Sex differences in the trajectories of plasma biomarkers, brain atrophy, and cognitive decline relative to amyloid onset.

Introduction: The factors that influence the progression of Alzheimer's disease (AD) after individuals become amyloid-positive are poorly understood. This study examines how sex influences the longitudinal trajectories of plasma AD and neurodegenerative biomarkers in the years following a person's estimated onset of amyloid-β.

Methods: Linear mixed-effects modeling investigated overall and sex-specific longitudinal trajectories of plasma biomarkers, brain volumes, and cognition relative to the estimated age of amyloid onset in a cohort of 78 amyloid-positive Baltimore Longitudinal Study of Aging (BLSA) participants (n = 45 male; follow-up time: 6.8 years [SD 3.31]). Amyloid status was ascertained with C-Pittsburgh compound B (PiB) PET imaging.

Results: After amyloid onset, men displayed steeper increases in pTau181, pTau231, and neurofilament light (NfL) compared to women. In this same period, men demonstrated steeper declines in brain volume and cognitive performance.

Discussion: These findings suggest that sex influences the trajectory of AD pathology, neuronal injury, and symptom progression after individuals become amyloid-positive.

Highlights: Steeper rates of increase in pTau and GFAP among amyloid-positive individuals. After amyloid onset, steeper increases in pTau and NfL concentrations in men than in women. Steeper declines in brain volume and cognition in men corroborate biomarker results.