tomography (PET) scans using the [18F]-Flortaucipir (FTP) tracer. Linear regression analyses were performed to assess sex-specific tau spreading throughout the Braak stages among three clinical groups. Results The median (interquartile range) age of all samples was 73.5 (68 to 78.2) years. In total, 170 participants (54%) were female. In the A+ CU group, females exhibited higher tau-PET SUVR levels in all Braak I, III-IV, and V-VI. We found that the spreading pattern of tau may vary by sex and AD stages. In the A+ CI individuals, there was an observed interaction between the female sex and baseline tau SUVRs in Braak stages III-IV ( p < 0.0001 and Bonferroni-corrected p < 0.0023), affecting longitudinal accumulation of tau in later Braak stages V-VI. Conclusions Our findings found a sex-specific pattern of tau spreading from Braak stages III-IV to V-VI in A+ CI older adults. This disadvantage may indicate that females might experience faster tau spreading and quicker disease progression when the condition develops to more advanced disease stages.