Abstract
Lifespan trajectories of psychiatric and neurodegenerative risk show robust overlap and marked sex differences. Nonetheless, their neurobiological underpinnings are still poorly understood. One potential culprit is the predominant categorical definition of sex, which overlooks the tapestry of sex-dependent and sex-independent features recently shown to typify each human brain. Shifting from a holistic, dichotomous approach to regionally specific, continuous assessments of sex differences in brain function could help identify individualized therapeutic targets for both psychiatric and neurological conditions. To probe the psychiatric and neurological relevance of functional alignment with sex-typical brain architecture, we analyzed longitudinal neuroimaging and clinical data from a healthy aging cohort (N = 353, aged 36-87 years). We identified complementary patterns of deviance from sex-typical brain architecture along the canonical sensorimotor-to-association axis, which overlapped areas enriched in microglial genes and genes regulating sex steroid metabolism. The two connectivity patterns differentiated longitudinally between psychiatric symptoms and neurodegeneration as a function sex and age: one connectivity pattern related to more severe future depression in younger women, whereas the second related to later neurodegeneration (higher GFAP and pT217 blood concentration) and poorer fluid cognition (inhibition, episodic memory, processing speed, working memory) in older men. The aforementioned effects showed some context-specificity, as they involved connectivity patterns characterized during awake rest and cognitive control, but not associative memory performance. Taken together, our findings attest to the value of integrating regionally specific, continuous assessments of sex differences in brain function with inflammation-relevant biomarkers in order to support precision medicine approaches across the life course.