Disentangling sex-dependent effects of APOE on diverse trajectories of cognitive decline in Alzheimer's disease.

• The statistical model on change point detection offers a new window to stratify the diverse trajectories of cognitive decline in the temporal domain. • The relationship between tau biomarkers and MMSE manifests multiple change points occurring at the ages of 72, 78, and 83. • T biomarker exhibits higher sensitivity in tracking cognitive decline than A and [N] biomarkers. AT[N] biomarkers are more sensitive to the decline of executive function compared to memory performance. • Biological sex moderates the rate of cognitive decline associated with APOE4 genotype. • Higher levels of education, a marker of cognitive reserve, may moderate the effects of APOE4 and play an important role on cognitive decline. Current diagnostic systems for Alzheimer's disease (AD) rely upon clinical signs and symptoms, despite the fact that the multiplicity of clinical symptoms renders various neuropsychological assessments inadequate to reflect the underlying pathophysiological mechanisms. Since putative neuroimaging biomarkers play a crucial role in understanding the etiology of AD, we sought to stratify the diverse relationships between AD biomarkers and cognitive decline in the aging population and uncover risk factors contributing to the diversities in AD. To do so, we capitalized on a large amount of neuroimaging data from the ADNI study to examine the inflection points along the dynamic relationship between cognitive decline trajectories and whole-brain neuroimaging biomarkers, using a state-of-the-art statistical model of change point detection. Our findings indicated that the temporal relationship between AD biomarkers and cognitive decline may differ depending on the synergistic effect of genetic risk and biological sex. Specifically, tauopathy-PET biomarkers exhibit a more dynamic and age-dependent association with Mini-Mental State Examination scores (p < 0.05), with inflection points at 72, 78, and 83 years old, compared with amyloid-PET and neurodegeneration (cortical thickness from MRI) biomarkers. In the landscape of health disparities in AD, our analysis indicated that biological sex moderates the rate of cognitive decline associated with APOE4 genotype. Meanwhile, we found that higher education levels may moderate the effect of APOE4 , acting as a marker of cognitive reserve. [ABSTRACT FROM AUTHOR]